Figure 23.1 Interstitial nephritis in a 66-year-old patient who did not have any identifiable underlying etiology but had peripheral eosinophilia. A: Interstitial mononuclear cell infiltrate with edema. (PAS, ×100.) B: Focally large numbers of eosinophils were present in the interstitium. (H&E, ×400.) C: In several foci, the inflammatory cells infiltrated the tubular epithelium (tubulitis). (PAS, ×600.)

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Title: Hepinstall's Pathology of the Kidney, 6th Edition

Copyright ©2007 Lippincott Williams & Wilkins

> Table of Contents > Volume Two > 23 - Acute and Chronic Tubulointerstitial Nephritis


Acute and Chronic Tubulointerstitial Nephritis

Tibor Nadasdy

Daniel Sedmak



1). Councilman also determined that these kidneys did not contain bacteria (they were sterile). He called the condition acute interstitial nephritis. The term interstitial nephritis connotes predominant involvement of the renal interstitium and tubules by inflammatory cells, often with edema or fibrosis and tubular atrophy. Because interstitial nephritis is commonly accompanied by variable tubular damage, the term tubulointerstitial nephritis, or , is preferable and is often used interchangeably with interstitial nephritis. Tubulointerstitial nephritis has two common clinical presentations: sudden onset and rapid decline in renal function—acute tubulointerstitial nephritis—and protracted onset and slow decline in renal function—chronic tubulointerstitial nephritis. Because chronic tubulointerstitial nephritis may present with prominent fibrosis and few inflammatory cells, the term chronic tubulointerstitial fibrosis, or chronic tubulointerstitial nephropathy, is used by many. Tubulitis refers to infiltration of the tubular epithelium by leukocytes, usually mononuclear cells. Obviously acute tubulointerstitial nephritis, with time, can turn into chronic tubulointerstitial nephritis; therefore, overlaps between these two entities often exist.

The term primary tubulointerstitial nephritis refers to cases where the inflammation is essentially limited to the tubules and interstitium; glomeruli and vessels are uninvolved or show minor changes. Secondary tubulointerstitial nephritis implies tubulointerstitial inflammation associated with a primary glomerular, vascular, or systemic disease. Idiopathic tubulointerstitial nephritis is a primary tubulointerstitial nephritis whose etiologic agent or cause is unknown.

Reactive tubulointerstitial nephritis connotes tubulointerstitial inflammation from the effects of systemic infections; the kidneys usually are sterile. Infectious tubulointerstitial nephritis denotes tubulointerstitial inflammation from the effects of localization of live micro-organisms in the kidney, where they can be identified and from which they often can be cultured.

Interstitial nephritis is commonly secondary to infection. These include acute and chronic pyelonephritis by bacteria or fungus, viral infection, and protozoal infections. Infection-associated interstitial nephritis is discussed in Chapter 22.


The exact incidence of tubulointerstitial nephritis is unknown. Available figures vary and reflect differences in the populations considered. For unselected, asymptomatic individuals, Petterson et al (2) reported an incidence of 0.7 cases per 100,000 persons. For selected, asymptomatic individuals with abnormal urinalysis, the incidence in the same population was 1.2% (2). Among symptomatic patients with acute renal failure, the incidence ranged from 8% to 10.7% (3,4), and among symptomatic patients with chronic renal failure, the incidence ranged from about 22% to 33.5% (5,6). Among unselected patients with acute tubulointerstitial nephritis, 40% (12 of 30 patients) of cases were caused by drug reactions (7). Among unselected patients with chronic tubulointerstitial nephritis, 31%


(9 of 29 patients) of cases were caused by drugs and about 28% (8 of 29 patients) of cases were idiopathic (8).

It is important to establish the diagnosis of tubulointerstitial nephritis through kidney biopsy for the following reasons: (a) clinical and laboratory data alone often do not differentiate between tubulointerstitial nephritis and other renal diseases attended by renal insufficiency or renal failure; (b) most acute tubulointerstitial nephritides can be successfully treated; (c) untreated acute tubulointerstitial nephritis may result in interstitial fibrosis and irreversible renal disease (); (d) the use of molecular and other techniques permits the disclosure of possible genetic abnormalities (10) and the underlying mechanisms of tissue injury (11).

Etiologic Agents and Causes

The etiologic agents and causes of tubulointerstitial nephritis are varied but can be grouped into broad categories. The classification that we follow in our outline has been modified from those of Churg et al (12) and Colvin and Fang (13). Some causes of tubulointerstitial nephritis including infectious etiologies are covered in other chapters. Tubulointerstitial nephritis is often multifactorial, and several etiologic agents or causes, such as concurrent infection and obstruction, may contribute to tubulointerstitial renal disease in the same patient (). In a recent paper, Baker and Pusey (14) pooled their own data with two contemporary series from the literature (15,16). They found that based on recent data, the most frequent cause of interstitial nephritis is drug related (71.1%) with antibiotics accounting for about a third of these cases. Interstitial nephritis cases that were secondary to infection accounted for 15.6% and 7.8% were idiopathic. Tubulointerstitial nephritis and uveitis syndrome (TINU) was responsible for 4.7% of cases, and only 0.8% of the biopsies were diagnosed as sarcoidosis.

Clinical Features of Primary Tubulointerstitial Nephritis

Various nonspecific clinical and laboratory findings may occur. Acute interstitial nephritis may develop at any age and is associated with a variable degree of acute renal insufficiency. The acute renal failure tends to be more prominent in the elderly. Systemic manifestations of hypersensitivity, such as erythematosus, maculopapular skin rash, arthralgias, fever, and peripheral eosinophilia may occur primarily in drug-induced acute interstitial nephritis, but these findings are frequently absent. Urinalysis reveals usually microscopic hematuria. Very rarely, gross hematuria or red blood cell casts may be seen. Typically, these patients have white blood cells in the urine and urine cultures are negative (sterile pyuria). Eosinophils in the urine, particularly if this number is greater than 1% of the cells, is thought to be a very characteristic finding in acute interstitial nephritis. Ruffing et al (17) addressed the diagnostic accuracy of this test. In a selected group of patients, in which the diagnosis of acute interstitial nephritis was suspected by the nephrologist, the sensitivity of eosinophiluria was 40% and the specificity was 72% with a positive predictive value of only 38%. The same authors also examined consecutive patients with white blood cells in the urine who did not have interstitial nephritis. Four of these patients had urinary eosinophils greater than 1%. Eosinophiluria is not uncommon in secondary forms of interstitial nephritis, particularly in those that are associated with crescentic glomerulonephritis (vasculitis).

Mild proteinuria, usually less than 1 g/24 hours, is frequently seen, but nephrotic-range proteinuria is rare. Nephrotic syndrome may occur if interstitial nephritis is associated with minimal change disease secondary to nonsteroidal anti-inflammatory drugs (NSAIDs). If the inflammation affects primarily the proximal tubule, it may result in renal glucosuria, aminoaciduria, phosphaturia, and uricosuria. If the distal tubule is primarily damaged, potassium secretion and sodium balance regulation suffer. Renal tubular acidosis may occur following the damage of both distal and proximal tubules. It is worth noting that in many instances, both the proximal and distal tubules are equally undergoing injury. Medullary inflammation may be associated with inappropriate urinary concentration and polyuria.

Pathology of Primary Tubulointerstitial Nephritis

The details of gross and histologic features underlying the pathology of tubulointerstitial nephritides associated with various agents or conditions are provided in the following sections. In this section, we present an overview of the pathology of primary tubulointerstitial nephritis. Pyelonephritis and other infection-related interstitial nephritides are discussed in Chapter 22.

Acute Tubulointerstitial Nephritis

Grossly, the kidneys are pale, edematous, and enlarged, with the degree of enlargement proportional to the extent of involvement. The external surface is smooth.

Microscopically, the cellular infiltration and edema are multifocal and vary in intensity. Although neutrophils are common in acute tubulointerstitial nephritis, mononuclear cells, including lymphocytes and macrophages, also participate and are usually the predominant cell types (Fig. 23.1). Drug reactions, such as those to antibiotics, are often associated with mononuclear cell infiltrates, including lymphocytes, and frequently eosinophils. Most mononuclear cells in the inflammatory infiltrate are T cells (Fig. 23.2) (18,19,20). Overall, CD4+ T cells predominate relative


to CD8+ T cells. However, in the report of Bender et al (18), nine patients with drug-induced tubulointerstitial nephritis had nephrotic-range proteinuria and predominance of CD8+ T cells in the interstitial infiltrate. Similarly, in the report of D'Agati et al (21), CD8+ T cells outnumbered CD4+19,20). Eosinophils are common in drug-induced cases, but their absence does not exclude a drug-induced form of interstitial nephritis (22). After a few days or weeks have elapsed, a variable accumulation of plasma cells and histiocytes may be present (Fig. 23.3). Although not a common component of acute tubulointerstitial nephritis, granuloma formation may occur in drug reactions, sarcoidosis, and idiopathic forms (Fig. 23.4).


Figure 23.2 Immunohistochemistry reveals many T cells in the interstitial inflammatory cell infiltrate in this biopsy from a patient with Sjögren's syndrome. (Immunoperoxidase with an anti-CD3 antibody, ×400.)

Tubular injury includes tubulitis (Fig. 23.1C), breaks of tubular basement membrane (TBM), necrosis of tubular cells and atrophy and loss of tubules, depending on the etiologic agent. According to Ivanyi et al (23), tubulitis more often involves the distal nephron. Biopsies taken several days after the initial insult show features of tubular cell regeneration manifest as flattening of the epithelial lining, cytoplasmic basophilia, and enlarged nuclei with frequent and prominent nucleoli. Although not a common component of acute tubulointerstitial nephritis, some interstitial fibrosis, as part of the reparative process, may be seen in late biopsies. The presence of monocytes/macrophages and granulomas and some degree of fibrosis encountered in some forms of acute tubulointerstitial nephritis emphasize the overlap that exists between acute and chronic

tubulointerstitial nephritis (Figs. 23.3,23.4,23.5). Tamm-Horsfall protein (THP) may find its way into the interstitium following tubular rupture (Fig. 23.6). Interstitial THP is commonly found in nephron obstruction, but it is by no means a diagnostic finding of obstructive nephropathy.


Figure 23.3 Many plasma cells in an acute and chronic interstitial nephritis, in a patient with Sjögren's syndrome. (H&E, ×600.)

Immunofluorescence and immunohistochemical techniques are rarely helpful in determining the underlying cause. Linear deposits of antibody and complement along the TBM suggest antibody directed to or cross-reactive with the TBM. Granular deposits of antibody and complement in the TBM, interstitium, or both suggest an immune complex pathogenesis. However, granular or linear TBM staining for complement (particularly C3) is a frequent nonspecific finding, especially in the basement membrane of atrophic tubules.


Figure 23.4 Different appearances of granulomatous interstitial nephritis. A: Ill-defined interstitial granulomas in a biopsy from a patient who was treated with cephalosporin, vancomycin, and clindamycin because of a staphylococcal infection. (H&E, ×400.) B: Well-defined epithelioid granuloma in the renal biopsy of a patient with sarcoidosis. (H&E, ×100.)


Figure 23.5 Note the active appearing interstitial inflammatory cell infiltrate with eosinophils in the background of interstitial fibrosis and tubular atrophy. This patient had a long history of gout and multiple medication use. (H&E, ×200.)

Electron microscopy is also of limited value. Ultrastructural examination may occasionally reveal electron-dense immune-type deposits along the TBM or in the interstitium, particularly if there is underlying systemic lupus erythematosus. Crystalline inclusions in tubular epithelial cells or finely granular electron-dense deposits along the TBM indicate monoclonal immunoglobulin deposition. Rarely, electron microscopy may be helpful in detecting viral particles in infected tubular epithelial cells.

In acute tubulointerstitial nephritis, the glomeruli are mostly spared. Arterial and arteriolar changes are usually absent. When present in older persons, they are unrelated to the primary tubulointerstitial process and reflect aging, associated hypertension, or both.


Figure 23.6 Tubular rupture with expulsion of Tamm-Horsfall protein from the tubule into the interstitium. Note the interstitial inflammatory cell infiltrate around the Tamm-Horsfall protein. This is a nonspecific finding that can occur in any renal injury with tubular disruption and secondary interstitial Tamm-Horsfall protein deposits. (PAS, ×400.)


The morphology of acute interstitial nephritis is nonspecific, and only in rare instances is it possible to define the exact cause. If typical viral inclusions are present or other micro-organisms can be identified or if characteristic immune complex deposits are present, an etiologic diagnosis may be possible. A more detailed description of the morphologic findings will be given in this chapter in the section describing the different forms of acute interstitial nephritis.

Chronic Tubulointerstitial Nephritis

Common causes of chronic tubulointerstitial nephritis are infections, drug reactions (e.g., analgesics, lithium), urinary tract obstruction and sterile reflux of urine, some forms of immune-mediated tubulointerstitial nephritis, plasma cell dyscrasias, metabolic disorders, exposure to heavy metals, hereditary diseases, and various chronic nephropathies, including idiopathic tubulointerstitial nephritis. Chronic tubulointerstitial nephritis always develops if a progressive chronic primary glomerular disease is present. It is also a common finding in systemic disorders involving the kidney, including systemic autoimmune diseases, monoclonal gammopathies, and metabolic diseases. Vascular diseases are also frequently associated with chronic tubulointerstitial nephritis, particularly vasculitis and chronic forms of thrombotic microangiopathies but also ischemia secondary to atherosclerosis, and hypertension can induce chronic tubulointerstitial injury with some degree of inflammation.

Grossly, kidneys with chronic tubulointerstitial nephritis become small, contracted, and pale. Variable papillary involvement, including papillary necrosis, sclerosis, and calcification may be evident. The external surface is usually scarred or finely granular from small vessel disease, compensatory hypertrophy of residual nephrons, or both. The corticomedullary junction is usually poorly demarcated. The intrarenal vessels are prominent and may have thickened walls.

Microscopically, the inflammatory cell infiltrate is made up of variable numbers of lymphocytes, monocytes/macrophages, and plasma cells. Granulomas may be seen in tubulointerstitial nephritis because of drugs; infections with mycobacteria, fungi, and parasites; sarcoidosis; and vasculitis. Some are idiopathic (24). Tubular atrophy and interstitial fibrosis are the histologic hallmarks of chronic interstitial nephritis, usually associated with some degree of interstitial mononuclear cell infiltrate. Tubular atrophy has three morphologic subtypes (25) (Fig. 23.7). The most common type is the “classic”-type atrophic tubule with prominently thickened, frequently wrinkled, and lamellated basement membrane. The “endocrine”-type atrophic tubule has a narrow lumen or no lumen at all, is usually prominently reduced in diameter, and has simplified epithelium and a thin basement membrane. These endocrine-type atrophic tubules usually occur in clusters. The “thyroid”-type atrophic tubule has only mildly thickened basement membrane, a simplified flattened epithelium, and a lumen filled with eosinophilic PAS positive homogenous proteinaceous material; therefore, the tubule resembles a thyroid follicle. These thyroid-type atrophic tubules also occur in clusters, and in occasional cases of renal scarring, the parenchyma resembles thyroid gland. The diagnostic significance of these different types of atrophic tubules is somewhat limited. The endocrine-type atrophic tubule is frequently seen in chronic ischemia, including renal artery stenosis. The thyroid-type atrophic tubule is a common finding in chronic pyelonephritic scars, but we have also frequently observed thyroidization of tubules in ischemic scars, including kidneys with interstitial fibrosis secondary to antiphospholipid antibodies.

In chronic tubulointerstitial injury, tubules frequently undergo compensatory hypertrophy, disregarding the cause. These hypertrophic tubules are lined usually with tall proximal-appearing tubular epithelial cells. The lumen is dilated and commonly irregular (Fig. 23.8). Microcystic dilatation of tubules in scarred interstitial areas may also occur. These microcystic tubules usually have a thin simplified epithelium and are filled by proteinaceous homogeneous material. Sometimes the microcysts may have a scalloped outline (Fig. 23.9).

Interstitial fibrosis, a characteristic feature of chronic tubulointerstitial nephritis, must be considered according to location. In the cortex, the interstitial volume is uniform and composes 7% of the cortical volume (26), whereas in the medulla, the interstitial space increases from the


outer stripe of the inner medulla to the tip of the renal papilla. For example, in the rat the interstitial space at the base of the inner medulla is about 10% of the medullary space but attains 30% of the interstitial space at the tip of the papilla (27). Interstitial fibrosis may be multifocal or diffuse, and the deposited extracellular matrix is a combination of various types of collagens, including types I, III, and V, derived from interstitial fibroblasts (2829). Interstitial fibrosis and tubular atrophy are


cardinal features for the diagnosis of chronic tubulointerstitial nephritis because inflammatory cells may be scarce or absent.


Figure 23.7 Different histologic appearances of atrophic tubules. A: Prominently thickened and wrinkled PAS-positive basement membranes of so-called classic atrophic tubules. Note the simplified epithelium lining the atrophic tubules. The section was also stained with  lectin (brown color along the apical cell membrane), a marker of proximal renal tubular epithelium, indicating proximal tubular origin of these tubules. (PAS with Tetragonolobus purpurasB: Endocrine-type atrophic tubules surrounding a sclerotic glomerulus. In this type of endocrine tubule, the basement membrane is thin and the epithelium is simplified with no or only very narrow lumen. These tubules resemble endocrine glands. (PAS, ×400.) C. Thyroidization of tubules in a scarred area of renal cortex. Thyroid-type atrophic tubules have flattened epithelium and PAS-positive proteinaceous filling the lumen, resembling thyroid follicles. (PAS, ×400.)


Figure 23.8 It is common to see large hypertrophic tubules with thick, hypertrophic epithelial lining in any type of advanced chronic renal injury. (H&E, ×100.)


Figure 23.9 Microcystic dilatation of tubules with scalloped outline. Such tubules can be seen in any kind of chronic tubulointerstitial injury. (PAS, ×100.)

Immunofluorescence and immunohistochemical techniques enable delineation of pathogenic mechanisms in a few cases, in a manner similar to that already described for acute tubulointerstitial nephritis. Granular deposits of immunoglobulin and complement along the TBM and interstitium may indicate tubulointerstitial injury mediated by immune complexes. But one has to remember that C3 deposition is a very common nonspecific finding in the basement membrane of atrophic tubules. Immunohistochemical techniques also can be used to identify the segment of the nephron that is involved (Fig. 23.7A30) to develop functional correlates of tissue injury (). For example, when tubulointerstitial nephritis involves predominantly the proximal tubules, proximal renal tubular acidosis (type II) develops owing to loss of proximal tubule resorbate (e.g., glucose, phosphate, uric acid, organic acids, low–molecular-weight proteins), with or without Fanconi's syndrome. When distal tubules are predominantly involved, distal renal tubular acidosis (type I) ensues caused by failure to lower the urinary pH, with or without hyperkalemia and salt wasting. When collecting ducts and papillary involvement predominate, water conservation is compromised by the decreased ability to concentrate urine. Molecular techniques have enabled the detection of deletions of genetic material as a possible cause of tubulointerstitial nephritis (10,32).

Electron microscopy in chronic tubulointerstitial nephritis has limited diagnostic value, as indicated above in the discussion of acute interstitial nephritis. The basement membrane of atrophic tubules is not only thickened on ultrastructural examination, but is usually also lamellated. This lamellation is probably the result of repeated tubular epithelial injury and regeneration. The regenerating renal epithelium probably creates newer and newer thin layers of basement membrane material, which will lend a lamellated pattern to the thickened tubular basement membrane (Fig. 23.10). Aggregates of granular to microspherical material in the thickened basement membranes of atrophic tubules are not uncommon (Fig. 23.11). This material should not be misinterpreted as immune complex deposition.


Figure 23.10 Thickened lamellated basement membrane of an atrophic tubule. (Uranyl acetate and lead citrate, ×3000.)


Figure 23.11 Deposits of granular to microspherical material in the tubular basement membrane is a common finding in atrophic tubules. Under low magnification, these structures may be misinterpreted as electron-dense immune-type deposits in the tubular basement membrane. (Uranyl acetate and lead citrate, ×20,000.)

In contrast to acute tubulointerstitial nephritis, in which glomeruli are usually spared, glomeruli in chronic tubulointerstitial nephritis often show changes. These glomerular changes are frequently secondary to poor glomerular blood perfusion and include tuft wrinkling and collapse, thickening of Bowman's capsule, periglomerular fibrosis, and glomerular obsolescence. Occasionally, segmental glomerulosclerosis may develop. Arterial and arteriolar changes such as intimal thickening and medial hyperplasia are usually present and reflect aging and associated hypertension.

Pathogenesis of Tubulointerstitial Nephritis


Reactive tubulointerstitial nephritis appears to result from systemic release of lymphokines that are filtered and reabsorbed by the kidneys, thereby promoting chemoattraction and activation of mononuclear cells in the kidneys (113,33,34).  results


from three basic mechanisms of tissue injury (35Chapter 22.

Drug-induced tubulointerstitial nephritis is most likely immunologically mediated. The most widely accepted theory is that drugs behave as haptens after binding to extrarenal proteins that later will be planted in the kidney, or to renal proteins (36). This will be discussed in detail in the following section of this chapter. Drug-induced acute interstitial nephritis occurs in only a small percentage of patients taking a medication, is not dose dependent, and exacerbation occurs after re-exposure to the drug. Also, systemic signs of hypersensitivity may be evident.

Tubulointerstitial nephritis owing to anti-TBM antibodies involves predominantly IgG antibodies directed against different autoantigens in basement membranes, including a 58-kDa protein called tubulointerstitial nephritis antigen (37,38,39,40Tubulointerstitial nephritis owing to immune complexes involves predominantly IgG antibodies, but the nature of target antigens, with a few possible exceptions (41,42), is unknown. Tubulointerstitial injury may depend on complement activation by antibody (43,44), release of chemoattractants, and activation of leukocytes with release of chemokines, cytokines, proteases, and toxic oxygen radicals (34,45). In many forms of interstitial nephritis, eosinophils are prominent in the interstitium, which may be related to a chemotactic cytokine, eotaxin, produced locally by renal parenchymal cells (46). Tubulointerstitial nephritis owing to cell-mediated mechanisms encompasses two types of reactions. First, delayed-type hypersensitivity reaction, which requires prior sensitization and is caused by CD4+11). Second, cytotoxic T-cell injury, which requires no prior sensitization, is mediated by CD4+ and CD8+ T cells (11).

Tubulointerstitial inflammation, fibrosis, and tubular atrophy, common to most chronic tubulointerstitial nephropathies, can be induced by various agents and causes. If the underlying cause is persistent and cannot be eliminated, eventually all etiologic agents will cause chronic tubulointerstitial injury. Various pathogenetic factors are involved in the generation of interstitial fibrosis and tubular atrophy including ischemia, reactive oxygen species, toxic agents, or immunologic injury. It is likely that an important role in the common final pathway leading to fibrosis can be attributed to the transforming growth factor beta (TGF-beta)/Smad3 signaling pathway (,4849). TGF-beta is up-regulated in response to injurious stimuli, by angiotensin II (49). This accounts, at least in part, for the beneficial effect of angiotensin convertase inhibition slowing the progression of chronic renal injury. TGF-beta transmembrane receptors transduce downstream signals via cytoplasmic latent transcription factors called Smad proteins. Smad 2 and 3 are phosphorylated and they bind to Smad 4 and translocate to the nucleus where they act as transcriptional regulators of target genes. Disruption of the TGF-beta/Smad signaling pathway inhibits interstitial fibrosis in experimental animals (47). Connective tissue growth factor (CTGF) is a downstream mediator of the profibrotic effects of TGF-beta. Recent data indicate that CTGF may play a pivotal role in the pathogenesis of TGF-beta–dependent interstitial fibrosis (50). There is growing evidence that TGF-beta is also capable of inducing epithelial-myofibroblast transdifferentiation of renal tubular epithelial cells (). This transdifferentiation process of the injured tubular epithelial cells may be a key pathogenetic step in the development of chronic interstitial nephritis (Fig. 23.12).


Figure 23.12 Scattered cytokeratin-positive cells are commonly found in the fibrotic renal interstitium. It is theoretically possible that these cytokeratin-positive cells represent cells undergoing epithelial to mesenchymal transformation. (Immunoperoxidase, ×600.)


The kidney is adversely affected by a wide range of therapeutic and diagnostic agents and toxic compounds. However, there are only a limited number of patterns of injury produced in the kidney. These may affect any of the compartments of the kidney including tubulointerstitial, glomerular, and vascular pathology (52,53,54). In the previous edition of this book, an entire chapter was devoted to all forms of renal injury caused by therapeutic and diagnostic agents (52). Now, in the following section, we will focus only on acute and chronic tubulointerstitial nephritis induced by drugs. Other patterns of renal injury associated with drug reactions, including acute tubular necrosis,


glomerular changes, and vascular changes, will be discussed in other chapters.

It should be recognized that it is often difficult to establish a pathogenetic link between a pathologic lesion and a particular drug or toxin. Several factors contribute to this uncertainty, including concurrent factors that may produce renal injury such as administration of several potentially nephrotoxic drugs at the same time, lack of or inadequacy of morphologic data in reported cases of drug toxicity, and the fact that some drugs may have multiple effects. Moreover, experimental models of toxicity may not be relevant to a particular clinical context owing to interspecies variation and markedly different dosing of drugs in these models. In general, we limit our discussion to those drugs for which toxicity has been well documented in humans by disappearance of toxic effects when the drug is withdrawn, reoccurrence of symptoms on rechallenge, or both.

As pointed out earlier, today the most common form of interstitial nephritis is drug induced. Many drugs, including a range of widely used therapeutic agents, produce unpredictable idiosyncratic systemic reactions that may manifest in the kidney primarily as tubulointerstitial nephritis.

Clinical Features

Tubulointerstitial nephritis caused by drug or toxin exposure develops in a few patients who receive the drug; reactions can sometimes be predicted if the patient has had a reaction to the same or a similar agent. The reaction is generally unrelated to the cumulative dose of the drug. Exposure to the offending agent typically occurs days to a few weeks before presentation (55). Patients may show signs of a systemic syndrome that include fever, skin rash, eosinophilia, and arthralgias. However, only a few patients will have this classic constellation of symptoms (16). Affected individuals may note fluid retention or a fall in urine output and occasionally patients may experience back or flank pain (56). Many patients show symptoms of acute renal failure (ARF).

Analysis of the urine typically reveals pyuria, with numerous mononuclear cells, including lymphocytes and monocytes. There may also be eosinophils, which researchers have touted as a specific marker for allergic interstitial nephritis (57). However, eosinophiluria is not specific for drug-induced interstitial nephritis (58). Eosinophils may best be detected by the use of special stains, such as the Hansel stain (59). Hematuria is not uncommon and is usually microscopic. Mild proteinuria may also be detected, and proteinuria may occasionally be in the nephrotic range, especially in those cases caused by drugs that also produce minimal change disease in the glomeruli; nonsteroidal anti-inflammatory drugs (NSAIDs) most commonly cause this constellation of symptoms. Urine cultures are routinely negative.

Because the interstitial inflammatory process can result in tubular injury, there may be evidence of tubular dysfunction. Patients may have glycosuria, aminoaciduria, and phosphaturia; occasionally, Fanconi's syndrome has been described. In addition, tubular acidosis, electrolyte losses, or concentrating defects may be documented. On ultrasound, the kidneys are seen to be of normal size or enlarged. The parenchyma is typically echogenic, a finding that has been correlated with the extent of inflammatory infiltrate (and with the development of long-term changes in the interstitium).

Patients may have renal dysfunction without other accompanying symptoms. Because drug-induced interstitial nephritis is eminently reversible in the early stages, it is important to recognize the etiologic agent so that long-term damage can be avoided. Some drugs produce more insidious changes, resulting in protracted injury without an obvious acute phase. Classic examples are lithium and analgesic compounds. These patients may show initial signs of salt wasting or acid-base imbalances and evidence of progressive tubular injury. In cases with sloughing of necrotic papillae, the initial symptoms are acute with renal colic.


Gross Findings

In acute tubulointerstitial nephritis, the kidney is usually pale and swollen. Areas of congestion and hyperemia may be seen at the corticomedullary junction. In chronic tubulointerstitial nephritis, the kidney is smaller with thinning of the cortex. The surface of the kidney may become granular. Parenchymal cysts may develop as interstitial fibrosis progresses. The cortex may become pale owing to a combination of fibrosis and inflammatory cells.

Light Microscopy


Glomeruli are typically spared. Occasionally, the interstitial inflammatory infiltrate may breach Bowman's capsule. In later stages of chronic interstitial nephritis, glomeruli may show nonspecific ischemic collapse and sclerosing changes. Periglomerular fibrosis is common in chronic cases.


In acute interstitial nephritis (AIN), there are patchy or diffuse edema and inflammatory infiltrates. The infiltrate is predominantly mononuclear (Fig. 23.1). Both CD4+ and CD8+ T cells have been detected in varying proportions. B cells and monocyte/macrophages can also be found. Eosinophils typically make up 10% or less of the infiltrating cells. The eosinophils in the infiltrate may be focal


and, rarely, they form clusters resembling a microabscess (Fig. 23.1B) (57). Eosinophils are typically seen in reactions to antibiotics, especially penicillins, sulfonamides, and rifampicin, more than in response to various other drugs. Neutrophils are usually rare. Basophils, which are difficult to detect without special stains, have been reported to constitute 1% to 2% of infiltrating cells (60). Steroid treatment may reduce the severity of the inflammation and, in particular, lessen accompanying edema.

Table 23.1; Fig. 23.4A). Granulomas, typically noncaseating and composed of epithelioid histiocytes, lymphocytes, and a few giant cells, are scattered in the interstitium. Penicillins, sulfonamides, polymyxin B, allopurinol (61), diuretics (62), rifampicin, acyclovir, NSAIDs, omeprazole (63), lamotrigine (64), levofloxacin (65), nitrofurantoin (66), and ciprofloxacin have all been reported to cause inflammatory infiltrates with granulomas.

In chronic drug-induced interstitial nephritis, the defining feature is interstitial fibrosis. An interstitial inflammatory infiltrate often persists, but it is usually mild and composed largely of nonactivated lymphocytes, plasma cells, and macrophages. These infiltrates are often nodular and localized to fibrotic areas. Although drug-induced acute tubulointerstitial nephritis occasionally may persist and lead to chronic interstitial nephritis, some drugs have a propensity to produce subclinical progression to chronic renal failure. These drugs include analgesics, lithium, and cyclosporine.

