DA1C17FF1

Figure 17.1 Glomerulus from woman with preeclampsia. The tuft appears bloodless, and the capillary lumina are reduced (so-called endotheliosis lesion.) There is no cellular increase. (PAS, ×400.) (Courtesy of Dr. Charles Jennette.)

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Editors: Jennette, J. Charles; Olson, Jean L.; Schwartz, Melvin M.; Silva, Fred G.

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

Copyright ©2007 Lippincott Williams & Wilkins

> Table of Contents > Volume One > 17 - Renal Diseases in Pregnancy

 

 

Agnes B. Fogo

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Effects of Normal Pregnancy on the Kidney

Structural Changes in Pregnancy

1). The calyces and ureters dilate markedly during pregnancy, beginning as early as the seventh week and progressing gradually until term. By 1 week postpartum, these portions of the collecting system return to the prepregnant state in one third of women. In an additional one third, this dilation reverts by 1 month postpartum, and nearly all remaining patients return to normal by 2 months postpartum (2,3). The dilation is nearly always more prominent on the right, possibly because of the abrupt angle of the right ureter as it descends into the pelvic cavity. These changes may be influenced by several factors. The enlarged uterus physically contributes to ureteral compression. The upper ureter also develops increased tone during pregnancy because of hypertrophy of its smooth muscle and hyperplasia of surrounding connective tissue (1,4). These factors may also contribute to UTI by increasing urinary volume within the collecting system and by increased stasis (see Urinary Tract Infections below).

Understandably, there are very limited renal biopsy data from any normal populations without renal disease, and in particular of normal pregnant women. No microscopic morphologic changes are usually observed in the kidney during normal pregnancy (1). A small study of renal biopsies in 12 healthy pregnant controls describes the small lesions of endotheliosis, a term used to describe the characteristic endothelial cell swelling seen in preeclampsia/eclampsia (see below), that may be present even in normal pregnancy. In contrast, a small study in 1960 investigated five healthy pregnant controls, none of whom showed signs of endotheliosis (5). Thus the presence of endotheliosis may not be pathognomonic for preeclampsia; rather, its extent may be what distinguishes the pathologic condition (6).

Functional Changes in Pregnancy

Pregnancy is a volume-expanded condition, with increased circulating volume and interstitial volume and apparent resetting of volume-sensitive receptors to sense this expansion as normal. Thus, in normal pregnancy, blood pressure decreases despite increased volume as a result of decreased peripheral resistance, even though cardiac output increases by 30% to 50% by the end of the second trimester (7). Effective renal plasma flow increases 60% to 80% during pregnancy, with slightly less increase, by about 50%, in the glomerular filtration rate (GFR) (8). Direct micropuncture measurements in animals during pregnancy show moderate renal vasodilatation with similar reduction in resistances of afferent and efferent arterioles; thus, glomerular pressure is not increased (9). Direct measurements of glomerular pressures are not possible in humans. However, functional studies based on dextran sieving in normal and preeclamptic pregnancy have shown that increased filtration in late pregnancy was associated with increases in renal plasma flow and in the ultrafiltration coefficient Kf, whereas in preeclamptic late pregnancy there was a loss of permselectivity with accompanying decreases in Kf and renal plasma flow (10). Functional assessment with computation of Kf was also done in another study of patients immediately postpartum and the second week after birth. Even at postpartum day 1 there was marked glomerular hyperfiltration, with data suggesting that decreased glomerular capillary oncotic pressure was the main determinant of this change. These changes resolved largely by postpartum week 2 with increases in oncotic pressure to supranormal levels, and thus GFR was then only modestly elevated. Theoretical analysis suggested that transcapillary hydraulic pressure and/or increased Kf would have to be present to account for this persistent hyperfiltration (11). In an additional group of pregnant women studied in late pregnancy and 4 months postpartum, increased GFR was contributed to both by increased renal plasma flow and decreased glomerular oncotic pressure, with calculated increased K (12).

Possible hormonal mediators of the gestational increase in the GFR include primary gestational hormones (progesterone). However, progesterone, administered exogenously in pregnant animals, has no direct influence on renal hemodynamics (1). Other candidate vasoactive hormones that may change and affect renal vasodilatation include prostaglandins, the renin-angiotensin system, atrial natriuretic peptide, and endothelin. Conclusive evidence is lacking to implicate specific mediators of altered renal hemodynamics in pregnancy.

Tubular function is also altered during pregnancy. Sodium retention occurs gradually over the course of pregnancy. Although the precise site of action has not been defined, this appears to be due largely to increased distal nephron reabsorption (1). The exact mechanisms underlying the increased retention of sodium have not been delineated, although effects of increased estrogen, placental lactogen, prolactin, growth hormone, desoxycorticosterone, renin-angiotensin, and aldosterone may contribute (7). Effects on potassium are dissociated from these effects on sodium, and tubular potassium loss is not excessive.

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Proteinuria is increased in normal pregnancy, with increase in nondiscriminatory shunt pathways and an upward shift in pore size distribution deduced by dextran-sieving data (). Some investigators have suggested that proteinuria up to 0.3 g/24 hours should be regarded as within normal limits during pregnancy. However, increased proteinuria is also an early sign of preeclampsia. Kincaid-Smith and Fairley (13) have therefore advocated a cutoff for normal proteinuria in pregnancy of 0.15 g/24 hours, similar to that in nonpregnant women. This guideline would direct further investigation of proteinuria beyond this level and would maximize early detection of preeclampsia.

Hematuria occurs frequently in normal pregnancy. In a case-control prospective study of 902 women, 20% had dipstick-positive hematuria on at least two occasions during pregnancy. There was no increased development of preeclampsia, gestational hypertension, or small-for-gestational-age baby in those with versus those without hematuria. Thus, transient hematuria during pregnancy seldom signifies a disorder with likely adverse effects on pregnancy (14).

Glycosuria also occurs commonly in pregnancy and returns to normal within 1 week postpartum (8). This finding appears related to change in tubular function and does not necessarily reflect glucose intolerance. The increased glucose in urine may facilitate development of bacteriuria (see below). Tubular reabsorption of uric acid is decreased early in pregnancy and leads to relative hypouricemia at this stage. In contrast, preeclamptic women show hyperuricemia (see Preeclampsia and Eclampsia, p. 771). Thus, an increased serum uric acid level is a useful indicator of preeclampsia early in pregnancy. However, uric acid reabsorption increases normally in the third trimester, and serum levels then approach or exceed nonpregnant levels (8). Hypercalciuria also occurs commonly in pregnancy, yet urolithiasis is uncommon. This phenomenon may be due to the accompanying increase of nephrocalcin, a protein that can inhibit urinary crystallization (15). Additional factors that contribute to a decreased risk for calcium stone formation in pregnancy include increased citrate and magnesium excretion (7

Urinary Tract Infections (UTI)

 

Significant numbers of bacteria can be found in urine cultures in patients without clear clinical manifestations of UTI. This situation occurs particularly in women and has been called asymptomatic, or covert, bacteriuria (16). Its importance lies in its relation to overt UTI and in particular to the associated risks in pregnancy for the mother and fetus. The prevalence of bacteriuria increases with age in nonpregnant women by approximately 1% per decade (17). In pregnancy, bacteriuria is estimated to occur in 4% to 7% of women (17). This prevalence is comparable to the rate in sexually active nonpregnant women of reproductive age (). Thus, pregnancy does not necessarily predispose to the development of asymptomatic bacteriuria, at least in developed countries (see later this section). Rather, it is possible that detection of this asymptomatic condition is increased during pregnancy.

p. 766) is thought to contribute to the development of upper UTI, because infection localizes to the dilated side in bacteriuric women with unilateral ureteral and calyceal dilation (2,3,). Both increased urine volume within the dilated collecting system and increased urinary stasis (see p. 766) likely contribute to this increased risk of infection.

Increased frequency of asymptomatic bacteriuria is seen with increased sexual activity, parity, sickle cell trait, and diabetes and in women with a history of previous UTI (17,20,21). In one study, compared with a 6% prevalence of asymptomatic bacteriuria in pregnancy in otherwise healthy women, the rate was 12.2% in diabetic women and 18.7% in women with a history of previous UTI (20). Higher rates of bacteriuria are also seen in women in public health clinics compared with women who are patients of private practitioners. The incidence of bacteriuria appears to be increased in both pregnant and nonpregnant women in developing countries compared with developed countries. In a large series from Nigeria (22), bacteriuria was present in 23.9% of pregnant women and in 12.2% of nonpregnant women. These data suggest that bacteriuria is increased in economically disadvantaged patients with limited health care, especially during pregnancy. Whether these data reflect poor personal hygiene, differing environmental or genetic factors affecting bacterial colonization, or limited medical care and less use of antibiotics for other indications in these patients that could perhaps decrease bacterial colonization has not been shown.

3). Although not peculiar to pregnancy, the virulence factors of organisms and the status of the host's uroepithelium are clearly important. At particular risk are patients unable to secrete water-soluble blood group antigens whose uroepithelial cells allow greater adherence of uropathogenic strains of organisms. The modification of cell-bound glycoconjugates with ABH blood group–specific structures is controlled by the Se gene. Patients who lack the Se gene, so-called nonsecretors, have unmodified cell antigens that bind bacterial cell wall components (adhesins) avidly. This matter is fully discussed under Host-Pathogen Interactions in Chapter 22. These patients have a higher incidence and greater

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recurrence rate of UTI (23) and show apparent increased risk of scarring with UTI. In a study of girls with recurrent UTI, 38% of patients with renal scarring were nonsecretors, in contrast to 22% in the control population (24). Thus, secretor status is postulated to influence mucosal resistance to infection.

The altered hormonal milieu of pregnancy could contribute to increased symptomatic infections. In experimental models, estrogen facilitated infection with some pyelonephritic strains of Escherichia coli (25). Pregnancy is a condition of immunosuppression without generalized increased susceptibility to infection (26). However, overall bacteriuria is increased, and organisms of reduced virulence can cause acute pyelonephritis in pregnancy. The importance of the humoral immune response in susceptibility to UTI has been investigated in experimental animal models. Immunodeficient mice have intact resistance to experimental UTI (27), a finding suggesting that the decreased antibody response may not be pivotal in the increased susceptibility of pregnant women to these infections. Failure of an inflammatory response in the Lpsd mouse strain is associated with heightened susceptibility to  UTI (27). Interleukin-6 is especially important in differentiation of immunoglobulin A (IgA)–committed mucosal B lymphocytes, and it is postulated to be crucial in modulating the mucosal inflammatory response. Interleukin-6 levels and antibody activity to antigens from pathogenic E. coli strains were decreased in pregnant women compared with nonpregnant women with acute pyelonephritis (28). The reduced interleukin-6 response in pregnancy to bacteriuria could therefore underlie decreased mucosal inflammation, with resulting enhanced susceptibility to infection.

The most common organism causing bacteriuria during pregnancy is E. coliKlebsiella sp., Enterobacter sp., Proteus sp.). Other reported organisms include Staphylococcus saprophyticus, which promotes stone formation as well. If fastidious organisms such as Ureaplasma urealyticum and Gardnerella vaginalis29).

Asymptomatic or Covert Bacteriuria

Effects on the Kidney

Other kidney abnormalities may develop or may be detected in patients with asymptomatic or covert bacteriuria during pregnancy. First is the issue of underlying structural urologic abnormalities or evidence of chronic pyelonephritis. Pregnant patients with asymptomatic bacteriuria showed a high prevalence of urinary tract abnormalities in a series of patients with urologic studies performed postpartum (30). Ten percent of these patients showed evidence of chronic pyelonephritis (31). In four large series of pregnant women with asymptomatic bacteriuria who were followed for 2 to 14 years (31,32,33,34), bacteriuria was present in 16% to 29% during follow-up, and radiologic evidence of chronic pyelonephritis was seen in 9% to 29%. Many patients had underlying abnormalities, including bifid pelvis and ureteric duplication, and 27% showed signs of chronic pyelonephritis, such as calyceal blunting, diminished cortical thickness, and irregular renal contour. Despite these significant abnormalities, long-term follow-up of patients with asymptomatic bacteriuria during pregnancy has shown only rare cases of deterioration of renal function (31,,33,34).