Table 23.1 Causes of Granulomatous Interstitial Nephritis

Infection (see Chapter 22)


  Fungal Infections




  Sulfonamides (144)

  Penicillins (73,364)

  Fluoroquinolones (65,76,105)

  Vancomycin (148)

  Gentamicin (24)

  Nitrofurantoin (66)

  Allopurinol (61)

  Furosemide (62)

  Hydrochlorothiazide (501)

  Omeprazole (63)

  Lamotrigine (64)

  Nonsteroidal anti-inflammatory drugs (NSAIDs) (189)

  Bisphosphonates (Alendronate) (504)

  Diphenylhydantoin (245)

  Carbamazepine (503)

  Oxycodone (500)

Sarcoidosis (354, 355, 356, 357, 358, 359, 360, 361, 362, 363)

Tubulointerstitial nephritis and uveitis syndrome (TINU) (499)

Granulomatous vasculitis (Wegener's) (24,364,365

Oxalosis (Chapter 25)

Gout (Chapter 25)


Idiopathic (366, 367, 368, 369, )


Fig. 23.1C). Although these characteristics are often described in the proximal nephron, a few investigators have reported that tubular injury and tubulitis may be more severe in the distal nephron (22,23). With a severe inflammatory reaction, the TBM may be disrupted. In the circumstance of chronic interstitial nephritis, tubular atrophy is typically seen to be associated with fibrosis in the interstitium. Focal tubulitis may be present as well.


Vessels are usually uninvolved, though a few drugs may produce vasculitis.


Fibrin is often detected in the interstitium by immunofluorescence, reflecting interstitial edema. Immunoglobulin-G (IgG) and C3 have been reported to be deposited in a linear pattern along the TBM in some cases of apparent drug-induced interstitial nephritis, including cases induced by penicillins (57,67,68,69) and rifampicin (70). Minetti et al (71) have also reported granular peritubular IgG in one case owing to rifampicin. In cases of methicillin-induced AIN, a drug antigen has been immunolocalized along the TBM as well (67,).

Electron Microscopy

Ultrastructural examination is usually of limited informative value in drug-induced interstitial nephritis. Electron microscopy of the interstitium in cases of drug-induced interstitial nephritis reveals edema, infiltrating inflammatory cells, and tubulitis. Olsen et al (72) have described severe reduction of the proximal tubular brush border and proximal and distal tubular basolateral infoldings in this context, reflecting tubular injury. In some areas, there may be thinning or disruption of the TBM. Electron-dense immune-type deposits are usually not present in TBMs.


Etiology and Pathogenesis

Three major types of immune mechanisms may lead to tubulointerstitial nephritis in response to drugs. These include hypersensitivity/allergic, immune complex, and cell-mediated reactions. Each of these types is discussed in turn. In a few individual cases, mechanisms of action are clearly defined, but for others, pathogenetic mechanisms are assumed, often based on morphologic and clinical findings. It is possible that several mechanisms of action are at work in an individual patient.

Allergic-type hypersensitivity reactions are idiosyncratic and not related to dose. The reaction to the agent is presumably caused by previous sensitization, and, indeed, patients may give a history of exposure to the ingested drug or a similar drug. The reaction in the kidney is often part of a systemic hypersensitivity reaction, which may include fever, arthralgias, and skin rash. Eosinophils are often a significant component of cells in the inflammatory infiltrate, and, as noted earlier, there is often a peripheral eosinophilia as well.

Reactions involving immune complex deposition are of two types: those with formation of immune complexes that are deposited around tubules and those owing to formation of antibodies directed against antigens at or in the TBM. In a few cases, antigens from the drug have been immunolocalized to the TBM. The inciting drug may serve as a hapten, leading to antibody formation. In a few patients, anti-TBM antibodies have been found; Colvin and Fang (13), in one review, reported that these antibodies are frequently found in patients with different forms of AIN if they are sought. In many cases, however, it is unclear whether these antibodies are of clinical significance, and the specificity of the methodologies to detect these antibodies is not always high. The finding of linear staining for IgG along the TBM is not a specific test to detect anti-TBM antibodies; proof of presence of anti-TBM antibodies requires demonstration of the antibody in the serum or renal eluates. Complexing of antibody to antigen may lead to complement binding and activation, triggering a cascade of events that result in inflammatory infiltrates and tissue injury.

Cell-mediated immunity has also been implicated in the genesis of drug-induced interstitial nephritis. The presence of granulomas in the kidney, in a number of cases of interstitial inflammatory reaction to drugs, is consistent with delayed-type hypersensitivity. T-cell reactivity has been documented in some patients with drug-induced hypersensitivity reactions (73,74). Cytotoxic lymphocytes, which were reactive against autologous renal cell line, have been isolated from one patient being treated with recombinant interleukin 2 (IL2) (75).

Chronic interstitial nephritis with fibrosis resulting from a prolonged inflammatory process is likely mediated by inflammatory cells and the cytokines released by them. Some drugs appear to produce persistent tubulointerstitial damage without an acute injury phase. They include phenacetin-containing analgesics and lithium. Persistent changes produced by analgesics presumably result in part from ischemia produced by imbalances in the vasodilatory versus vasoconstrictor prostaglandins over a prolonged period (see later section on analgesics and nonsteroidal anti-inflammatory drugs). Chronic tubulointerstitial nephritis is associated with prominent loss of the peritubular capillaries, which may further aggravate the ischemic injury (76). As pointed out earlier, certain cytokines, such as TGF-beta, enhance production and release of matrix from epithelial and mesenchymal cells and likely also play a role in bringing about interstitial fibrosis through promoting epithelial-mesenchymal transdifferentiation of renal tubular epithelial cells (12,13).

Clinical Course

Drug-induced interstitial nephritis is generally reversible by withdrawal of the offending agent. Steroid therapy may enhance the rate of recovery and is frequently given along with withdrawal of the drug. A typical and diagnostic feature of drug-induced interstitial nephritis is its recurrence on re-exposure to the drug or a related compound. Although recovery of renal function is the rule if the drug is withdrawn immediately, a study from Germany indicates that permanent renal insufficiency remained in 88% of drug-induced acute tubulointerstitial nephritis cases if the suspected drug was taken for more than a month before the diagnosis (77). Also, the same authors suggest that NSAID-induced interstitial nephritis has a worse outcome compared with other drug-induced forms.

Specific Agents

Antimicrobial Agents


The cephalosporin group of antibiotics comprises several generations of these useful agents, defined on the basis of antimicrobial activity. The first generation includes cefazolin, cephalothin, and cephalexin. Cefamandole, cefonicid, cefuroxime, cefaclor, cefoxitin, and cefotetan are second generation, whereas the third generation includes ceftazidime, cefotaxime, and ceftriaxone. Cefepime is a fourth-generation cephalosporin more resistant to beta-lactamases than the previous agents. These drugs may be nephrotoxic, particularly in patients with pre-existing renal insufficiency. Cephaloridine, the most toxic of the group, is no longer available in the United States, but is used experimentally for toxicity studies.

Clinical Presentation.

The cephalosporins are most likely to produce renal failure in patients with pre-existing renal


insufficiency (79), in those with drug overdose (80), and in those receiving other antibiotics (80). Patients simultaneously receiving furosemide (80) are also at increased risk, which is probably related to the ability of furosemide to prolong the half-life of the cephalosporins (81

has been reported to cause ARF, often as the result of oliguria (80,82). Cephalothin given alone (,84) or with gentamicin, tobramycin (82,85), or other substances (8678,79). The ARF is usually reversible. Cephalexin is less likely to cause nephrotoxicity than cephaloridine or cephalothin, but hematuria, eosinophilia, and a transient rise in blood urea nitrogen (BUN) have been reported (8784,88). Rare cases of skin rash, eosinophilia, fever, and renal insufficiency with ceftriaxone have been reported (89).


Renal biopsies have been obtained in relatively few cases of cephalosporin-induced renal injury, usually in those in which the older cephalosporins were given. Biopsies have shown a picture of interstitial edema with variable numbers of mononuclear cells, accompanied by a variable degree of acute tubular injury (82,90,91,92). No immunoglobulins or complement have been seen with immunofluorescence techniques.


Cephalosporins appear to be capable of producing direct toxic injury to tubular cells. Tune and Hsu (93) have shown that cephalosporins interfere with mitochondrial function in the renal tubule. Cephaloridine has structural homology to carnitine and it has toxic effects on carnitine transport and fatty acid metabolism in rabbit renal cortical mitochondria in vivo; in vitro effects on pyruvate metabolism have been seen, albeit at very high concentrations (93). Cephaloridine also produces lipid peroxidation and acylation and inactivation of some tubular cell proteins. Other cephalosporins, which lack cephaloridine's side group constituents, largely affect tubular cell proteins and especially mitochondrial anionic substrate transporters (93). In vitro, proximal tubular cells show evidence of cytotoxicity on exposure to cephaloridine, cephalexin, and cephalothin whereas distal tubules do not. These studies provide evidence of the role of oxidative stress, cytochrome P450 activation, and mitochondrial dysfunction in tubular cell toxicity (94

In addition, cephalosporins are known to cause hypersensitivity reactions. In some cases, there has been resolution with drug withdrawal and, in a few cases, recurrence on rechallenge (90). The cephalosporins are structurally similar to the penicillins, which produce similar reactions (see later), and cross-reactivity may occur in 1% to 20% of patients (95,96). No specific cephalosporin is more likely than others to cause such a reaction.


Clinical Presentation.

Fluoroquinolones are relatively new antimicrobial agents. Ciprofloxacin, the most widely used of these drugs, has been reported to produce ARF. Levofloxacin, norfloxacin, and tosufloxacin have also been associated with interstitial nephritis (76,97,98). There is typically fever, eosinophilia, and skin rash (99,100,101,102,103), but systemic manifestations may not be present (). Onset of symptoms is generally within 2 to 12 days of beginning either oral or intravenous therapy. Patients have responded to withdrawal of the drug and, generally, concomitant treatment with immunosuppressive agents.


Renal biopsies in cases of fluoroquinolone-associated renal dysfunction have revealed interstitial nephritis. In a few cases there were granulomatous features in the interstitial inflammatory infiltrate (76,103105). Shih et al (103) have reported a necrotizing vasculitis in the kidney in two patients being treated with ciprofloxacin. An interesting case from Japan was reported in which a patient developed crystal-forming chronic interstitial nephritis following long-term exposure to tosufloxacin (98). The crystals were present in interstitial macrophages, but the crystals did not contain immunoglobulin. The patient's renal function improved following discontinuation of the drug.


The mechanism of pathogenesis appears to be a hypersensitivity reaction, with evidence of a cell-mediated process in the few cases with granulomatous features. As with many drug reactions, the possibility that another drug or underlying disease process may have produced the renal effects cannot be ruled out in several of these cases.


In the following section, adverse reactions to ampicillin, methicillin, and penicillin are discussed in detail. AIN has been reported with other penicillins as well, including cloxacillin (106) and piperacillin (107,108).

Clinical Presentation.

109,110,111,112). Fever, skin rash, and eosinophilia may be found and may antedate renal symptoms. Renal manifestations may be mild, with hematuria and a small amount of


proteinuria, or severe, with acute oliguric renal failure. Rapid recovery is the rule. Time to onset varies, but renal symptoms generally appear within a few days of administration of ampicillin; other manifestations, such as fever and skin rash, develop within 24 hours. In several cases, there had been prior treatment with penicillin, methicillin, or tetracycline.

There are many reports of renal damage caused by methicillin. Nephrotoxicity with methicillin is not dose dependent. Onset of toxic reactions usually begins between the 2nd and 37th day after initiation of the drug. Patients typically manifest fever and skin rash, and 73% of patients in a review of 68 patients were male (). Patients of all ages are at risk, though renal failure appears to be more common in older patients. Eosinophilia is a typical feature and may reach very high levels (57). Hematuria may occur; it is often the first sign of renal involvement. Proteinuria is seen in some cases but is generally mild. White blood cells are frequently found in the urine, which is usually sterile, and eosinophils are present in the urine in a high proportion of patients (57,113). Azotemia occurs in over half of patients and oliguria in one third. Complete recovery of renal function is the rule, though azotemia may persist in less than 10% of patients (114).

Penicillin has been widely used for almost 50 years, and there have been few reports of nephrotoxicity ascribed to the drug. Appel and Neu (115) summarized the reported adverse reactions to penicillin under three main headings: various vascular and glomerular lesions, acute anuric renal failure after a single injection, and AIN. In a number of cases, there is fever, skin rash, and eosinophilia, suggesting a hypersensitivity reaction. The patients have hematuria with varying degrees of proteinuria, and renal failure may ensue.


On histology, the predominant finding in cases associated with ampicillin is interstitial nephritis with edema and variable numbers of inflammatory cells. Tubules may show focal necrosis or degenerative changes, and calcification is occasionally reported (110). Glomeruli exhibit no changes, except for rare reports of mild hypercellularity (110,112) and minimal change disease (116). Immunofluorescence studies generally show negative results. Electron-dense fibrillar deposits and viruslike particles have been seen in basal areas of the distal convoluted tubules (112). The fibrillary densities are of unknown significance (probably nonspecific), but they are similar to those described after methicillin (109).

Pathologic findings have been reported in many cases of methicillin-induced nephrotoxicity. In most cases, the glomeruli are reported to be normal, but in one case described by Woodroffe et al (112), mild mesangial hypercellularity was recorded. Necrotizing and proliferative glomerulitis was reported in another case (117), but this patient had also received ampicillin. The main changes are found in the tubules and interstitium. Tubules show various lesions, including necrosis, cell loss, regeneration, and in some cases, tubular atrophy. Desquamated cells and occasional polymorphonuclear leukocytes may be found in tubular lumens. Olsen and Asklund (69) have reported a predominance of involvement of distal tubules over proximal tubules. There is interstitial edema with variable numbers of inflammatory cells, including small lymphocytes, plasma cells, eosinophils, and polymorphonuclear leukocytes. They frequently surround tubules, suggesting a relationship to the tubular damage. Several authors have described epithelioid cells in the interstitium, sometimes forming granulomas (69,118,119). Although blood vessels are usually normal, vasculitis involving arterioles and small arteries has been recorded (57,117). Discontinuation of the drug is usually followed by resolution of the changes. In rare instances, a follow-up biopsy may show interstitial fibrosis (Figs. 23.8,23.9,23.10,23.11,23.12) (120).

Results of immunofluorescence studies in most patients with methicillin-induced lesions have been negative (,69). In others, weak staining for C3 in glomeruli and focal peritubular IgG, IgA, and C3 have been reported (120). Some biopsies, however, have shown linear staining of the TBM for IgG (67,68,121,122) with or without C3 present in glomeruli. In two biopsies (67,68), dimethoxyphenyl penicilloyl (DPO), the major haptenic antigen determinant of methicillin, was found in a linear pattern in relation to TBMs; in one (67), IgG was also deposited in a linear pattern in the glomerular tufts. Prior absorption by DPO-amylamine or methicillin-treated rabbit red cells blocked the positive staining for DPO. In addition, anti-TBM antibody was demonstrable in the serum in a few cases (68,118); DPO in these cases may be acting as a hapten, binding to the TBM and inducing antibody formation (67). Electron microscopy in some cases has revealed loose fibrillar electron-dense deposits in glomerular epithelial cells and in tubular cells adjacent to the basement membrane (10957).

The renal lesion on biopsy or at autopsy in penicillin nephrotoxicity is similar to that of methicillin; acute tubulointerstitial nephritis is found on histologic examination (6067). Immunofluorescence studies in one report (60) revealed irregular fibrinogen or fibrin deposits, traces of IgG in the interstitium, and rare granular deposits of C3 near tubules. In that report, a rabbit antiserum to penicillin G bound diffusely in the interstitium and to tubular and glomerular basement membranes, but it also bound to normal autopsied kidneys from patients who had received penicillin and oxacillin with ampicillin or cephalothin for several days before death.

Based on the above, it is apparent that morphologic examination cannot differentiate between interstitial


nephritides caused by different penicillins. In fact, the histology does not even tell whether the interstitial nephritis is secondary to penicillin or some other drug or injurious agent. Pirani et al (123) compared beta-lactam–induced interstitial nephritis with NSAID-induced interstitial nephritis and found that the beta-lactam–induced cases contained more eosinophils. Both types contained primarily mononuclear cells with some plasma cells in the infiltrate. Still, these are histologic findings of low specificity.


Nephrotoxicity of the penicillins is not dose dependent, and the clinical picture overall is that of a hypersensitivity reaction. In several studies, immunofluorescence microscopy provides evidence that anti-TBM antibodies may play a role (67,68,118,121). Cell-mediated mechanisms may also be involved in some cases, based on the nature of the inflammatory infiltrate and the absence of antibody and complement deposition. Gilbert et al (109) have reported exacerbation of the reaction to methicillin by inadvertent exposure to ampicillin, a closely related drug. In addition, some case histories suggest that ampicillin can trigger a hypersensitivity reaction in patients who might have been sensitized to other penicillins. In one of these cases, antibodies against ampicillin were detected in the patient's serum (111). In a few studies, hypocomplementemia provided additional evidence of an immune reaction (109,118


Clinical Presentation.

Rifampicin is a drug used in the treatment of tuberculosis. When it is given intermittently, it causes various adverse reactions, including fever, chills, dizziness, nausea, and diarrhea (124,125). There have been several reports of acute oliguric renal failure during intermittent rifampicin therapy (117,124,125,126,127,128). The most common clinical scenario is ARF following a single dose of rifampicin after a drug-free period. Most patients recover when the drug is withdrawn (125); a few cases have been reported to result in permanent renal damage (127,129).


Renal biopsies in cases of rifampicin toxicity typically show interstitial edema with variable numbers of mononuclear cells, and eosinophils have also been found (70). Rarely, granulomas may be seen (130). There may be patchy necrosis of the tubular epithelium. Even patchy cortical necrosis has been described (129); in that case, there was residual renal dysfunction. However, the degree of tubular necrosis is often not severe, and in one case the tubules were described as unaffected (124). In addition, pigmented casts may be evident. Although glomeruli and vessels are usually normal, rarely glomerulonephritis, including crescentic and necrotizing glomerulonephritis, has been noted (70,125). On immunofluorescence microscopy, it has usually not been possible to establish the presence of immunoglobulins or complement (126,127,128), although C3 has been found in the mesangium and in the TBM (,131) (common nonspecific findings).


Antibodies to rifampicin have been detected in patients (132,133); in one study, they were present in one third of 49 patients (132). The various adverse reactions reported in this series, including renal dysfunction, were found more commonly in patients with antibodies than in patients without them. These authors suggest that the drug acts as a hapten, which, after it has become bound to macromolecules in the plasma, becomes antigenic with the formation of antibodies. The antibodies are considered to be directed against the drug, with formation of hapten–antibody complexes when the drug is given again.


The sulfonamides have been widely used, with relatively few renal complications. Alleged hypersensitivity reactions in the early days of their use were associated with polyarteritis or acute interstitial nephritis (134,135). However, acute interstitial nephritis secondary to sulfonamides has become a rare event and only a few cases have been reported (136,137). In one case, acute oliguric renal failure developed in a patient being treated with sulfadiazine. The patient recovered after 6 weeks of oliguria (137). Cotrimoxazole (sulfamethoxazole and trimethoprim) has occasionally been found to cause deterioration of renal function (138,139).

Patients in whom crystalline precipitates develop with the use of sulfonamides have microscopic or gross hematuria, crystalluria, and renal colic, and in some cases they become oliguric or anuric (115,140). Occasionally, urolithiasis may evolve. In one series of 40 patients, the urinary bladder was the most common location of stones (141). Sulfasalazine (a combination of 5-amino salicylic acid and sulfapyridine) has recently been reported to cause obstructive uropathy secondary to calculi (142). Less soluble forms, including sulfapyridine, sulfathiazole, and sulfadiazine, are most frequently associated with crystalline obstruction (143). Fortunately, this complication became rarer when sulfonamides of greater solubility became available. Rapid improvement may take place with discontinuation of the drug, fluid administration, and alkalinization of the urine.

The typical pathologic finding is interstitial nephritis. Eosinophils are a typical component of the infiltrate (136,139,144144). In patients with crystallization of sulfonamide in the kidney, some pathologic changes are owing to obstruction as a consequence of crystal formation.


Vancomycin is a glycopeptide antibiotic used increasingly to treat infections caused by organisms resistant to other


antibiotics such as methicillin-resistant Staphylococcus aureus. Nephrotoxicity is a known complication of the drugs when given alone or in combination with other drugs, especially aminoglycosides (145,146). Pediatric patients may be less susceptible to the toxic effects of vancomycin combination therapy (147). Some patients have an associated rash and eosinophilia, suggesting a hypersensitivity reaction. In addition to these adverse renal effects, in some cases, patients have an anaphylactoid reaction to the drug, with generalized flushing—the so-called red-man syndrome.

Tubulointerstitial nephritis with many eosinophils has been documented in renal biopsies in a number of cases of vancomycin-associated renal toxicity (148,149,150). With increasing incidence of methicillin-resistant staphylococci, the use of vancomycin is becoming more and more widespread. Therefore we may encounter increasing numbers of renal biopsies with vancomycin-induced interstitial nephritis.

The pathogenesis of renal toxicity is not well defined clinically, but experimental studies suggest that it stems from tubular cell injury. In some patients, the constellation of clinical symptoms and pathologic features indicate a hypersensitivity reaction, but many patients do not develop such a syndrome. The potentiation of toxic reactions when vancomycin is used with aminoglycosides may be owing, at least in part, to enhancement of aminoglycoside binding to brush border and, presumably, its uptake into tubular cells, with subsequent cellular injury (151).

Analgesics and Nonsteroidal Anti-Inflammatory Drugs

Anti-inflammatory agents can be classified as steroidal and nonsteroidal. However, by convention, the generic term nonsteroidal anti-inflammatory drugs (NSAIDs) has come to refer to specific prostaglandin (PG) synthase (cyclooxygenase) inhibitors, exclusive of aspirin. This causes some conceptual confusion because aspirin, in fact, is a PG synthase inhibitor. These drugs are used for their analgesic, antipyretic, and anti-inflammatory effects. Cyclooxygenase (COX) has two isoforms. COX-1 is the constitutive isoform normally expressed in the tissues, and COX-2 is the inducible isoform. The hypothesis was that COX-1–derived prostaglandins are responsible for regulating physiologic functions whereas COX-2–derived prostaglandins play a more important role in the pathogenesis of inflammation and tissue damage. The older generation of NSAIDs block both COX-1 and COX-2. A new generation of drugs selectively inhibits COX-2, and the assumption was made that these would not be associated with serious gastrointestinal and renal side effects. This led to the finding that constitutive tissue expression is present not only for COX-1 but also for COX-2. COX-2 has been detected in normal renal tissue in the medullary interstitial cells, in the macula densa, in the thick ascending limb of Henle, and also in smooth muscle cells and endothelial cells of arterioles and veins (152,153).

Importantly, more and more data indicate that renal toxicity, including ARF with interstitial nephritis and also heavy proteinuria, may be associated not only with conventional NSAIDs but also with COX-2 inhibitors (154,155,156,157,158,159). At the time of writing this chapter, there is considerable controversy about COX-2 inhibitors and their cardiovascular side effects, which resulted in the withdrawal of rofecoxib (Vioxx) from the market. The future of these otherwise promising anti-inflammatory medications is currently uncertain.

Under euvolemic conditions, renal prostaglandin (PG) synthesis is low; however, if the renal blood flow is compromised, PG exerts a compensating influence on renal function. Some PGs induce renal vasodilatation that counterbalances vasoconstrictor effects of angiotensin-II and norepinephrine. They also affect sodium excretion, and, as a consequence of renal vasodilatation, they may increase the filtered load of sodium. They also increase medullary blood flow and reduce hypertonicity of the loop of Henle. PGs also have natriuretic effect by direct inhibition of sodium transport in the loop of Henle and distal nephron, and they also oppose the hydro-osmotic effects of vasopressin (). There are several different PGs with diverse effects. The above list of the actions of PGs is not complete, highlighting the complexity of their effect on renal function under normal and pathologic conditions.

Acetaminophen is frequently not classified as an NSAID because it has no anti-inflammatory effect, and it is not a PG synthase inhibitor. It is, however, one of the most widely used analgesic and antipyretic drugs and is discussed under the category of NSAIDs by many pharmacology textbooks. For convenience, we discuss acetaminophen with NSAIDs (Table 23.2). The gastrointestinal toxicity of these agents is well known, but their adverse effect on renal function became apparent only in the past three decades.


The incidence of NSAID nephrotoxicity is not well established. Taking into consideration their over-the-counter availability and the frequency with which people take them for pain relief or fever, the incidence appears to be rather low. On the other hand, because of their widespread use and availability, many patients with renal impairment have a history of NSAID use. In a number of such patients, the association of NSAIDs and renal failure is incidental. A causative relationship between NSAIDs and renal impairment should be considered if the initiation of NSAID therapy and the renal impairment show a close temporal association, if other etiologic factors can be excluded, and if renal function improves following discontinuation of NSAIDs.

Approximately 50 million Americans per year are likely to take NSAIDs, and some 500,000 (1%) of them are thought to experience renal side effects (160,161). Murray


and Brater (162), in a prospective study, found renal impairment in 18% of patients treated with ibuprofen. Kleinknecht et al (163), in a prospective study, collected 2160 cases of ARF, 146 of which (6.8%) were attributed to NSAIDs. ARF was defined as a greater than 50% rise in the serum creatinine level or an increase to greater than 2.4 mg/dL from the baseline value. Data from the Boston Drug Surveillance Program on 122,000 hospitalized patients taking NSAIDs indicate that the serum creatinine did not increase compared with levels in patients not receiving NSAIDs (164). A meta-analysis reviewing 1368 patients taking NSAIDs found only 3 patients in whom the serum creatinine concentration increased to greater than 2 mg/dL (165). Corwin and Bonventre (166) reviewed 26 patients with ARF owing to NSAID treatment. The serum creatinine increased from a mean value of 1.6 ± 0.1 to 3.3 ± 0.3 mg/dL following 4.2 ± 0.7 days' mean duration of treatment, and the serum creatinine returned to normal following withdrawal of NSAIDs. They estimated the incidence of ARF, defined as the number of recognized cases per inpatient days of therapy, and found it to be 0.001, 0.0003, 0.0001, and 0.0001 for indomethacin, ibuprofen, zomepirac, and sulindac, respectively (166). The incidence may be overestimated in some of these studies because hospitalized patients already represent a selected population and may have risk factors for NSAID toxicity (see later).

Table 23.2 Nonsteroidal Anti-Inflammatory Drugsa

Nonselective prostaglandin synthase inhibitors (COX-1 and -2) Carboxylic acids

  Salicylic acid derivatives




  Acetic acids








  Propionic acids







  Fenamic acids




  Enolic acids



Selective COX-2 inhibitors




Nonprostaglandin synthase inhibitors




aSpecific anti–rheumatoid arthritis agents and antigout agents are not included.


Clinical Presentation

is the typical clinical presentation and may be accompanied by varying degrees of proteinuria (157,166,167,168). The condition usually develops within a few days to weeks after initiation of therapy. Sodium retention and edema may occur, and occasionally hyperkalemia may develop, presumably as the result of reduced renal PG production and a subsequent decrease in serum aldosterone (169,170). Calvo-Alen et al (171) found that prolonged use of NSAIDs leads to subclinical renal failure, which manifests first in decreased renal concentrating capacity and is correlated with the cumulative intake of the drug.

Proteinuria172,173). A group of researchers from Chicago found that 9% of their adult cases of minimal change nephrotic syndrome were associated with NSAIDs (174173,174). Rarely COX-2 inhibitors may also induce nephrotic syndrome as has been reported with celecoxib (157). The proteinuria typically subsides within a few weeks after discontinuation of the NSAIDs, but may worsen with re-exposure to the drug. The usual glomerular lesion is minimal change disease and is discussed in Chapter 4.

The concurrence of renal insufficiency and severe proteinuria, particularly if the renal failure is nonoliguric, is strongly suggestive of AIN (172,173123). Hematuria may also be present. The male-to-female ratio is 1:2. The symptoms usually appear weeks to months after initiation of NSAID therapy and may resolve within days or weeks afterwards (123,174,175). Recovery is not always the case for NSAID-associated AIN, and cases of patients who progress to end-stage renal disease have been reported (163,175176). Approximately 20% of AIN cases are associated with acetic acid derivatives. However, other NSAIDs, including mefenamic acid, niflumic acid, and many others including COX-2 inhibitors, are reported to induce AIN (123,154,155,156,157,158,159,174,175,176).


Oligohydramnios with congenital renal insufficiency may follow in utero exposure of the fetus to NSAIDs, which also may cause bleeding diathesis, premature closure of the ductus arteriosus, and ileal perforation. Tubular dysgenesis with incomplete differentiation of the proximal tubules as well as tubular microcystic dilatation has been described (177,178,179), and the renal damage is severe and irreversible. Most reported cases are related to prolonged in utero indomethacin exposure (177,178).

Risk Factors

NSAIDs do not alter the glomerular filtration rate (GFR) in healthy, euvolemic individuals (180), but they reduce the GFR in patients with chronic renal disease or with pre-existing impaired renal function (161,180,). Elderly patients are particularly vulnerable to the toxic effects of NSAIDs (162,182), which can be explained by the fact that aging is associated with a progressive decline in the GFR and impaired pharmacokinetics of NSAIDs (168). Dehydration and decreased cardiac output are also associated with an increased risk of nephrotoxicity; diminished GFR may be the main risk factor in these conditions as well (58,166). Patients with liver cirrhosis are also at higher risk, which may be related, in part, to the impaired hepatic metabolism of NSAIDs and to renal impairment associated with chronic hepatic failure (168183).

Certain types of NSAIDs are more likely to cause renal injury than others. Approximately 20% of the cases of interstitial nephritis are related to indomethacin and other indoleacetic derivatives (176). Baisac and Henrich (184), in their review of 59 cases of NSAID-induced minimal change nephrotic syndrome, found that 28 of the 59 cases were related to fenoprofen. Whelton et al (170) found that in patients with asymptomatic renal failure, ibuprofen is more frequently associated with ARF than are sulindac and piroxicam. There are also data that suggest that sulindac has less nephrotoxic potential than other NSAIDs. Sulindac does not reduce the excretion of urinary PGs and appears to be a safe drug even in patients with pre-existing renal failure (168). The kidney has the ability to metabolize sulindac into an inactive sulfone metabolite, thus protecting its own PG metabolism against the drug (168). In spite of the occasional renal side effects, it appears that selective COX-2 inhibitors are perhaps less nephrotoxic than other NSAIDs; however, reliable epidemiologic data are not available yet. Acetaminophen and aspirin are usually not associated with acute renal injury, but large doses of these drugs may cause ARF (185,187).


Acute tubular necrosis may be present, but the tubular degenerative and regenerative changes are frequently coupled to interstitial nephritis, minimal change disease, or both (Fig. 23.13) (123).


Figure 23.13 Mild interstitial edema and inflammation, associated with acute tubular injury, in a patient following NSAID administration. The glomerulus is unremarkable. This patient had nephrotic syndrome and acute renal failure. The renal failure and proteinuria reversed after discontinuation of NSAIDs. (H&E, ×200.)

The morphologic features of NSAID-associated AIN are similar to those of other interstitial nephritides and are characterized by a mononuclear interstitial infiltrate. However, minor differences do exist. Pirani et al (123) compared NSAID and beta-lactam antibiotic-associated renal changes and found that in NSAID-induced interstitial nephritis there is less intensive infiltrate and the proportion of eosinophils is substantially smaller. The paucity of eosinophilic cells in the infiltrate was also reported by Bender et al (18). It is worth noting that routine staining methods may not reveal degranulated eosinophils; thus, the actual number of eosinophils may be underestimated. There are also fewer plasma cells, and tubulitis as well as granulomatous features are less common (123). There is agreement that the infiltrate consists mainly of lymphocytes, primarily T lymphocytes, but plasma cells, B lymphocytes, and polymorphonuclear leukocytes may also be present in substantial numbers (17,123,188). There are few data regarding T-lymphocyte subsets, and these are controversial. Initial studies indicated a predominance of cytotoxic/suppressor T cells (17,176), but other researchers have found a helper/inducer cell predominance (188). The different types of antibodies used and the diverse methodologies, forms of fixation, and selection biases may account for the divergent results.

Occasionally, NSAID-associated interstitial nephritis may have granulomatous features (189). The condition has to be differentiated from sarcoidosis and infectious granulomatous interstitial nephritis, including tuberculosis. The


differential diagnosis should not be based on the morphologic characteristics alone because the histologic changes are usually not distinctive. In NSAID-associated interstitial nephritis, the granulomas are usually, but not always, less distinct than in sarcoidosis. The clinical history is the most important factor in making the correct diagnosis. Discontinuation of NSAIDs usually leads to resolution (189).

Either the glomeruli show no changes on electron microscopy, or, if nephrotic-range proteinuria is present, minimal change disease can be seen with the effacement of podocyte foot processes (123,173,174,190,191). Baisac and Henrich (184) reviewed 59 cases of NSAID-induced minimal change nephrotic syndrome and found that interstitial nephritis was also present in 43 patients. Occasionally, glomerular lesions other than minimal change disease (e.g., membranous glomerulopathy) are reported. These NSAID-induced glomerular diseases are discussed in the appropriate chapters (Chapters 4 and 6).


There is agreement that NSAIDs exert their toxic effect on the kidney through their interference with renal PG metabolism (152,153). PGI2 is the most abundant PG in the cortex; it is produced primarily by arterioles and glomeruli. PGE2 is the most abundant PG synthesized by the tubular epithelium, primarily in the distal nephron segments (distal tubules, collecting ducts) (192). Thromboxane A2 is produced by the glomeruli, and PGF22α is produced by the tubules. The effect of PGs on the renal vasculature is primarily vasodilatory (193). Vasoconstrictive mediators, such as angiotensin II, sympathetic stimuli, norepinephrine, arginine vasopressin, and endothelin, also stimulate PGI2 and PGE2 synthesis, which, in turn, will counterbalance the vasoconstriction. PGs also inhibit tubular water and salt reabsorption (168). In contrast, in conditions where the systemic hemodynamic conditions are compromised, NSAIDs may have a deleterious effect on the renal circulation. Owing to the inhibition of cyclooxygenase, the synthesis of vasodilatory PGI2 and PGE2 is diminished, and severe unbalanced renal vasoconstriction may develop, resulting in ARF (168,194).

The development of AIN is probably related to a delayed-type hypersensitivity response to NSAIDs, which is also reflected in the composition of the infiltrate (17,123). This suggestion is also supported by the prolonged exposure and the infrequency of hypersensitivity symptoms. This condition is somewhat different from antibiotic-associated interstitial nephritides, where hypersensitivity signs are more common and eosinophil cells are more prominent in the infiltrate.

The pathogenesis of NSAID-associated severe proteinuria is unclear. In fact, there is some evidence that NSAIDs may ameliorate glomerular proteinuria (195). Why in certain patients the opposite happens is unresolved. The fact that nephrotic-range proteinuria and interstitial nephritis are frequently present at the same time suggests the role of mediators such as lymphokines released from interstitial or circulating inflammatory cells, which could alter glomerular permeability. In addition, the inhibition of PG synthesis by NSAIDs may hamper the inhibitory effects of PGs on T-cell function, thus intensifying immune activation and cytokine release. The inhibition of cyclooxygenase may also result in a shift of arachidonic acid metabolism toward the lipoxygenase pathway, which may result in the enhanced production of proinflammatory leukotrienes (167,173).

Analgesic Nephropathy

Analgesic nephropathy is a chronic progressive tubulointerstitial disease induced by the prolonged use (abuse) of analgesics and potentially addictive substances, such as caffeine or codeine. Analgesic nephropathy was first described in the 1950s (196) and was further characterized in the following decades. It became apparent that the chronic use of analgesics, primarily phenacetin, might be associated with the development of renal failure. However, larger case-control studies demonstrating this relationship were published only more recently (197,198,199,200,201). The definition of analgesic abuse is quite variable and arbitrary in the different studies, but the consumption of daily analgesics for 1 year or more or a cumulative intake greater than 1000 units (tablets) is the minimum criterion required by most investigators. However, true analgesic abuse and subsequent nephropathy is associated with higher cumulative intake (usually more than 5000 units).


The incidence varies greatly from study to study, depending primarily on the region or country where the investigation was performed. In Europe, the percentage of analgesic nephropathy among patients undergoing long-term dialysis secondary to end-stage renal disease (ESRD) varies widely, from only 0.1% in Ireland, Norway, Poland, and Hungary to 18.1% in Switzerland (202). According to the Analgesic Nephropathy Network of Europe study, the average European incidence of analgesic nephropathy among patients who were started on renal replacement therapy in 1991 to 1992 was 6.4% (198). In Australia and Canada, 11% and 2.5% incidence rates have been reported, respectively (203,204). In the United States, 1.7% to 10% of the ESRD cases are thought to be the result of analgesic nephropathy in various regions (199,205). These large geographic differences may be explained by differences in local habits, psychosocial factors, availability of these drugs, and probably also the frequency of correct diagnosis and reporting.


The removal of phenacetin from the market as well as other regulations (restricting over-the-counter sales and marketing smaller packages) resulted in a decline of the proportion of patients requiring dialysis therapy for analgesic nephropathy in Australia and Sweden, and in Berlin, Germany (204,,207). Still, the incidence remains high in many countries, indicating that drugs other than phenacetin, such as acetaminophen and NSAIDs, are responsible for the development of the disease (197,206). Some authors believe that combination analgesics (acetaminophen and salicylates or aspirin) are more likely to induce analgesic nephropathy than single-drug usage (197). Recently Michielsen and Schepper (208) reviewed data on analgesic nephropathy in two highly endemic regions: Belgium and New South Wales, Australia. In Belgium, the sale of phenacetin was banned but other combined analgesics remained on the market. In contrast, in New South Wales, not only phenacetin but all combined analgesics were prohibited. Still, the downward trend and prevalence of analgesic nephropathy was very similar during the follow-up period, indicating that nonphenacetin mixed analgesics probably do not play a significant role in the development of analgesic nephropathy (208). The cumulative dose of analgesics appears to be an important factor. Perneger et al (197). However, the true incidence of analgesic nephropathy is difficult to determine. The Ad Hoc Committee of the International Study Group on Analgesics and Nephropathy critically reviewed the available data of the association between NSAID and renal disease (209). They found that many studies on analgesic nephropathy are inconclusive because of sparse information and substantial methodologic problems. Also, they emphasized that the diagnosis of analgesic nephropathy in different studies can vary, and in many cases the diagnosis is based primarily on information about drug ingestion without any specific imaging or histologic studies. Therefore, the committee decided that there is no convincing evidence that nonphenacetin combined analgesics are truly associated with nephropathy (209).

Data from the physicians' health study recently indicated that analgesic use in healthy male patients is not associated with the risk of subsequent renal failure (210). The study involved 4772 healthy male physicians with normal serum creatinine levels in 1982. During a follow-up period of 14 years, there was no evidence of renal impairment in these patients, not even in those who consumed more than 7000 analgesic pills (210). This study somewhat contradicts previous data, but it emphasizes that a pre-existing underlying renal condition or other coexisting aggravating pathogenetic factors (such as hypertension, diabetes, obesity, and so on) may be important in the pathogenesis of analgesic nephropathy and analgesic intake by itself may not be deleterious to the kidney if no other coexistent or pre-existent pathologic factors are present (211). In spite of this contradictory data, considering the widespread use and abuse of analgesics, analgesic nephropathy has to be considered an important public health issue.


The typical patient is a middle-aged woman with various symptoms, frequently including headaches and some degree of acute and/or chronic renal failure. The decline in the GFR may be caused by vasoconstriction, vascular damage, or tubular obstruction (212). Tubular damage is reflected in defects of urinary concentration, acidification, and sodium retention. Microscopic hematuria occurs in 40% of patients (). Gross hematuria with loin pain and ARF are suggestive of papillary necrosis (213). Occasionally, full-blown papillary necrosis occurs. If the necrotic papilla is sloughed into the renal pelvis, fragments of necrotic papilla segments may cause obstruction or be voided in the urine. Significant proteinuria (greater than 0.3 g/24 hours) is present in half of the patients, but nephrotic-range proteinuria is uncommon (212). Hypertension develops in a substantial number of patients.

The diagnosis of analgesic nephropathy should not be solely based on renal biopsy. Renal imaging techniques, such as sonography and particularly computed tomography, are the best methods for diagnosis in the appropriate clinical context (198). The Analgesic Nephropathy Network of Europe study showed that shrinkage of renal mass (sensitivity 96%, specificity 37%), bumpy renal contours (sensitivity 57%, specificity 92%), and the presence of papillary calcifications (sensitivity 85%, specificity 93%) are the most useful criteria in diagnosing analgesic nephropathy. The combination of these three criteria resulted in a sensitivity of 85% and a specificity of 93% (198). Radiocontrast examinations may be helpful in the diagnosis of papillary necrosis. The specificity and sensitivity of diagnostic imaging studies have been reviewed by De Broe and Elseviers (214).

Pathologic Findings

Gross Appearance.

In the full-blown form, both kidneys are somewhat contracted, and the subcapsular surface shows irregularly alternating depressed areas and raised nodules, the latter sometimes assuming a characteristic ridged form (215216). The depressed areas correspond to atrophic, scarred portions of the cortex above a necrotic papilla. The nodular areas correspond to the hypertrophic


areas of the cortex above the columns of Bertin. The papillae are shrunken and withered and may be pale or brown (Fig. 23.14). Calcification may be present, primarily in the medulla. In early-stage papillary necrosis, yellow stripes radiating outward from the tip of the medulla may be seen, separated by dark zones. This appearance may be confined to the tip or may extend through the entire papilla. Later, the yellow appearance becomes confluent and extends to the border of the inner and outer medullas. In some cases, only the tip of the papilla becomes necrotic;in others, the necrosis is found only in the central part of the papilla. Occasionally, the necrotic papillae become sequestered and may be found lying free in the pelvis. Soft phosphate stones may also be noted in the pelvis in association with papillary necrosis. A characteristic brown pigmentation of the pelvic mucosa may be observed, which is thought to be the result of lipid deposition (217,218).


Figure 23.14 Portion of a kidney with advanced analgesic nephropathy. Note the pale grey-white papilla, representing papillary sclerosis/necrosis.

Light Microscopy.

The earliest change is the sclerosis (basement membrane thickening) of capillaries beneath the urothelial mucosa (Fig. 23.15) (216,218,219216). At a more advanced stage (in early stages of papillary necrosis), the capillary sclerosis involves the peritubular capillaries in the papilla and inner medulla. The ascending loop of Henle also exhibits a substantially thickened basement membrane, but the basement membranes of the collecting ducts, descending loop of Henle, and vasa recta are not affected or are only mildly affected. The thickened basement membranes are PAS-positive and contain lipid as well as calcium deposits (Fig. 23.16). Ultrastructurally, this basement membrane thickening consists of numerous thin layers of basement membrane material (Fig. 23.15B), which probably forms as the result of repeated injury of the capillary endothelium and the epithelium of the thin limb of Henle (216,220). Early on, these changes are confined to the central part of the inner medulla, but as the disease progresses, the affected small foci become confluent and may involve the entire inner medulla.

As full-blown papillary necrosis develops, the collecting ducts and the vasa recta become necrotic as well, and a ghost outline of the original structure is present (Fig. 23.17). Renal papillary necrosis is not associated with the influx of neutrophils into the necrotic areas or the bordering preserved renal parenchyma. There may be focal collections of lymphocytes and macrophages. If the necrotic portion of the papilla sloughs into the lumen of the renal pelvis, the resulting cavity will re-epithelialize. The necrotic material may also remain in place, and in such cases calcification of the necrotic papilla is common, with possible bone formation (Fig. 23.18).

The cortical changes are thought to stem from the alterations in the papilla (221,222). The cortex may be normal in the early and intermediate forms. The cortical changes consist of tubular loss and tubular atrophy with interstitial fibrosis and a varying degree of interstitial infiltration of chronic inflammatory cells (). Lipofuscin accumulation is frequently noted in the epithelium of atrophic tubules. These are nonspecific changes and cannot be reliably differentiated from other forms of chronic tubulointerstitial injury. It appears that the necrotic papilla, in some ways analogous to obstructive nephropathy, is responsible for the cortical changes. This is also supported by the fact that the columns of Bertin are often spared.

The glomerular changes are presumably the result of the tubulointerstitial changes and are quite nonspecific as well. In the atrophic suprapapillary cortex, periglomerular fibrosis, glomerular ischemia, obsolescence, and sclerosis may occur. In the columns of Bertin, where compensatory hypertrophy is common, some glomeruli may undergo segmental hyalinosis and sclerosis (216,223). Zollinger (223) called this change “overload glomerulitis,” which is in fact identical to glomerular hyperperfusion injury. Except for the medullary and pelvic capillary sclerosis, there are no vascular changes characteristic of analgesic nephropathy. Arteriolar hyalinosis and varying degrees of arterial intimal fibrosis may develop, particularly in older patients and in patients with arterial hypertension.

Differential Diagnosis

The key to the differential diagnosis is the clinical history. From the point of view of morphology, the gross findings are at least as characteristic as the histologic appearance. The irregular bumpy cortical contours with underlying papillary necrosis and sclerosis are distinct from the medullary



and cortical scarring with caliceal deformities in chronic pyelonephritis/reflux nephropathy. Obstructive uropathy with renal pelvis dilatation and parenchymal atrophy is easy to recognize. However, analgesic nephropathy predisposes patients to infections, and both acute and chronic pyelonephritis are much more common than in the normal population (216). Diabetic nephropathy with papillary necrosis may have a similar gross and microscopic appearance with basement membrane thickening of the loop of Henle and peritubular capillaries. However, the capillary sclerosis beneath the urothelium is not seen. Papillary necrosis may occur in sickle cell disease and, rarely, in vasculitis and systemic lupus erythematosus (213). In these conditions, as well as in diabetes, the characteristic features of the underlying disease assist in making the diagnosis.


Figure 23.15 Appearance of capillaries in the submucosa of the renal pelvis in analgesic nephropathy. A: A section of the submucosa at the upper end of the ureter from a patient who had abused analgesics shows extreme thickening of the capillary walls. It may be so pronounced as to render the capillaries solid. (PAS, ×350.) (Prepared from a slide supplied by Dr. H.U. Zollinger.) B: Electron micrograph of a capillary obtained by biopsy of the renal pelvis of a patient who had abused analgesics. Numerous new basement membrane lamellae have been formed, and the multilayering is responsible for the appearance in (A). (×7050.) (From

Mihatsch MJ, et al. The morphologic diagnosis of analgesic (phenacetin) abuse. Pathol Res Pract 1979;164:68.



Figure 23.16 Calcium deposits in the basement membranes of the vasa recta in the renal papilla in analgesic nephropathy. (Von Kossa, ×200.)


Figure 23.17 Low-magnification picture taken from the specimen shown in Figure 23.14. In analgesic nephropathy, typically there is no inflammatory reaction around a necrotic/sclerotic papilla. The ghost structure of the renal papilla is still recognizable. (H&E, ×10.)


Figure 23.18 Bone formation in a necrotic papilla from a patient who had abused analgesics and who survived several years after the initial diagnosis. (H&E, ×145.)


One theory is that the papillary changes are caused by insufficient blood supply (224,225). Lagergren and Ljungqvist (226) were unable to demonstrate the postglomerular vessels of juxtamedullary glomeruli, indicating


decreased blood supply of the papilla. A reduction in number and dimension of the vasa recta in a rat model of analgesic nephropathy was noted by Kincaid-Smith et al as well (224). Molland (225) suggested that the reduced medullary blood flow in analgesic nephropathy is the consequence of disturbed autoregulation.


Figure 23.19 Interstitial fibrosis and tubular atrophy in the cortex of a kidney with analgesic nephropathy. Note that most glomeruli in this section are preserved; only scattered sclerotic glomeruli are seen. (H&E, ×40.)

Certainly, capillary sclerosis can compromise the medullary blood flow, but it appears that capillary sclerosis itself is the consequence of toxic effects (227). The concentric lamellated ultrastructure of the thickened basement membranes of the peritubular and pelvic capillaries and the loop of Henle suggests repeated injury and subsequent repair of the capillary endothelium and loop of Henle's epithelium, respectively. Analgesic drugs are highly lipophilic, and they can easily diffuse out of the urine into the medullary and papillary interstitium and cause capillary damage. It has been shown that the concentration of analgesic substances in the renal medulla can be many times higher than in the blood (228). Thus, it appears that the topographic distribution of renal injury is related to the local concentration of analgesics and their metabolites. The primary injury appears to be toxic capillary damage, which in turn, through ischemia, aggravates the injury and leads eventually to papillary necrosis.

The natural history of the medullary/papillary changes is unclear. We had the opportunity to examine a cadaveric donor kidney from a semiprofessional athlete who died because of an automobile accident (Fig. 23.20). Organ donation was considered, but the kidneys were not transplanted because of very poor perfusion on the perfusion pump. Gross examination of the kidney revealed prominent edematous renal papillae (Fig. 23.20A). Histologically, in the prominently edematous papilla, calcium deposits, including capillary calcification, were noted (Fig. 23.20B and C). Otherwise, the renal parenchyma, including the renal cortex, was normal and there was no evidence of renal impairment in the donor. After questioning family members, it turned out that the athlete had been taking large amounts of analgesics for several years before his death. There was no evidence of impairment of renal function. Therefore, it is quite possible that this kidney represented an early stage of analgesic nephropathy, which in this particular patient may have been secondary to the combined effect of periodic dehydration because of the strenuous exercise and the large doses of analgesics.


Figure 23.20 This is a nephrectomy specimen from a young athlete who used large doses of analgesic medications for many years and died of an automobile accident. A: Note the edematous papillae. B: Histologic examination revealed prominently edematous renal papillae with compression of the vasa recta. (H&E, ×100.) C: von Kossa stain revealed finely granular calcium deposits in the basement membranes of the vasa recta and collecting ducts. (×400.)

The pathogenesis of cortical changes is most likely secondary to medullary damage. The nephrons from the columns of Bertin drain into the forniceal region of the calyx, which explains their escape from obstruction and subsequent injury in papillary necrosis (,222). Furthermore, cortical atrophy and chronic interstitial nephritis develop primarily in areas where the underlying papilla remains in situ and undergoes sclerosis with the obstruction of the urine flow. If the separation of the necrotic papilla ensues, the urine flow may persist and less cortical damage will develop (215,216,222). An alternate theory is that the



The exact pathogenesis of the toxicity of analgesic compounds and the primary target of the toxic reactions are unknown. Inhibition of PG synthesis and immunologic reactions are unlikely causes (216). It is possible that metabolites of phenacetin, aspirin, or paracetamol, under the influence of P450 mono-oxygenase, bind covalently to cellular proteins and cause toxic damage (212).

Another possible explanation is cellular glutathione depletion with subsequent lipid peroxide production (229). This theory is based on the observation that combination analgesics are more prone to cause damage. Acetaminophen becomes concentrated in the papillae and there undergoes oxidative metabolism, which turns it into a reactive quinone imine that becomes conjugated to glutathione. If acetaminophen is ingested alone, there is sufficient glutathione generated to detoxify the reactive metabolites. If acetaminophen is taken in combination with aspirin or salicylates (aspirin will be converted to salicylate as well), the papillary concentration of salicylates will also be very high. Salicylates potently deplete glutathione, probably through the inhibition of NADPH production. Thus, with the combination of acetaminophen and salicylates or aspirin, glutathione depletion in the papilla may ensue and result in the production of lipid peroxides by the reactive acetaminophen metabolites. This subsequently leads to local tissue damage, resulting in papillary necrosis (229).

There are a few animal models for analgesic nephropathy. Moeckel et al (230) administered COX-2 inhibitors to mice and found that COX-2 inhibition dramatically reduced osmolyte accumulation in medullary interstitial cells. Exogenous osmolytes reversed COX-2–induced cell death in cultured renal medullary cells. They proposed that the reduction of osmolytes may have a pathogenetic role in analgesic nephropathy (230). In another mouse model of acetaminophen-induced nephrotoxicity, a nitric oxide donor prevented renal injury as measured by blood urea nitrogen levels and renal pathology (interstitial congestion, proximal tubular cell degeneration, and necrosis) (). The authors proposed that the protective mechanism is secondary to attenuation of lipid peroxidation in the kidney. Ahmed et al (232) described an animal model with nephropathy following the administration of phenacetin and chloroquine. The renal injury was prevented by the administration of the nitric oxide synthase inhibitor L-nitro-arginine ethylester (L-NAME). A more recent experiment, however, indicated that COX-2 inhibitors may actually be protective against renal injury in an animal model. Administration of COX-2 inhibitor and then an angiotensin-1 receptor inhibitor prevented progressive renal injury in a 5/6 renal ablation model in the rat (233,233). However, there are clear differences in rodent and human responses to drugs. Chronic aspirin administration can cause renal papillary necrosis in rodents, which has not been reported in humans (234). Therefore, interpreting the somewhat controversial experimental data has to be done with caution. Perhaps nonrodent animals may provide a better model for human analgesic nephropathy.

Urothelial Cancer and Analgesic Abuse

It is now widely accepted that there is an association between analgesic abuse and transitional cell carcinoma of the renal pelvis and urinary tract (235,236,237). The incidence is variable, and according to Mihatsch and Knüsli (236), it may occur in at least 10% of phenacetin abusers. The latent period can be two or more decades (237235,237); however, longer follow-up is needed for definitive proof. Although renal papillary necrosis has been found in a high proportion of patients with transitional cell carcinoma associated with analgesic abuse, it is not a prerequisite for the development of these tumors. Occasional publications also implicate an increased number of renal cell carcinomas in analgesic abusers. However, a study from the National Cancer Institute did not confirm this finding (238).

5-Aminosalycilic Acid

5-Aminosalycilates are anti-inflammatory medications widely used for the treatment of inflammatory bowel disease. Two forms of these medications, mesalazine and sulfasalazine, are used. Based on data from the United Kingdom General Practice Research Database, it appears that the incidence of renal failure in patients on 5-aminosalycilic medications is low (0.17 cases per 100 patients per year) (239). This database indicates that the risk of renal failure is comparable with mesalazine and sulfasalazine use. Examining the renal side effects, Ransford and Langman (240) found that interstitial nephritis was described only following the use of mesalazine. This is intriguing because the difference between mesalazine and sulfasalazine is that in sulfasalazine, 5-amniosalycilic acid is combined with sulfapyridine (a sulfonamide). Therefore, theoretically one might expect a higher prevalence of interstitial nephritis with sulfasalazine. Arend and Springate (241) reviewed mesalazine-induced interstitial nephritis recently. They concluded that mesalazine-related renal insufficiency occurs in approximately 1 in 100 to 500 patients. In patients with biopsy-proven interstitial nephritis, the frequency of residual renal insufficiency is 61%, and 13% of



Other Medications


The drug diphenylhydantoin (Dilantin) is used extensively for the treatment of seizures and arrhythmias. There are several side effects, but adverse reactions involving the kidney are rare. A few cases of oliguric ARF and interstitial nephritis have been reported (242,243,244). Hyman et al (243) described the case of an 8-year-old girl who showed cutaneous and systemic signs of hypersensitivity 22 days after starting a course of diphenylhydantoin. This was followed 10 days later by the appearance of nephrotic syndrome, hematuria, and azotemia. A renal biopsy revealed interstitial nephritis by light microscopy and linear deposits of IgG along TBMs on immunofluorescence. Diphenylhydantoin antigen was found along TBMs by immunohistochemistry. Anti-TBM antibody was present in the serum, and peripheral blood lymphocyte transformation was observed following incubation with diphenylhydantoin. The suggestion was made that cellular hypersensitivity to deposits of diphenylhydantoin on TBMs could have induced antigenic alterations, resulting in the production of anti-TBM antibody.

It is well known that vascular changes take place with the use of diphenylhydantoin, and granulomatous arteritis can be seen in patients hypersensitive to this drug (245). Gaffey et al (245) reviewed eight cases of vasculitis caused by hypersensitivity to Dilantin. The kidney was involved in six cases; three patients had granulomatous interstitial nephritis. Blood eosinophilia of more than 14% occurred in four patients.


The widespread use of lithium carbonate in psychiatric practice for the treatment of manic-depressive states has been associated with occasional cases of ARF, the more common occurrence of a diabetes insipidus-like state, and permanent impairment of renal function in others.

Clinical Presentation.

Nephrogenic diabetes insipidus (polyuria, polydipsia, and impaired renal concentrating capacity) is the most usual renal complication of maintenance lithium therapy (246). Defective distal tubular acidification owing to low fractional excretion of bicarbonate, with normal serum levels of bicarbonate and phosphate and normal ammonia excretion, is also common. Hypercalcemia may also occur (247). These side effects are usually reversible; however, there are reports that chronic irreversible renal injury may develop following maintenance lithium therapy (248,249).

The frequency with which chronic renal insufficiency and permanent morphologic damage occur in patients receiving long-term lithium therapy has been considered by several authors (250,251,252). Walker and Edwards (252) summarized the results of seven longitudinal studies between 1981 and 1988 and found little potential for decreased GFR in lithium-treated patients. In a prospective study of 65 lithium-treated patients, Jorkasky et al (251) found a mild decline in the GFR in men but not in women. They questioned whether the reduction in the GFR was progressive and would lead to clinically significant renal insufficiency. A recent study from France indicates that the prevalence of lithium nephrotoxicity among end-stage renal disease patients is two per 1000 dialysis patients (247). They calculated that the lithium therapy duration until ESRD was 19.8 years and the estimated cumulative lithium salt given was 5231 grams per patient. Cases of the nephrotic syndrome have been rarely reported (247,253,254). Interestingly, a study from the Columbia University indicates that 25% of patients who underwent kidney biopsy and were diagnosed to have lithium nephrotoxicity also had nephrotic syndrome (254). These patients had the light microscopic pattern of focal segmental glomerular sclerosis. Lithium nephrotoxicity appears to be a slowly progressive disease, and discontinuation of lithium will result in improved renal function only if the chronic injury is relatively mild.

Pathologic Findings.

The sparse reports on the renal pathologic features of acute lithium toxicity (255,256) have disclosed little apart from dilated convoluted tubules with some pyknotic nuclei, hyaline droplets, and vacuolated tubular epithelial cells. Chronic lithium nephrotoxicity is associated with progressive chronic tubulointerstitial nephritis.

The original concern about chronic renal disease was raised by the study on the pathologic characteristics of lithium-induced renal disease by Hestbech et al (249). In this study, renal biopsies were done on 14 patients receiving long-term treatment (1 to 15 years) with lithium carbonate for manic-depressive disease. Thirteen of the biopsies showed pronounced tubular atrophy, interstitial fibrosis, interstitial lymphocytes, and glomerular sclerosis. When the biopsies were assessed by morphometric methods and compared with an age-matched control group without renal disease (transplant donor kidneys for the most part), the lithium patients had twice the amount of interstitial connective tissue, three times the degree of tubular atrophy, and five times the number of sclerotic glomeruli. The intensity of interstitial mononuclear cell infiltrate was relatively mild, compared with the degree of interstitial fibrosis. In addition, two kidneys from patients taking lithium were seen at autopsy, and those had a granular surface and contained small cortical cysts. Renal cortical microcysts, along with fibrosis, have been described in patients on long-term lithium therapy (Fig. 23.21) (254,257). Markowitz et al (254), using nephron-specific markers, determined


that the microcysts are of distal nephron origin. Other investigators questioned the relevance of these findings (250,258,259). In spite of these controversial studies, there is now agreement that chronic lithium nephrotoxicity is a cause of chronic tubulointerstitial nephritis with the above described morphologic changes (247,254).


Figure 23.21

Kincaid-Smith et al (258) and Walker et al (260) described a peculiar tubular lesion in biopsies from patients treated with lithium. They found this lesion in the distal convoluted tubules and collecting ducts. It consists of cytoplasmic ballooning or vacuolation with strands of PAS-positive material in the vacuolated cytoplasm, sometimes radiating from the nucleus to the periphery of the cells. The change was regarded as unique; it appeared shortly after the start of lithium therapy and disappeared when treatment was stopped. Other investigators only rarely see this tubular lesion (254).

Glomerular changes are usually secondary and include scattered globally sclerotic glomeruli. Rare cases of minimal change disease and focal segmental glomerular sclerosis have been reported (253,261). Interestingly, Markowitz et al (254) found that 50% of their biopsies from patients with chronic lithium nephrotoxicity had the glomerular pattern of focal segmental glomerular sclerosis. Half of these patients also had nephrotic syndrome.

None of the above detailed morphologic changes appear to be specific. A characteristic finding is the microcystic dilatation of tubules, which is seen in most cases. One has to remember, however, that microcystic dilatation of the tubules is a nonspecific finding and is commonly seen in any chronic tubulointerstitial disorder. Therefore, obviously, chronic lithium nephrotoxicity is not a renal biopsy diagnosis and the correct diagnosis can be made only following careful correlation of the clinical and morphologic findings.


The pathogenesis of diabetes insipidus secondary to lithium treatment is most likely the result of the down-regulation of aquaporin-2 expression in the distal nephron (262). The pathogenesis of possible chronic tubulointerstitial injury is much more obscure; it is probably associated with a series of repeated acute injuries and repair. The nephrotic syndrome, seen only occasionally, could be the result of the interaction of lithium with anionic sites on the glomerular basement membranes (253).