Assessment of these various series (3132,33,34) is difficult for several reasons. First is the danger of considering bacteriuria of pregnancy a specific complication acquired during pregnancy. The appreciable prevalence of asymptomatic bacteriuria in children and nulliparous women (35,36) raises the possibility that asymptomatic bacteriuria may be present before conception. Sleigh et al (36) found bacteriuria in 8% of 397 nulliparous married women compared with 6.6% of pregnant women. Many girls with asymptomatic bacteriuria have bacteriuria when they grow up and become pregnant. From 40% to 64% of women with a history of asymptomatic bacteriuria during childhood have bacteriuria during pregnancy (3738,39). Further, it is difficult to assess whether asymptomatic bacteriuria is detrimental to kidney function because of the lack of prepregnancy measurements of renal function or serial radiographic studies. In addition, the radiologic abnormalities described in the previous paragraph in many patients with asymptomatic bacteriuria could indicate a predisposition to infection or a consequence of infection, or they may even be unrelated to infection (31,40). Whether the renal scars detected radiologically reflect injury from bacteriuria occurring in adulthood or from childhood UTI also is not clear.

Second is the potential of asymptomatic bacteriuria to cause acute pyelonephritis and its associated complications, including preterm labor, low birth weight, and growth retardation (). The early studies of Kass and Zinner (16,40,42) showed that bacteriuria in pregnancy leads to acute symptomatic infection in 20% to 40% of patients, an outcome confirmed in more recent studies (29,30). Conversely, women without bacteriuria early in pregnancy rarely develop symptomatic urinary tract disease. Successful treatment of bacteriuria largely prevents the development of acute pyelonephritis (17,43). The consequences of symptomatic UTI are discussed below.

Finally, asymptomatic bacteriuria has been associated with increased incidences of preeclampsia and hypertension. Further, preeclamptic women with bacteriuria showed increased proteinuria and hypertension compared with those without bacteriuria (34,44,45). However, treatment of the bacteriuria did not affect the incidence of preeclampsia, a finding that casts doubt on a causal

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link between asymptomatic bacteriuria and preeclampsia (17,34,45).

Effects on Pregnancy

The effect of asymptomatic bacteriuria on pregnancy outcome is controversial. In early studies, Kass () reported higher rates of prematurity in patients with asymptomatic bacteriuria and a decrease in this complication by eradicating the bacteria. Subsequent studies have not uniformly confirmed these initial observations. Although an increased rate of prematurity was found in women with bacteriuria by Kincaid-Smith and Bullen (34), treatment of bacteriuria did not reduce the rate of prematurity, which was believed to reflect the high rate of underlying renal disease in these women. A study by Gilstrap et al (46) found no difference in pregnancy outcome in women with bacteriuria compared with controls. However, a retrospective study showed increased prematurity, intrauterine growth retardation, and low birth weights when pregnancy was complicated by UTI compared with controls (47). A meta-analysis of the relationship between asymptomatic bacteriuria and prematurity or low birth weight found that nonbacteriuric patients had only two thirds the risk of delivering low-birth-weight infants and half the risk of preterm delivery as bacteriuric patients (48). In a review from the Collaborative Prenatal Study, Naeye () found that the apparent relationship between both symptomatic and asymptomatic bacteriuria and low birth weight could be explained by preterm deliveries and fetal growth retardation resulting from underlying renal disease. The authors of this study postulated that asymptomatic bacteriuria was a marker for underlying renal infection and disease that produced a higher risk of delivering preterm and low-birth-weight infants (49

Symptomatic Urinary Tract Infection and Pyelonephritis

Consequences and Complications

The exact extent of the urinary tract that is involved by infection cannot be readily assessed without invasive tests. Therefore, the term symptomatic bacteriuria is used by many authors to encompass both acute pyelonephritis and symptomatic infection of the lower urinary tract. Although risk factors for bacteriuria may overlap with those in asymptomatic infection, as discussed in Asymptomatic or Covert Bacteriuria (p. 768), the consequences differ. In contrast to the uncertain effects on renal function and pregnancy outcome of asymptomatic bacteriuria, as discussed in Asymptomatic or Covert Bacteriuria, symptomatic UTI has well-defined serious consequences during pregnancy. Acute pyelonephritis in pregnancy is associated with bacteremia in 10% and endotoxic shock in up to 3% of patients (50,51).

The ability to predict which patients with asymptomatic bacteriuria will develop symptomatic infection is not established. This inability relates in part to a lack of understanding of the mechanisms that allow asymptomatic bacteriuria to become symptomatic, presumably reflecting upper UTI in most patients. A history of previous symptomatic UTI greatly increases the risk of progressing from asymptomatic to symptomatic infection during pregnancy (52). Possibly, underlying abnormalities, such as reflux, predispose to progression from asymptomatic to symptomatic infections. Despite the dilation of the collecting system that normally occurs in pregnancy, reflux is uncommon, detected in only 0% to 3%, and likely does not play a significant role in the development of symptomatic infection in most patients (53). However, when reflux is present in pregnancy, the incidence of pyelonephritis is higher (54). Acute pyelonephritis complicated 6% of pregnancies in patients with reflux in one series (5556). These findings indicate that reflux cannot be regarded as the only mechanism for development of upper UTI in these patients. It is possible that the apparent greater ease of ascending infection in pregnancy is due to mechanical changes in the setting of altered immunity, and decreased mucosal inflammation also promotes colonization and infection (see p. 767–768).

The importance of preceding asymptomatic infection in the development of symptomatic infection has been clearly demonstrated. Screening programs to detect and treat asymptomatic bacteriuria in pregnancy decrease the incidence of pyelonephritis (57). This effect was shown dramatically by Kincaid-Smith and Bullen (34), who noted a 3.3% prevalence of symptomatic bacteriuria in a treated group of patients with asymptomatic bacteriuria versus a prevalence of 36.6% in a placebo-treated group. Despite treatment, however, one third of women will have recurrence of asymptomatic bacteriuria during pregnancy (see Treatment, below) (58).

The prevention of pyelonephritis during pregnancy has important implications for subsequent pregnancies as well. Patients treated for acute pyelonephritis have frequent occurrences of symptomatic UTI, both later in pregnancies and when not pregnant (). This situation may result from increased susceptibility to repeated infection once parenchymal scarring has occurred. Radiologic findings of chronic pyelonephritis were present at follow-up in 14% to 27% of women who had bacteriuria detected during pregnancy (31,60). Women with renal scars resulting from childhood UTI had a higher incidence of bacteriuria during pregnancy than when scarring was absent (47% versus 27%) (). Patients with renal scars also had a significantly increased relative risk of hypertension and a 7.6-fold increased risk of preeclampsia during subsequent

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pregnancies compared with controls. In contrast, patients without scars had only a slightly increased, but not significant, risk of hypertension during the last trimester even in the presence of reflux (21). However, whether pregnancy affects the course of the underlying condition or merely increases the detection of infection and renal scarring has not been proven.

Symptomatic UTI has serious consequences for the pregnancy as well as for the mother. Prematurity occurred in 20% to 50% of pregnant women with symptomatic UTI (46,62). The fetal mortality rate was 2.4 times the normal rate (47). In a large multicenter prospective study, the perinatal mortality rate was found to be especially increased when infection occurred within 15 days of delivery (49). Production of phospholipase A2 by the infecting organism may contribute to preterm labor by liberating arachidonic acid esters from phospholipids of infected amnionic and chorionic membranes, thus increasing levels of prostaglandin E2 and F2, which can trigger labor (41,63). More recent studies have suggested a role for cytokines induced by infection, such as tumor necrosis factor and cachectin, in preterm labor ().

An additional serious complication of pyelonephritis in pregnancy is the occurrence of pulmonary insufficiency resembling adult respiratory distress syndrome, estimated to occur in 2% to 8.5% of pregnant patients with acute pyelonephritis (65,66,67). In one study, patients with pyelonephritis were particularly at risk for this complication when gestation was beyond 20 weeks, maternal heart rate was more than 110 beats/minute, and body temperature was greater than 103°F for 12 to 24 hours (67). This pulmonary injury may be related to endotoxin, prompted by lysis of bacteria in response to treatment ().

Treatment

Cost-effectiveness and cost-to-benefit analyses have supported screening for and treatment of asymptomatic bacteriuria to prevent pyelonephritis in pregnancy (68). Currently, screening cultures are recommended for all pregnant women, preferably during the 16th gestational week for greatest potential impact on pregnancy outcome. Once asymptomatic bacteriuria is detected and treated, urine cultures should be repeated monthly throughout pregnancy, because as many as one third will have relapse or recurrence during pregnancy (58). If more than one relapse occurs, intravenous pyelography is recommended after 6 weeks postpartum. Urologic evaluation during pregnancy has been recommended if asymptomatic bacteriuria recurs or if appropriate treatment fails to eradicate bacteriuria. Either setting indicates a possible underlying urologic anomaly, obstruction, or abscess that should be treated as promptly as possible to avoid serious consequences for the mother and fetus (18,69). Treatment of pyelonephritis is approached in a similar manner to that in nonpregnant patients.

Hypertensive Disorders of Pregnancy

Hypertension is a common problem during pregnancy. It may be pre-existing, or caused by, or exacerbated by the pregnancy. These complexities have led to difficulties in establishing the causes of hypertensive conditions in pregnancy. Although many classifications have been proposed, this discussion is based on the classification used by Lindheimer and Katz (70), suggested by the American College of Obstetricians and Gynecologists, which divides these disorders into chronic hypertension, chronic hypertension with superimposed preeclampsia, late or transient hypertension, and preeclampsia and eclampsia.

Chronic Hypertension

The most common cause of hypertension during pregnancy is preeclampsia (see p. 771), followed by essential hypertension and secondary causes, among which renal disorders are the most common. In one busy clinical practice (71), 16% of such patients were found to have renal disease. Not surprisingly, populations with a higher general incidence of hypertension also show a higher incidence of hypertension detected during pregnancy. Thus, in a study from South Africa, Black women showed a higher prevalence of hypertension during pregnancy than that seen in other predominantly White populations: 23% versus 7% to 10% (73).

Although pregnant women with mild essential hypertension do have a greater risk of developing superimposed preeclampsia, most of these patients do not experience complications during pregnancy. However, if hypertension in pregnancy is associated with proteinuria greater than 500 mg/day, increased maternal complications and worse fetal outcome are seen (74). Marked proteinuria in preeclamptic patients also predicts a worse prognosis, especially for the fetus (75). Thus, renal insufficiency has developed in 4% of nonproteinuric versus 24% of proteinuric patients with de novo onset of hypertension during pregnancy. It is possible, although not proven, that the worse prognosis in patients with increased proteinuria is related to pre-existing subclinical hypertension-related

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injury. (The effects of nephrosclerosis on pregnancy-related renal disease and preeclampsia are discussed below.)

Poor outcomes and even death may occur when hypertension is secondary to scleroderma, cocaine ingestion, or pheochromocytoma. Fibromuscular dysplasia is a frequent cause of renal artery stenosis in young women, and it should be considered when hypertension precedes pregnancy. An apparent paradox is observed in patients with renal artery stenosis: they may actually have reduced hypertension during pregnancy because altered tubular function in pregnancy leads to less potassium loss and less induction of aldosterone (76). Correction of the stenosis by angioplasty with resolution of hypertension decreases risk of fetal and maternal complications ().