Proton-Pump Inhibitors

Proton-pump inhibitors are commonly used in the treatment of acid peptic disorders. More and more recent publications indicate that AIN may be a complication of these medications (263,264,265,266,267266) found that in 8 out of 14 drug-related acute interstitial nephritis cases at their institution, the etiologic agents were probably proton-pump inhibitors. AIN is diagnosed in and average of 2.7 months following administration of proton-pump inhibitors (263). Clinical presentation and the morphologic findings do not differ from other forms of drug-induced interstitial nephritides. Among the proton-pump inhibitors, Omeprazole appears to be the drug most commonly associated with AIN (263).

Protease Inhibitors

Protease inhibitors have become the mainstay of current therapy in patients with AIDS. Renal complications, particularly crystalluria, were recognized early as a complication of these medications. However, recent reports indicate that acute interstitial nephritis may also be associated with protease inhibitors, primarily with indinavir (268,269). Two patients have been reported who developed acute interstitial nephritis with foreign body-type giant cells, presumably secondary to the crystalluria caused by indinavir (270271

Tubulointerstitial Nephritis Mediated by Immunologic Mechanisms

Tubulointerstitial nephritis owing to immune mechanisms may be mediated by antibodies, immune complexes, or T cells. Experimental aspects of tubulointerstitial nephritis have been reviewed by McCluskey (11), Kelly et al (45), and Wuthrick and Sibalic (272). A brief discussion of immune mechanisms and the various human interstitial nephritides in which such mechanisms are presumed to be operational is offered in this section. In most forms of acute and chronic tubulointerstitial nephritis, immunologic mechanisms are likely to play a pathogenic role, regardless of the initial inciting agent or cause of tissue injury.


Tubulointerstitial Nephritis With Anti-Tubular Basement Membrane Antibodies

The presence of linear deposits of immunoglobulins and complement in TBM together with tubulointerstitial inflammation is presumptive evidence of anti-TBM antibody disease. However, the significance of TBM deposits of immunoglobulins or complement alone is difficult to ascertain, because such deposition can occur in diabetes (273) and other advanced chronic renal injuries with tubular atrophy. Complement (C3) may be focally present along the TBM even in normal human kidneys (274). Therefore, detection of circulating anti-TBM antibodies in the serum or elution of the antibodies from the renal tissue is important to prove the association with interstitial nephritis antibodies. Drug-induced tubulointerstitial nephritis with anti-TBM antibodies was discussed earlier in this chapter.

Primary Anti-Tubular Basement Membrane Antibody Nephritis

Primary anti-TBM antibody nephritis is a form of tubulointerstitial nephritis with linear deposits of IgG and complement along the TBM, presence of anti-TBM antibodies in serum, mononuclear cell and neutrophilic infiltration of the interstitium and tubules, and edema and tubular cell injury. Glomeruli and vessels are normal or show nonspecific changes. Very few instances of primary anti-TBM nephritis have been reported. The two patients described by Clayman et al (275) and Brentjens et al () fulfill the criteria delineated earlier. One of the patients, a 27-year-old woman, presented with nausea, vomiting, fever, and generalized body aches. She became rapidly anuric, and a renal biopsy demonstrated intense inflammatory cell infiltrate in the interstitium with neutrophils and mononuclear cells and linear deposits of IgG, C3, and the terminal components of complement in the TBM. The glomeruli demonstrated no deposits of immunoreactants, and anti-TBM antibodies were detected in the serum. This patient recovered renal function after intensive steroid therapy, but features of renal tubular acidosis persisted. The other patient, a 36-year-old man, presented with end-stage renal disease. Both patients had circulating antibodies that were reactive with a 48- to 58-kDa TBM protein, and in both, this antibody activity could be inhibited with a rodent antibody to a cross-reactive antigen. This 58-kDa protein in the TBM was later called tubulointerstitial nephritis antigen (277278), also an instance of primary anti-TBM nephritis, describes a 6-year-old boy who presented with polydipsia, polyuria, microscopic hematuria, proteinuria, and glucosuria. The renal biopsy demonstrated mononuclear cell infiltrate with occasional lymphoid follicles, pronounced interstitial fibrosis, and tubular atrophy and loss (Fig. 23.22) associated with linear deposits of IgG and C3 in the TBM (Fig. 23.18). The glomeruli demonstrated no deposits of immunoreactants. Anti-TBM antibodies were demonstrated in the serum and were not reactive with glomerular basement membrane (GBM) antigens. The reports of Rakotoarivony et al (279), Laberke and Bohle (7), Freycon et al (280), and Helczynski and Landing (281) probably include instances of primary tubulointerstitial nephritis with anti-TBM antibodies.


Figure 23.22 Primary tubulointerstitial nephritis with anti-tubular basement membrane (TBM) antibodies is detected by linear fluorescence for IgG along the TBM. (From

Bergstein J, Litman NN. Interstitial nephritis with anti-tubular basement membrane antibody. N Engl J Med 1975;292.


Secondary Anti-Tubular Basement Membrane Antibody Nephritis

Included in the category of secondary anti-TBM antibody nephritis are various types of primary glomerulonephritides and allograft nephropathy in which there is an associated component of tubulointerstitial nephritis with linear deposits of IgG and complement in the TBM.

Anti-Glomerular Basement Membrane Antibody Disease

Anti-GBM antibody disease, with or without pulmonary hemorrhage, is an autoimmune disease owing to


antibodies reactive exclusively, or principally, with the noncollagenous domain—NC1—of the α3 chain of type IV collagen (282). Anti-TBM antibodies are found in 50% (283) to 70% (284) of patients with anti-GBM nephritis. In general, tubular linear deposits are focal, they are less intense than deposits along the GBM, and they often involve proximal tubules. In the series of Lehman et al (274), 23 of 26 patients with Goodpasture's syndrome (88.4%) and 13 of 21 patients with anti-GBM antibody disease without pulmonary hemorrhage (61.9%) had linear TBM deposits of IgG, sometimes accompanied by C3. In the series of Graindorge and Mahieu (284a), 9 of 11 patients with linear deposits of immunoglobulins along the GBM had anti-TBM antibodies by radioimmunoassay (82%), and 8 of these 9 patients showed linear deposits of IgG along the TBM. Anti-TBM antibodies are detected more frequently in kidney eluates than in serum (274).

Although anti-TBM antibodies are usually of the IgG class, Border et al (285) reported anti-TBM antibodies of the IgA class in a patient with Goodpasture's syndrome. The specificity of anti-TBM antibodies in patients with Goodpasture's syndrome is unknown, but they probably are nephritogenic. Andres et al (283286) described autoreactive T cells that recognize the N-terminal NC1 domain of α3 chain of type IV collagen in patients with Goodpasture's syndrome. Whether T cells exert a pathogenic role in the tubulointerstitial nephritis of such patients is unknown.

Membranous Glomerulopathy

Some patients with membranous glomerulopathy may show evidence of anti-TBM antibodies in kidney biopsies, serum, or both (287,288). Males are more often affected than females, and in most patients, the disease occurs before 5 years of age (289). HLA haplotypes B7 and DRw8 provide susceptibility to disease (288). In the publications of Levy et al (287), Katz et al (288), and Makker et al (289), patients presented with proteinuria or the nephrotic syndrome and tubular dysfunction with features of Fanconi's syndrome. Some cases have occurred in families (280,281,290). In the report of Makker et al (), the putative antigen in glomerular deposits was determined to be human gp330, the Heymann antigen, or megalin (291). However, in most cases, the target antigen in the TBM is the 58-kDa TIN antigen (,289,292). The disease progresses to chronic renal failure (289,292). Ivanyi et al (292) reported a child who developed progressive membranous glomerulopathy with circulating antibodies to the TIN antigen. The patient did not develop recurrent disease in his allograft after a 2-year follow-up.

Renal Allografts

Linear deposits of immunoglobulins and complement in TBM are found with variable frequency in patients with renal allografts. In the report by Rotellar et al (), IgG and complement were present in 18 (2.7%) of 662 biopsies, and they occurred 3 to 13 months after transplantation. Of the 18 patients, circulating anti-TBM antibodies were detected in 10, and in 5 of these 10 patients, anti-TBM antibodies were detected in sera before linear TBM deposits could be found in renal biopsies. Linear deposits of IgG and C3 also were detected in patients who were clinically stable (not rejecting). In 10 of 15 patients who were subjected to sequential biopsies, linear TBM deposits disappeared. Overall, circulating anti-TBM antibodies were detected predominantly in the first 6 months after transplantation; they persisted for an average of 3 months and did not recur after they disappeared (293). Because graft survival was the same in patients with or without anti-TBM antibodies, the investigators (293) concluded that the presence of anti-TBM antibodies in renal allografts was not contributory to deterioration of graft function. Renal allograft recipients develop anti-TBM antibodies as a result of antigenic polymorphism, and the target antigen is the 48- to 58-kDa TBM protein (284,294,295). However, TBM staining for IgG and complement is a frequent nonspecific finding in renal allograft biopsies, particularly if chronic injury is already evident. Therefore, such TBM staining has to be interpreted with caution.

Miscellaneous Diseases

Morel-Maroger et al (296) reported a patient with crescentic poststreptococcal glomerulonephritis, the nephrotic syndrome, and renal insufficiency. This patient underwent four renal biopsies within 28 weeks, but only the last biopsy revealed linear deposits of IgG and C3 along the TBM. There was also interstitial inflammation with mononuclear cells, tubular atrophy, and interstitial fibrosis. This patient's serum was reactive with TBM of one of his previous biopsies that had been found to be negative for TBM deposits. Anti-TBM antibodies also have been described in patients with systemic lupus erythematosus (297), Kimura disease (), polyglandular autoimmune syndrome (299) and in isolated cases of IgA nephropathy, focal segmental


glomerulosclerosis, lipoid nephrosis, and malignant hypertension (122).

Pathologic Findings

The kidney size varies and shows multifocal or diffuse infiltration with mononuclear cells with occasional neutrophils, edema, and tubular cell injury. Most of the changes occur in proximal tubules (122,279,283). Depending on the time of the biopsy relative to the onset of disease, tubular atrophy and thickening and redundancy of TBM, with or without TBM disruption and associated interstitial fibrosis, also may be present. By immunofluorescence, linear deposits of IgG and rarely other immunoglobulins, often with complement, are detected along the TBM (Fig. 23.22) (122,274,276). In primary anti-TBM nephritis, glomeruli are normal or show nonspecific changes. In secondary anti-TBM nephritis, the glomerular changes vary and include crescentic (274,296), membranous (287,288,290,292), lupus (297), or mesangioproliferative glomerulonephritis or focal segmental glomerulosclerosis (122). Arteries and arterioles may show hypertensive or age-related changes. Electron microscopy does not reveal electron-dense immune-type deposits along the TBM.

Etiology and Pathogenesis

To establish that tubulointerstitial nephritis is mediated by anti-TBM antibodies, it is necessary to demonstrate linear deposits of immunoglobulins, commonly IgG, and complement along the TBM (11); to detect antibodies specific for TBM antigens in the circulation (11); to demonstrate that antibodies are concentrated severalfold in renal eluates relative to their concentration in plasma; to demonstrate that the antibody activity can be abolished by incubation of plasma or eluate with TBM antigen; and to demonstrate that the antibodies have a pathogenic role, for example, by transferring tubulointerstitial nephritis to syngeneic recipients through injection of antibodies alone. Because only some of these requirements can be satisfied, the diagnosis of human tubulointerstitial nephritis associated with anti-TBM antibodies is inferential and by analogy to data derived from experimental models (11,272). The anti-TBM antibodies usually arise because of renal damage, and they recognize at least three major antigens present in collagenase digests of TBM.

The first antigen (or group of antigens), a 48- to 54-kDa (37,39) or 58-kDa protein (38), is the target of autoantibodies in idiopathic anti-TBM disease. The latter is called TIN antigen. Differences in reported size of glycoproteins may be owing to technical differences in Western blotting (284) or to multiple antigens sharing common nephritogenic epitopes (277). The antigen is referred to as 48- to 54-kDa protein (37,39), 58-kDa protein (38), or 48- to 58-kDa protein () and as 3M-1 antigen (300). The antigen, isolated from collagenase solubilized TBM of rabbits, is localized predominantly on the abluminal surface of the TBM of the proximal tubules (300). According to Crary et al (38), antibodies raised against preparations containing the 58-kDa protein and other minor proteins (i.e., 300, 175, 160, 100, and 50 kDa) localize the referenced antigens to basement membranes of proximal tubules and other sites: distal tubules, Bowman's capsule, peritubular capillaries, small bowel, skin, and cornea, but not the GBM or mesangial matrix (38). Some of these minor proteins may represent higher–molecular-weight forms of the 58-kDa protein (288,301). Purified 3M-1 protein induces antibodies to TBM and tubulointerstitial nephritis in susceptible hosts; TBM preparations selectively depleted of 3M-1 protein do not (275). Studies by Yoshioka et al (300) demonstrated that sera from patients with anti-TBM nephritis bind to both 48- and 54-kDa antigens, and the studies of Miyazato et al (302) demonstrated that the 48- and 54-kDa glycoproteins share the same epitope but are encoded by different mRNA. The cDNA encoding the 58-kDa TBM antigen has been cloned (277). The predicted amino acid sequence contains a highly conserved epidermal growth factor-like repeat in the NH2 terminus, common to several classes of extracellular matrix adhesive proteins, whereas extensive homology with the cathepsinlike family of cysteine proteinases is present in the carboxy terminus (277). The protein may contribute to basement membrane assembly and cellular adhesion (303) through interaction with α3β1 and αvβ3 integrins (304) and also play an important role in renal development (305,306).
The second antigen, a 70-kDa protein, is the target of autoantibodies present in patients with anti-GBM nephritis and in some patients with lupus nephritis. This antigen is present in the GBM and TBM (274).
The third antigen, a 45- to 50-kDa protein, is target of autoantibodies in patients with anti-GBM disease (307) and of antibodies that developed in one patient with Alport's syndrome after renal transplantation (40). This antigen, distributed in various basement membranes (e.g., glomerular, tubular, alveolar, epidermal, placental), is absent in patients with Alport's syndrome because of mutations or deletions in the gene coding for the α5 chain of collagen IV on the X chromosome.

The antibodies involved have been predominantly IgG and, rarely, other immunoglobulins (274,276). Interaction of antigen and antibody results in complement activation and deposition of C3 in TBM. That complement is required for inflammatory infiltration and tubular epithelial cell injury is indicated by the studies of Hatanaka et al (43


308). Tubulointerstitial injury results from release of proteases and reactive oxygen species; repair and fibrosis results from release of cytokines, growth factors, activation of fibroblasts, and collagen deposition (309).

Tubulointerstitial Nephritis With Immune Complexes

Tubulointerstitial nephritis with immune complexes implies the presence of granular deposits of immunoglobulins and complement in the TBM, interstitium, or both. Deposits often are associated with an underlying renal disease, usually a form of glomerulonephritis mediated by immune complexes, and the incidence of tubulointerstitial immune complex deposits in renal biopsies varies: 1.5% (16 of 1100 biopsies) in the series of Orfila et al (122274), and 42.9% (6 of 14 biopsies) in the study of Levy et al (287). In these three series, the underlying conditions were various glomerulonephritides (e.g., lupus, membranous, cryoglobulinemic, membranoproliferative, focal proliferative, crescentic, postinfectious, shunt nephritis), minimal change glomerular disease, allograft rejection, graft versus host reaction, idiopathic tubulointerstitial nephritis, hepatitis B infection, and syphilis. We would like to reiterate that complement and even IgG staining may occur nonspecifically in the TBM, particularly if the tubules are atrophic and if the patient is diabetic. Granular or finely vacuolar deposits are commonly seen in the basement membranes of atrophic tubules by electron microscopy. On low magnification, these nonspecific deposits may appear as discrete immune-type electron-dense deposits. Therefore, before the diagnosis of immune complex deposits in the TBM is made, careful morphologic examination and correlation of the findings with laboratory results are necessary.

Primary Tubulointerstitial Nephritis With Immune Complexes

Primary tubulointerstitial nephritis with immune complexes is rare. Klassen et al (294) reported the case of a 12-year-old boy who presented with fever, abdominal pain, rash, microscopic hematuria, and proteinuria. A renal biopsy showed focal interstitial infiltrates with lymphocytes and tubular atrophy associated with granular C3, C1q, and electron-dense deposits in the TBM of proximal tubules. Glomeruli were normal. Ellis et al () reported one patient with proximal tubule dysfunction and tubulointerstitial nephritis with granular deposits of immunoglobulins and complement in tubules and interstitium; the glomeruli were normal.

Granular deposits of IgE have been detected in at least two patients with tubulointerstitial nephritis. The first patient was a 54-year-old woman who presented with anemia, diverticulitis, hypocomplementemia, eosinophilia, and renal insufficiency. The patient had no allergic or drug history and no evidence of systemic connective tissue disease. The kidney biopsy demonstrated tubulointerstitial nephritis with granular TBM deposits for IgE, IgG, IgM, and C3; deposits of IgE predominated (311). The second patient was a 72-year-old man who had a positive antinuclear antibody (ANA) assay but no evidence of systemic lupus erythematosus. The kidney biopsy demonstrated advanced tubulointerstitial nephritis with prominent granular IgE deposits (13).

Recently, Kambham et al (44) reported 8 patients who had interstitial nephritis in their renal biopsies associated with tubulointerstitial immune complex deposition and hypocomplementemia. They used the term “idiopathic hypocomplementemic interstitial nephritis” to designate this entity. None of these patients had evidence of SLE or Sjögren's syndrome. In six of their eight patients, complement levels were available. C3 and C4 levels were depressed in all patients except one, in whom C3 was normal and C4 levels were low. In one of their patients, the infiltrate was suggestive of a marginal zone lymphoma and heavy chain gene rearrangement studies indicated monoclonality (44). Immunofluorescence revealed granular tubular basement deposits for IgG in all cases. C1q was detected in six of eight cases and C3 in only four of the eight cases. Electron microscopy revealed discrete electron-dense immune-type deposits in all biopsies. In two cases, the tubular basement membrane deposits had a paracrystalline fingerprintlike substructure. Follow-up data were available in six of their patients, and five of them responded favorably to immunosuppressive medication. Immunosuppression included prednisone and a combination of tacrolimus, prednisone, and mycophenolate mofetil in the patient who had the monoclonal cell population (161). We have recently encountered a very similar case. The patient was a 52-year-old female with serum creatinine of 2.6 mg/dL, no proteinuria, and only very mild hematuria. She had a history of hypothyroidism, hypertension, obesity, and anemia. All serologies, including ANA, were negative. Both C3 and C4 were low. Light microscopy revealed moderate interstitial inflammatory cell infiltrate with focal plasma cell aggregate (Fig. 23.23A). By immunofluorescence, granular deposition of IgG, kappa and lambda light chains, and C3 were present along the tubular basement membrane and the interstitium (Fig. 23.23B). The deposits were not positive for IgA, IgM, and C1q. Ultrastructural examination revealed numerous electron-dense immune-type deposits in the tubular basement membranes and


along peritubular capillaries (Fig. 23.23C). Only rare, small mesangial dense deposits were identified. No endothelial tubuloreticular inclusions were seen. Rare older and more recent case reports have been published describing very similar primary immune complex tubulointerstitial cases with hypocomplementemia (311,312,313).


Figure 23.23 A: A mixed interstitial inflammatory cell infiltrate in a patient who developed idiopathic hypocomplementemic interstitial nephritis with tubulointerstitial immune complex deposition. (H&E, ×200.) B: Immunofluorescence revealed widespread granular tubular basement membrane and interstitial immune complex deposits positive for IgG. (Immunofluorescence with anti–human IgG, ×400.) C: Electron microscopy revealed abundant electron-dense immune-type deposits along the tubular basement membranes. (Uranyl acetate and lead citrate, ×20,000.)

Markowitz, et al (314) described a patient whose peculiar kidney biopsy showed polyclonal large electron-dense deposits along the tubular basement membranes between the tubular epithelial cells and the basement membrane. These deposits were IgG-positive and had a distinctive curvilinear substructure. The patient had underlying diabetic nephropathy, but it did not show evidence of active interstitial nephritis.

Secondary Tubulointerstitial Nephritis With Immune Complexes

Included in the category of secondary tubulointerstitial nephritis with immune complexes are various glomerulonephritides and other renal diseases in which there is tubulointerstitial inflammation associated with granular deposits of immunoglobulins and complement in the interstitium or TBM.

Systemic Lupus Erythematosus (SLE)

SLE is the most common form of tubulointerstitial disease associated with granular deposits of immunoglobulins and complement. Almost one half of the kidney biopsies from


patients with SLE have such deposits. The inflammatory infiltrate is variable, but includes large numbers of mononuclear cells and occasional neutrophils (21,315,316). The deposits include IgG, IgM, rarely IgA, and complement components C3 and C1q (318). The deposits can be found on various locations: interstitial side of the TBM, intramembranous, around peritubular capillaries, and in the interstitium. Rarely, tubulointerstitial immune complex disease may occur in patients with systemic lupus erythematosus in the absence of significant glomerular disease. Renal disease, including interstitial nephritis in SLE, is discussed in Chapter 12.

Sjögren's Syndrome

Sjögren's syndrome is an immunologic disorder characterized by progressive destruction of the exocrine glands leading to mucosal and conjunctival dryness (i.e., sicca syndrome) associated with autoimmune disease affecting various organs. The disease is discussed in detail in Chapter 12.

Renal changes consist of interstitial inflammation with mononuclear cells including histiocytes, plasma cells, and lymphocytes. Plasma cells may occasionally be abundant (Fig. 23.3). Several cases have been reported in which immunofluorescence and electron microscopy revealed immune deposits along the tubular basement membranes. However, in our experience, and based on literature review, it appears that most cases do not have obvious tubulointerstitial immune complex deposits detectable by immunofluorescence and/or electron microscopy. Clinically, many patients present with renal failure and renal tubular acidosis. Patients with Sjögren's syndrome are prone to develop lymphoma, in particular, marginal zone lymphoma (mucosa-associated lymphoid tissue [MALT] lymphoma). The lymphoma primarily involves the salivary glands and head and neck lymph nodes. Involvement of the kidney by lymphoma in Sjögren's syndrome is exceptional (). Steroid treatment is beneficial. For more details see Chapter 12.

Membranoproliferative Glomerulonephritis

Membranoproliferative glomerulonephritis occasionally may manifest with granular deposits of immunoglobulins or complement in TBM. In type II membranoproliferative glomerulonephritis (dense-deposit disease), the characteristic very electron-dense ribbonlike deposits may occasionally be seen along the TBM as well.

Mixed Cryoglobulinemia

Mixed cryoglobulinemia usually manifests with proliferative glomerulonephritis, and some patients can present with focal interstitial inflammation, including mononuclear cells, edema, and tubular cell injury associated with granular IgG and C3 deposits in the TBM (274). In our experience, TBM deposits in cryoglobulinemic glomerulonephritis are rare.

Membranous Glomerulonephritis

A few patients with membranous glomerulonephritis have tubulointerstitial inflammation with monocytes, plasma cells and eosinophils, and granular deposits of immunoglobulins and complement in the TBM (122,310,320). In the series of Orfila et al (122), 2 of 57 patients with membranous glomerulonephritis had such deposits. In the patient reported by Douglas et al (321), granular GBM and TBM deposits were reactive with antiserum to FX1A. This antiserum recognizes antigens present in crude cortical extracts, including gp330 or megalin, one of the putative antigens in Heymann nephritis (322). The reactivity of circulating antibodies to tubular brush border antigen could be abolished by absorption with human FX1A antigenic preparation. More recently, Markowitz et al (323) reported three biopsies with membranous glomerulopathy and tubular basement membrane deposits. They were unable to detect autoantibodies to normal renal epithelial structures or matrix constituents using immunofluorescence and enzyme-linked immunosorbent assay (ELISA), respectively.

Familial Immune Complex Tubulointerstitial Nephritis

Familial immune complex tubulointerstitial nephritis is a syndrome characterized by familial occurrence of tubulointerstitial immune complex disease, often with membranous glomerulopathy. Patients present with diarrhea, dermatitis, proteinuria or the nephrotic syndrome, and renal insufficiency (310). Tubulointerstitial nephritis is characterized by a mononuclear cell infiltrate, variable tubular atrophy, and interstitial fibrosis. By immunofluorescence, granular deposits of immunoglobulin and complement are found in the TBM. Chronic tubulointerstitial disease and villous atrophy of the small intestine were found in two first cousins (310). Both had proximal tubule dysfunction and malabsorption syndrome with granular deposits of IgG and C3 in intestinal epithelial cells, and their sera (IgG) were reactive with intestinal epithelial antigen. Membranous glomerulopathy was detected in only one of these patients; the other had normal glomeruli.

Other Miscellaneous Diseases

Patients with various types of crescentic glomerulonephritis (283,287,294), graft versus host reaction (), autoimmune pancreatitis (326) postinfectious glomerulonephritis, shunt nephritis, hepatitis B, syphilis (287325) may show tubulointerstitial nephritis with granular deposits of immunoglobulins or complement in the interstitium, the TBM, or both.

Pathology of Tubulointerstitial Nephritis With Immune Complexes

The kidney size varies and may be normal, enlarged, or reduced, depending on whether tubulointerstitial nephritis


is acute or chronic. The interstitial infiltrate is multifocal or diffuse and is composed predominantly of lymphocytes, monocytes, and plasma cells (Fig. 23.23A) (287). Neutrophils may be present. By immunofluorescence, granular deposits of immunoglobulins, often with complement, are seen in the TBM, the interstitium, or both (Fig. 23.23B) (122,287). By electron microscopy, dense deposits are usually present in the same location (Fig. 23.23C). Overall, dense deposits are more frequently seen in biopsies of patients with systemic lupus erythematosus. We would like to reiterate that one has to be careful evaluating the immunofluorescence and electron microscopy findings for TBM deposits because C3 deposits are commonly seen along the TBM, particularly in biopsies with chronic injury and tubular atrophy. Also, granular cell debris in the tubular basement membrane may mimic electron-dense immune-type deposits on electron microscopy if the TBM is examined only under low magnification (Fig. 23.11).

Tubular atrophy and interstitial fibrosis are usually absent from early lesions, but are present in patients with chronic renal insufficiency. In primary tubulointerstitial nephritis, glomeruli are normal or show nonspecific changes. In secondary tubulointerstitial nephritis, glomeruli may show crescentic, membranous, proliferative, exudative, or segmental changes according to the primary disease. Arteries and arterioles are normal or show hypertensive or age-related changes.

Pathogenesis of Tubulointerstitial Nephritis With Immune Complexes

To establish that tubulointerstitial nephritis is mediated by immune complexes, the same basic requirements delineated for anti-TBM nephritis apply, except that deposits of antibody, usually IgG, and complement have a granular configuration and localize in the TBM and interstitium, and antigen targets differ and are essentially unknown. Because only some of the requirements can be satisfied, the diagnosis of human tubulointerstitial nephritis with immune complexes also is inferential and based on data derived from experimental models.

In one experimental model of Heymann nephritis, the putative antigen, gp330 or megalin, is present in the GBM (291) and in the brush border of proximal tubules (326). Immune complexes formed in the GBM result in membranous nephropathy and the nephrotic syndrome (327); passive transfer of antibodies to brush border antigens result in complement-independent tubular cell injury (328). Douglas et al (321) provided evidence that, in some patients with membranous nephropathy, an antigen related to or comparable to Heymann antigen may be involved.

In another experimental model developed by Hoyer (329), the putative antigen is Tamm-Horsfall glycoprotein, synthesized and secreted by epithelial cells of the thick ascending limb of Henle. Rats and mice immunized with Tamm-Horsfall glycoprotein develop granular TBM deposits of immunoglobulins and complement, electron-dense deposits along the base of tubular cells of thick ascending limb of loops of Henle, and tubulointerstitial mononuclear cell infiltration (,330,331). The distribution of Tamm-Horsfall protein varies with species, and in mice immune deposits also are formed in the TBM of distal convoluted tubules (330). Deposits are formed in situ by interaction of circulating antibodies with antigen present in the abluminal side of the tubular cells. Ureteral obstruction in mice promotes the localization of such deposits in extratubular sites and apparently contributes to interstitial inflammation and scarring (332). Tamm-Horsfall glycoprotein does elicit weak antibody response in humans (333), and a component of interstitial inflammation may be related to extravasation of this glycoprotein into the interstitium. Antibodies to E. coli that are cross-reactive with Tamm-Horsfall glycoprotein (334) and some anti-DNA antibodies cross-reactive with heparan sulfate (335) provide examples in which autoimmunity may contribute to tubulointerstitial nephritis mediated by immune complexes. Heymann nephritis is an accepted animal model of human membranous nephropathy (322), but whether Hoyer's animal model has a human counterpart is unknown (336).

In human tubulointerstitial nephritis with immune complexes, antigens involved, with few possible exceptions (41,42), are unknown. Antibodies are usually of the IgG class and, less frequently, of other classes (274). Immune deposits may result from immune complexes formed in the circulation, or they may result from local interaction between free antibody and antigen in tissues. Both mechanisms may be operational in systemic lupus erythematosus, in which immune complexes activate complement, as judged by the presence of C3 and terminal components of complement in electron-dense deposits (318). Complement also can be activated by mechanisms other than those involving immune complexes. For example, ammonia can trigger the alternative pathway of complement activation and cause tubulointerstitial inflammation and injury (337). Based on experimental models, some forms of tubulointerstitial nephritis may require complement activation by antibody, release of chemoattractants, activation of leukocytes, and release of proteases and toxic oxygen radicals (45

Tubulointerstitial Nephritis With T-Cell Mechanisms

Tubulointerstitial nephritis in which T-cell mechanisms have been implicated are probably more common than


appreciated and include drug reactions; reactions to allograft antigens; systemic disease with renal involvement; reactions to renal localization of various micro-organisms, foreign bodies, and crystals; renal involvement in sarcoidosis; and most forms of progressive renal disease.

Primary Tubulointerstitial Nephritis With T-Cell Mechanisms

Allograft Rejection

Chapter 28.

Tubulointerstitial Nephritis With Uveitis

The syndrome of tubulointerstitial nephritis with uveitis was described in 1975 by Dobrin et al (338). The two patients reported presented with acute renal failure owing to tubulointerstitial nephritis, with predominance of eosinophils in the infiltrate associated with anterior uveitis and granulomas in bone marrow and lymph nodes. These patients were Caucasian females, 14 and 17 years of age. Both recovered renal function, but one required treatment with corticosteroids for about 1 year. The syndrome has been reported mainly in children (339,340,341,342,343344,345). It may occur in siblings with identical haplotypes (346) and monozygotic twins (343). Females are affected more often than males.

Patients may present with one or more of the following features: proximal tubule dysfunction, including Fanconi's syndrome, renal insufficiency and proteinuria, renal failure, and ocular symptoms (341,347). Uveitis may precede or follow renal dysfunction or acute renal failure.

The kidney shows inflammatory infiltrates comprising mononuclear cells, including many lymphocytes and fewer plasma cells and macrophages. Eosinophils, prominent in the initial cases presented by Dobrin, are less commonly seen by others. By immunofluorescence, immunoreactants usually are not found in the TBM, and repeat or late biopsies may show variable amounts of interstitial fibrosis and fewer inflammatory cells. Inflammatory cells are mostly T cells, but the predominance of a CD4+ or CD8+ phenotype varies (,347,348,349,350). The proximal tubules show the greatest degree of alterations, with circular arrays of infiltrating mononuclear cells. Acute tubular endothelial injury and flattening of the tubular epithelium often occur. Noncaseating granulomas may be found in bone marrow, lymph nodes, and the kidneys (338).

Morino et al (346) reported two sisters with tubulointerstitial nephritis and chronic sialoadenitis, one of them with recurrent uveitis; this patient also had an immune complex–mediated glomerulonephritis, which is not a component of the syndrome. It is conceivable that the syndrome encompasses other manifestations, as reported, or that the referenced patient had an overlap syndrome with features of Sjögren syndrome. Recovery by spontaneous remission (338,341,345,351) or in response to corticosteroids (348) does occur in children. Some degree of permanent renal dysfunction may remain in adults (344).

The cause of the disease is unknown, but an autoimmune pathogenesis is suspected. Although uveitis appears to be mediated by immune complexes (346,351), possibly formed locally (351), the interstitial inflammation in the kidney has the characteristics of a T-cell–mediated reaction. Lymphocyte reactivity has been detected against antigens from renal tubular epithelia using an assay of inhibition of leukocyte migration (352). One case report describes a patient who had circulating antibodies to a 125-kDa protein localized to the cytoplasm of renal cortical tubular epithelial cells (342). A genetic predisposition to an autoimmune pathogenesis also finds support in the observation that the syndrome has been reported in identical twins (353) and in siblings with identical haplotypes (346


Sarcoidosis is a chronic disorder, involving multiple systems and characterized by accumulation of lymphocytes and other mononuclear cells forming noncaseating epithelioid granulomas. Most patients present with enlarged lymph nodes, cough, weight loss, fever, dyspnea, polyuria, increased serum calcium concentrations, and occasionally with proteinuria and microscopic hematuria (354,355,356). Sarcoidosis is more common in males and in blacks, and the peak incidence occurs in the second and third decades of life (356). Serum levels of angiotensin-converting enzyme (ACE) are frequently high. Renal involvement, manifested by renal dysfunction, is rare and occurs in only 1% to 2% of all patients with sarcoidosis. For example, of 75 cases of sarcoidosis reviewed by Richmond et al (357), only 1 patient had tubulointerstitial nephritis (1.3%). However, this low incidence of clinically manifest renal disease is misleading, because in autopsy series an incidence of 9% to 25% has been reported (356,358,359). A more recent publication from Heidelberg, Germany, describes 46 patients with sarcoidosis and 48% of them had renal abnormalities (359). The patients underwent renal biopsies—6 of these 10 patients had nephrocalcinosis and only 3 patients had interstitial nephritis; 1 patient had IgA nephropathy. Five of the six patients with nephrocalcinosis had hypercalcemia. These authors found a positive correlation between serum ACE levels and granuloma formation in the renal tissue (359). The most common renal complication in patients with sarcoidosis is related to disturbance in calcium metabolism. Hypercalciuria is present in 50% to 60% of patients with sarcoidosis, and 10% to 20% of them also have hypercalcemia (172,).


In renal sarcoidosis, granulomas are abundant and are sharply delineated with many epithelioid cells and many giant cells (Fig. 23.4B). The granulomas are associated with an inflammatory infiltrate of mononuclear cells, including many plasma cells and lymphocytes (24,,360,361). Differentiation of sarcoid granulomas from other granulomas causing granulomatous interstitial nephritis, such as drug-induced granulomas, can be difficult; however, drug-induced granulomas are usually less distinct (Fig. 23.4A). Also, granulomas may be missed in a kidney biopsy specimen and sometimes just an interstitial mononuclear cell infiltrate is seen. ACE levels are often high in many patients' sera, and they can also be detected in the giant cells and epithelioid cells in the granulomas. Unfortunately, this methodology is not commonly used by renal pathologists to differentiate granulomas in sarcoidosis; we could find only one case report describing ACE-positive epithelioid granulomas in a renal biopsy from a patient with sarcoidosis (362). For the same reason, the specificity of this methodology in renal biopsies cannot be assessed. Renal function may improve after early corticosteroid therapy; however, serum creatinine rarely returns to normal, and long-term follow-up has shown that some patients develop permanent renal dysfunction (363) or chronic renal failure (172,354,355,360,361). Current views on the pathogenesis of sarcoidosis implicate an immune mechanism whereby T cells and macrophages are involved (24,360).

Granulomatous Tubulointerstitial Nephritis

A list of agents and conditions that can be associated with granulomatous interstitial pathogenic nephritis is given in Table 23.1. This list is always incomplete because additional causes of granulomatous interstitial nephritis are constantly reported. All these causes should be carefully considered in the differential diagnosis, but one has to remember that, occasionally, granuloma formation can probably be associated with any etiologic agent causing interstitial nephritis.

The most common cause of granulomatous tubulointerstitial nephritis is exposure to drugs. This was discussed previously in this chapter. For example, in the report by Mignon et al (364) of 32 patients studied, 28% were owing to drugs, 16% to Wegener's granulomatosis, and 9% each to tuberculosis and sarcoidosis. Most infectious granulomatous tubulointerstitial nephritides are caused by infection with bacteria, fungi, or parasites and are discussed in chapter 22.

Oxalosis or hyperoxaluria after small intestine bypass is associated with granulomatous reaction to deposited oxalate crystals. In general, the inflammatory reaction is discrete and granulomas are few and are of the giant cell foreign body type. Other particles or crystals, as may occur in intravenous drug abuse and gout, also can result in granulomatous tubulointerstitial nephritis. In granulomatous tubulointerstitial nephritis associated with Wegener's granulomatosis, the number of granulomas varies, but in general, few are found in kidney biopsies (365). The granulomas in vasculitis (such as Wegener's granulomatosis) are usually localized around crescent damage and/or involve arteries.

Several cases of so-called idiopathic granulomatous interstitial nephritis have been reported (366,367,368,369,370). Some authors consider granulomatous idiopathic interstitial nephritis with sarcoid features as cases of isolated renal sarcoidosis (368,369). They base their assumption on elevated ACE levels in some patients and a positive response to steroids. However, steroid treatment is not always successful in idiopathic granulomatous interstitial nephritis (369). Interestingly, a recent report describes a good response and recovery of renal function following treatment with an antibody to tumor necrosis factor alpha (infliximab) (370).

Secondary Tubulointerstitial Nephritis With T-Cell Mechanisms

Tubulointerstitial Nephritis Associated With Progressive Nephropathies

Chronic interstitial disease is present in almost all forms of progressive glomerular and vascular disease of the kidney. This subject has been reviewed by Pichler et al (371), Strutz and Neilson (372), and Dodd (373) and is considered here because cell-mediated immunity appears to play a major role in its pathogenesis. Tubulointerstitial nephritis accompanying various renal diseases progresses from an inflammatory to a fibrotic phase.

During the inflammatory phase, inflammatory cells accumulate in the interstitium in response to deposition or local formation of immune complexes or in response to cytokines and other mediators released from injured glomeruli into the filtrate and subsequently to the tubules. Cytokines may also exit the glomeruli through Bowman's capsule, the vascular pole, and the efferent arteriole (371). In response to cytokines and other mediators, adhesion molecules (374) and growth factors (375) are expressed or overexpressed, and inflammatory cells, mostly lymphocytes and macrophages, accumulate in the interstitium.

Pathology of Tubulointerstitial Nephritis With T-Cell Mechanisms

The kidneys are usually enlarged and show variable edema, and the inflammatory infiltrate consists of lymphocytes, plasma cells, and few eosinophils. Lymphocytes account for more than 50% of the infiltrating cells, and monocytes/macrophages and plasma cells account for most of the remainder (376,377


are seen. Tubular atrophy and interstitial fibrosis are variable and more likely to be present in patients who have biopsies late in the course of their disease or in chronic forms. By immunofluorescence, deposits of immune complexes are absent from glomeruli or tubules. Vessels are normal or show hypertension and age-related changes. In secondary tubulointerstitial nephritis with T-cell mechanisms, the glomeruli or vessels may show active, healing, or healed lesions characteristic of the underlying glomerulonephritis and vasculitis.

Pathogenesis of Tubulointerstitial Nephritis With T-Cell Mechanisms

The mechanism by which inflammatory cells induce fibrosis has been reviewed (47,48,372) and will be discussed here briefly. To establish that tubulointerstitial nephritis is mediated by cellular mechanisms, it is necessary to demonstrate that the transfer of T cells, but not of serum, from a donor with tubulointerstitial nephritis to a normal syngeneic recipient results in tubulointerstitial nephritis in the recipient of T cells (11) or that neonatal thymectomy obviates the expression of tubulointerstitial nephritis (378). Because studies of this type cannot be performed with humans, the diagnosis of cell-mediated tubulointerstitial nephritis is inferential and based on animal models in which T cells have been demonstrated to have a pathogenic role.

Mononuclear cells can mediate tubulointerstitial nephritis by two types of reactions (379). The first, delayed-type hypersensitivity, involves prior exposure and sensitization of the host and is caused by CD4+ T cells and macrophages resulting in production of various lymphokines and a granulomatous reaction. Interstitial lymphocytes interact with monocytes/macrophages, endothelial cells, and possibly with tubular epithelial cells (380) in antigen presentation, resulting in a delayed-type cell-mediated reaction. IFN-γ augments but is not a necessary requirement for up-regulation of class I and class II molecule expression in renal tubules (381378).

The mechanism of interstitial inflammation involves several biologic events, as discussed previously. Briefly, CD4+ T cells become activated by cells expressing class II MHC antigens (382), including tubular epithelial cells (383). Activated T cells, monocytes/macrophages, and renal tubular epithelial cells release chemokines and cytokines (e.g., macrophage colony-stimulating factor [M-CSF], platelet-derived growth factor [PDGF], TGFβ) that induce chemotaxis of cells to inflammatory sites (299,305,313,375,384,385) and various enzymes that degrade collagens and facilitate fibroblast motility (386). It is now evident that renal tubular epithelial cells are a major site of M-CSF production. Therefore, activated/injured tubular epithelial cells in interstitial nephritis, in turn, may further attract macrophages into the kidney and interstitium, aggravating the disease process (33,34). TGFβ and PDGF activate fibroblasts (387,388), enhance collagen deposition, and promote fibrogenesis (47,48,49). TGFβ also appears to have an important role in the induction of tubular epithelial cell/myofibroblast transdifferentiation, which is increasingly recognized and accepted as an important pathogenetic factor in progressive interstitial fibrosis (51). Other cytokines (IL-1, TNFα, IFN-γ), modulate inflammation and fibrogenesis (389,390,391).

Tubulointerstitial Nephropathy Associated with Metabolic Disorders or Monoclonal Gammopathies

Tubulointerstitial nephropathy associated with metabolic disorders is reviewed in Chapter 25. Tubulointerstitial nephropathy associated with monoclonal gammopathies is reviewed in Chapter 19.

Tubulointerstitial Nephropathy Associated with Heavy Metal Exposure

Exposure to heavy metals results in tubular dysfunction and acute or chronic renal disease. The nephropathies caused by chronic exposure to the most abundant toxic metals—lead, cadmium, and mercury—are considered here in some detail; other nephropathies associated with heavy metal exposure are mentioned briefly. Acute tubular toxicity of heavy metals is discussed in .

Lead Nephropathy

Lead exposure in the form of inhaled fumes and dust is an occupational illness for industrial workers (i.e., painters, printers, welders, foundry workers, and electric storage battery makers). In the form of dust and contaminating fluids and surfaces, it is still of some risk to the general population, in spite of banning lead as an additive in gasoline (392,393). Soil and paints containing lead are sources of lead exposure, particularly for children (394). Absorbed lead is widely distributed, but the principal sites of long-term storage are the bones, in which 94% of the lead in the body is found. This storage site constitutes a slow-exchange pool, and the biologic half-life of lead in bone is about


16 years (). Another 4% is present in the blood, tissue fluids, and soft tissues, and these constitute a rapid-exchange pool. The remaining 2% is distributed between actively exchanging parts of the skeleton and soft tissues. Chronic lead intoxication has been widespread, and its history and effects on health are appreciated and well documented as a result of contamination of foods and as an occupational hazard of mining and smelting operation as early as 2500 BCE (396). An epidemic of childhood lead poisoning in Queensland, Australia, established lead nephropathy as a recognized clinical and pathologic entity (397).

Clinical Presentation

The clinical diagnosis of lead nephropathy is based on history of exposure, evidence of renal dysfunction, and a positive calcium disodium edetate (EDTA) mobilization test. The test measures urinary excretion of lead after two 1-g doses of EDTA 12 hours apart (). The test suggests lead nephropathy if excretion of lead is greater than 650 mg in 24 hours. Because the half-life of circulating lead is about 1 month, the test reflects only recent exposure (394), and the result can be normal for patients with chronic lead toxicity (,398). The lead concentration can also be measured in tissues (primarily bone) by x-ray fluorescence and neutron activation analyses (395). In addition to its use as a diagnostic test, EDTA has also been advocated as a therapeutic agent (,398). EDTA causes disruption of the lead inclusions and may contribute to their removal from tissues (399).

Many studies have confirmed a relationship between lead exposure and chronic renal disease (398400,401402,403,404,405). However, a well-controlled, prospective study comparing two groups of patients, one with high (more than 100 mg/dL) and the other with low (less than 40 mg/dL) lead concentrations in the blood failed to show significant differences in blood pressure and in various tests of renal function between these two groups 17 to 23 years after chelation therapy (406). On the other hand, a study from Taiwan recently examined the effect of environmental lead exposure on the progression of chronic renal disease and found that even low-level environmental lead exposure is associated with progressive renal insufficiency (402). One hundred and twenty one patients were included in the study with a baseline creatinine level between 1.5 and 3.9 mg/dL. Seventeen patients doubled their baseline serum creatinine volume within the follow-up period of 48 months. Blood lead levels and body lead burden at baseline were the most important risk factors to predict progression of renal insufficiency. None of the patients had a history of lead exposure, and all of them had blood lead levels and body lead burden above acceptable levels (402).

Staessen et al (407) investigated the effects of lead exposure in the general population and found that patients with decreased renal function had increased lead content in the blood and that the decrease in renal function was proportionate to increased lead concentration in the blood. Because of the nature of their study, they could not conclude whether lead exposure resulted in impaired renal function or whether impaired renal function caused increased concentration of lead in the blood. Chronic lead intoxication is manifested by proximal tubular defects, and decreased glucose reabsorptive capacity is an early indicator of tubular cell injury (408). Most patients have recurrent gout, hyperuricemia, and hypertension (409). Whether hypertension and hyperuricemia are caused by lead exposure, however, is controversial (394,396,403,404,410). Both increased uric acid levels and hypertension are more common in patients with renal insufficiency; therefore, it is difficult to decide whether these are secondary to the lead exposure itself or rather to the subsequent chronic renal injury. However, recent studies support the fact that lead can cause decreased renal uric acid excretion and uric acid deposition in the kidney, which may be one important factor in the development of chronic lead nephropathy (403,404,409). Also, long-term accumulation of lead in the body is probably an independent risk factor for the development of hypertension (403,405409).

Pathologic Findings

The kidneys are reduced in size, show a finely granular surface with reduction of the cortex, and may weigh one third of normal (397). There is variable multifocal tubular atrophy, tubular loss, and interstitial fibrosis (,411). Nuclear inclusions seen in acute lead nephropathy (see Chapter 24) are not a common feature. Glomeruli are normal (411), and arteries and arterioles demonstrate medial thickening and luminal narrowing, probably related to hypertension. Urate, in the form of microtophi, may be seen in the medulla (397). Immunofluorescence studies are noncontributory or show only nonspecific findings. The glomeruli and vessels may be spared, except in patients with end-stage renal disease, whose kidneys may show features of nephrosclerosis because of the frequently severe hypertension in these patients.

Etiology and Pathogenesis

,412). A cleavage product of α2-microglobulin is the principal component of complexed lead that makes Pb2+ available to enzymes (δ-aminolevulinic acid dehydrase) and mediates intranuclear transport and chromatin binding, resulting in changes in gene expression. Lead interacts with renal

membranes and enzymes; disrupts energy production, calcium metabolism, and glucose homeostasis; and interferes with ion transport. Oxidative stress most likely plays a significant role in the pathogenesis because serum levels of oxidative stress markers show a close correlation with lead exposure levels (412). It appears that urine level of alpha glutathione S-transferase, a marker of proximal tubular injury, may be an early marker of lead nephrotoxicity (412). The clinical usefulness of this marker needs further confirmation.

Cadmium Nephropathy

Cadmium exposure from inhalation of cadmium oxide dust or cadmium fumes is an occupational illness (392) that occurs in the manufacture of pigments, plastics, electric storage batteries, and metal alloys. In the general population, exposure occurs by the oral route through contaminated water or food. Cigarette smoking is another potential source of exposure, because cadmium aerosol, produced during smoking, facilitates absorption of the metal (413). The kidney content of cadmium is greater in smokers than in nonsmokers (414). Cadmium has a biologic half-life of more than 30 years (399).

Clinical Presentation

Cadmium toxicity is manifested by increased excretion of high– and low–molecular-weight proteins, such as β2-microglobulin (415), kidney-derived antigens, enzymes, prostanoids, glycosaminoglycans, sialic acid (416), glucose, and amino acids (417) or the full complement of substances seen in the Fanconi syndrome (413,418). Subclinical changes in tubular function also occur in the general population above a threshold excretion of urinary cadmium of 2 mg in 24 hours (419). Once manifested, renal injury tends to be progressive, even if exposure is discontinued (420). In addition to irreversible dysfunction of proximal tubules, excess cadmium exposure is also known to cause hypercalciuria, nephrolithiasis, and osteomalacia. Nogawa (417) reported low-level prolonged environmental exposure to cadmium through contaminated water in the Kakehashi River basin in Japan. Patients in this area suffered from Itai-Itai disease (i.e., ouch-ouch disease), with bone pain from osteomalacia. Hypertension is present in patients with cadmium toxicity (421), but whether cadmium causes hypertension is controversial (414). A recent study from Sweden examined the effects of occupational and nonoccupational exposure to cadmium on the development of end-stage renal disease in a population working and/or living around a cadmium battery factory (415). They found a 2.3-fold increase in the ratio of end-stage renal disease in the population with occupational exposure and even a 1.4-fold increase in the patients with low exposure living between 2 and 10 km away from the cadmium battery factory.

Pathologic Findings

Very little is known about the pathologic findings in chronic cadmium nephrotoxicity. Yasuda et al (422) reported 15 cases of Itai-Itai disease. The kidneys were red-brown, had a granular surface described as sandpaperlike, were decreased in size, had a hard consistency, and weighed about 60 g each. Microscopically, there were extensive tubular atrophy and interstitial fibrosis involving preferentially the outer cortex. Inflammatory cells were present in small numbers. Some degree of glomerular sclerosis was present. However, five patients in the autopsy series of Smith et al (423), and three patients in the series of Kazantzis et al (424), including one autopsy case, showed no significant renal pathology. As judged by excessive mortality from chronic renal failure in areas of environmental cadmium pollution, tissue changes may be proportionate to the quantity of cadmium deposits, and accordingly, tissue changes may occur only in patients with substantial exposure (425).

Etiology and Pathogenesis

The pathogenesis of chronic cadmium nephrotoxicity is poorly understood. Once absorbed, cadmium is initially deposited in the liver, where it is bound to metallothionein-forming complexes that are released in the circulation and are widely distributed. Filtered by the glomeruli, cadmium–metallothionein complexes are absorbed by proximal tubular epithelial cells and are degraded in lysosomes with release of Cd2+ to the cytosol, where it is bound to metallothionein and to non–metallothionein-binding proteins. Cadmium complexed with non–metallothionein-binding proteins probably interferes with biogenesis of lysosomes, because it is this fraction that is temporally associated with cell injury and tubular dysfunction, as denoted by increased numbers of electron-dense lysosomes, decreased lysosomal protease activity, appearance of cellular vesiculation, increased excretion of low–molecular-weight protein, calciuria, and enzymuria (413,419,427). Renal excretion of cadmium occurs only after a threshold is exceeded (426). A pathogenetic role for heat shock protein (427) and oxidative stress has been raised (412).

Mercury Nephropathy

Mercury exposure results from accidental or suicidal ingestion of inorganic mercurial compounds (e.g., mercuric chloride), from occupational activity (392) owing to inhalation of mercury vapors in the manufacture of scientific instruments and amalgam handling for dental fillings, from use of various products (e.g., topical ointments,


cathartics, cosmetics, paints, pesticides), and from consumption of contaminated food. Mercury salts are methylated by bacteria in the environment, and the product, methyl mercury, finds its way into the food chain by accumulating in marine life, particularly in fish. Chronic mercury poisoning is becoming uncommon because of the elimination of mercury from most of these compounds. However, environmental pollution and the accumulation of mercury in fish still represent a slight risk. Mercury can be quantified in the kidneys by means of x-ray fluorescence analysis. In 20 exposed workers, excessive deposition of mercury was detected in the kidneys of 9 patients using this method of determination (428). Mercury can cause autoimmune disease in humans and in experimental animals (429).

Chronic mercury poisoning results in kidneys of normal or slightly decreased size. Initially interstitial edema, inflammatory infiltration with lymphocytes, and tubular cell changes such as necrosis, flattening of epithelium, and desquamation of epithelial cells are present (430,,432,433). Later, there is progressive loss of tubules and interstitial fibrosis (431). Glomerular pathology is limited to membranous nephropathy (,435).

Inorganic mercury affects proximal tubules and causes vesiculation and exfoliation of brush border membrane, followed by calcium influx and cell death. Mercury also inhibits water permeability in epithelia stimulated by vasopressin () and depolarizes mitochondria inner membrane, resulting in increased hydrogen peroxide production and oxidative tissue injury and in loss of respiratory function because of interference with the heme biosynthetic pathway in mitochondria.

Miscellaneous Heavy Metal Nephropathy

gold are used in the treatment of rheumatoid arthritis. Gold salts cause various autoimmune diseases in humans (429). Patients chronically exposed to gold compounds develop proteinuria or the nephrotic syndrome (secondary to membranous glomerulonephritis), microscopic hematuria, tubular injury, and chronic tubulointerstitial nephritis with lymphocytic inflammatory infiltrate (437). Gold inclusions are often found in the cytoplasm of epithelial cells and free in the interstitium (437). The pathogenesis of gold nephropathy is unknown. Patients with HLA-DQA haplotype are more susceptible to develop gold nephropathy (see Chapter 6).

Exposure to copper and iron results in deposits of these metals in tubular cells. Iron may induce tubular cell necrosis and acute renal failure when ingested in large doses as sulfate salts (12). Copper also may cause tubulointerstitial nephritis. In the case reported by Hocher et al (438), tubulointerstitial nephritis, with diffuse inflammatory infiltration by lymphocytes and eosinophils and renal failure requiring dialysis, was induced by a copper-containing intrauterine device. Removal of the device was followed by near normalization of renal function.

Cis-platinum is a chemotherapeutic agent whose major toxicity is renal (439). Cis-platinum administration results in variable renal dysfunction and tubular cell injury, including flattening of epithelial cells, dilation of tubules, necrosis and desquamation of epithelial cells, and focal edema and interstitial fibrosis. Acute cis-platinum nephrotoxicity is discussed in Chapter 24. Cis-platinum has been associated with contracted kidneys (439). Studies in which platinum analogs were administered to rats suggest that nephrotoxicity is characterized by early inhibition of protein synthesis and late mitochondrial dysfunction (440).

Intoxication with arsenic is uncommon. Arsenic exposure can result in chronic renal injury (441) in the form of tubulointerstitial nephritis with interstitial fibrosis manifesting with the Fanconi syndrome and renal insufficiency (441). The source of arsenic was tentatively traced to consumption of “organic health foods” (442). Diagnosis rests on heavy metal screening.

The nephrotoxicity of uranium in humans is somewhat controversial, but it has been reported in uranium mill workers (443). There is now renewed interest in the toxicity of depleted uranium in soldiers exposed on battlefields. So far, there is no evidence that depleted uranium is associated with nephrotoxicity (444). Recent studies describing uranium nephrotoxicity are experimental ().

Tubulointerstitial Nephropathy Associated with Hereditary Diseases

The pathology of Alport's syndrome is discussed in Chapter 11. Tubulointerstitial diseases in renal developmental defects and cystic diseases, as well as familial metabolic renal diseases are discussed in Chapters 26 and 25, respectively. In this section, only two somewhat controversial entities will be addressed: familial tubulointerstitial nephritis with hypokalemia and familial tubulointerstitial nephritis secondary to mitochondrial DNA abnormalities.

Familial Tubulointerstitial Nephritis With Hypokalemia

Patients with chronic tubulointerstitial nephritis and hypokalemia have been reported in three families (446,447,448). The interstitial inflammatory cells are predominantly lymphocytes, and there is associated interstitial fibrosis and variable tubular atrophy. In the report of Gullner et al (446) of three siblings, a characteristic tubular lesion was described wherein proximal tubular cells stained very darkly with methylene–basic fuchsin stain; TBMs were thickened; and the mitochondria showed dense, flocculent material


and appeared enlarged. We have seen a kidney biopsy from a 16-year-old male with familial hyperkalemia who had mild interstitial nephritis and ultrastructural findings similar to those described by Gullner et al (446) (Fig. 23.24).


Figure 23.24 Abnormally shaped and focally quite swollen mitochondria with flocculent electron-dense inclusions in the mitochondrial matrix in a biopsy from a 16-year-old patient with familial hypokalemic interstitial nephritis. (Uranyl acetate and lead citrate, ×20,000.)

Familial tubulointerstitial nephritis with hypokalemia has an autosomal recessive mode of inheritance that is MHC linked, and one or more genes that control potassium reabsorption, present in the short arm of chromosome 6, appear to be involved (448). The pathogenesis is unknown. Although acquired hypokalemia owing to malnutrition or abuse of laxatives has been reported to result in chronic tubulointerstitial nephritis and chronic renal failure (449), this hypothesis is debated (450). Familial chronic tubulointerstitial nephritis with hypokalemia must be differentiated from nonfamilial chronic tubulointerstitial nephritis with secondary hypokalemia. This latter condition is possibly immune mediated, and the loss of potassium may be hormonally driven (451). Most affected patients are postpubertal females with systemic features of autoimmune disease (451). In one of the three families reported initially, renal failure developed in three siblings (448).

Chronic Tubulointerstitial Nephritis Secondary to Mitochondrial Abnormalities

In 1994, Szabolcs et al (10) from Columbia University reported on an 8-year-old girl who had megaloblastic anemia, growth retardation, and progressive renal insufficiency. Renal biopsy revealed chronic tubulointerstitial disease with tubular atrophy and interstitial fibrosis. Ultrastructural examination showed extremely dysmorphic, bizarre mitochondria. Molecular analysis of the mitochondrial DNA detected a 2.7-kb mitochondrial DNA deletion. A year later, a group from France reported a young patient with progressive tubulointerstitial nephritis and leukodystrophy who had a 2.6-kb mitochondrial DNA deletion (32). Consequently, two groups described point mutations in mitochondrial DNA that was associated with progressive interstitial nephritis in three families (452,453). The patients of Zsurka et al (452), the patients had thoracolumbar scoliosis, muscle weakness, breathing difficulties, mitral prolapse, cardiac conduction defects, pigmented retinopathy, and psychiatric disorders. The patients of Tzen et al (453) had myopathy and central nervous system abnormalities. Some patients also had Fanconi's syndrome.

The morphologic findings in the kidney were dominated by chronic tubulointerstitial injury. The light microscopy and immunofluorescence obviously did not provide a diagnostic clue. Ultrastructurally, all patients had bizarre, sometimes curvilinear-appearing mitochondria (10,32,452). The mitochondrial also had abnormal cristae and inclusions. One has to keep in mind that dysmorphic, bizarre mitochondria are not necessarily diagnostic of mitochondrial DNA abnormality-associated renal diseases because abnormal mitochondria can occasionally be seen in various conditions, including drug toxicity (e.g., cyclosporine) (Fig. 23.25). Mitochondrial DNA abnormalities are associated not only with chronic progressive tubulointerstitial


injury in the kidney, as cases of focal segmental glomerulosclerosis secondary to mitochondrial DNA abnormalities have now been reported (see Chapter 5).


Figure 23.25 A bizarre mitochondrion in a tubular epithelial cell in the renal biopsy from a patient with a history of hypertension, rheumatoid arthritis, and obesity. He developed acute renal insufficiency following contrast media administration and NSAID treatment. Light microscopy revealed acute tubular injury, mild to moderate interstitial fibrosis, and enlarged glomeruli. The patient was on many medications in addition to NSAID. Such bizarre mitochondria may occasionally occur in renal biopsies, and they most frequently probably represent toxic injury. (Uranyl acetate and lead citrate, ×7000.)


Tubulointerstitial Nephropathy Associated with Miscellaneous Disorders

Systemic Karyomegaly

Mihatsch et al (456) in 1979 reported chronic tubulointerstitial nephritis concurrent with karyomegaly in three patients between 26 and 29 years of age, whose tubulointerstitial nephritis progressed to end-stage renal disease within 4 to 6 years. Spoendlin et al (457) reported four additional patients whose presentation in the third decade of life was asymptomatic but later experienced progressive renal failure associated with infections of the upper respiratory tract. Several additional cases have been reported (458,459460,461), some of them in siblings. (459,461,462).

Renal changes include interstitial infiltration with mononuclear cells, tubular cell injury with focal loss of tubular cells, tubular atrophy, variable interstitial fibrosis, and nuclear changes in proximal and distal tubules. The nuclei are enlarged and measure up to 30 µm in diameter (). Enlarged nuclei are found in other cells such as those of bile duct, bronchi, smooth muscle, bowel, vessels, skeletal muscle, and connective tissue (456,458). The enlarged nuclei are polyploid (463). By immunofluorescence studies, no deposits of immunoreactants are found and electron microscopy is not helpful. No convincing viral particles have been found.