In patients with chronic hypertension without superimposed preeclampsia, most (more than 85%) experience uncomplicated pregnancies. However, birth weights are lower and the perinatal mortality rate is increased in patients with severe hypertension compared with normotensive patients (71). Whether treatment of mild chronic hypertension affects the risks of premature delivery and superimposed preeclampsia is controversial. Methyldopa has been recommended as the drug of choice. The angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, which are widely used in many other settings of hypertension and cardiovascular disease, are contraindicated in pregnancy because of their association with both neonatal acute renal failure and birth defects (76,).

Chronic Hypertension With Superimposed Preeclampsia

Patients with this disorder have underlying hypertension in combination with a further elevation of blood pressure and the appearance of or increase in proteinuria. Edema may also develop. To justify this diagnosis, there must be evidence of chronic hypertension and a superimposed acute process (79). It may be difficult to distinguish the development of preeclampsia from aggravation of the underlying disease. Indeed, in a series of 13 women with pre-existing essential hypertension or renal disease who were suspected of having superimposed preeclampsia clinically, only 7 of the biopsies showed typical changes of preeclampsia (80). Preeclampsia in this population frequently occurs in midpregnancy or early in the third trimester. An acute medical emergency can arise in this setting, and fetal outcome may be jeopardized (70).

Late or Transient Hypertension

Transient hypertension, which usually develops in the last trimester or in the puerperium, typically does not affect the outcome of pregnancy. Blood pressure normalizes within 10 days, but late hypertension may recur in subsequent pregnancies (76).

 

Clinical Findings

Toxemia of pregnancy, including both preeclampsia and eclampsia, occurs in 6% to 7% of pregnant women in the United States (81). The worldwide prevalence varies from 0.05% to 27% (82). True eclampsia, defined as the occurrence of convulsions in association with the signs and symptoms of preeclampsia, was found in nearly 4.9 per 10,000 pregnancies in one study from the United Kingdom (83). This rate is similar to that seen in the United States (4.3 of 10,000) (84), but it is higher than the rate in Sweden (2.7 of 10,000) (85). The rate in the United Kingdom reflects a substantial decrease from 1922, when the incidence was 80 cases per 10,000 pregnancies, likely reflecting increased early recognition of preeclampsia with successful intervention (83). Preeclampsia is primarily a disease of the nullipara and manifests usually after the 20th week of gestation. Before the 20th week of gestation, preeclampsia is most frequently associated with molar pregnancy or its degeneration. When the disease occurs for the first time in multiparas, it is typically associated with multiple-birth gestation, fetal hydrops, pre-existing vascular disease, or renal disease (79). A large study systematically reviewing control studies published from 1966 to 2002 examined unadjusted relative risk for development of preeclampsia based on factors that could be determined at the initial visit. Increased risk of preeclampsia was seen in patients with a history of previous eclampsia, antiphospholipid antibodies, pre-existing diabetes, multiple pregnancy, nulliparity, family history of preeclampsia, increased diastolic blood pressure at initial visit, increased body mass index before pregnancy or even at initial visit, and maternal age of 40 years or older. There was also an increased risk with an interval of 10 years or more since a previous pregnancy, with autoimmune disease, renal disease, and chronic hypertension (86).

Preeclampsia is characterized by hypertension (>140/90 mm Hg or marked increase over baseline), proteinuria, and edema, especially of face and hands. Severity of blood pressure elevation is best evaluated by diastolic pressures. The labile hypertension and altered circadian rhythm of blood pressure in preeclampsia, with higher levels at night, may lead to difficulty in detecting the increased blood pressure if blood pressure is measured only during the day (7). Wide fluctuations in blood pressure, even including the normal range, are thought to reflect increased sensitivity to vasoconstrictors (7). Proteinuria is usually not marked, but the nephrotic syndrome with protein loss of up to 23 g/day has been reported (87,88,). The condition occasionally progresses to a convulsive phase, termed eclampsia, which may be life threatening. Data from the United Kingdom showed that nearly 2% of eclamptic women died, as did 7% of their

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offspring (83). Eclampsia may also develop without an obvious preceding stage of preeclampsia (83). In some patients, hypertension, proteinuria, and convulsions may occur in the immediate postpartum period (so-called “late postpartum eclampsia”). Preeclampsia and eclampsia may occur de novo, or they may be superimposed on pre-existing hypertensive disorders, as mentioned below.

In preeclampsia, the GFR is decreased, but this change may not be detectable because of the preceding normal increase of the GFR seen with pregnancy. Detailed studies have now elucidated further the functional implications of the endotheliosis lesion that characteristically occurs in preeclampsia/eclampsia. Patients with preeclampsia had markedly decreased GFR levels, 91 ± 23 versus 149 ± 34 mL/min/1.73 m2 in normals, whereas renal plasma flow and oncotic pressures were similar to that in normal pregnancy. Combined physiologic and morphometric studies were used to estimate the glomerular ultrafiltration coefficient (Kf) in normal pregnancy and preeclampsia. The decrease of both density and size of endothelial fenestrae and the substantial subendothelial accumulation of lucent material were postulated to lower glomerular hydraulic permeability in preeclampsia. The presence of cellular interposition, i.e., infiltrating cells, usually monocyte/macrophages, interposed between the endothelium and the GBM, also was postulated to contribute to decrease in effective filtration surface area, so that single nephron Kf estimated in this matter was well below control. These changes occurred despite significantly larger glomerular volume in preeclampsia so that actual filtration surface area was reduced to only a minor extent (90). These morphologic findings suggest that structural lesions could be a major contribution to decreased GFR owing to the decrease in Kf and that hemodynamic changes may have less influence than previously thought (91).

Hyperuricemia resulting from decreased clearance predates heavy proteinuria in nearly all cases of preeclampsia. Sodium is retained, contributing to edema. Peripheral resistance and vascular sensitivity to angiotensin II are increased (92). This finding is in contrast to the blunted responsiveness to angiotensin in normal pregnancy (13,93,94). Red blood cell fragmentation may occur even in the absence of the postpartum hemolytic-uremic syndrome (see p. 788). Platelet counts are decreased, whereas Fibrin degradation products and fibronectin levels in plasma are increased, indicative of fibrinolysis and vascular injury (95,). Despite the vascular injury, serum complement levels are usually not different in normal and preeclamptic pregnancies (97). Urinalysis is nonspecific and may show occasional red blood cells, white blood cells, and casts.

Differential Diagnosis

Because the clinical findings of preeclampsia are largely nonspecific, misclassification occurs commonly. Thus, several studies of postpartum renal biopsies in women thought to have preeclampsia clinically showed other renal lesions in as many as half these patients (89,90,98,99). Underlying renal biopsy lesions included chronic glomerulonephritis, tubulointerstitial lesions, membranous glomerulonephritis, sickle cell nephropathy, acute poststreptococcal glomerulonephritis, minimal change nephrotic syndrome, and diabetic nephropathy, in descending order of frequency. In some patients, lesions of preeclampsia were superimposed on specific findings of these renal diseases (80,100). The clinical diagnosis is inaccurate even in a large proportion of primiparas: 25% in one series of patients with clinically diagnosed preeclampsia actually had chronic glomerulonephritis (101). In patients with apparent preeclampsia before the third trimester, an especially high prevalence of underlying disease has been found. When preeclampsia was diagnosed clinically before 37 weeks' gestation, 67% of patients in one study had disease other than preeclampsia, including glomerulonephritis (IgA nephropathy, other mesangial glomerulonephritis, reflux nephropathy, polycystic kidneys, and diabetes) and essential hypertension (102).

The effect of pregnancy on pre-existing renal disease is discussed below on p. 790. These patients represented a population referred for evaluation of possible renal disease postpartum, and many had hematuria. In one study, women with clinical diagnoses of either preeclampsia or gestational hypertension without clinical evidence of underlying disease during pregnancy were evaluated postpartum for evidence of renal disease. This clinical evaluation showed evidence of underlying renal disease in only 7 of the 87 (8%) women with a diagnosis of preeclampsia and in 16 of the 99 (16%) patients with apparent gestational hypertension (72). However, renal biopsy was performed only in the single patient who had hematuria in this series (demonstrating thin basement membrane lesion). Two points emerge from these studies. First, the incidence of underlying renal disease varies among patients with apparent preeclampsia, depending on patient referral and selection criteria. Second, the exact structural lesions underlying renal dysfunction cannot be known precisely in the absence of renal biopsy.

Nonrenal disorders may also be associated with preeclampsia-like syndromes. A case report describes the occurrence of a reversible preeclampsia-like syndrome during pregnancy in a hypothyroid patient (103). Renal biopsy showed enlarged, bloodless glomerular tufts with endothelial cell swelling and mesangial interposition, similar to findings seen in hypothyroidism without pregnancy and to the typical lesions of preeclampsia (see Pathologic Changes, p. 773).

Course and Prognosis

Clinical signs and symptoms of preeclampsia and eclampsia resolve with cessation of pregnancy, typically within

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24 hours of delivery. If the patient is near term, preeclampsia is best treated by induction of labor. If the fetus is immature, treatment with bed rest and sedation may allow continuation of the gestation unless findings of HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome (see HELLP syndrome, p. 785) are present. Intravenous magnesium sulfate is used for impending eclampsia because of its antihypertensive effects and amelioration of central nervous system symptoms of preeclampsia and eclampsia (7). Other treatment strategies focus on antihypertensives and fluid and electrolyte management. However, the basic nature of volume homeostasis in preeclampsia has not been defined. Some investigators view this as a condition with volume overload, whereas others point to evidence of decreased plasma volume in preeclampsia (93). Thus, diuretics and volume expansion have variously been advocated in the treatment of preeclampsia.

Hypocalcemia is observed in preeclampsia, and treatment of preeclamptic patients with calcium contributes to normalization of blood pressure. Prophylactic calcium supplementation also reduced the risk of pregnancy-induced hypertension and preeclampsia by 33% versus a placebo-treated group (104). Increased emphasis on the possible participation of thromboxane and prostacyclin in the pathogenesis of vasospasm and thrombocytopenia has led to several trials of low-dose aspirin for the prevention of preeclampsia. However, a specific, effective prophylactic approach has not been defined, in part because of a lack of understanding of the pathogenesis of preeclampsia.

The consequences of preeclampsia and eclampsia are difficult to assess because of several factors. First, clinical diagnosis of preeclampsia is not accurate, as discussed in Differential Diagnosis (p. 772). Therefore, the long-term consequences of preeclampsia may reflect the course of underlying disease and not the pregnancy-induced injury. Second, clinical parameters are not sensitive indicators of renal injury, and long-term follow-up is necessary to realize fully the impact of an injury on progressive renal dysfunction. Finally, limited renal biopsy studies have been performed. Although definitive diagnosis of preeclampsia can be achieved only with renal biopsy, most clinicians do not advocate this procedure in this setting. To complicate matters further, the timing of biopsies in relation to the preeclampsia-associated injury varies greatly. Furthermore, even normal pregnancies may be associated with mild focal endotheliosis lesions in biopsies (6). With these shortcomings in mind, preeclampsia itself appears to have little deleterious effect on long-term kidney function in most patients. Even heavy proteinuria typically resolves by 3 months postpartum, and the typical glomerular lesion of preeclampsia, that is, endothelial swelling, also appears to be completely reversible (see , below). In contrast, persistent proteinuria, hypertension, and abnormal urinalysis findings beyond 3 months postpartum suggest other underlying renal disease (see Differential Diagnosis) (71). No significant difference in prevalence of chronic hypertension was seen in a large series of White patients with eclampsia in first pregnancies compared with women matched for age and race (105106,107). These investigators concluded that eclampsia and true preeclampsia did not predict or cause hypertension, and women who did develop remote hypertension were those with inherent risks for hypertension, such as positive family history. As noted in Differential Diagnosis, some patients with a clinical diagnosis of preeclampsia actually have underlying renal disease that does not become manifest until pregnancy. This point was illustrated in a study by Gaber and Spargo (108) of vascular changes in patients with preeclampsia. When nephrosclerosis, i.e., sclerosis of vessels and glomeruli, was present in the renal biopsy, 74% of patients had hypertension on follow-up. In contrast, only 9.4% of preeclamptic patients without vascular lesions developed hypertension, not significantly different from age-, sex-, and race-matched control populations. These data were taken to suggest that persistent hypertension after preeclampsia reflected pre-existing disease and was not a consequence of preeclampsia. However, because baseline biopsies are typically not available, this issue has not been directly proved. Limited studies with follow-up biopsies have directly examined the reversibility of renal lesions in preeclamptic patients. In a small study of patients with nephrosclerosis detected in immediate postpartum biopsies, follow-up biopsies revealed persistent arteriolar changes, and four of these patients developed hypertension again in subsequent pregnancies (109). Taken together, these data suggest that arteriolar sclerosis may be irreversible and associated with increased risk for subsequent hypertension. Furthermore, based on the nature of the morphologic changes, the presence of arteriosclerosis or arteriolosclerosis in patients with preeclampsia likely reflects incipient hypertensive nephrosclerosis.