The pathogenesis is unknown. Mihatsch et al (456459) and Hassen et al (461), high concentrations of ochratoxin, a mycotoxin that interferes with mitotic activity, was found in the blood of affected siblings. Spoendlin et al (457) studied Ki67 and proliferating cell nuclear antigen in tissues of four patients and concluded that there was inhibition of mitosis in karyomegalic cells. The hypothesis that the karyomegaly is secondary to a block in the G2 phase of the cell cycle has been proposed (457,463). MHC typing revealed the A9/B35 haplotype, which suggested a genetic defect in chromosome 6 that was linked to the MHC locus. However, the study of Bhandari et al (463), based on their six patients, did not confirm clustering of A9 or B35.


Figure 23.26

Balkan Endemic Nephropathy

Balkan endemic nephropathy is found in Croatia, Bosnia, Serbia, Bulgaria, and Romania. In villages where the disease is endemic, the prevalence varies between 2% and 10%. The disease occurs in families but is not hereditary, and most affected persons are farmers (464). The condition is geographically localized and occurs along major tributaries of the Danube river basin. It does not affect children and rarely is seen in patients younger than 20 years of age. Individuals who have lived for a short time in the endemic area do not develop the condition, but individuals from nonendemic areas who spend several years in villages where the condition is endemic may become ill (464).

Clinical Presentation

Typical manifestations of the disease occur between 30 and 50 years of age, and the clinical presentation is insidious with weakness, anorexia, anemia, weight loss, copper-yellow skin, orange palms and soles, lumbar pain, mild proteinuria, and microscopic hematuria (465). Hypertension is relatively rare. Renal dysfunction, manifested by tubular proteinuria of usually less than 2 g/day with increased excretion of β-microglobulin, is an early sign of the nephropathy.


Pathologic Findings

The kidneys are reduced in size and can weigh as little as 20 g each (466). The external surface is finely granular or smooth, and the cortex is thin. The predominant microscopic changes are in the tubules and interstitium. There are abundant interstitial fibrosis and variable amounts of interstitial inflammatory cells. Nephrons in the superficial cortex are predominantly involved, and there is extensive solidification of glomeruli (467). Based on a study of 50 kidney biopsies, Ferluga et al (468) described multifocal interstitial fibrosis spreading from the superficial to the deep cortex and tubular atrophy in most of their patients. Figures 23.27 and 23.28, which depict specimens from patients with Balkan endemic nephropathy, show prominent involvement of the superficial cortex with preservation of glomeruli in deeper cortex. By immunofluorescence, Ferluga et al (468) reported prominent glomerular capillary deposits of IgM in 16 of 50 patients. Papillary necrosis is uncommon, but benign and malignant tumors may be found in the pelvis and in the ureters (442,468,469). About 30% to 48% of Balkan nephropathy patients develop tumors of the upper urothelium, most frequently transitional cell carcinoma. These tumors can be bilateral. Tumors other than transitional cell carcinoma have been reported, including papillomas and squamous cell carcinomas (470).


Figure 23.27 Balkan endemic nephropathy. There is prominent involvement of the superficial cortex (top) by a process of solidification. In the deeper cortex (bottom), the glomeruli are little affected, and some tubules persist. (H&E, ×71.) (Material courtesy of Dr. G. J. Dammin.)


Figure 23.28 Balkan endemic nephropathy. There is dense interstitial fibrosis in the deeper cortex with preservation of glomeruli. (H&E, ×70.) (Material courtesy of Dr. G. J. Dammin.)


The pathogenesis is unknown. A recent study indicated that Balkan endemic nephropathy is associated with the GSTM-1 allele of the glutathione S-transferase (471). However, the absence of association with these and other examined alleles has been reported by others (472). Similarly conflicting data have been published regarding viruses, including the possible role of coronavirus (473,474). Heavy metals (475), silica (476), low–molecular-weight proteins (477478,479) have been implicated but not substantiated. Pigs fed on barley contaminated with ochratoxin A, which is a fungal metabolite, develop tubular atrophy and interstitial fibrosis comparable to that seen in Balkan endemic nephropathy (480). The potential etiologic role of ochratoxin A or other mycotoxins as causative agents of Balkan endemic nephropathy is strengthened by the observation that 10% to 20% of cereals, pork meat, and bread from endemic regions are contaminated with ochratoxin A (481,482).


Another possibility, raised by the similarity of renal changes between Balkan endemic nephropathy and Chinese herbs nephropathy (483), implicates aristolochic acid, a nephrotoxin and carcinogenic agent present in Aristolochia, one of the Chinese herbs contaminating herbal preparations taken for weight reduction (484). Apparently, Aristolochia clematis, which contain aristolochic acid, is common in the endemic areas, and its seeds were found to be contaminants of wheat grains in endemic regions (485

Chinese Herb Nephropathy

During 1992 and 1993, an outbreak of rapidly progressive renal failure associated with a slimming regimen containing Chinese herbs occurred in Belgium (486). Withdrawal of the herbs did not prevent progression to chronic renal failure. A large body of subsequent literature appeared on herbal-induced nephropathies, initially mainly from Belgium (483,484485,486,487,488,489,490,491492). Subsequently, series of patients have been reported from Taiwan (493,494) and Japan (495,496). It became quickly evident that Chinese herb nephropathy is very similar to Balkan endemic nephropathy (487). There is some controversy about the name of the disease. Some investigators suggested that the term “Chinese herb nephropathy” should be abandoned because most of the cases occurred in Belgium and the term is prejudicial (496). They recommended using the term “aristolochic acid-associated nephropathy.” Perhaps a more politically correct term would be simply “herbal nephropathy,” but the name Chinese herb nephropathy remains the most widely accepted.

In a substantial proportion of patients, transitional cell carcinoma develops. The prevalence of carcinoma was 46% among patients with Chinese herb nephropathy who underwent nephrectomy (488484).

Clinical Presentation

Most patients present with rapidly progressive renal failure leading to end-stage renal disease typically within months. Proteinuria is mild and microscopic hematuria may be present. Hypokalemia or hyperkalemia may occur and Fanconi's syndrome is common in Japanese patients (495,496). Most patients in the Belgian studies are female, which may be related to gender differences in taking the diet aid. Males are frequently affected in far Eastern countries (495). Although many aspects of Chinese herb nephropathy are similar to Balkan endemic nephropathy, the clinical course is clearly different. Balkan endemic nephropathy leads to end-stage renal disease after many years (usually 20 years) whereas Chinese herb nephropathy is rapidly progressive.

Pathologic Findings

Renal biopsy findings include extensive interstitial fibrosis with tubular atrophy and loss involving predominantly the outer cortex. Interlobular arteries frequently show fibromucoid intimal thickening. In the glomeruli, global sclerosis, collapse, and ischemic changes are common (485,486,487). The interstitial inflammatory cell infiltrate is usually sparse (Fig. 23.29). Immunofluorescence and ultrastructural studies are noncontributory. Scattered deposits of C3 may be present in the TBM and interstitium.


Figure 23.29 Prominent hypocellular interstitial fibrosis in the renal biopsy of a patient who developed rapidly progressive renal insufficiency following use of Chinese herbal medications. (H&E, ×100.)


There is now widespread agreement that Chinese herb nephropathy is primarily caused by aristolochic acid, which is the constituent of the Chinese herb Stephania tetrandra (489,490). Aristolochic acid can form premutagenic aristolochic acid—DNA adducts in the kidney and urothelium and aristolochic acid; DNA adducts have been detected in a renal biopsy by Lo et al (497). Interestingly, the patient developed transitional cell carcinoma 5 months later. It appears that the cumulative dose of aristolochic acid and the progression rate of renal failure show a positive correlation (491492498). However, we would like to note that there are occasional case reports stating that Chinese herb nephropathy develops in the absence of aristolochic acid. In fact, we have encountered a case with typical historic and morphology of Chinese herb nephropathy, but we were unable to prove that the herbal medications the patient was taking contained aristolochic acid.


Idiopathic Tubulointerstitial Nephritis

Idiopathic tubulointerstitial nephritis probably encompasses a group of diverse conditions. This diagnosis is applied only after known causes or etiologic agents of tubulointerstitial nephritis have been considered and excluded. To exclude every possibility, it is imperative to perform a full renal biopsy workup, including immunofluorescence and electron microscopy. Without immunofluorescence or electron microscopy, the possibility of underlying immune complex disease, anti-tubular basement membrane disease, monoclonal immunoglobulin deposition disease, mitochondrial abnormalities, and other forms of underlying diseases cannot be excluded. It is also very important to review the clinical history in detail and consider all possible pathogenetic factors to which the patient may have been exposed. The diagnosis of idiopathic tubulointerstitial nephritis reflects only that we are unable to identify the etiologic factor(s).


1. Councilman W. Acute interstitial nephritis. J Exp Med 1898;3: 393.

2. Pettersson E, von Bonsdorff M, Tornroth T, Lindholm H. Nephritis among young Finnish men. Clin Nephrol 1984;22:217.

3. Linton AL, Clark WF, Driedger AA, et al. Acute interstitial nephritis due to drugs: Review of the literature with a report of nine cases. Ann Intern Med 1980;93:735.

4. Wilson DM, Turner DR, Cameron JS, et al. Value of renal biopsy in acute intrinsic renal failure. Br Med J 1976;2:459.

5. Murray T, Goldberg M. Chronic interstitial nephritis: Etiologic factors. Ann Intern Med 1975;82:453.

6. Rostand SG, Kirk KA, Rutsky EA, Pate BA. Racial differences in the incidence of treatment for end-stage renal disease. N Engl J Med 1982;306:1276.


8. Farrington K, Levison DA, Greenwood RN, et al. Renal biopsy in patients with unexplained renal impairment and normal kidney size. Q J Med 1989;70:221.

9. Fried T. Acute interstitial nephritis: Why do the kidneys suddenly fail? Postgrad Med 1993;93:105.

10. Szabolcs MJ, Seigle R, Shanske S, et al. Mitochondrial DNA deletion: A cause of chronic tubulointerstitial nephropathy. Kidney Int 1994;45:1388.

11. McCluskey R. Immunologically mediated tubulo-interstitial nephritis. Contemp Issues Nephrol 1983;10:121.

12. Churg J, Cotran R, Sinniah R, et al. Classification and atlas of tubulo-interstitial diseases. Tokyo, Igaku-Shoin, 1984.

13. Colvin R, Fang L. Interstitial nephritis. In: Tisher C, Brenner B, eds. Renal Pathology with Clinical and Functional Correlations, vol 1. Philadelphia: JB Lippincott, 1994:723.

14. Baker RJ, Pusey CD. The changing profile of acute tubulointerstitial nephritis. Nephrol Dial Transplant 2004;19:8.

15. Distler A, Keller F, Kunzendorf U, et al. The outcome of acute interstitial nephritis: Risk factors for the transition from acute to chronic interstitial nephritis. Clin Nephrol 2003;59:65.

16. Buysen JG, Houthoff HJ, Krediet RT, Arisz L. Acute interstitial nephritis: A clinical and morphological study in 27 patients. Nephrol Dial Transplant 1990;5:94.

Ruffing KA, Hoppes P, Blend D, et al. Eosinophils in urine revisited. Clin nephrol 1994;41:163.

18. Bender WL, Whelton A, Beschorner WE, et al. Interstitial nephritis, proteinuria, and renal failure caused by nonsteroidal anti-inflammatory drugs. Iimmunologic characterization of the inflammatory infiltrate. Am J Med 1984;76:1006.

19. Pamukcu R, Moorthy V, Singer JR, et al. Idiopathic acute interstitial nephritis: Characterization of the infiltrating cells in the renal interstitium as T helper lymphocytes. Am J Kidney Dis 1984;4:24.

20. Kobayashi Y, Honda M, Yoshikawa N, Ito H. Immunohistological study in sixteen children with acute tubulointerstitial nephritis. Clin Nephrol 1998;50:14.

21. D'Agati VD, Appel GB, Estes D, et al. Monoclonal antibody identification of infiltrating mononuclear leukocytes in lupus nephritis. Kidney Int 1986;30:573.

22. Hawkins EP, Berry PL, Silva FG. Acute tubulointerstitial nephritis in children: Clinical, morphologic, and lectin studies. A report of the southwest pediatric nephrology study group. Am J Kidney Dis 1989;14:466.

23. Ivanyi B, Marcussen N, Kemp E, Olsen TS. The distal nephron is preferentially infiltrated by inflammatory cells in acute interstitial nephritis. Virchows Arch A Pathol Anat Histopathol 1992;420:37.

24. Viero RM, Cavallo T. Granulomatous interstitial nephritis. Hum Pathol 1995;26:1347.

25. Nadasdy T, Laszik Z, Blick KE, et al. Tubular atrophy in the end-stage kidney: A lectin and immunohistochemical study. Hum Pathol 1994;25:22.

26. Pfaller W, Rittinger M. Quantitative morphology of the rat kidney. Int J Biochem 1980;12:17.

Knepper MA, Danielson RA, Saidel GM, Post RS. Quantitative analysis of renal medullary anatomy in rats and rabbits. Kidney Int 1977;12:313.

28. Muller GA, Rodemann HP. Characterization of human renal fibroblasts in health and disease. I. immunophenotyping of cultured tubular epithelial cells and fibroblasts derived from kidneys with histologically proven interstitial fibrosis. Am J Kidney Dis 1991;17:680.

29. Tang WW, Feng L, Xia Y, Wilson CB. Extracellular matrix accumulation in immune-mediated tubulointerstitial injury. Kidney Int 1994;45:1077.

30. Silva FG, Nadasdy T, Laszik Z. Immunohistochemical and lectin dissection of the human nephron in health and disease. Arch Pathol Lab Med 1993;117:1233.

31. Cogan M. Classification and patterns of renal dysfunction. Contemp Issues Nephrol 1983;10:35.

32. Rotig A, Goutieres F, Niaudet P, et al. Deletion of mitochondrial DNA in patient with chronic tubulointerstitial nephritis. J Pediatr 1995;126:597.

33. Isbel NM, Hill PA, Foti R, et al. Tubules are the major site of M-CSF production in experimental kidney disease: Correlation with local macrophage proliferation. Kidney Int 2001;60:614.

34. Rovin BH. Beyond a glomerulocentric view of inflammation. Kidney Int 2001;60:797.

35. Samuelson J, Von Lichtenberg F. Infectious diseases. In: Cotran R, Kumar V, Robbins S, eds. Robbins Pathologic Basis of Disease. Philadelphia: WB Saunders, 1994:305.

36. Rossert J. Drug-induced acute interstitial nephritis. Kidney Int 2001;60:804.

37. Clayman MD, Michaud L, Brentjens J, et al. Isolation of the target antigen of human anti-tubular basement membrane antibody-associated interstitial nephritis. J Clin Invest 1986;77:1143.

38. Crary GS, Katz A, Fish AJ, et al. Role of a basement membrane glycoprotein in anti-tubular basement membrane nephritis. Kidney Int 1993;43:140.

39. Yoshioka K, Morimoto Y, Iseki T, Maki S. Characterization of tubular basement membrane antigens in human kidney. J Immunol 1986;136:1654.

40. Kashtan C, Fish AJ, Kleppel M, et al. Nephritogenic antigen determinants in epidermal and renal basement membranes of kindreds with Alport-type familial nephritis. J Clin Invest 1986;78:1035.

41. Koffler D, Schur PH, Kunkel HG. Immunological studies concerning the nephritis of systemic lupus erythematosus. J Exp Med 1967;126:607.


42. Tax WJ, Kramers C, van Bruggen MC, Berden JH. Apoptosis, nucleosomes, and nephritis in systemic lupus erythematosus. Kidney Int 1995;48:666.

43. Hatanaka Y, Yuzawa Y, Nishikawa K, et al. Role of a rat membrane inhibitor of complement in anti-basement membrane antibody-induced renal injury. Kidney Int 1995;48:1728.

44. Kambham N, Markowitz GS, Tanji N, et al. Idiopathic hypocomplementemic interstitial nephritis with extensive tubulointerstitial deposits. Am J Kidney Dis 2001;37:388.

45. Kelly C, Tomaszewski J, Neilson E. Immunopathogenic mechanisms of tubulointerstitial injury. In: Tisher C, Brenner B, eds. Renal Pathology with Clinical and Functional Correlations, vol 1. Philadelphia: JB Lippincott, 1994:699.

46. Wada T, Furuichi K, Sakai N, et al. Eotaxin contributes to renal interstitial eosinophilia. Nephrol Dial Transplant 1999;14:76.

47. Sato M, Muragaki Y, Saika S, et al. Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J Clin Invest 2003;112:1486.

48. Bottinger EP, Bitzer M. TGF-beta signaling in renal disease. J Am Soc Nephrol 2002;13:2600.

49. August P, Suthanthiran M. Transforming growth factor beta and progression of renal disease. Kidney Int 2003;Nov(suppl):S99.

Okada H, Kikuta T, Kobayashi T, et al. Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis. J Am Soc Nephrol 2005;16:133.

51. Lan HY. Tubular epithelial-myofibroblast transdifferentiation mechanisms in proximal tubule cells. Curr Opin Nephrol Hypertens 2003;12:25.

52. Nadasdy T, Racusen L. Renal injury caused by therapeutic and diagnostic agents and abuse of analgesics and narcotics. In: Jennette J, Olson J, Schwartz M, Silva F, eds. Heptinstall's Pathology of the Kidney, 5th ed. Philadelphia: Lippincott-Raven, 1998:811.

53. Silva FG. Chemical-induced nephropathy: A review of the renal tubulointerstitial lesions in humans. Toxicol Pathol 2004; 32(suppl 2):71.

Markowitz GS, Perazella MA. Drug-induced renal failure: A focus on tubulointerstitial disease. Clin Chim Acta 2005;351:31.

55. Cameron JS. Allergic interstitial nephritis: Clinical features and pathogenesis. Q J Med 1988;66:97.

56. Karras DJ. Severe low back pain secondary to acute interstitial nephritis following administration of ranitidine. Am J Emerg Med 1994;12:67.


58. Corwin HL, Korbet SM, Schwartz MM. Clinical correlates of eosinophiluria. Arch Intern Med 1985;145:1097.

59. Nolan CR 3rd, Anger MS, Kelleher SP. Eosinophiluria—a new method of detection and definition of the clinical spectrum. N Engl J Med 1986;315:1516.

60. Colvin RB, Burton JR, Hyslop NE Jr, et al. Letter: Penicillin-associated interstitial nephritis. Ann Intern Med 1974;81:404.

61. Parra E, Gota R, Gamen A, et al. Granulomatous interstitial nephritis secondary to allopurinol treatment. Clin Nephrol 1995;43:350.

62. Jennings M, Shortland JR, Maddocks JL. Interstitial nephritis associated with furosemide. J R Soc Med 1986;79:239.

63. Montseny JJ, Meyrier A. Immunoallergic granulomatous interstitial nephritis following treatment with omeprazole. Am J Nephrol 1998;18:243.

64. Fervenza FC, Kanakiriya S, Kunau RT, et al. Acute granulomatous interstitial nephritis and colitis in anticonvulsant hypersensitivity syndrome associated with lamotrigine treatment. Am J Kidney Dis 2000;36:1034.

65. Ramalakshmi S, Bastacky S, Johnson JP. Levofloxacin-induced granulomatous interstitial nephritis. Am J Kidney Dis 2003; 41:E7.

66. Korzets Z, Elis A, Bernheim J, Bernheim J. Acute granulomatous interstitial nephritis due to nitrofurantoin. Nephrol Dial Transplant 1994;9:713.

67. Baldwin DS, Levine BB, McCluskey RT, Gallo GR. Renal failure and interstitial nephritis due to penicillin and methicillin. N Engl J Med 1968;279:1245.

68. Border WA, Lehman DH, Egan JD, et al. Antitubular basement-membrane antibodies in methicillin-associated interstitial nephritis. N Engl J Med 1974;291:381.

69. Olsen S, Asklund M. Interstitial nephritis with acute renal failure following cardiac surgery and treatment with methicillin. Acta Med Scand 1976;199:305.

70. Gabow PA, Lacher JW, Neff TA. Tubulointerstitial and glomerular nephritis associated with rifampin. report of a case. JAMA 1976;235:2517.

Minetti L, Barbiano di Belgioioso G, Busnach G. Immunohistological diagnosis of drug-induced hypersensitivity nephritis. Contrib Nephrol 1978;10:15.

72. Olsen TS, Wassef NF, Olsen HS, Hansen HE. Ultrastructure of the kidney in acute interstitial nephritis. Ultrastruct Pathol 1986;10:1.

73. Joh K, Aizawa S, Yamaguchi Y, et al. Drug-induced hypersensitivity nephritis: Lymphocyte stimulation testing and renal biopsy in 10 cases. Am J Nephrol 1990;10:222.

74. Shibasaki T, Ishimoto F, Sakai O, et al. Clinical characterization of drug-induced allergic nephritis. Am J Nephrol 1991;11:174.

75. Vlasveld LT, van de Wiel-van Kemenade E, de Boer AJ, et al. Possible role for cytotoxic lymphocytes in the pathogenesis of acute interstitial nephritis after recombinant interleukin-2 treatment for renal cell cancer. Cancer Immunol Immunother 1993;36:210.

76. Choi YJ, Chakraborty S, Nguyen V, et al. Peritubular capillary loss is associated with chronic tubulointerstitial injury in human kidney: Altered expression of vascular endothelial growth factor. Hum Pathol 2000;31:1491.

77. Schwarz A, Krause P, Kunzendorf U, et al. The outcome of acute interstitial nephritis: Risk factors for the transition from acute to chronic interstitial nephritis. Clin Nephrol 2003;59:65.

78. Benner EJ. Renal damage associated with prolonged administration of ampicillin, cephaloridine, and cephalothin. Antimicrobial Agents Chemother 1969;9:417.

79. Pickering MJ, Spooner GR, de Quesada A, Cade JR. Declining renal function associated with administration of cephalothin. South Med J 1970;63:426.

80. Foord RD. Cephaloridine, cephalothin and the kidney. J Antimicrob Chemother 1975;1:119.

81. Norrby R, Stenqvist K, Elgefors B. Interaction between cephaloridine and furosemide in man. Scand J Infect Dis 1976;8:209.

82. Fillastre JP, Kleinknecht D. Acute renal failure associated with cephalosporin therapy. Am Heart J 1975;89:809.

83. Burton JR, Lichtenstein NS, Colvin RB, Hyslop NE Jr. Acute renal failure during cephalothin therapy. JAMA 1974;229:679.


85. Wade JC, Smith CR, Petty BG, et al. Cephalothin plus an aminoglycoside is more nephrotoxic than methicillin plus an aminoglycoside. Lancet 1978;2:604.

86. Dodds MG, Foord RD. Enhancement by potent diuretics of renal tubular necrosis induced by cephaloridine. Br J Pharmacol 1970;40:227.

87. Verma S, Kieff E. Cephalexin-related nephropathy. JAMA 1975;234:618.

88. Barza M. The nephrotoxicity of cephalosporins: An overview. J Infect Dis 1978;137(suppl):S60.

89. Mancini S, Iacovoni R, Fierimonte V, et al. Drug-induced interstitial nephritis. A case report. Minerva Pediatr 1994;46:557.

90. Goddard JK, Janning SW, Gass JS, Wilson RF. Cefuroxime-induced acute renal failure. Pharmacotherapy 1994;14:488.

91. Barrientos A, Bello I, Gutierrez-Millet V. Letter: Renal failure and cephalothin. Ann Intern Med 1976;84:612.

92. Perkins RL, Apicella MA, Lee IS, et al. Cephaloridine and cephalothin: Comparative studies of potential nephrotoxicity. J Lab Clin Med 1968;71:75.


93. Tune BM, Hsu CY. Toxicity of cephaloridine to carnitine transport and fatty acid metabolism in rabbit renal cortical mitochondria: Structure-activity relationships. J Pharmacol Exp Ther 1994;270:873.

94. Lash LH, Tokarz JJ, Woods EB. Renal cell type specificity of cephalosporin-induced cytotoxicity in suspensions of isolated proximal tubular and distal tubular cells. Toxicology 1994;94:97.

95. Levine BB. Antigenicity and cross-reactivity of penicillins and cephalosporins. J Infect Dis 1973;128(suppl):S364.

96. Saxon A, Hassner A, Swabb EA, et al. Lack of cross-reactivity between aztreonam, a monobactam antibiotic, and penicillin in penicillin-allergic subjects. J Infect Dis 1984;149:16.

97. Hadimeri H, Almroth G, Cederbrant K, et al. Allergic nephropathy associated with norfloxacin and ciprofloxacin therapy. Report of two cases and review of the literature. Scand J Urol Nephrol 1997;31:481.

98. Okada H, Watanabe Y, Kotaki S, et al. An unusual form of crystal-forming chronic interstitial nephritis following long-term exposure to tosufloxacin tosilate. Am J Kidney Dis 2004;44:902.

99. Allon M, Lopez EJ, Min KW. Acute renal failure due to ciprofloxacin. Arch Intern Med 1990;150:2187.

100. Helmink R, Benediktsson H. Ciprofloxacin-induced allergic interstitial nephritis. Nephron 1990;55:432.

101. Hootkins R, Fenves AZ, Stephens MK. Acute renal failure secondary to oral ciprofloxacin therapy: A presentation of three cases and a review of the literature. Clin Nephrol 1989;32:75.

102. Rastogi S, Atkinson JL, McCarthy JT. Allergic nephropathy associated with ciprofloxacin. Mayo Clin Proc 1990;65:987.

103. Shih DJ, Korbet SM, Rydel JJ, Schwartz MM. Renal vasculitis associated with ciprofloxacin. Am J Kidney Dis 1995;26:516.

104. Lo WK, Rolston KV, Rubenstein EB, Bodey GP. Ciprofloxacin-induced nephrotoxicity in patients with cancer. Arch Intern Med 1993;153:1258.

105. Lien YH, Hansen R, Kern WF, et al. Ciprofloxacin-induced granulomatous interstitial nephritis and localized elastolysis. Am J Kidney Dis 1993;22:598.

106. Garcia-Ortiz R, Espinoza RS, Silva GR, et al. Cloxacillin-induced acute tubulo interstitial nephritis. Ann Pharmacother 1992;26:1241.

107. Soto J, Bosch JM, Alsar Ortiz MJ, et al. Piperacillin-induced acute interstitial nephritis. Nephron 1993;65:154.

108. Pill MW, O'Neill CV, Chapman MM, Singh AK. Suspected acute interstitial nephritis induced by piperacillin-tazobactam. Pharmacotherapy 1997;17:166.

109. Gilbert DN, Gourley R, d'Agostino A, et al. Interstitial nephritis due to methicillin, penicillin and ampicillin. Ann Allergy 1970;28:378.

110. Ruley EJ, Lisi LM. Interstitial nephritis and renal failure due to ampicillin. J Pediatr 1974;84:878.

111. Tannenberg AM, Wicher KJ, Rose NR. Ampicillin nephropathy. JAMA 1971;218:449.

112. Woodroffe AJ, Weldon M, Meadows R, Lawrence JR. Acute interstitial nephritis following ampicillin hypersensitivity. Med J Aust 1975;1:65.

113. Ditlove J, Weidmann P, Bernstein M, Massry SG. Methicillin nephritis. Medicine (Baltimore) 1977;56:483.

114. Jensen HA, Halveg AB, Saunamaki KI. Permanent impairment of renal function after methicillin nephropathy. Br Med J 1971;4:406.

115. Appel GB, Neu HC. The nephrotoxicity of antimicrobial agents (first of three parts). N Engl J Med 1977;296:663.

116. Rennke HG, Roos PC, Wall SG. Drug-induced interstitial nephritis with heavy glomerular proteinuria. N Engl J Med 1980;302: 691.

117. Minetti L, di Belgiojoso GB, Civati G, et al. Drug induced hypersensitivity nephritis. Proc Eur Dial Transplant Assoc 1975; 11:526.

118. Mayaud C, Kanfer A, Kourilsky O, Sraer JD. Letter: Interstitial nephritis after methicillin. N Engl J Med 1975;292:1132.

119. Mery J, Morel-Maroger L. Acute interstitial nephritis: A hypersensitivity reaction to drugs. In: Giovannetti S, Bonomini V, D'Amico, eds. Proceedings of the Sixth International Congress of Nephrology. Basel: Karger, 1976:524.


Hansen ES, Tauris P. Methicillin-induced nephropathy. A case with linear deposition of IgG and C3 on the tubular-basement-membrane. Acta Pathol Microbiol Scand (A) 1976;84:440.

122. Orfila C, Rakotoarivony J, Durand D, Suc JM. A correlative study of immunofluorescence, electron, and light microscopy in immunologically mediated renal tubular disease in man. Nephron 1979;23:14.

123. Pirani CL, Valeri A, D'Agati V, Appel GB. Renal toxicity of nonsteroidal anti-inflammatory drugs. Contrib Nephrol 1987;55: 159.

124. Flynn CT, Rainford DJ, Hope E. Acute renal failure and rifampicin: Danger of unsuspected intermittent dosage. Br Med J 1974;2:482.

125. Muthukumar T, Jayakumar M, Fernando EM, Muthusethupathi MA. Acute renal failure due to rifampicin: A study of 25 patients. Am J Kidney Dis 2002;40:690.

126. Campese VM, Marzullo F, Schena FP, Coratelli P. Acute renal failure during intermittent rifampicin therapy. Nephron 1973;10:256.

127. Cordonnier D, Muller JM. Acute renal failure after rifampicin. Lancet 1972;2:1364.

128. Ramgopal V, Leonard C, Bhathena D. Acute renal failure associated with rifampicin. Lancet 1973;1:1195.

129. Cochran M, Morrhead PJ, Platts M. Letter: Permanent renal damage with rifampicin. Lancet 1975;1:1428.

130. Quinn BP, Wall BM. Nephrogenic diabetes insipidus and tubulointerstitial nephritis during continuous therapy with rifampin. Am J Kidney Dis 1989;14:217.

131. Minetti L, Barbiano di Belgioioso G, et al. Nephritis caused by drug hypersensitivity (DHN). Clinico-histological observations in 15 cases [in Italian]. Minerva Nefrol 1974;21:197.

132. Poole G, Stradling P, Worlledge S. Potentially serious side effects of high-dose twice-weekly rifampicin. Br Med J 1971;3:343.

133. Tomonaga H. Detection of antibody specific to rifampicin metabolite by ELISA–mechanism of sensitization by rifampicin. Arerugi 1993;42:854.

134. French A. Hypersensitivity in the pathogenesis of the histopathologic changes associated with sulfonamide chemotherapy. Am J Pathol 1946;22:679.

More R, McMillan G, Duff G. The pathology of sulfonamide allergy in man. Am J Pathol 1946;22:703.


137. Robson M, Levi J, Dolberg L, Rosenfeld JB. Acute tubulo-interstitial nephritis following sulfadiazine therapy. Isr J Med Sci 1970;6:561.

Bailey RR, Little PJ. Deterioration in renal function in association with co-trimoxazole therapy. Med J Aust 1976;1:914–916.

139. Kalowski S, Nanra RS, Mathew TH, Kincaid-Smith P. Deterioration in renal function in association with co-trimoxazole therapy. Lancet 1973;1:394.

140. Farina LA, Palou Redorta J, Chechile Toniolo G. Reversible acute renal failure due to sulfonamide-induced lithiasis in an AIDS patient. Arch Esp Urol 1995;48:418.

141. Albala DM, Prien EL Jr, Galal HA. Urolithiasis as a hazard of sulfonamide therapy. J Endourol 1994;8:401.

142. Russinko PJ, Agarwal S, Choi MJ, Kelty PJ. Obstructive nephropathy secondary to sulfasalazine calculi. Urology 2003;62:748.

143. Dowling H, Lepper M. Toxic reactions following therapy with sulfapyridine, sulfathiazole and sulfadiazine. JAMA 1943;121:1190.

144. Cryst C, Hammar SP. Acute granulomatous interstitial nephritis due to co-trimoxazole. Am J Nephrol 1988;8:483.

145. Cimino MA, Rotstein C, Slaughter RL, Emrich LJ. Relationship of serum antibiotic concentrations to nephrotoxicity in cancer patients receiving concurrent aminoglycoside and vancomycin therapy. Am J Med 1987;83:1091.


146. Rybak MJ, Albrecht LM, Boike SC, Chandrasekar PH. Nephrotoxicity of vancomycin, alone and with an aminoglycoside. J Antimicrob Chemother 1990;25:679.

147. Nahata MC. Lack of nephrotoxicity in pediatric patients receiving concurrent vancomycin and aminoglycoside therapy. Chemotherapy 1987;33:302.

148. Codding CE, Ramseyer L, Allon M, et al. Tubulointerstitial nephritis due to vancomycin. Am J Kidney Dis 1989;14:512.

149. Wai AO, Lo AM, Abdo A, Marra F. Vancomycin-induced acute interstitial nephritis. Ann Pharmacother 1998;32:1160.

150. Hsu SI. Biopsy-proved acute tubulointerstitial nephritis and toxic epidermal necrolysis associated with vancomycin. Pharmacotherapy 2001;21:1233.

151. Yano Y, Hiraoka A, Oguma T. Enhancement of tobramycin binding to rat renal brush border membrane by vancomycin. J Pharmacol Exp Ther 1995;274:695.

152. Harris RC. Cyclooxygenase-2 in the kidney. J Am Soc Nephrol 2000;11:2387.

153. Galli G, Panzetta G. Do non-steroidal anti-inflammatory drugs and COX-2 selective inhibitors have different renal effects? J nephrol 2002;15:480.

154. Rocha JL, Fernandez-Alonso J. Acute tubulointerstitial nephritis associated with the selective COX-2 enzyme inhibitor, rofecoxib. Lancet 2001;357:1946.

155. Demke D, Zhao S, Arellano FM. Interstitial nephritis associated with celecoxib. Lancet 2001;358:1726.

156. Henao J, Hisamuddin I, Nzerue CM, et al. Celecoxib-induced acute interstitial nephritis. Am J Kidney Dis 2002;39:1313.

Alper AB Jr, Meleg-Smith S, Krane NK. Nephrotic syndrome and interstitial nephritis associated with celecoxib. Am J Kidney Dis 2002;40:1086.

158. Brewster UC, Perazella MA. Acute tubulointerstitial nephritis associated with celecoxib. Nephrol Dial Transplant 2004;19:1017.

159. Szalat A, Krasilnikov I, Bloch A, et al. Acute renal failure and interstitial nephritis in a patient treated with rofecoxib: Case report and review of the literature. Arthritis Rheum 2004;51:670.

160. Whelton A, Hamilton CW. Nonsteroidal anti-inflammatory drugs: Effects on kidney function. J Clin Pharmacol 1991;31: 588.

161. Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: Physiologic foundations and clinical implications. Am J Med 1999;106:13S.

162. Murray MD, Brater DC. Adverse effects of nonsteroidal anti-inflammatory drugs on renal function. Ann Intern Med 1990; 112:559.

163. Kleinknecht D, Landais P, Goldfarb B. Analgesic and non-steroidal anti-inflammatory drug-associated acute renal failure: A prospective collaborative study. Clin Nephrol 1986;25:275.

164. Fox DA, Jick H. Nonsteroidal anti-inflammatory drugs and renal disease. JAMA 1984;251:1299.

165. Bonney SL, Northington RS, Hedrich DA, Walker BR. Renal safety of two analgesics used over the counter: Ibuprofen and aspirin. Clin Pharmacol Ther 1986;40:373.

166. Corwin HL, Bonventre JV. Renal insufficiency associated with nonsteroidal anti-inflammatory agents. Am J Kidney Dis 1984; 4:147.

167. Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1984;310:563.

168. Palmer BF, Henrich WL. Clinical acute renal failure with nonsteroidal anti-inflammatory drugs. Semin Nephrol 1995;15:214.

169. Marasco WA, Gikas PW, Azziz-Baumgartner R, et al. Ibuprofen-associated renal dysfunction. Pathophysiologic mechanisms of acute renal failure, hyperkalemia, tubular necrosis, and proteinuria. Arch Intern Med 1987;147:2107.

170. Whelton A, Stout RL, Spilman PS, Klassen DK. Renal effects of ibuprofen, piroxicam, and sulindac in patients with asymptomatic renal failure. A prospective, randomized, crossover comparison. Ann Intern Med 1990;112:568.

171. Calvo-Alen J, De Cos MA, Rodriguez-Valverde V, et al. Subclinical renal toxicity in rheumatic patients receiving longterm treatment with nonsteroidal antiinflammatory drugs. J Rheumatol 1994;21:1742.

172. Carmichael J, Shankel SW. Effects of nonsteroidal anti-inflammatory drugs on prostaglandins and renal function. Am J Med 1985;78:992.

173. Kleinknecht D. Interstitial nephritis, the nephrotic syndrome, and chronic renal failure secondary to nonsteroidal anti-inflammatory drugs. Semin Nephrol 1995;15:228.

174. Warren GV, Korbet SM, Schwartz MM, Lewis EJ. Minimal change glomerulopathy associated with nonsteroidal antiinflammatory drugs. Am J Kidney Dis 1989;13:127.

175. Lantz B, Cochat P, Bouchet JL, Fischbach M. Short-term niflumic-acid-induced acute renal failure in children. Nephrol Dial Transplant 1994;9:1234.

176. Kleinknecht D. Diseases of the kidney caused by nonsteroidal anti-inflammatory drugs. In: Stewart J, ed. Analgesic and NSAID-Induced Kidney Disease. Oxford: Oxford University Press, 1993: 160.

177. Kaplan BS, Restaino I, Raval DS, et al. Renal failure in the neonate associated with in utero exposure to non-steroidal anti-inflammatory agents. Pediatr Nephrol 1994;8:700.

178. van der Heijden BJ, Carlus C, Narcy F, et al. Persistent anuria, neonatal death, and renal microcystic lesions after prenatal exposure to indomethacin. Am J Obstet Gynecol 1994;171:617.

Voyer LE, Drut R, Mendez JH. Fetal renal maldevelopment with oligohydramnios following maternal use of piroxicam. Pediatr Nephrol 1994;8:592.

180. Ciabattoni G, Cinotti GA, Pierucci A, et al. Effects of sulindac and ibuprofen in patients with chronic glomerular disease. Evidence for the dependence of renal function on prostacyclin. N Engl J Med 1984;310:279.

181. Unsworth J, Sturman S, Lunec J, Blake DR. Renal impairment associated with non-steroidal anti-inflammatory drugs. Ann Rheum Dis 1987;46:233.

182. Gurwitz JH, Avorn J, Ross-Degnan D, Lipsitz LA. Nonsteroidal anti-inflammatory drug-associated azotemia in the very old. JAMA 1990;264:471.

183. Gentilini P. Cirrhosis, renal function and NSAIDs. J Hepatol 1993;19:200.

184. Baisac J, Henrich WL. Nephrotoxicity of nonsteroidal anti-inflammatory drugs. Miner Electrolyte Metab 1994;20:187.

185. Bjorck S. Paracetamol-induced renal tubular cell necrosis. In: Stewart J, ed. Analgesic and NSAID-Induced Kidney Disease. Oxford: Oxford University Press; 1993:174.

186. Blantz RC. Acetaminophen: Acute and chronic effects on renal function. Am J Kidney Dis 1996;28:S3.

187. D'Agati V. Does aspirin cause acute or chronic renal failure in experimental animals and in humans? Am J Kidney Dis 1996;28:S24.

188. Cheng HF, Nolasco F, Cameron JS, et al. HLA-DR display by renal tubular epithelium and phenotype of infiltrate in interstitial nephritis. Nephrol Dial Transplant 1989;4:205.

189. Schwarz A, Krause PH, Keller F, et al. Granulomatous interstitial nephritis after nonsteroidal anti-inflammatory drugs. Am J Nephrol 1988;8:410.

190. Feinfeld DA, Olesnicky L, Pirani CL, Appel GB. Nephrotic syndrome associated with use of the nonsteroidal anti-inflammatory drugs. Case report and review of the literature. Nephron 1984;37:174.

191. Maniglia R, Schwartz AB, Moriber-Katz S. Non-steroidal anti-inflammatory nephrotoxicity. Ann Clin Lab Sci 1988;18:240.

192. Schlondorff D. Renal prostaglandin synthesis. Sites of production and specific actions of prostaglandins. Am J Med 1986;81:1.

193. Anderson RJ, Berl T, McDonald KM, Schrier RW. Prostaglandins: Effects on blood pressure, renal blood flow, sodium and water excretion. Kidney Int 1976;10:205.

194. Zambraski EJ. The effects of nonsteroidal anti-inflammatory drugs on renal function: Experimental studies in animals. Semin Nephrol 1995;15:205.

195. Remuzzi A, Remuzzi G. The effects of nonsteroidal anti-inflammatory drugs on glomerular filtration of proteins and their therapeutic utility. Semin Nephrol 1995;15:236.

196. Spuhler O, Zollinger HU. Chronic interstitial nephritis. Z Klin Med 1953;151:1.


197. Elseviers MM, De Broe ME. A long-term prospective controlled study of analgesic abuse in Belgium. Kidney Int 1995;48:1912.

198. Elseviers MM, Waller I, Nenoy D, et al. Evaluation of diagnostic criteria for analgesic nephropathy in patients with end-stage renal failure: Results of the ANNE study. Analgesic Nephropathy Network of Europe. Nephrol Dial Transplant 1995;10:808.

199. Perneger TV, Whelton PK, Klag MJ. Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs. N Engl J Med 1994;331:1675.


201. Sandler DP, Smith JC, Weinberg CR, et al. Analgesic use and chronic renal disease. N Engl J Med 1989;320:1238.

202. Elseviers M, De Broe M. The implication of analgesic in human kidney disease. In: Stewart J, ed. Analgesic and NSAID-Induced Kidney Disease. Oxford: Oxford University Press, 1993:32.

203. Gault MH, Wilson DR. Analgesic nephropathy in Canada: Clinical syndrome, management, and outcome. Kidney Int 1978; 13:58.

204. Kincaid-Smith P. Analgesic nephropathy and the effect of non-steroidal anti-inflammatory drugs on the kidney. In: Catto G, ed. Drugs and the Kidney. Dordrecht: Kluwer Academic, 1990:1.

205. Gonwa TA, Hamilton RW, Buckalew VM Jr. Chronic renal failure and end-stage renal disease in northwest North Carolina. Importance of analgesic-associated nephropathy. Arch Intern Med 1981;141:462.

206. Elseviers M, De Broe M. Epidemiology of analgesic nephropathy. J nephrol 1992;5:94.

207. Schwarz A, Preuschof L, Zellner D. Incidence of analgesic nephropathy in Berlin since 1983. Nephrol Dial Transplant 1999;14:109.

208. Michielsen P, de Schepper P. Trends of analgesic nephropathy in two high-endemic regions with different legislation. J Am Soc Nephrol 2001;12:550.

209. Feinstein AR, Heinemann LA, Curhan GC, et al. Relationship between nonphenacetin combined analgesics and nephropathy: A review. Ad Hoc Committee of the International Study Group on Analgesics and Nephropathy. Kidney Int 2000;58:2259.

210. Kurth T, Glynn RJ, Walker AM, et al. Analgesic use and change in kidney function in apparently healthy men. Am J Kidney Dis 2003;42:234.


212. Nanra R. Functional defects in analgesic nephropathy. In: Stewart J, ed. Analgesic and NSAID-Induced Kidney Disease. Oxford: Oxford University Press, 1993: 102.

213. Griffin MD, Bergstralhn EJ, Larson TS. Renal papillary necrosis—a sixteen-year clinical experience. J Am Soc Nephrol 1995;6:248.

214. De Broe ME, Elseviers MM. Analgesic nephropathy. N Engl J Med 1998;338:446.

215. Burry A. Pathology of analgesic nephropathy: Australian experience. Kidney Int 1978;13:34.

216. Mihatsch M, Zollinger H. The pathology of analgesic nephropathy. In: Stewart J, ed. Analgesic and NSAID-Induced Kidney Disease. Oxford: Oxford University Press; 1993:67.

Berneis K, Korteweg E, Mihatsch MJ. Characterization of the brown pigment of the mucosa of the urinary tract. Virchows Arch A Pathol Anat Histopathol 1983;402:203.

218. Gloor F. Capillary sclerosis of the urinary tract caused by abuse of an analgesic agent (phenacetin) [in German]. Pathologe 1982;3:132.

219. Mihatsch MJ, Hofer HO, Gudat F, et al. Capillary sclerosis of the urinary tract and analgesic nephropathy. Clin Nephrol 1983;20:285.

220. Mihatsch MJ, Torhorst J, Steinmann E, et al. The morphologic diagnosis of analgesic (phenacetin) abuse. Pathol Res Pract 1979;164:68.

221. Burry A. The evolution of analgesic nephropathy. Nephron 1967;5:185.

222. Kincaid-Smith P. Pathogenesis of the renal lesion associated with the abuse of analgesics. Lancet 1967;1:859.

223. Zollinger H. Niere und albeitende Harnwege. Berlin: Springer Verlag, 1966.

224. Kincaid-Smith P, Saker BM, McKenzie IF, Muriden KD. Lesions in the blood supply of the papilla in experimental analgesic nephropathy. Med J Aust 1968;1:203.

225. Molland EA. Experimental renal papillary necrosis. Kidney Int 1978;13:5.

226. Lagergren C, Ljungqvist A. The intrarenal arterial pattern in renal papillary necrosis. A micro-angiographic and histologic study. Am J Pathol 1962;41:633.

227. Prescott LF. Analgesic nephropathy: A reassessment of the role of phenacetin and other analgesics. Drugs 1982;23:75.

228. Duggin GG. Mechanisms in the development of analgesic nephropathy. Kidney Int 1980;18:553.


230. Moeckel GW, Zhang L, Fogo AB, et al. COX2 activity promotes organic osmolyte accumulation and adaptation of renal medullary interstitial cells to hypertonic stress. J Biol Chem 2003;278:19352.

231. Li C, Liu J, Saavedra JE, et al. The nitric oxide donor, V-PYRRO/NO, protects against acetaminophen-induced nephrotoxicity in mice. Toxicology 2003;189:173.

232. Ahmed MH, Ashton N, Balment RJ. Renal function in a rat model of analgesic nephropathy: Effect of chloroquine. J Pharmacol Exp Ther 2003;305:123.

233. Goncalves AR, Fujihara CK, Mattar AL, et al. Renal expression of COX-2, ANG II, and AT1 receptor in remnant kidney: Strong renoprotection by therapy with losartan and a nonsteroidal anti-inflammatory. Am J Physiol Renal Physiol 2004;286:F945.

234. Schnellmann RG. Analgesic nephropathy in rodents. J Toxicol Environ Health B Crit Rev 1998;1:81.

235. Credie M. Analgesics as human carcinogens: Clinical and epidemiological evidence. In: Stewart J, ed. Analgesic and NSAID-Induced Kidney Disease. Oxford: Oxford University Press, 1993:211.

236. Mihatsch MJ, Knusli C. Phenacetin abuse and malignant tumors. An autopsy study covering 25 years (1953–1977). Klin Wochenschr 1982;60:1339.

237. Taylor J. Carcinoma of the renal pelvis. In: Stewart J, ed. Analgesic and NSAID-Induced Kidney Disease. Oxford: Oxford University Press, 1993:211.

238. Chow WH, McLaughlin JK, Linet MS, et al. Use of analgesics and risk of renal cell cancer. Int J Cancer 1994;59:467.

239. Van Staa TP, Travis S, Leufkens HG, Logan RF. 5-Aminosalicylic acids and the risk of renal disease: A large British epidemiologic study. Gastroenterology 2004;126:1733.

240. Ransford RA, Langman MJ. Sulphasalazine and mesalazine: Serious adverse reactions re-evaluated on the basis of suspected adverse reaction reports to the committee on safety of medicines. Gut 2002;51:536.

241. Arend LJ, Springate JE. Interstitial nephritis from mesalazine: Case report and literature review. Pediatr Nephrol 2004;19:550.

242. Agarwal BN, Cabebe FG, Hoffman BI. Diphenylhydantoin-induced acute renal failure. Nephron 1977;18:249.

243. Hyman LR, Ballow M, Knieser MR. Diphenylhydantoin interstitial nephritis. Roles of cellular and humoral immunologic injury. J Pediatr 1978;92:915.

244. Matson JR, Krous HF, Blackstock R. Diphenylhydantoin-induced hypersensitivity reaction with interstitial nephritis. Hum Pathol 1985;16:94.

245. Gaffey CM, Chun B, Harvey JC, Manz HJ. Phenytoin-induced systemic granulomatous vasculitis. Arch Pathol Lab Med 1986; 110:131.

Walker RG. Lithium nephrotoxicity. Kidney Int 1993;42(suppl): S93.

247. Presne C, Fakhouri F, Noel LH, et al. Lithium-induced nephropathy: Rate of progression and prognostic factors. Kidney Int 2003;64:585.


248. Bucht G, Wahlin A, Wentzel T, Winblad B. Renal function and morphology in long-term lithium and combined lithium-neuroleptic treatment. Acta Med Scand 1980;208:381.

249. Hestbech J, Hansen HE, Amdisen A, Olsen S. Chronic renal lesions following long-term treatment with lithium. Kidney Int 1977;12:205.

250. Cox M. Lithium in the kidney. Kidney Int 1981;19:379.


252. Walker R, Edwards J. Lithium and the kidney: An update [editorial]. Psychol Med 1989;19:825.

253. Tam VK, Green J, Schwieger J, Cohen AH. Nephrotic syndrome and renal insufficiency associated with lithium therapy. Am J Kidney Dis 1996;27:715.

254. Markowitz GS, Radhakrishnan J, Kambham N, et al. Lithium nephrotoxicity: A progressive combined glomerular and tubulointerstitial nephropathy. J Am Soc Nephrol 2000;11:1439.

255. Dias N, Hocken AG. Oliguric renal failure complicating lithium carbonate therapy. Nephron 1973;10:246.

256. Lavender S, Brown JN, Berrill WT. Acute renal failure and lithium intoxication. Postgrad Med J 1973;49:277.

257. Aurell M, Svalander C, Wallin L, Alling C. Renal function and biopsy findings in patients on long-term lithium treatment. Kidney Int 1981;20:663.

258. Kincaid-Smith P, Burrows GD, Davies BM, et al. Renal-biopsy findings in lithium and prelithium patients. Lancet 1979;2:700.

259. Walker RG, Escott M, Birchall I, et al. Chronic progressive renal lesions induced by lithium. Kidney Int 1986;29:875.

260. Walker RG, Bennett WM, Davies BM, Kincaid-Smith P. Structural and functional effects of long-term lithium therapy. Kidney Int Suppl 1982;11:S13.

261. Santella RN, Rimmer JM, MacPherson BR. Focal segmental glomerulosclerosis in patients receiving lithium carbonate. Am J Med 1988;84:951.

262. Christensen BM, Marples D, Kim YH, et al. Changes in cellular composition of kidney collecting duct cells in rats with lithium-induced NDI. Am J Physiol Cell Physiol 2004;286:C952.

263. Myers RP, McLaughlin K, Hollomby DJ. Acute interstitial nephritis due to omeprazole. Am J Gastroenterol 2001;96:3428.

264. Delve P, Lau M, Yun K, Walker R. Omeprazole-induced acute interstitial nephritis. N Z Med J 2003;116:U332.

265. Moore I, Sayer JA, Nayar A, et al. Pantoprazole-induced acute interstitial nephritis. J Nephrol 2004;17:580.

266. Torpey N, Barker T, Ross C. Drug-induced tubulo-interstitial nephritis secondary to proton pump inhibitors: Experience from a single UK renal unit. Nephrol Dial Transplant 2004;19:1441.

267. Geevasinga N, Kairaitis L, Rangan GK, Coleman PL. Acute interstitial nephritis secondary to esomeprazole. Med J Aust 2005; 182:235.

268. Sarcletti M, Petter A, Zangerle R. Indinavir and interstitial nephritis. Ann Intern Med 1998;128:320.

Olyaei AJ, deMattos AM, Bennett WM. Renal toxicity of protease inhibitors. Curr Opin Nephrol Hypertens 2000;9:473.

270. Jaradat M, Phillips C, Yum MN, et al. Acute tubulointerstitial nephritis attributable to indinavir therapy. Am J Kidney Dis 2000;35:E16.

271. Brewster UC, Perazella MA. Acute interstitial nephritis associated with atazanavir, a new protease inhibitor. Am J Kidney Dis 2004;44:e81.

272. Wuthrich RP, Sibalic V. Autoimmune tubulointerstitial nephritis: Insight from experimental models. Exp Nephrol 1998;6:288.

273. Miller K, Michael AF. Immunopathology of renal extracellular membranes in diabetes mellitus: Specificity of tubular basement-membrane immunofluorescence. Diabetes 1976;25:701.

274. Lehman DH, Wilson CB, Dixon FJ. Extraglomerular immunoglobulin deposits in human nephritis. Am J Med 1975;58:765.

275. Clayman MD, Martinez-Hernandez A, Michaud L, et al. Isolation and characterization of the nephritogenic antigen producing anti-tubular basement membrane disease. J Exp Med 1985;161:290.

276. Brentjens JR, Matsuo S, Fukatsu A, et al. Immunologic studies in two patients with antitubular basement membrane nephritis. Am J Med 1989;86:603.

277. Nelson TR, Charonis AS, McIvor RS, Butkowski RJ. Identification of a cDNA encoding tubulointerstitial nephritis antigen. J Biol Chem 1995;270:16265.

278. Bergstein J, Litman N. Interstitial nephritis with anti-tubular-basement-membrane antibody. N Engl J Med 1975;292:875.

279. Rakotoarivony J, Orfila C, Segonds A, et al. Human and experimental nephropathies associated with antibodies to tubular basement membrane. Adv Nephrol Necker Hosp 1981;10:187.


281. Helczynski L, Landing BH. Tubulointerstitial renal diseases of children: Pathologic features and pathogenetic mechanisms in Fanconi's familial nephronophthisis, antitubular basement membrane antibody disease, and medullary cyst disease. Pediatr Pathol 1984;2:1.

282. Kalluri R, Wilson CB, Weber M, et al. Identification of the alpha 3 chain of type IV collagen as the common autoantigen in antibasement membrane disease and Goodpasture syndrome. J Am Soc Nephrol 1995;6:1178.

283. Andres G, Brentjens J, Kohli R, et al. Histology of human tubulo-interstitial nephritis associated with antibodies to renal basement membranes. Kidney Int 1978;13:480.

284. Biancone L, Andres G, Stamenkovic I. Autoimmune disease of the kidney: An update. Proc Soc Exp Biol Med 1996;212:225.

284a. Graindorge PP, Mahieu PR. Radioimmunologic method for detection of antitubular basement membrane antibodies. Kidney Int 1978;14:594.

285. Border WA, Baehler RW, Bhathena D, Glassock RJ. IgA antibasement membrane nephritis with pulmonary hemorrhage. Ann Intern Med 1979;91:21.

286. Merkel F, Kalluri R, Marx M, et al. Autoreactive T-cells in Goodpasture's syndrome recognize the N-terminal NC1 domain on alpha 3 type IV collagen. Kidney Int 1996;49:1127.

Levy M, Guesry P, Loirat C, et al. Immunologically mediated tubulo-interstitial nephritis in children. Contrib Nephrol 1979;16:132.

288. Katz A, Fish AJ, Santamaria P, et al. Role of antibodies to tubulointerstitial nephritis antigen in human anti-tubular basement membrane nephritis associated with membranous nephropathy. Am J Med 1992;93:691.

289. Makker S, Widstrom R, Huang J. Characterization of glomerular antigen of membranous nephropathy (MN) in the syndrome of MN, tubulointerstitial nephritis (TN) and Fanconi syndrome. J Am Soc Nephrol 1995;6:925.

290. Tay AH, Ren EC, Murugasu B, et al. Membranous nephropathy with anti-tubular basement membrane antibody may be X-linked. Pediatr Nephrol 2000;14:747.

291. Kerjaschki D, Farquhar MG. Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats. J Exp Med 1983;157:667.

292. Ivanyi B, Haszon I, Endreffy E, et al. Childhood membranous nephropathy, circulating antibodies to the 58-kD TIN antigen, and anti-tubular basement membrane nephritis: An 11-year follow-up. Am J Kidney Dis 1998;32:1068.

293. Rotellar C, Noel LH, Droz D, et al. Role of antibodies directed against tubular basement membranes in human renal transplantation. Am J Kidney Dis 1986;7:157.

294. Klassen J, Kano K, Milgrom F, et al. Tubular lesions produced by autoantibodies to tubular basement membrane in human renal allografts. Int Arch Allergy Appl Immunol 1973;45:675.


296. Morel-Maroger L, Kourilsky O, Mignon F, Richet G. Antitubular basement membrane antibodies in rapidly progressive poststreptococcal glomerulonephritis: Report of a case. Clin Immunol Immunopathol 1974;2:185.

297. Makker SP. Tubular basement membrane antibody-induced interstitial nephritis in systemic lupus erythematosus. Am J Med 1980;69:949.


298. Dixit MP, Scott KM, Bracamonte E, et al. Kimura disease with advanced renal damage with anti-tubular basement membrane antibody. Pediatr Nephrol 2004;19:1404.

299. Hannigan NR, Jabs K, Perez-Atayde AR, Rosen S. Autoimmune interstitial nephritis and hepatitis in polyglandular autoimmune syndrome. Pediatr Nephrol 1996;10:511.

Yoshioka K, Hino S, Takemura T, et al. Isolation and characterization of the tubular basement membrane antigen associated with human tubulo-interstitial nephritis. Clin Exp Immunol 1992;90:319.

301. Butkowski RJ, Kleppel MM, Katz A, et al. Distribution of tubulointerstitial nephritis antigen and evidence for multiple forms. Kidney Int 1991;40:838.

302. Miyazato H, Yoshioka K, Hino S, et al. The target antigen of anti-tubular basement membrane antibody-mediated interstitial nephritis. Autoimmunity 1994;18:259.

303. Kalfa TA, Thull JD, Butkowski RJ, Charonis AS. Tubulointerstitial nephritis antigen interacts with laminin and type IV collagen and promotes cell adhesion. J Biol Chem 1994;269:1654.

304. Chen Y, Krishnamurti U, Wayner EA, et al. Receptors in proximal tubular epithelial cells for tubulointerstitial nephritis antigen. Kidney Int 1996;49:153.

305. Kanwar YS, Kumar A, Yang Q, et al. Tubulointerstitial nephritis antigen: An extracellular matrix protein that selectively regulates tubulogenesis vs. glomerulogenesis during mammalian renal development. Proc Natl Acad Sci U S A 1999;96:11323.

306. Yoshioka K, Takemura T, Hattori S. Tubulointerstitial nephritis antigen: Primary structure, expression and role in health and disease. Nephron 2002;90:1.

307. Yoshioka K, Kleppel M, Fish AJ. Analysis of nephritogenic antigens in human glomerular basement membrane by two-dimensional gel electrophoresis. J Immunol 1985;134:3831.

308. Tang WW, Feng L, Mathison JC, Wilson CB. Cytokine expression, upregulation of intercellular adhesion molecule-1, and leukocyte infiltration in experimental tubulointerstitial nephritis. Lab Invest 1994;70:631.

309. Neilson EG. Pathogenesis and therapy of interstitial nephritis. Kidney Int 1989;35:1257.

310. Ellis D, Fisher SE, Smith WI Jr, Jaffe R. Familial occurrence of renal and intestinal disease associated with tissue autoantibodies. Am J Dis Child 1982;136:323.

311. Hyun J, Galen MA. Acute interstitial nephritis. A case characterized by increase in serum IgG, IgM, and IgE concentrations. Eosinophilia, and IgE deposition in renal tubules. Arch Intern Med 1981;141:679.

312. Tokumoto M, Fukuda K, Shinozaki M, et al. Acute interstitial nephritis with immune complex deposition and MHC class II antigen presentation along the tubular basement membrane. Nephrol Dial Transplant 1999;14:2210.

313. Takeda S, Haratake J, Kasai T, et al. IgG4-associated idiopathic tubulointerstitial nephritis complicating autoimmune pancreatitis. Nephrol Dial Transplant 2004;19:474.

314. Markowitz GS, Fine PL, Kunis CL, et al. Polyclonal immunoglobulin G deposition diseas: A unique entity. Am J Kidney Dis 1998;32:328.

315. Brentjens JR, Sepulveda M, Baliah T, et al. Interstitial immune complex nephritis in patients with systemic lupus erythematosus. Kidney Int 1975;7:342.

316. Park MH, D'Agati V, Appel GB, Pirani CL. Tubulointerstitial disease in lupus nephritis: Relationship to immune deposits, interstitial inflammation, glomerular changes, renal function, and prognosis. Nephron 1986;44:309.

Schwartz MM, Fennell JS, Lewis EJ. Pathologic changes in the renal tubule in systemic lupus erythematosus. Hum Pathol 1982; 13:534.

318. Biesecker G, Katz S, Koffler D. Renal localization of the membrane attack complex in systemic lupus erythematosus nephritis. J Exp Med 1981;154:1779.

319. Pijpe J, Vissink A, Van der Wal JE, Kallenberg CG. Interstitial nephritis with infiltration of IgG-kappa positive plasma cells in a patient with Sjögren's syndrome. Rheumatology (Oxford) 2004;43:108.