 

Historical Perspective

The glomerular changes of preeclampsia in autopsy specimens were initially described in detail by Löhlein in 1918 () and a few years later by Fahr (111,112). These investigators noted glomerular tuft swelling and expansion of the glomerular capillary wall, resulting in a bloodless appearance of the capillaries and capillary lumen occlusion. Subsequently, Bell (113) suggested that basement membrane thickening was responsible for the capillary occlusion. Sheehan (114) reported an extensive autopsy experience of patients with toxemia who died of apparent incidental obstetric complications. Remarkably, most

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of these autopsies were performed within 15 minutes to 2 hours after death, thereby avoiding artifacts from extensive autolysis (114,115). Sheehan, with only light microscopic studies available, noted glomerular endothelial cell swelling and fibrils between the cells and the basement membranes and postulated that endothelial cell changes accounted for the thickened capillary wall. Dieckmann et al (116) were among the first to examine renal biopsy material in preeclampsia, and they confirmed many autopsy findings. These early light microscopic studies focused on the thickened glomerular capillary wall, thought to represent a thickened glomerular basement membrane. However, not until electron microscopic examination became available were these light microscopic observations further elucidated. Spargo et al (117) and Farquhar (118) demonstrated by electron microscopy that the thickening of the glomerular capillary wall seen by light microscopy was not due to glomerular basement membrane thickening in that the lamina densa of the glomerular basement membrane consistently was normal. However, these ultrastructural studies confirmed the presence of endothelial cell swelling. The term glomerular endotheliosis was coined by Spargo et al for the described lesion. Other investigators confirmed the presence of glomerular endothelial cell swelling (119,120121,122) and also described swelling of the glomerular visceral epithelial cells (121,122123). These deposits and the presence of a translucent subendothelial zone, possibly relating to Fibrin deposition, were described in detail by Kincaid-Smith in 1973 (124). Furthermore, mesangial interposition was recognized to contribute to glomerular capillary wall thickening by Altchek (119) and Ishikawa (125).

Gross Appearance

Judging by the older reports on autopsies in cases of eclampsia, the kidneys show no distinctive changes visible to the naked eye (126). They are of normal size or are slightly enlarged; the cortex is pale and widened in the larger kidneys, whereas the glomeruli can often be seen to be unduly prominent and gray if looked at with a hand lens.

Microscopic Findings

The renal lesions are not substantially different in preeclampsia and eclampsia. The severity of morphologic alterations, which primarily affect the glomeruli, parallels the severity of clinical disease.

Glomeruli.

The glomeruli are diffusely slightly enlarged and swollen and they appear bloodless (Figs. 17.1 and 17.2). In one postmortem study (126), glomerular size was approximately 10% larger than normal. The glomeruli show a characteristic lobular pattern from capillary expansion producing cigar-shaped lobules. The glomerular capillary lumina are narrowed or even obstructed because of marked mesangial and endothelial cell swelling and hypertrophy, so-called glomerular capillary endotheliosis (117). The glomerular capillary loops are dilated, so-called ballooning, particularly at the tubular pole. This may result in herniation of the glomerular tuft into the proximal tubule (so-called pouting; Fig. 17.3) (126). This extension involved about half of the glomeruli in this study (126), with capillary loops extending on average 50 µm into the proximal tubule. Glomerular capillary endotheliosis has been viewed by Gaber et al (127) as pathognomonic for preeclampsia. Although it is well accepted that this lesion is part of the glomerular structural changes in preeclampsia,

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and the fully developed lesion as assessed by light and electron microscopy is characteristic, other lesions also occur in varying proportion, depending on the timing of the biopsy and the severity of the disease. Finally, endotheliosis-like lesions may not be uniquely present in preeclampsia. Normotensive patients with abruptio placentae showed lesions similar to, albeit milder than, those described in this section (128). Furthermore, in a study of renal biopsies performed 8 to 10 days postpartum in 32 women with gestational hypertension without proteinuria or clinical evidence of preeclampsia, 12 biopsies revealed the “specific” pattern of preeclampsia (). A recent small study revealed that even some normal pregnancies may also be associated with small areas of endotheliosis-type lesions (6).

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Glomerulus from a patient with preeclampsia. The tuft is bloodless and appears solidified (so-called endotheliosis lesion.) Features are similar to those in Figure 17.1, but the lesion is more severe. (H&E, ×450.) (Courtesy of Dr. Charles Jennette.)

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Figure 17.3 Glomerulus from patient with preeclampsia showing similar features as in Figures 17.1 and 17.2, as well as herniation of the tip of the swollen glomerulus into the proximal tubule (so-called pouting), which is a characteristic but not specific feature of preeclampsia/eclampsia. (Jones silver stain, ×400.) (Courtesy of Dr. Charles Jennette.)

Glomerular cellularity may be normal or slightly increased with only rare, or no, neutrophils. Mesangial and endothelial cell vacuolization with accumulation of fluid and lipid is visualized well on osmium-fixed toluidine blue–stained thick sections (99). The foamy, bubbly appearance of glomerular endothelial, or to some extent mesangial, cells, or even cholesterol clefts at later stages, may relate to severe proteinuria (Fig. 17.4117). Fibrils within swollen glomerular endothelial cell cytoplasm adjacent to the basement membrane may be visualized (114,115). Mesangial cells and matrix may be mildly increased, and processes may extend between the glomerular basement membrane and endothelium (mesangial interposition). Mesangial interposition is especially prominent in more severe disease and in the healing stage (124,126,130). Glomerular visceral epithelial cells are swollen and prominent and may contain hyaline droplets that are positive for periodic acid–Schiff stain (Fig. 17.5). Crescents are seen only in the most severe cases of preeclampsia and eclampsia (115,126).

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Glomerulus from patient with preeclampsia revealing a pronounced bubbly appearance in the consolidated areas, caused by swollen endothelial cells and podocytes (PAS, ×400.) (Courtesy of Dr. Vivette D'Agati.)

The glomerular capillary wall is thickened. Its components may be distinguished by the Alcian blue/periodic acid–Schiff stain, which stains the glomerular basement membrane magenta and the cytoplasm blue. Silver stain may show a double contour, in part because of the interposition of mesangial cell cytoplasm processes (Fig. 17.6) (124). Glomerular basement membrane remodeling is associated with increased staining for laminin, type IV collagen, fibronectin, and proteoglycan (131). Although an early study suggested the presence of increased juxtaglomerular cells in preeclampsia (81), carefully performed studies

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from biopsy material have revealed no distinct changes of the juxtaglomerular apparatus (132).

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Figure 17.5 Glomerulus from patient with preeclampsia revealing similar lesions as above in Figure 17.4 and segmental hyaline droplets in the podocytes (H&E, ×400.) (Courtesy of Dr. Vivette D'Agati.)

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Figure 17.6 Glomerulus from patient with preeclampsia showing widespread glomerular basement membrane splitting, revealed by electron microscopy (see Figs. 17.16 and 17.17) to be due to interposition and increased lamina rara interna. (Jones silver stain, ×1000.) (Courtesy of Dr. Vivette D'Agati.)

Time Course of Glomerular Lesions.

Endotheliosis, as described and coined by Spargo et al (117), has often been regarded as the pathognomonic feature of preeclampsia. However, depending on the timing of the biopsy, other features may also be prominent. Various series have shown remarkable differences in frequency of detection of glomerular subendothelial deposits of fibrin or fibrinoid material (88,117,121,123,124,128,130). The analyses of Kincaid-Smith (130) of the evolution of lesions during pregnancy and postpartum indicate that these fibrinlike deposits may disappear quickly postpartum. Subendothelial deposits are most consistently present in biopsies done during the first few postpartum days (130). Rapid fibrinolysis can occur, and thus fibrin would be less likely to be present after delivery and resolution of the preeclamptic injury cascade. Focal thrombotic microangiopathy may also be present in clinically severe cases of preeclampsia or full-blown eclampsia, mirroring the severity of the disease (Figs. 17.7 and 17.8).

Similarly, the extent of foam cells is correlated with the timing of biopsy. In postpartum biopsies as studied by Spargo et al (117), glomerular endothelial and, to a lesser extent, mesangial foam cells are nearly universally present as part of the endotheliosis lesion, a finding confirmed by Seymour et al (13313) and the extensive autopsy experience of Sheehan (114) documented only sparse foam cells. After the immediate postpartum period, cellular edema was reduced, whereas endothelial proliferation and increased mesangial cells persisted (134). Basement membrane duplication also appears to resolve rapidly after pregnancy, although these changes may persist for months in some cases (,130). Focal segmental glomerulosclerosis occurs in some cases and is discussed on page 778.

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Figure 17.7 Glomerulus from patient with severe preeclampsia revealing endotheliosis lesion and segmental early thrombotic microangiopathy. (Jones silver stain, ×400.) (Courtesy of Dr. Vivette D'Agati.)

Tubulointerstitium.

Tubulointerstitial changes are nonspecific. Atrophy of tubules and interstitial fibrosis parallel glomerular sclerotic changes. Proximal tubules may show protein reabsorption droplets and lipid droplets (99). Casts are found, particularly in collecting ducts, and some contain hemoglobin and stain for iron.

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Figure 17.8 Glomerulus from patient with severe preeclampsia/eclampsia revealing endotheliosis lesion and extensive severe thrombotic microangiopathy (H&E, ×400.) (Courtesy of Dr. Vivette D'Agati.)

Blood Vessels.

Renal biopsies contain limited samples of large vessels, and the vascular changes observed in biopsies from preeclamptic patients are usually nonspecific. Multiple mechanisms may contribute to the lesions. Medial hypertrophy of renal and extrarenal interlobular arteries and arterioles in preeclampsia (98) may result from increased sensitivity to vasoactive substances such as angiotensin II (see Clinical Findings, p. 771p. 779) (82,108,127). This lesion of intimal sclerosis of arteries or arterioles was found in approximately one third of patients with pregnancy-related hypertension and in 10 of 14 patients with known hypertension or renal disease before pregnancy (98). Vascular lesions of malignant hypertension were found in some patients with pre-existing renal disease and severe toxemia resulting in death, although hypertension was not at malignant levels clinically (135,136). These data could be taken to indicate that more severe toxemia occurs with more severe pre-existing vascular lesions. On the other hand, severe vascular lesions of apparent “malignant hypertension” in these early reports may have been related to thrombotic microangiopathy (Fig. 17.9), discussed briefly on page 776 and in Kincaid-Smith and Fairley (13). Severe vascular lesions, including possible vasculitis and thrombosis, can also occur when antiphospholipid antibodies are present (see p. 794).

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Figure 17.9 Patient with severe preeclampsia and glomerular endotheliosis lesion with severe arteriolar lesion with fibrinoid necrosis and intraluminal fibrin. (H&E, ×400.) (Courtesy of Dr. Vivette D'Agati.)

Electron Microscopic Findings

Early biopsy studies with electron microscopy shed light on the precise cellular abnormalities in preeclampsia (81,117,118,121,137). Swelling of glomerular endothelial cells and, to a lesser extent, of mesangial cells is a prominent feature (Figs. 17.10 and ). Lysosomes may be present in both cell types. Mesangial cells and matrix are increased, and mesangial cell interposition contributes to glomerular capillary wall thickening. Vacuolization, droplets, cytoplasmic strands, lipid, dense bodies, myelin figures, and increased numbers of cell organelles can be seen in both glomerular endothelial and mesangial cells (Fig. 17.12). Glomerular epithelial cell vacuolization and swelling are also frequent (13121,122). Foot process effacement is seen only focally, and it does not appear to correlate with the degree of proteinuria (88). Epithelial cell droplets were shown by immunoelectron microscopy to contain immunoglobulin complement, fibrinogen, and larger amounts of albumin (130). Lipid droplets, both extracellular and intracellular, can be present.

Glomerular subendothelial and occasional mesangial vague densities are present, depending on the timing of biopsies (Figs. 17.13 and 17.14). The material can appear fibrillar, as more or less localized dense deposits, or as granular deposits. In severe cases, fibrin tactoids may be present in glomerular subendothelial areas, the mesangium, and, rarely, the urinary space (Fig. 17.15) (98,99). Most investigators have identified fibrillar fibrin within dense glomerular subendothelial deposits (13,98,99,130,133,138139). Fibrin- or fibrinogen-related breakdown products, fibronectin, and matrix components localized to these areas immunohistochemically (131,138130).

The lamina densa is not increased in thickness. The glomerular basement membrane shows increased lucency of the lamina rara interna. Thus, by electron microscopy, several elements are seen to contribute to the thickened glomerular capillary wall and reduplication of basement membrane seen by light microscopy: endothelial cell swelling, mesangial cell interposition with new basement membrane formation (Fig. 17.16), and an increased lucent zone of the lamina rara interna (Fig. 17.17

Immunofluorescence Findings

In early studies, Pirani et al (121) and Thomson et al (128) proposed that subendothelial deposits were derived from fibrinogen. Demonstration of fibrin or fibrinogen by immunofluorescence further provided support for abnormal intravascular coagulation in studies by Vassalli et al (138) and by Fiaschi and Naccarato (134) (Fig. 17.18). Immunofluorescence showed IgM and fibrinogen staining of

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mesangial and glomerular capillary areas and arterioles in most patients (24 of 36), with an additional few patients showing staining with either antisera. Occasional biopsies stained with IgA, IgG, or complement components C3 and C1q, mainly in mesangial areas (98,133,140). Glomerular staining for fibrinogen and fibrin was more pronounced in biopsies taken within the first 2 weeks postpartum, although immunofluorescence positivity and deposits were occasionally observed as late as 2 months after delivery (134,138), with no staining at 3 months in one series (140). The relatively rare dense deposits visualized by electron microscopy support the concept that the immunofluorescence staining represents insudation or hyalin with varying degrees of fibrin-related products rather than immune complexes.

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Figure 17.10 Electron micrograph from a 19-year-old woman with eclampsia. The capillary lumen is decreased secondary to swelling of the endothelial cell (END.) The intercapillary cell mass, including mesangium (MES), appears increased, and there is an increase in amorphous material along the inner surface of basement membrane, especially in the region of the intercapillary cell mass. Epithelial cell (EPITH) changes are mild, except for occasional large blebs showing almost no filamentous matrix or cytoplasmic particulates. (Transmission electron microscopy ×9000.) (Courtesy of Dr. Ben Spargo.)

Prognostic Markers

Typical glomerular lesions of endotheliosis are reversible over weeks to months without permanent sequelae. The duration of hypertension after delivery correlated with the severity of glomerular lesions, but not with vascular, i.e., arteriolar/arterial, lesions in a series of 20 cases of preeclampsia. All of these patients became normotensive within 3 months, and proteinuria disappeared (141). The presence of additional vascular lesions may signify a worse renal prognosis. Vascular lesions of arteriosclerosis or arteriolosclerosis in patients with preeclampsia are associated with a high incidence of chronic hypertension (see Course and Prognosis, p. 772) (88,99). The presence of these vascular lesions should arouse suspicion that the patient has essential hypertension, and persistent hypertension and an increased risk of renal insufficiency therefore likely reflect the natural history of this underlying condition.

Focal Segmental Glomerulosclerosis Lesions in Preeclampsia

Idiopathic focal segmental glomerulosclerosis associated with the nephrotic syndrome is discussed in Chapter 5. The effect of this disease on pregnancy and vice versa

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is discussed under Specific Renal Disease and Pregnancy (p. 793). However, the lesion of focal and segmental glomerulosclerosis occurs as a manifestation of nonspecific chronic injury in many settings. The significance of this focal and segmental lesion of glomerulosclerosis in pregnancy is controversial. Although the lesion itself has been well described, its relation to preeclampsia or other underlying mechanisms has been debated. Several reports indicate that focal and segmental hyalinosis and glomerulosclerosis may occur de novo during pregnancy with preeclampsia (Fig. 17.19) (108,,143,144,145,146). These lesions of glomerulosclerosis in pregnancy with preeclampsia resemble those of the cellular lesion of idiopathic focal and segmental glomerulosclerosis. Sclerotic segments of the glomerulus show adhesions with segmentally collapsed capillaries and wrinkled glomerular basement membranes. Overlying glomerular visceral epithelial cells show hyperplasia and frequent vacuoles. Furthermore, some of the subendothelial dense or granular deposits observed in preeclampsia are virtually indistinguishable from the hyalinosis seen in conjunction with idiopathic focal and segmental glomerular lesions in the nephrotic syndrome. Segmental sclerosis involves appreciable numbers of glomeruli, 28% to 62% in one study and 10% to 50% in another (143,146).

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Figure 17.11 Electron micrograph of the same case as in Figure 17.3 showing a prominent mesangium separating two areas of highly vacuolated endothelial cells. Other features are described in Figure 17.3. END, endothelial cell; EPITH, epithelial cell; MES, mesangium. (Transmission electron microscopy ×9000.) (Courtesy of Dr. Ben Spargo.)

Difficulties arise in establishing a causal link between preeclampsia and biopsy lesions because of the imprecision of the clinical diagnosis of preeclampsia, the variable timing of biopsies, and the lack of prepregnancy or follow-up data. Gaber and Spargo (108) have suggested that lesions other than endotheliosis represent pre-existing disease processes other than preeclampsia. These investigators studied renal biopsies performed on average 8 days postpartum from 20 patients with severe preeclampsia characterized by marked hypertension, proteinuria, and edema. Focal segmental sclerosis was present in seven patients, five of whom also had arteriosclerosis. The authors suggested that the focal sclerosis related to underlying nephrosclerosis and not to preeclampsia. They further suggested that the prognosis would be that of patients with preeclampsia with underlying nephrosclerosis, 74% of whom develop persistent hypertension. Unfortunately,

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no follow-up was reported for the patients in this series to explore this hypothesis further.

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Figure 17.12 Electron micrograph shows a glomerular intracapillary cell with numerous empty spaces from an 18-year-old patient with preeclampsia. New basement membrane formation is also apparent. (Transmission electron microscopy ×4656.)

In another series of preeclamptic patients with focal

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segmental glomerulosclerosis (145), 2 of 13 showed frequent hyaline arteriolosclerosis, a lesion that does not itself indicate pre-existing nephrosclerosis (127). Milder arteriolar lesions were seen in four additional cases. Vascular lesions were less pronounced in a control group of six patients with typical preeclampsia lesions without segmental glomerulosclerosis lesions. However, seven patients with focal segmental glomerulosclerosis did not have arteriosclerosis, in contrast to the findings of Gaber and Spargo (108). In another study of eight patients with focal segmental glomerulosclerosis and preeclampsia (144), none showed intimal fibroplasia, again supporting the concept that vascular disease does not account for the development of these glomerular lesions. Nochy et al (,146) found the focal segmental glomerulosclerotic lesion in patients with preeclampsia who did not have pre-existing hypertension or proteinuria before pregnancy. Further interesting evidence supports the concept that glomerulosclerosis may be part of the spectrum of injuries induced by preeclampsia. A patient with repeated hypertension during her pregnancies had an initial renal biopsy with only typical changes of preeclampsia and no vascular lesions, followed by a later biopsy with focal segmental glomerulosclerosis (98).

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Figure 17.13 Electron-dense material on the endothelial side of glomerular basement membrane (upper part of picture.) (Transmission electron microscopy ×6500.) (Courtesy of Dr. Mary MacDonald.)

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Figure 17.14 Fibrillar electron-dense material on the endothelial side of basement membrane. (Transmission electron microscopy ×31,000.) (Courtesy of Dr. John Lee.)

Patients with preeclampsia and additional focal segmental glomerulosclerosis differ in several respects from those who have only preeclampsia. In a large study by Nochy et al (146), renal biopsies obtained 8 to 10 days postpartum were analyzed. In all 42 women with a clinical diagnosis of preeclampsia, the typical morphologic lesions described in Pathologic Changes (p. 773) were present: endothelial cell swelling, double contour of the glomerular basement membrane, and occasional glomerular subendothelial

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deposition of IgM and fibrin (146). Superimposed focal segmental glomerulosclerosis was present in 19 of these 42 women. The patients in this group more commonly were multiparas and had more severe hypertension, and nearly all presented with the nephrotic syndrome (18 of 19 versus 5 of 23 among women without these lesions). Despite these findings suggesting more severe injury, all patients had resolution of proteinuria within 3 months of delivery, and only one patient showed persistent hypertension during the follow-up period.

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Figure 17.15 Mesangial and endothelial cell swelling, subendothelial densities, and fibrin tactoids in a glomerulus from a patient with severe preeclampsia. The biopsy was performed 5 days postpartum. (Transmission electron microscopy, ×8330.)

145). Renal biopsies were performed on average 18 days after delivery. Typical changes of preeclampsia were present in all biopsies:

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moderate endothelial swelling, circumferential mesangial interposition, and increased lucency of the lamina rara interna. In addition, focal segmental glomerulosclerosis with occasional hyaline deposits and increased glomerular visceral epithelial cell droplets were observed in 13 of the 19 patients. These lesions involved on average 20.7% of glomeruli (range, 3.1% to 56.5%), the extent of sclerosis correlating with duration of marked proteinuria after delivery. These sclerotic lesions were not restricted to the urinary pole, but also occurred at the vascular pole and at

intermediate glomerular locations. Proteinuria disappeared in all patients after pregnancy, although it persisted longer in patients with focal segmental glomerulosclerosis (5.7 versus 2.3 months). One patient with a second biopsy showed less severe glomerular and vascular lesions than in the first biopsy. Remarkably, in three patients, no proteinuria or hypertension developed during a second pregnancy, including the patient with the most extensive glomerulosclerosis. These studies show that focal segmental glomerulosclerotic lesions are not infrequent among preeclamptic women who undergo renal biopsies, and these lesions do not necessarily impart a poor prognosis (Table 17.1). Thus, these patients with preeclampsia and focal segmental glomerulosclerosis did not show the striking increase of hypertension at long-term follow-up seen in patients with nephrosclerosis and superimposed preeclampsia, nor did they show the progressive renal failure typical of idiopathic focal segmental glomerulosclerosis.

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Figure 17.16 Glomerulus from a patient months after severe preeclampsia. The numerous double contours seen by light microscopy are revealed to be owing to interposition and increased lamina rara interna. (Transmission electron microscopy ×4000.) (Courtesy of Dr. Vivette D'Agati.)