320. Tung K, Black W. Association of renal glomerular and tubular immune complex disease and antitubular basement membrane antibody. Lab Invest 1975;32:696.

321. Douglas MF, Rabideau DP, Schwartz MM, Lewis EJ. Evidence of autologous immune-complex nephritis. N Engl J Med 1981;305:1326.


323. Markowitz GS, Kambham N, Maruyama S, et al. Membranous glomerulopathy with Bowman's capsular and tubular basement membrane deposits. Clin Nephrol 2000;54:478.

324. Ohsawa I, Ohi H, Fujita T, et al. Glomerular and extraglomerular immune complex deposits in a bone marrow transplant recipient. Am J Kidney Dis 2000;36:E3.

324a. Cornell LD, Chicano SL, Deshpande V, et al. IgGt immune complex tubulointerstitio nephritis associated with autoimmune pancreatitis. Lab Invest 2006;86:261A.

325. Adeyi OA, Sethi S, Rennke HG. Fibrillary glomerulonephritis: A report of 2 cases with extensive glomerular and tubular deposits. Hum Pathol 2001;32:660.

326. Kerjaschki D, Farquhar MG. The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border. Proc Natl Acad Sci U S A 1982;79:5557.

Kerjaschki D. Molecular pathogenesis of membranous nephropathy. Kidney Int 1992;41:1090.

328. Nobel R, Andres G, Brentjens J. Passively transferred anti-brush border antibodies induce injury of proximal tubules in absence of complement. Clin Exp Immunol 1983;56:281.

329. Hoyer JR. Tubulointerstitial immune complex nephritis in rats immunized with Tamm-Horsfall protein. Kidney Int 1980;17: 284.

330. Fasth A, Hoyer JR, Seiler MW. Renal tubular immune complex formation in mice immunized with Tamm-Horsfall protein. Am J Pathol 1986;125:555.

331. Seiler MW, Hoyer JR. Ultrastructural studies of tubulointerstitial immune complex nephritis in rats immunized with Tamm-Horsfall protein. Lab Invest 1981;45:321.

332. Fasth AL, Hoyer JR, Seiler MW. Extratubular Tamm-Horsfall protein deposits induced by ureteral obstruction in mice. Clin Immunol Immunopathol 1988;47:47.

333. Benkovic J, Jelakovic B, Cikes N. Antibodies to Tamm-Horsfall protein in patients with acute pyelonephritis. Eur J Clin Chem Clin Biochem 1994;32:337.

334. Fasth A, Ahlstedt S, Hanson LA, et al. Cross-reactions between the Tamm-Horsfall glycoprotein and Escherichia coli. Int Arch Allergy Appl Immunol 1980;63:303.

335. Faaber P, Rijke TP, van de Putte LB, et al. Cross-reactivity of human and murine anti-DNA antibodies with heparan sulfate. The major glycosaminoglycan in glomerular basement membranes. J Clin Invest 1986;77:1824.

336. Thomas DB, Davies M, Williams JD. Tamm-Horsfall protein: An aetiological agent in tubulointerstitial disease? Exp Nephrol 1993;1:281.

337. Nath KA, Hostetter MK, Hostetter TH. Pathophysiology of chronic tubulo-interstitial disease in rats. Interactions of dietary acid load, ammonia, and complement component C3. J Clin Invest 1985;76:667.

338. Dobrin RS, Vernier RL, Fish AL. Acute eosinophilic interstitial nephritis and renal failure with bone marrow-lymph node granulomas and anterior uveitis. A new syndrome. Am J Med 1975;59:325.

339. Spital A, Panner BJ, Sterns RH. Acute idiopathic tubulointerstitial nephritis: Report of two cases and review of the literature. Am J Kidney Dis 1987;9:71.

340. Ten RM, Torres VE, Milliner DS, et al. Acute interstitial nephritis: Immunologic and clinical aspects. Mayo Clin Proc 1988;63:921.

341. Takemura T, Okada M, Hino S, et al. Course and outcome of tubulointerstitial nephritis and uveitis syndrome. Am J Kidney Dis 1999;34:1016.

342. Wakaki H, Sakamoto H, Awazu M. Tubulointerstitial nephritis and uveitis syndrome with autoantibody directed to renal tubular cells. Pediatrics 2001;107:1443.



344. Burnier M, Jaeger P, Campiche M, Wauters JP. Idiopathic acute interstitial nephritis and uveitis in the adult. report of 1 case and review of the literature. Am J Nephrol 1986;6:312.

345. Iida H, Terada Y, Nishino A, et al. Acute interstitial nephritis with bone marrow granulomas and uveitis. Nephron 1985;40:108.

346. Morino M, Inami K, Kobayashi T, et al. Acute tubulointerstitial nephritis in two siblings and concomitant uveitis in one. Acta Paediatr Jpn 1991;33:93.

347. Lessard M, Smith JD. Fanconi syndrome with uveitis in an adult woman. Am J Kidney Dis 1989;13:158.

348. Hirano K, Tomino Y, Mikami H, et al. A case of acute tubulointerstitial nephritis and uveitis syndrome with a dramatic response to corticosteroid therapy. Am J Nephrol 1989;9:499.

349. Itami N, Akutsu Y, Yasoshima K, et al. Acute tubulointerstitial nephritis with uveitis. Arch Intern Med 1990;150:688.

350. Yoshioka K, Takemura T, Kanasaki M, et al. Acute interstitial nephritis and uveitis syndrome: Activated immune cell infiltration in the kidney. Pediatr Nephrol 1991;5:232.

351. Van Acker KJ, Buyssens N, Neetens A, et al. Acute tubulo-interstitial nephritis with uveitis. Acta Paediatr Belg 1980;33:171.

352. Kikkawa Y, Sakurai M, Mano T, et al. Interstitial nephritis with concomitant uveitis. report of two cases. Contrib Nephrol 1975;4:1.

353. Gianviti A, Greco M, Barsotti P, Rizzoni G. Acute tubulointerstitial nephritis occurring with 1-year lapse in identical twins. Pediatr Nephrol 1994;8:427.

354. Hannedouche T, Grateau G, Noel LH, et al. Renal granulomatous sarcoidosis: Report of six cases. Nephrol Dial Transplant 1990;5:18.

355. Muther RS, McCarron DA, Bennett WM. Granulomatous sarcoid nephritis: A cause of multiple renal tubular abnormalities. Clin Nephrol 1980;14:190.

356. Ricker W, Clark M. Sarcoidosis: A clinicopathologic review of 300 cases including 22 autopsies. Am J Clin Pathol 1949;19:725.

357. Richmond JM, Chambers B, D'Apice AJ, et al. Renal disease and sarcoidosis. Med J Aust 1981;2:36.

358. Longcope WT, Freiman DG. A study of sarcoidosis; based on a combined investigation of 160 cases including 30 autopsies from the Johns Hopkins Hospital and Massachusetts General Hospital. Medicine (Baltimore) 1952;31:1.

359. Bergner R, Hoffmann M, Waldherr R, Uppenkamp M. Frequency of kidney disease in chronic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2003;20:126.

360. Gobel U, Kettritz R, Schneider W, Luft F. The protean face of renal sarcoidosis. J Am Soc Nephrol 2001;12:616.

361. Brause M, Magnusson K, Degenhardt S, et al. Renal involvement in sarcoidosis—a report of 6 cases. Clin Nephrol 2002;57:142.

Ito Y, Suzuki T, Mizuno M, et al. A case of renal sarcoidosis showing central necrosis and abnormal expression of angiotensin converting enzyme in the granuloma. Clin Nephrol 1994;42:331.

363. Farge D, Liote F, Turner M, et al. Granulomatous nephritis and chronic renal failure in sarcoidosis. Long-term follow-up studies in two patients. Am J Nephrol 1986;6:21.

364. Mignon F, Mery JP, Mougenot B, et al. Granulomatous interstitial nephritis. Adv Nephrol Necker Hosp 1984;13:219.

365. Fauci AS, Wolff SM. Wegener's granulomatosis: Studies in eighteen patients and a review of the literature 1973. Medicine (Baltimore) 1994;73:315.

366. Caruana RJ, Carr AA, Rao RN. Idiopathic granulomatous nephritis in a patient with hypertension and an atrophic kidney. Nephron 1982;32:83.

367. Okada H, Konishi K, Suzuki H, et al. Steroid-responsive renal insufficiency due to idiopathic granulomatous tubulointerstitial nephritis. Am J Nephrol 1993;13:164.

368. O'Riordan E, Willert RP, Reeve R, et al. Isolated sarcoid granulomatous interstitial nephritis: Review of five cases at one center. Clin Nephrol 2001;55:297.

369. Robson MG, Banerjee D, Hopster D, Cairns HS. Seven cases of granulomatous interstitial nephritis in the absence of extrarenal sarcoid. Nephrol Dial Transplant 2003;18:280.

370. Thumfart J, Muller D, Rudolph B, et al. Isolated sarcoid granulomatous interstitial nephritis responding to infliximab therapy. Am J Kidney Dis 2005;45:411.

371. Pichler R, Giachelli C, Young B, et al. The pathogenesis of tubulointerstitial disease associated with glomerulonephritis: The glomerular cytokine theory. Miner Electrolyte Metab 1995; 21:317.

372. Strutz F, Neilson EG. The role of lymphocytes in the progression of interstitial disease. Kidney Int 1994;45(suppl):S106.

373. Dodd S. The pathogenesis of tubulointerstitial disease and mechanisms of fibrosis. Curr Top Pathol 1995;88:51.

374. Roy-Chaudhury P, Wu B, King G, et al. Adhesion molecule interactions in human glomerulonephritis: Importance of the tubulointerstitium. Kidney Int 1996;49:127.

375. Kliem V, Johnson RJ, Alpers CE, et al. Mechanisms involved in the pathogenesis of tubulointerstitial fibrosis in 5/6-nephrectomized rats. Kidney Int 1996;49:666.


377. Husby G, Tung KS, Williams RC Jr. Characterization of renal tissue lymphocytes in patients with interstitial nephritis. Am J Med 1981;70:31.

378. Neilson EG. The nephritogenic T lymphocyte response in interstitial nephritis. Semin Nephrol 1993;13:496.

379. McCluskey RT, Bhan AK. Cell-mediated immunity in renal disease. Hum Pathol 1986;17:146.

380. Rubin-Kelley VE, Jevnikar AM. Antigen presentation by renal tubular epithelial cells. J Am Soc Nephrol 1991;2:13.

381. Haas C, Ryffel B, Aguet M, Le Hir M. MHC antigens in interferon gamma (IFN gamma) receptor deficient mice: IFN gamma-dependent up-regulation of MHC class II in renal tubules. Kidney Int 1995;48:1721.

382. Unanue ER, Allen PM. The basis for the immunoregulatory role of macrophages and other accessory cells. Science 1987;236:551.

383. Kelley VR, Singer GG. The antigen presentation function of renal tubular epithelial cells. Exp Nephrol 1993;1:102.

384. Shimokado K, Raines EW, Madtes DK, et al. A significant part of macrophage-derived growth factor consists of at least two forms of PDGF. Cell 1985;43:277.


386. Postlethwaite A, Seyer J, Kang A. Chemotactic attraction of human fibroblasts to type I, II, III collagens and collagen-derived peptides. Proc Natl Acad Sci 1978;75:871.

387. Roberts AB, Flanders KC, Kondaiah P, et al. Transforming growth factor beta: Biochemistry and roles in embryogenesis, tissue repair and remodeling, and carcinogenesis. Recent Prog Horm Res 1988;44:157.

388. Tang WW, Ulich TR, Lacey DL, et al. Platelet-derived growth factor-BB induces renal tubulointerstitial myofibroblast formation and tubulointerstitial fibrosis. Am J Pathol 1996;148:1169.

389. Bornstein P, Sage H. Regulation of collagen gene expression. Prog Nucleic Acid Res Mol Biol 1989;37:67.

390. Schmidt JA, Mizel SB, Cohen D, Green I. Interleukin 1, a potential regulator of fibroblast proliferation. J Immunol 1982;128:2177.

391. Vilcek J, Palombella VJ, Henriksen-DeStefano D, et al. Fibroblast growth enhancing activity of tumor necrosis factor and its relationship to other polypeptide growth factors. J Exp Med 1986;163:632.

392. Newman LS. Occupational illness. N Engl J Med 1995;333:1128.

393. Lockitch G. Perspectives on lead toxicity. Clin Biochem 1993; 26:371.

394. Ibels LS, Pollock CA. Lead intoxication. Med Toxicol 1986;1:387.


395. Borjesson J, Mattsson S. Toxicology; in vivo x-ray fluorescence for the assessment of heavy metal concentrations in man. Appl Radiat Isot 1995;46:571.

Bernard BP, Becker CE. Environmental lead exposure and the kidney. J Toxicol Clin Toxicol 1988;26:1.

397. Inglis JA, Henderson DA, Emmerson BT. The pathology and pathogenesis of chronic lead nephropathy occurring in Queensland. J Pathol 1978;124:65.

398. Wedeen RP, Malik DK, Batuman V. Detection and treatment of occupational lead nephropathy. Arch Intern Med 1979;139:53.

399. Goyer RA. Effect of toxic, chemical, and environmental factors on the kidney. Monogr Pathol 1979;20:202.

400. Bennett WM. Lead nephropathy. Kidney Int 1985;28:212.

401. Cooper WC. Deaths from chronic renal disease in U.S. battery and lead production workers. Environ Health Perspect 1988;78:61.

402. Yu CC, Lin JL, Lin-Tan DT. Environmental exposure to lead and progression of chronic renal diseases: A four-year prospective longitudinal study. J Am Soc Nephrol 2004;15:1016.

403. Perazella MA. Lead and the kidney: Nephropathy, hypertension, and gout. Conn Med 1996;60:521.

404. Weaver VM, Jaar BG, Schwartz BS, et al. Associations among lead dose biomarkers, uric acid, and renal function in Korean lead workers. Environ Health Perspect 2005;113:36.

405. Hu H, Aro A, Payton M, et al. The relationship of bone and blood lead to hypertension. The Normative Aging Study. JAMA 1996;275:1171.

406. Moel DI, Sachs HK. Renal function 17 to 23 years after chelation therapy for childhood plumbism. Kidney Int 1992;42:1226.

407. Staessen JA, Lauwerys RR, Buchet JP, et al. Impairment of renal function with increasing blood lead concentrations in the general population. The Cadmibel Study Group. N Engl J Med 1992;327:151.

408. Hong CD, Hanenson IB, Lerner S, et al. Occupational exposure to lead: Effects on renal function. Kidney Int 1980;18:489.


410. Sharp DS, Becker CE, Smith AH. Chronic low-level lead exposure. Its role in the pathogenesis of hypertension. Med Toxicol 1987;2:210.

411. Cramer K, Goyer RA, Jagenburg R, Wilson MH. Renal ultrastructure, renal function, and parameters of lead toxicity in workers with different periods of lead exposure. Br J Ind Med 1974;31:113.

412. Garcon G, Leleu B, Zerimech F, et al. Biologic markers of oxidative stress and nephrotoxicity as studied in biomonitoring of adverse effects of occupational exposure to lead and cadmium. J Occup Environ Med 2004;46:1180.

413. Friberg L. Cadmium and the kidney. Environ Health Perspect 1984;54:1.

414. Scott R, Aughey E, Fell GS, Quinn MJ. Cadmium concentrations in human kidneys from the UK. Hum Toxicol 1987;6:111.

415. Hellstrom L, Elinder CG, Dahlberg B, et al. Cadmium exposure and end-stage renal disease. Am J Kidney Dis 2001;38:1001.

416. Roels H, Bernard AM, Cardenas A, et al. Markers of early renal changes induced by industrial pollutants. III. Application to workers exposed to cadmium. Br J Ind Med 1993;50:37.

417. Nogawa K. Biologic indicators of cadmium nephrotoxicity in persons with low-level cadmium exposure. Environ Health Perspect 1984;54:163.

418. Chan WY, Rennert OM. Cadmium nephropathy. Ann Clin Lab Sci 1981;11:229.

419. Bernard A, Roels H, Buchet JP, et al. Cadmium and health: The Belgian experience. IARC Sci Publ 1992;118:15.

420. Roels H, Lauwerys R, Buchet J, et al. Health significance of cadmium induced renal dysfunction: A five year follow up. Br J Ind Med 1989;46:755.

421. Geiger H, Bahner U, Anderes S, et al. Cadmium and renal hypertension. J Hum Hypertens 1989;3:23.

422. Yasuda M, Miwa A, Kitagawa M. Morphometric studies of renal lesions in Itai-Itai disease: Chronic cadmium nephropathy. Nephron 1995;69:14.

423. Smith J, Smith J, McCall A. Chronic poisoning from cadmium fume. J Pathol Bacteriol 1960;80:287.

424. Kazantzis G, Flynn FV, Spowage JS, Trott DG. Renal tubular malfunction and pulmonary emphysema in cadmium pigment workers. Q J Med 1963;32:165.

425. Lauwers R, De Wals P. Environmental pollution by cadmium and mortality from renal diseases. Lancet 1981;1:383.

426. Roels HA, Lauwerys RR, Buchet JP, et al. In vivo measurement of liver and kidney cadmium in workers exposed to this metal: Its significance with respect to cadmium in blood and urine. Environ Res 1981;26:217.

427. Weiss RA, Madaio MP, Tomaszewski JE, Kelly CJ. T cells reactive to an inducible heat shock protein induce disease in toxin-induced interstitial nephritis. J Exp Med 1994;180:2239.

428. Borjesson J, Barregard L, Sallsten G, et al. In vivo XRF analysis of mercury: The relation between concentrations in the kidney and the urine. Phys Med Biol 1995;40:413.

429. Bigazzi PE. Autoimmunity and heavy metals. Lupus 1994;3:449.

430. Burston J, Darmady EM, Stranack F. Nephrosis due to mercurial diuretics. Br Med J 1958;14:1277.

431. Joekes AM, Heptinstall RH, Porter KA. The nephrotic syndrome; a study of renal biopsies in 20 adult patients. Q J Med 1958;27:495.

432. Preedy JR, Russell DS. Acute salt depletion associated with the nephrotic syndrome developing during treatment with a mercurial diuretic. Lancet 1953;265:1181.

433. Riddle M, Gardner F, Beswick I, Filshie I. The nephrotic syndrome complicating mercurial diuretic therapy. Br Med J 1958;14:1274.

434. Mandema E, Arends A, Van Zeijst J, et al. Mercury and the kidney. Lancet 1963;1:1266.

435. Williams NE, Bridge HG. Nephrotic syndrome after the application of mercury ointment. Lancet 1958;2:602.

436. Grosso A, De Sousa RC. Mercury blockage of apical water channels in toad skin (bufo marinus). J Physiol 1993;468:741.

437. Cramer CR, Hagler HK, Silva FG, et al. Chronic interstitial nephritis associated with gold therapy. Arch Pathol Lab Med 1983;107:258.

438. Hocher B, Keller F, Krause PH, et al. Interstitial nephritis with reversible renal failure due to a copper-containing intrauterine contraceptive device. Nephron 1992;61:111.

439. Friedman AC, Lautin EM. Cis-platinum (II) diaminedichloride: Another cause of bilateral small kidneys. Urology 1980;16:584.

440. Leibbrandt ME, Wolfgang GH, Metz AL, et al. Critical subcellular targets of cisplatin and related platinum analogs in rat renal proximal tubule cells. Kidney Int 1995;48:761.

441. Prasad GV, Rossi NF. Arsenic intoxication associated with tubulointerstitial nephritis. Am J Kidney Dis 1995;26:373.

442. Petronic VJ, Bukurov NS, Djokic MR, et al. Balkan endemic nephropathy and papillary transitional cell tumors of the renal pelvis and ureters. Kidney Int Suppl 1991;34:S77.

443. Thun MJ, Baker DB, Steenland K, et al. Renal toxicity in uranium mill workers. Scand J Work Environ Health 1985;11:83.

444. Sztajnkrycer MD, Otten EJ. Chemical and radiological toxicity of depleted uranium. Mil Med 2004;169:212.

445. Tolson JK, Roberts SM, Jortner B, et al. Heat shock proteins and acquired resistance to uranium nephrotoxicity. Toxicology 2005;206:59.

446. Gullner HG, Gill JR Jr, Bartter FC, et al. A familial disorder with hypokalemic alkalosis, hyperreninemia, aldosteronism, high urinary prostaglandins and normal blood pressure that is not “Bartter's syndrome”. Trans Assoc Am Physicians 1979;92:175.

447. Potter WZ, Trygstad CW, Helmer OM, et al. Familial hypokalemia associated with renal interstitial fibrosis. Am J Med 1974;57:971.

448. Wallace MR, Bruton D, North A, Wild DJ. End-stage renal failure due to familial hypokalaemic interstitial nephritis with identical HLA tissue types. N Z Med J 1985;98:5.

449. Cremer W, Bock KD. Symptoms and course of chronic hypokalemic nephropathy in man. Clin Nephrol 1977;7:112.


450. Lelamali K, Khunkitti W, Yenrudi S, et al. Potassium depletion in a healthy north-eastern Thai population: No association with tubulo-interstitial injury. Nephrology (Carlton) 2003;8:28.

451. Wrong OM, Feest TG, MacIver AG. Immune-related potassium-losing interstitial nephritis: A comparison with distal renal tubular acidosis. Q J Med 1993;86:513.

452. Zsurka G, Ormos J, Ivanyi B, et al. Mitochondrial mutation as a probable causative factor in familial progressive tubulointerstitial nephritis. Hum Genet 1997;99:484.

453. Tzen CY, Tsai JD, Wu TY, et al. Tubulointerstitial nephritis associated with a novel mitochondrial point mutation. Kidney Int 2001;59:846.

454. Rotig A. Renal disease and mitochondrial genetics. J Nephrol 2003;16:286.

455. Peng M, Jarett L, Meade R, et al. Mutant prenyltransferase-like mitochondrial protein (PLMP) and mitochondrial abnormalities in kd/kd mice. Kidney Int 2004;66:20.

Mihatsch MJ, Gudat F, Zollinger HU, et al. Systemic karyomegaly associated with chronic interstitial nephritis: A new disease entity? Clin Nephrol 1979;12:54.

457. Spoendlin M, Moch H, Brunner F, et al. Karyomegalic interstitial nephritis: Further support for a distinct entity and evidence for a genetic defect. Am J Kidney Dis 1995;25:242.

458. Moch H, Spondlin M, Schmassmann A, Mihatsch MJ. Systemic karyomegaly with chronic interstitial nephritis: Discussion of the disease picture based on an autopsy case [in German]. Pathologe 1994;15:44.

459. Godin M, Francois A, Le Roy F, et al. Karyomegalic interstitial nephritis: Is ochratoxin A responsible? J Am Soc Nephrol 1995;6:997.

460. Vadiaka M, Sotsiou F, Koufos C. A case of systemic karyomegaly associated with interstitial nephritis. Ann Med Interne (Paris) 1998;149:291.

461. Hassen W, Abid-Essafi S, Achour A, et al. Karyomegaly of tubular kidney cells in human chronic interstitial nephropathy in Tunisia: Respective role of ochratoxin A and possible genetic predisposition. Hum Exp Toxicol 2004;23:339.


463. Bhandari S, Kalowski S, Collett P, et al. Karyomegalic nephropathy: An uncommon cause of progressive renal failure. Nephrol Dial Transplant 2002;17:1914.

464. Ceovic S, Hrabar A, Saric M. Epidemiology of Balkan endemic nephropathy. Food Chem Toxicol 1992;30:183.

465. Radonic M, Radosevic Z. Clinical features of Balkan endemic nephropathy. Food Chem Toxicol 1992;30:189.

466. Vukelic M, Sostaric B, Fuchs R. Some pathomorphological features of Balkan endemic nephropathy in Croatia. IARC Sci Publ 1991;115:37.

467. Hall PW 3rd, Dammin GJ, Griggs RC, et al. Investigation of chronic endemic nephropathy in Yugoslavia. II. Renal pathology. Am J Med 1965;39:210.

468. Ferluga D, Hvala A, Vizjak A, et al. Renal function, protein excretion, and pathology of Balkan endemic nephropathy. III. Light and electron microscopic studies. Kidney Int Suppl 1991;34:S57.

469. Toncheva D, Galabov AS, Laich A, et al. Urinary neopterin concentrations in patients with Balkan endemic nephropathy (BEN). Kidney Int 2003;64:1817.

470. Sostaric B, Vukelic M. Characteristics of urinary tract tumours in the area of Balkan endemic nephropathy in Croatia. IARC Sci Publ 1991;115:29.

471. Andonova IE, Sarueva RB, Horvath AD, et al. Balkan endemic nephropathy and genetic variants of glutathione S-transferases. J Nephrol 2004;17:390.

472. Toncheva DI, Von Ahsen N, Atanasova SY, et al. Identification of NQO1 and GSTs genotype frequencies in Bulgarian patients with Balkan endemic nephropathy. J Nephrol 2004;17:384.

473. Uzelac-Keserovic B, Spasic P, Bojanic N, et al. Isolation of a coronavirus from kidney biopsies of endemic Balkan nephropathy patients. Nephron 1999;81:141.

474. Riquelme C, Escors D, Ortego J, et al. Nature of the virus associated with endemic Balkan nephropathy. Emerg Infect Dis 2002;8:869.

Wedeen RP. Environmental renal disease: Lead, cadmium and Balkan endemic nephropathy. Kidney Int Suppl 1991;34:S4.

476. Radovanovic Z, Markovic-Denic L, Marinkovic J, et al. Well water characteristics and the Balkan nephropathy. Nephron 1991;57:52.

477. Batuman V. Possible pathogenetic role of low-molecular-weight proteins in Balkan nephropathy. Kidney Int 1991;34(suppl): S89.

478. Bozic Z, Duancic V, Belicza M, et al. Balkan endemic nephropathy: Still a mysterious disease. Eur J Epidemiol 1995;11:235.

479. Vrabcheva T, Petkova-Bocharova T, Grosso F, et al. Analysis of ochratoxin A in foods consumed by inhabitants from an area with Balkan endemic nephropathy: A 1 month follow-up study. J Agric Food Chem 2004;52:2404.

480. Krogh P, Axelsen NH, Elling F, et al. Experimental porcine nephropathy. Changes of renal function and structure induced by ochratoxin A-contaminated feed. Acta Pathol Microbiol Scand (A) 1974;0:1.

481. Krogh P, Elling F. Letter: Fungal toxins and endemic (Balkan) nephropathy. Lancet 1976;2:40.

Pavlovic M, Plestina R, Krogh P. Ochratoxin A contamination of foodstuffs in an area with Balkan (endemic) nephropathy. Acta Pathol Microbiol Scand (B) 1979;87:243.

483. Vanherweghem JL. A new form of nephropathy secondary to the absorption of Chinese herbs [in French]. Bull Mem Acad R Med Belg 1994;149:128 discussion 135.

484. Cosyns JP, Jadoul M, Squifflet JP, et al. Urothelial lesions in Chinese-herb nephropathy. Am J Kidney Dis 1999;33:1011.

485. Depierreux M, Van Damme B, Vanden Houte K, Vanherweghem JL. Pathologic aspects of a newly described nephropathy related to the prolonged use of Chinese herbs. Am J Kidney Dis 1994;24:172.

486. Vanherweghem JL, Depierreux M, Tielemans C, et al. Rapidly progressive interstitial renal fibrosis in young women: Association with slimming regimen including Chinese herbs. Lancet 1993;341:387.

487. Cosyns JP, Jadoul M, Squifflet JP, et al. Chinese herbs nephropathy: A clue to Balkan endemic nephropathy? Kidney Int 1994;45:1680.

488. Nortier JL, Martinez MC, Schmeiser HH, et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med 2000;342:1686.

489. Vanhaelen M, Vanhaelen-Fastre R, But P, Vanherweghem JL. Identification of aristolochic acid in Chinese herbs. Lancet 1994;343:174.

490. Cosyns JP. Aristolochic acid and ‘Chinese herbs nephropathy’: A review of the evidence to date. Drug Saf 2003;26:33.

491. Martinez MC, Nortier J, Vereerstraeten P, Vanherweghem JL. Progression rate of Chinese herb nephropathy: Impact of Aristolochia fangchi ingested dose. Nephrol Dial Transplant 2002;17:408.

492. Cosyns JP, Dehoux JP, Guiot Y, et al. Chronic aristolochic acid toxicity in rabbits: A model of Chinese herbs nephropathy? Kidney Int 2001;59:2164.

493. Yang CS, Lin CH, Chang SH, Hsu HC. Rapidly progressive fibrosing interstitial nephritis associated with Chinese herbal drugs. Am J Kidney Dis 2000;35:313.

494. Chang C, Wang Y, Yang A, Chiang S. Rapidly progressive interstitial renal fibrosis associated with Chinese herbal drugs. Am J Nephrol 2001;21:441.

495. Tanaka A, Nishida R, Maeda K, et al. Chinese herb nephropathy in Japan presents adult-onset Fanconi syndrome: Could different components of aristolochic acids cause a different type of Chinese herb nephropathy? Clin Nephrol 2000;53:301.

496. Tanaka A, Nishida R, Yoshida T, et al. Outbreak of Chinese herb nephropathy in Japan: Are there any differences from Belgium? Intern Med 2001;40:296.

Lo SH, Wong KS, Arlt VM, et al. Detection of Herba Aristolochia Mollissemae in a patient with unexplained nephropathy. Am J Kidney Dis 2005;45:407.


498. Sato N, Takahashi D, Chen SM, et al. Acute nephrotoxicity of aristolochic acids in mice. J Pharm Pharmacol 2004;56:221.

499. Nzerue C, Schlanger L, Jena M, et al. Granulomatous interstitial nephritis and uveitis presenting as salt-losing nephropathy. Am J Nephrol 1997;17:462.

500. Segal A, Dowling JP, Ireton HJ, et al. Granulomatous glomerulonephritis in intravenous drug users: A report of three cases in oxycodone addicts. Hum Pathol 1998;29:1246.

501. Enriquez R, Cabezuelo JB, Gonzalez C, et al. Granulomatous interstitial nephritis associated with hydrochlorothiazide/amiloride. Am J Nephrol 1995;15:270.

502. Nast CC, Cohen AH. Renal cholesterol granulomas: Identification and morphological pattern of development. Histopathology 1985;9:1195.

503. Hegarty J, Picton M, Agarwal G, et al. Carbamazepine-induced acute granulomatous interstitial nephritis. Clin Nephrol 2002;57:310.

Pena de la Vega L, Fervenza FC, Lager D, et al. Acute granulomatous interstitial nephritis secondary to bisphosphonate alendronate sodium. Ren Fail 2005;27:485.