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Figure 17.17 Glomerulus from a patient months after severe preeclampsia. There is marked increased lamina rara interna, which contribues to the split appearance of the GBM by light microscopy. (Transmission electron microscopy ×7000.) (Courtesy of Dr. Vivette D'Agati.)

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Figure 17.18 Glomerulus from a patient with preeclampsia showing positive fluorescence with antiserum to fibrinogen. The distribution is along the inside of the capillary walls. (Courtesy of Dr. R. T. McCluskey.)

Table 17.1 Frequency and course of glomerular lesions associated with preeclampsia

Lesion

Frequency

Course

Endotheliosis

Invariable

Reversible over weeks to months

Foam cells

Rare peripartum, more frequent postpartum

Resolve

Subendothelial deposits

Frequent peripartum

Electron microscopic deposits resolve over first week, Ig staining resolves over 2–3 months

Glomerular basement membrane reduplication

More common in severe disease

Usually resolves rapidly, may persist for months

Fibrin or related products

Rare by light microscopy; frequent by electron microscopy and immunofluorescence

Resolution over weeks

Focal segmental glomerulosclerosis

Variable:

  35% (7/20, ref. 108)

  45% (19/42, ref. 146)

  71% (13/19, ref. 145

Not clinically progressive

Several studies have investigated possible mechanisms contributing to this injury. Factors associated with progressive glomerulosclerosis include abnormal glomerular hemodynamics and abnormal glomerular growth factors that may manifest as abnormal glomerular enlargement. Morphometric analysis of preeclampsia-associated lesions of focal segmental glomerulosclerosis showed markedly increased glomerular size (129). In contrast, only moderate increase in glomerular size was seen in biopsies from patients with early gestational hypertension or preeclampsia without glomerulosclerosis. In another morphometric study (144), mesangial volume fraction was increased remarkably in patients with classic lesions of preeclampsia and focal segmental glomerulosclerosis compared even with primary focal segmental glomerulosclerosis or normal pregnancy. These data support the concept that abnormal glomerular growth and matrix expansion are prominent in preeclampsia-associated focal segmental glomerulosclerosis.

In summary, although the studies described in this section do not allow definite conclusions regarding the relation of preeclampsia to the focal segmental glomerulosclerosis lesion, some points can be made. The occurrence of apparent de novo focal segmental glomerulosclerosis associated with pregnancy supports a contribution of pregnancy or preeclampsia in their evolution. Furthermore, these focal and segmental glomerulosclerotic lesions in preeclampsia do not represent those of typical idiopathic focal segmental glomerulosclerosis, in which persistent nephrotic syndrome or proteinuria and progression of lesions occur. Most of these patients have a benign outcome at long-term follow-up. In contrast, patients with underlying nephrosclerosis have a high incidence of persistent hypertension after pregnancy (see Course and Prognosis, p. 772). Thus, these findings do not support the concept of underlying nephrosclerosis as a mechanism for the development of glomerulosclerotic lesions in preeclamptic patients. Although the long-term prognosis for this group of patients appears good, the presence of preeclampsia with focal segmental glomerulosclerosis lesions certainly represents more severe acute injury. Possibly, these severe lesions occur selectively in preeclamptic patients with pre-existing subclinical renal disease. On the other hand, the increased proteinuria, more severe hypertension, higher incidence of various vascular lesions, and, of course, the focal segmental glomerulosclerosis lesion itself may all represent a more severe manifestation of preeclampsia. The severity of endothelial injury combined with individual susceptibility could contribute to the wide spectrum of glomerular changes seen in preeclampsia. Endothelial injury, altered thrombotic mechanisms, hemodynamic factors, and growth or matrix-promoting factors are altered

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in preeclampsia-induced injury and could contribute to the evolution of segmental sclerotic lesions in preeclampsia.

HELLP Syndrome

The HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome is viewed by some investigators as part of a continuum that includes preeclampsia and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (147,148). This term was initially proposed by Weinstein (149) to describe this catastrophic complication of preeclampsia. The HELLP syndrome may develop rapidly, with progression in hours from an apparently benign condition with minimal abnormalities to a catastrophic illness. Patients may have life-threatening disease with mild (30%) or even absent (20%) hypertension and may not have proteinuria (148). The incidence of HELLP syndrome among patients with preeclampsia ranges from 4% to 18.9% (150). Patients usually present with nonspecific malaise, right upper quadrant pain, nausea, vomiting, and headache, or they may have various degrees of jaundice, gastrointestinal and gum bleeding, and hematuria. Laboratory findings are defined by the syndrome's acronym. Although HELLP syndrome typically occurs early in pregnancy, occasional patients may present postpartum.

Prognosis

This condition is life threatening because of the marked coagulation abnormalities, hemolysis, and serious abnormalities of liver function. Prompt termination of the pregnancy is necessary to save the mother's life (76,147,148). In a large series of 442 pregnancies with HELLP syndrome, maternal mortality was 1.1%. Perinatal mortality ranged from 7.7% to 60%, depending on the severity of the maternal complications and the degree of prematurity, and was increased in pregnancies with acute renal failure (150,151).

Long-term prognosis after HELLP syndrome with resulting acute renal failure was studied in 32 patients. Women with postpartum HELLP syndrome had higher incidence of acute renal failure than those presenting antepartum: 12% versus 5% (148148). These data indicate a poorer prognosis for subsequent pregnancy when HELLP syndrome occurs with pre-existing hypertension.

Etiology and Pathogenesis of Preeclampsia and Eclampsia

General

Recent data have suggested novel mechanisms in preeclampsia/eclampsia. We will focus on those related to the angiotensin type 1 receptor (AT1) agonistic antibodies, and to vascular endothelial growth factor (VEGF), and how these mechanisms may interact with placental alterations in preeclampsia.

Placental Mechanisms

Placental vascular abnormalities were recognized over 60 years ago in preeclampsia and eclampsia (152). Several obstetric conditions, such as hydatidiform mole, multiple-gestation births, and hydrops, and medical conditions such as diabetes and hypertension are associated with increased risk of preeclampsia. A possible common underlying feature is placental hypoperfusion related to underlying vascular injury. In normal pregnancy, cytotrophoblasts invade the endometrium and myometrium and penetrate the spiral arteries. The endothelial lining and most of the muscle layer of these spiral arteries are destroyed, contributing to their capacity to vasodilate during gestation. This remodeling process is dependent on phenotypic switch of cytotrophoblasts, a process referred to as pseudovasculogenesis (153154). The end result is faulty cytotrophoblast invasion of the decidua, with resulting shallow invasion that breaches fewer arterioles. Reduced trophoblastic invasion may be a pivotal injury leading to the cascade of events culminating in full-blown eclampsia. This initial failure to invade results in a hypoxic environment that further inhibits cytotrophoblast differentiation and invasion, thus perpetuating a deleterious feedback mechanism that sets the stage for later pregnancy complications such as preeclampsia (155). The result is acute atherosis of the placenta, which is characterized by fibrin deposition along the intima and fibrinoid necrosis and foam cell invasion of the media of the spiral arteries. These lesions lead to thrombosis and infarctions of and reduced blood flow to the uterus and placenta.

Endothelial injury is the most constant morphologic finding in renal biopsies of preeclampsia. Injured endothelium can result in altered elaboration of or sensitivity to vasoactive substances, increased thrombotic activity, and vascular permeability. Normal pregnancy is a condition with enhanced thrombotic and fibrinolytic activities, which typically return to normal prepregnant states within an hour after placental delivery (156). This balance of

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thrombosis and fibrinolysis is shifted further toward thrombosis in preeclampsia. Fibrin degradation products and beta-thromboglobulin are increased and thrombin activity is enhanced, whereas antithrombin levels are increased and platelets are decreased (156,157). Fibronectin and factor VIII antigen blood levels, known to be released from injured endothelial cells, are also increased in preeclampsia (156). A cascade of endothelial injury initiated by the injured trophoblasts has been hypothesized. The injured trophoblasts are proposed to release a factor into the systemic circulation that induces sublethal endothelial cell injury, resulting in low-grade intravascular coagulation, loss of normal permeability barrier, and increased sensitivity to pressors, culminating in the clinical syndrome of preeclampsia (156,158). Studies of cytotoxic effects of serum from preeclamptic women support this hypothesis: Cultured human endothelial cells showed greater injury when exposed to sera from preeclamptic women than sera from the same patients within 48 hours after delivery or from normal women before or after delivery (156). Recent data suggest that the soluble form of the VEGF receptor, sFlt-1, may be the elusive intermediary factor linking placental and renal injuries in VEGF, preeclampsia/ eclampsia (159,160161,162).

VEGF and Its Receptor sFlt-1

VEGF-A is a primary growth factor for endothelial cells and is produced in the glomerulus exclusively by the podocytes (163). Vascular factors such as VEGF and the angiopoietins are essential for glomerular endothelial cell growth, and VEGF is needed for maintenance of fenestrae (163,164). Thus, the kidney might be particularly susceptible to loss of VEGF, as the fenestrated endothelium is essential for normal glomerular function. VEGF is also implicated in the vascular remodeling that occurs when cytotrophoblasts convert from an epithelial- to an endothelial-type phenotype and invade maternal spiral arteries. This process is defective in preeclampsia, and the resultant ischemia is proposed to induce systemic endothelial dysfunction (162159). Indeed, this increase of sFlt-1 in preeclamptic patients was associated with decreased circulating levels of free VEGF and PlGF, to levels that may be below those required to maintain normal endothelial function. Experimental evidence proved the causality and clinical relevance of these alterations. Exogenous administration of sFlt-1 to pregnant rats induced hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia (160). Additional studies using podocyte-specific manipulation of VEGF-A showed that deletion of just one VEGF allele resulted in proteinuria and endotheliosis in mice. These studies thus demonstrate specifically that relative lack of VEGF could result in the endotheliosis lesion (163). The key initiating events that could up-regulate sFlt-1 expression in the placenta in preeclampsia have not been determined. The possibility of an interaction of AT1 receptor agonistic autoantibodies (see below) in contributing to this initial ischemic step is interesting, but has not been proven.

Renin-Angiotensin System

The renin-angiotensin system has long been studied in diseases manifesting hypertension, but observations that plasma renin activity and angiotensin II levels frequently are not increased in preeclampsia had led to less enthusiasm for a primary role of this pathway in its pathogenesis. However, recent exciting evidence has demonstrated the presence in many, albeit not all, preeclamptic patients of an IgG autoantibody that stimulates the angiotensin type 1 (AT1) receptor, presumably by altering conformation of the receptor and increasing its ability to bind circulating angiotensin II (165,166,167). The AT1 receptor transduces classic angiotensin actions, including vasoconstriction, aldosterone secretion, and growth and matrix synthesis. In addition to these agonist antibodies to the AT1 receptor, AT1 receptors may dimerize or heterodimerize with the bradykinin B2 receptor, resulting in enhanced angiotensin II responsiveness (168,169). The presence of this AT1 agonistic autoantibody was also linked to increased secretion of plasminogen activator inhibitor-1, PAI-1, a key modulator of fibrinolysis and proteolysis through its actions to inhibit tissue-type and urokinase-type plasminogen activators (t-PA, u-PA) (170). PAI-1 is increased in normal pregnancy, but increased even further in patients with preeclampsia, correlating with severity of placental damage (171). PAI-1 could also theoretically affect trophoblast invasion by preventing proteolysis and fibrinolysis (171). Interaction of these AT1 agonistic antibodies with the VEGF system has also been suggested. Thus, VEGF-mediated angiogenesis can be decreased with AT1 receptor blockers (166,172). The specific events that stimulate such autoantibodies have also not been defined (161).

Other Vasoactive Substances

Vasoactive substances are altered in preeclampsia. Although women with normal pregnancies show refractoriness to the pressor effects of infused angiotensin II, in preeclampsia the responsiveness is more similar to, or even increased over, that of nonpregnant women, perhaps reflecting agonistic AT1 autoantibodies (see above) (94,173).

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Other vasoactive substances may also contribute to the abnormal vasoconstriction in preeclampsia. Despite decreased plasma volume in preeclampsia, plasma atrial natriuretic peptide levels are elevated. Furthermore, women with preeclampsia have reduced prostacyclin and thromboxane excretion. In a study of severe preeclampsia, these mediators were correlated inversely with plasma creatinine and plasma renin (173). Endothelin levels were reported increased in women with preeclampsia and were correlated inversely with creatinine clearance (). However, another study failed to show increased endothelin activity in preeclampsia, and placental tissue mRNA levels for endothelin precursors were not increased compared with those in normal pregnancy (175). Additional studies have shown decreased density of umbilical artery dopaminergic receptors in preeclampsia, possibly contributing to impaired dopaminergic vasodilatory tone (176).

Immune Complex Mechanisms

Previously, immune mechanisms were sought in preeclampsia. Glomerular and vascular IgM deposits are present, as discussed in Pathologic Changes (p. 773). Circulating antilaminin antibodies have been detected in some preeclamptic patients (177). Circulating soluble immune complexes are not detected in preeclamptic patients (97).

 

The risk of preeclampsia is increased in nulliparous women with an affected mother or sister, fourfold and sixfold, respectively (178). This familial aggregation of preeclampsia has suggested a contribution of genetic factors. Interestingly, the risk of preeclampsia was increased in offspring from either men or women who were the product of a pregnancy complicated by preeclampsia, suggesting both maternal and paternal genetic contributions (179178). Underlying genetic factors likely also contribute to increased risk of preeclampsia in patients with underlying hypertension of renal disease. However, these conditions likely reflect polygenic traits for which precise risk and genetic basis are difficult to define. Studies of mutations of the renin-angiotensin system genes have shown linkage of a polymorphism of the angiotensinogen gene to preeclampsia in some patients. This polymorphism may have direct functional consequences in that the mutation resulted in increased reaction efficiency of angiotensinogen with both renin and angiotensin-converting enzymes (180). An increased prevalence of another angiotensinogen polymorphism, T235, was suggested in a series of 41 preeclamptic primigravidas (181), although this association was not seen in another smaller series ().

Numerous genes involved in the regulation of blood pressure or coagulation have been investigated to search for polymorphisms or mutations in preeclamptic women, without any conclusive evidence of such an effect (see above). However, a locus on chromosome 2p13 showed significant association with preeclampsia in a genome-wide scanning study of Icelandic families, confirmed in a study of patients from New Zealand and Australia (162). This site was distinct from that associated with linkage with the HELLP syndrome, localized to chromosome 12q. Importantly, this locus is distinct from the Flt-1 locus at 13q12. Of note, mothers carrying fetuses with trisomy 13 do interestingly show a higher incidence of preeclampsia than other trisomies, suggesting that perhaps overexpression of Flt-1 could be related to this trisomy 13. However, direct data, such as sFlt-1 levels, to further explore this hypothesis, were not obtained (183,184).

Acute Renal Failure in Pregnancy

The incidence of pregnancy-related acute renal failure varies worldwide according to the level of obstetric care. In industrialized countries, acute renal failure has become rare, occurring in an estimated 1 in 20,000 deliveries (). In contrast, in South Africa, despite advances in care, the incidence remains high in the indigent population. In 1978, acute renal failure occurred in 1 in 450 deliveries, improving to 1 in 1000 in the 1990s (186), primarily because of a decrease in septic abortions in that country (see Septic Abortion, p. 788). Similar prevalences of pregnancy- and abortion-related acute renal failure were reported from India and Argentina (185,187).

Acute renal failure may occur for any reason during pregnancy, including reasons not specific for pregnancy (188). Among 57 pregnant women with acute renal failure, causes included acute pyelonephritis, other infections, severe preeclampsia or eclampsia, abruptio placentae, prolonged intrauterine fetal death, uterine hemorrhage, and, in a small group, postpartum idiopathic acute renal failure (189). Pregnancy may also result in nonglomerular complications leading to acute renal failure, such as acute hydronephrosis presumed to result from obstruction. Spontaneous rupture of the renal pelvis has been reported (190). No specific site of obstruction was delineated, nor were calculi demonstrated.

This section is a discussion of some of the main causes of acute renal failure in pregnancy:

Acute pyelonephritis
Preeclampsia, eclampsia, and HELLP syndrome
Uterine hemorrhage
Septic abortion
Cortical necrosis
Acute fatty liver of pregnancy
Postpartum hemolytic uremic syndrome

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Acute Pyelonephritis

Acute pyelonephritis (see Chapter 22) is relatively common in pregnancy, affecting approximately 1% to 2% of gravidas (189), and it may cause a transient decrease in the GFR (191). Septic shock, and not pyelonephritis itself, underlies the rare occurrence of acute renal failure after acute pyelonephritis in pregnancy. In one series of acute renal failure in pregnancy (189

Preeclampsia, Eclampsia, and HELLP Syndrome

Acute renal failure is a rare complication of severe preeclampsia or eclampsia, possibly reflecting early recognition and treatment of preeclampsia in most cases. Patients with preeclampsia or eclampsia who developed acute renal failure tended to be multiparas and therefore also older than other preeclamptic patients (189,192). When acute renal failure in preeclamptic patients resulted in death, arteriolar and arterial changes were frequent (193); this finding indicates that these patients had pre-existing vascular disease and not pure preeclampsia. In a series of 154 patients with well-defined eclampsia, no cases of acute renal failure were found, further suggesting that acute renal failure is rare in pure preeclampsia or eclampsia (194). The acute renal failure appears to result from acute tubular necrosis or extensive cortical necrosis. The underlying mechanism is thought to be ischemia, which may be contributed to by glomerular occlusion by endotheliosis or intravascular coagulation. Coexistence of tubular necrosis and glomerular changes of preeclampsia has been reported (71). Fifty percent of patients with pure preeclampsia and acute renal failure thought to result from acute tubular necrosis required short-term dialysis in one series. These patients had underlying acute tubular necrosis, and they had full recovery of renal function within 6 weeks (147). Thus, when patients with acute renal failure and pure preeclampsia survive the acute illness, no residual deleterious effects on renal function have been documented (147). Patients with HELLP syndrome and hemorrhage are at particular risk of ischemia and resultant organ damage, including renal injury. The risk of acute renal failure is higher if HELLP syndrome develops postpartum (147,148). Acute renal failure occurs in as many of 8% of pregnancies in patients with HELLP syndrome (see HELLP Syndrome, p. 785).

Uterine Hemorrhage

Acute renal failure is especially common in pregnancy complicated by abruptio placentae and disseminated intravascular coagulation. Hemorrhage was implicated as a cause underlying acute renal failure in 7% of patients in one series from France (189) and in up to 58% to 79% of acute renal failure cases in pregnancy from Great Britain and India, respectively (195,196). Patients with preeclampsia may be especially susceptible to acute renal failure in response to hemorrhage (189,196). The mechanisms are unknown, but conceivably they relate to altered volume homeostasis and pressor sensitivity in preeclampsia.

Septic Abortion

In contrast to the low incidence of pregnancy-related acute renal failure in developed countries, the incidence in developing countries remains astonishingly high, mainly because of complications of septic abortion. In France, a decline in acute renal failure cases associated with abortion from 18.6% to 0.6% occurred over a 13-year span beginning in 1966 (197). In South Africa (186), acute renal failure occurred in 1 in 450 deliveries in 1978, improving to 1 in 1000 in the 1990s, associated with a marked decrease in acute renal failure cases caused by septic abortions from 65% to 29%. In a series of cases of pregnancy-related acute renal failure from India (195), 60% followed abortion. Most pregnancy-related acute renal failure resulted from septic abortion in Argentina as well; only 79% survived, with one survivor developing chronic renal failure (188). Although most of these patients had acute tubular necrosis as the proximal cause of acute renal failure, some developed cortical necrosis (see below).

Cortical Necrosis

In developing countries, acute renal cortical necrosis more commonly underlies acute renal failure than in the Western world. Furthermore, over half of the cases of acute cortical necrosis were related to pregnancy, a finding that perhaps reflects the high risk of bilateral cortical necrosis with acute renal failure in pregnancy (197). These findings are in contrast to a marked decline in acute cortical necrosis, in particular that resulting from obstetric causes, in Western countries, from 1 in 10,000 from 1961 to 1970 to less than 1 in 80,000 over the next 10 years in a series from Ireland (198).

The highest incidence of bilateral cortical necrosis occurs after abruption of the placenta or prolonged intrauterine fetal death (189). Bilateral renal cortical necrosis is also relatively frequent among patients with postpartum renal failure (21%), in contrast to only 1.5% in postabortion acute renal failure. In a series of 113 patients with tissue-proven diagnosis of cortical necrosis from India (187), 37% of cases were associated with complications with late pregnancy, and 20% followed septic abortion. Recovery of renal function may continue up to the third year (189).

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Acute Fatty Liver of Pregnancy

Acute fatty liver of pregnancy is a rare complication of late pregnancy that may be fatal. Patients develop fever, nausea, vomiting, abdominal pain, and jaundice. The liver shows swollen hepatocytes with microvesicular fat. Maternal and fetal death were common, although more recent advances in early recognition and treatment have improved maternal survival dramatically (199). Renal failure is typically not severe, although it occurs commonly (60%) (189). In severe cases, progressive encephalopathy, coagulopathy, acute renal failure, adult respiratory distress syndrome, and pancreatitis may develop. Renal biopsies have shown fatty vacuolization in renal tubules and findings of tubular regeneration or focal necrosis. Intraglomerular thrombi have been reported rarely (200).

Postpartum Hemolytic Uremic Syndrome

Clinical Findings

Postpartum hemolytic uremic syndrome typically manifests 1 day to several weeks postpartum. Hemolytic uremic syndrome (HUS) is discussed in further detail in Chapter 16. After a flu-like syndrome, severe acute renal failure and hypertension develop rapidly, often associated with microangiopathic hemolytic anemia. Some patients have preceding preeclampsia, whereas others have had normal pregnancies. Counihan and Doniach (201) were the first to recognize the association of hemolytic anemia with postpartum renal failure. Postpartum hemolytic uremic syndrome has been described in association with circulating lupus anticoagulant and anticardiolipin antibodies. In one case, termination of pregnancy was followed by marked increase of anticardiolipin antibodies, severe hypertension, and renal failure associated with microangiopathy (202). Recurrent thrombotic microangiopathy with pregnancy occurred in a renal transplant in a patient whose primary disease was postpartum thrombosis resulting from anticardiolipin antibody (203). Recurrent HUS may also result from alterations of complement or its regulatory molecules, or von Willebrand factor protease, also known as ADAMTS13, as discussed in detail in Chapter 16. Verotoxin has also been implicated in the pathogenesis of thrombotic microangiopathy in some patients (see Chapter 16204,205). Patients with lesions limited to glomeruli have a better prognosis than when larger arteries are involved, as in other causes of hemolytic uremic syndrome (205). Clinical diagnosis of hemolytic uremic syndrome cannot be based solely on the presence of schistocytes, because these may occur in other pregnancy-associated conditions, including preeclampsia and eclampsia (206). Furthermore, biopsies performed during pregnancy at times of deterioration of renal clinical parameters showed fibrin thrombi regardless of underlying renal disease (IgA nephropathy, reflux nephropathy, or focal sclerosis with hyalinosis). These lesions were not associated with clinical features of preeclampsia in these patients, and they are postulated to heal to form a lesion of segmental hyalinosis (13). Thus, the diagnosis of the hemolytic uremic syndrome cannot be based solely on the presence of fibrin thrombi.

Microscopic Findings

Glomeruli

Endothelial cell swelling and intraglomerular fibrin thrombi occur, consistent with thrombotic microangiopathy (see Fig. 17.8; see Chapter 16 for a full discussion) (189). When severe vascular lesions, such as extensive thrombi, are present, glomerular ischemic changes predominate.

Tubules

The kidney structure may be within normal limits, or focal tubular necrosis, tubular regeneration, or even cortical necrosis may be present.

Vessels

Vascular changes suggestive of nephrosclerosis, i.e., intimal fibrosis and medial hypertrophy, have been noted in addition to lesions consistent with thrombotic microangiopathy. Interlobular arteries show marked intimal thickening and occlusion by fibrin thrombi. In other cases, lesions similar to those of malignant hypertension or progressive systemic sclerosis have been described (Figs. 17.19 and 17.20) (207,208).

DA1C17FF19

Figure 17.19 Patient months after preeclampsia/eclampsia with occasional double contours of the GBM and well-developed segmental sclerosis and hyalinosis. (PAS, ×400.) (Courtesy of Dr. Vivette D'Agati.)

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Figure 17.20 Interlobular artery in patient after preeclampsia revealing intraluminal fibrin and early intimal proliferation. (Masson's trichrome, ×400.) (Courtesy of Dr. Vivette D'Agati.)

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Electron Microscopic Findings

Changes are those seen in other forms of hemolytic uremic syndrome and progressive systemic sclerosis and are thought to reflect a response to intravascular coagulation. There is lucency of the lamina rara interna with an expanded zone with finely fibrillar or finely particulate electron-dense material (Fig. 17.21). Interposed cells may also be present, but there are no immune complexes.

DA1C17FF21

Figure 17.21 Lucent expanded subendothelial zone with scattered granular material from a patient with postpartum acute renal failure. (Transmission electron microscopy, ×9000.) (Courtesy of Dr. Mary MacDonald.)

Immunofluorescence Findings

Findings are similar to those in other forms of hemolytic uremic syndrome. Fibrinogen and fibrin are typically present, with some biopsies showing staining with IgG and IgM and complement in vessels. Glomeruli typically are negative (205,209,210).

Pregnancy and Pre-Existing Renal Disease

211). Similarly, the effect of renal disease on pregnancy outcome is determined both by disease-specific factors and by factors related to the degree of renal dysfunction. Numerous studies have examined whether pregnancy adversely affects the natural course of underlying

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primary renal diseases and whether pregnancy outcome is influenced by this disease process, as reviewed by Jungers and Chauveau (212). Based on experimental data suggesting an adverse effect of abnormal hemodynamics on renal function, investigators have postulated that the increased renal plasma flow and glomerular filtration during pregnancy could exacerbate the course of renal disease (see Functional Changes in Pregnancy, p. 766). Whether pregnancy changes the natural history of various renal diseases is difficult to ascertain because the variable and slow course of many progressive renal diseases makes it difficult to use patients as their own controls. Few reported series have concurrent control populations, and this limitation adds to the difficulty in determining the effect of pregnancy on renal outcome. In a large controlled series of 148 women with various biopsy-proven renal diseases who were pregnant, the risk of developing chronic renal failure was not increased compared with the control group of women with similar glomerulonephritides who did not become pregnant (213). Patients with advanced chronic renal insufficiency have decreased fertility and are therefore much less likely to become pregnant. Renal dysfunction is often exacerbated during pregnancy; however, after delivery, no long-term deleterious effect is seen on renal function. Several risk factors for poor maternal and fetal outcomes have been identified. This discussion first focuses on general risk factors for poor long-term renal outcome, then on effects on pregnancy, followed by a brief description of disease-specific aspects of these risks (Table 17.2).

Table 17.2 Pregnancy and renal diseases: fetal and maternal outcomes

 

 

Effects on Kidney

Underlying Disease

Effects on Pregnancy

 

Long-Term

Focal segmental glomerulosclerosis

Fetal loss -20%, prematurity -30%

Decreased renal function in half, especially if abnormal at onset

5% with decreased glomerular filtration rate

IgA nephropathy

Fetal loss 10%, less with normal renal function

 

No proven effect

Lupus nephritis

Fetal loss 17%, prematurity in ~50%

Persistent or increased activity of active lupus; flare in 35% with prepregnancy quiescence

Poor kidney function with active proliferative lupus; good with mild, quiescent disease

Antiphospholipid antibodies

Fetal loss nearly invariable (~87%)

Thrombosis

Recovery depends on degree of thrombosis or necrosis

Membranous glomerulonephritis

Fetal loss 15%, mostly early, better with less proteinuria

Rare cases of decreased renal function

2% with decreased glomerular filtration rate

Reflux nephropathy

Fetal loss 15%

 

Decreased glomerular filtration rate in patients with initial renal insufficiency; increased preeclampsia especially with bilateral scars

Diabetes mellitus

Frequent adverse outcome if metabolic control not optimum

 

No proven effect

Wegener's granulomatosis

Unknown

Relapse may occur

Depends on severity of relapse

Anti-glomerular basement membrane antibody disease

Unknown

Pregnancy may ameliorate renal disease

Relapse after delivery reported

Polycystic kidney disease

Increased prematurity if complications occur

Increased preeclampsia, especially if hypertensive at onset (54%)

Persistent hypertension as sequela in nearly all who develop preeclampsia

Renal transplantation

Increased fetal toss with renal insufficiency

Increased proteinuria, decreased glomerular filtration rate common

No effect

Effects of Pregnancy on the Course of Renal Disease

Transient worsening of hypertension, proteinuria, and renal dysfunction are common during pregnancy in patients with pre-existing renal disease. Significant hypertension developed in 23% of pregnancies in one series of women with underlying renal disease. Hypertension occurred more commonly in patients with diffuse glomerulonephritis, focal glomerulonephritis, and arteriolar nephrosclerosis (80). Of these patients who developed moderate to severe hypertension during pregnancy, approximately one

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half were normotensive before pregnancy. Although genetic risks were not specifically evaluated, the highest elevations of blood pressure occurred in studies with a large proportion of African American patients. Among women with pre-existing hypertension in the absence of renal insufficiency, blood pressure elevations were often marked during pregnancy, even rarely leading to abruptio placentae and acute tubular necrosis. Markedly increased proteinuria, nephrotic in 68% of these, occurred in approximately half of the pregnancies, regardless of underlying renal disease (80). In a study of 82 pregnancies in 67 women with moderate to severe renal insufficiency (214), worsened renal function, hypertension, and obstetric complications occurred more frequently during pregnancy compared with rates expected in the general population. Nearly one third (31%) of patients had a persistent pregnancy-related decline of renal function at 6 months postpartum, whereas 51% showed stable renal function over this time period. Rapid progression to end-stage renal failure by 6 months postpartum occurred in 10% of the total group. The risk of pregnancy-associated renal damage was highest in women with more severe renal insufficiency before pregnancy (serum creatinine greater than 2.0 mg/dL) (214). These findings were echoed in a recent review. In patients with well-maintained GFR before conception, there usually were no ill effects of pregnancy on the underlying renal disease. When serum creatinine was greater than 1.4 mg/dL, adverse effects were observed, and if serum creatinine was greater than 2 mg/dL, one in three patients experienced increased progression with pregnancy (211).

Restoration of prepregnancy renal function and blood pressure levels occurred in most patients after delivery. However, follow-up at intervals of 3 months to 23 years after pregnancy in this series of 121 pregnancies in 89 women revealed 5 patients with end-stage renal failure, 1 with moderately severe hypertension. The onset of end-stage renal disease was weeks to over 8 years after delivery (80). Risks of permanent deterioration in renal function have been sought. On the one hand, normal renal function at the outset of pregnancy is usually associated with good prognosis for long-term renal function (215). However, in one series of 72 patients with renal disease who became pregnant, 6 of 8 women with a decline in renal function after delivery had normal renal function before pregnancy (216). Uncontrolled hypertension, nephrotic-range proteinuria, or impaired renal function at the time of conception or at early phases of pregnancy is associated with increased risk of deterioration of renal function (100,213,217,218219,220).

When the diagnosis of renal disease antedates pregnancy, the maternal and fetal outcomes are improved, reflecting intensive medical care by both nephrologists and obstetricians (219). This point was well illustrated by a large series reported from Melbourne, Australia, which analyzed 395 pregnancies in 238 women with glomerulonephritis (220). Only two patients had renal impairment before pregnancy, and pre-existing hypertension was present in 12%. More than half of the pregnancies resulted in hypertension during pregnancy. Hypertension persisted after delivery in 44 patients. Similarly, 59% of pregnancies resulted in increased proteinuria during pregnancy, with persistence in 15% of all patients. Decreased renal function was seen in 15% of pregnancies, with failure to resolve after delivery in 5% of the patients. Eleven women developed irreversible renal dysfunction or worsened renal function with pregnancy. Similar results have been reported in other large series (100,220). Overall, renal dysfunction during pregnancy and outcomes were improved when pregnancy took place after diagnosis of renal disease (219). However, independent of other risk factors, chronic kidney disease still is associated with substantially increased risk of adverse fetal and maternal events (adjusted odds ratio 4.07 for adverse maternal events and 1.76 for fetal events) (221).

Effects of Pre-Existing Renal Disease on Pregnancy Outcome

Fetal loss and prematurity are increased in pregnancies of women with underlying renal disease when renal function is impaired. In the large patient group from Melbourne described in the previous section, 20% of fetuses were lost and 24% were delivered prematurely (220). Impaired renal function, early or severe hypertension, and nephrotic-range proteinuria were associated with adverse pregnancy outcome (213,220). Renal biopsy lesions of tubulointerstitial injury, arteriolosclerosis, and severe arterial lesions also were associated with unfavorable delivery outcomes (216,220). Additional series show that fetal and maternal outcomes differ in pregnant patients with renal diseases and varying prevalence of associated risk factors. The incidence of normal delivery was highest among patients with membranous glomerulonephritis (84%), with 71% and 74% normal deliveries in patients with IgA nephropathy and proliferative glomerulonephritis, respectively (216). Neonatal or fetal death and premature delivery occurred more often when patients had diffuse or focal glomerulonephritis (80). One study demonstrated improved fetal survival in premature infants born to women with renal disease (214). Fetal mortality was only 7% in this group of 67 women with 82 pregnancies, compared with earlier reports with rates of 12% to 88% (213).

Intrauterine growth restriction is an additional important adverse event with profound consequences for the adult health of the offspring. Low birth weight of term-birth babies has been linked to increased cardiovascular and renal disease risk in adulthood by Barker et al and Brenner et al (222,223). The mechanism has not been proven, but low birth weight has been proposed to be linked with fewer nephrons, with resulting increased risk for hypertension and progressive renal disease in adulthood (223).

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Whether incidence of low birth weight of term births is increased in pregnancies of patients with renal disease has not been proven. Experimental evidence supports the concept that the induction of low birth weight by introducing intrauterine ischemia in pregnant rats could result in low-birth-weight offspring with increased hypertension in adulthood (224). In contrast to these studies in the rat, in a sheep model with intrauterine growth restriction owing to late gestational umbilicoplacental embolization or natural twinning, there was no decrease in nephron number with the late induction of intrauterine growth restriction, whereas growth restriction owing to twinning did result in decreased nephron number. These results suggest that not only is growth restriction of importance in determining nephron endowment, but the timing of the insult that decreases growth is crucial for effects on nephron development (225). Both maternal and genetic factors have been proposed to influence nephron endowment, including, for instance, maternal nutrition, altered hormones, or toxins or genetic factors (226). Thus, severe dietary protein restriction in midgestation, as seen in the Dutch famine of 1944/1945, was associated with increased adult hypertension and microalbuminuria (227). Animal studies support the concept that the mechanism of malnutrition on nephron number could be through impairment of renal development (228,229).

Pathogenesis

Complex changes occur in renal function during normal pregnancy (see p. 766), some of which are postulated to have adverse effects on renal disease. However, in contrast to the loss of nephrons, glomerular hyperfiltration and hypertension, and increased growth factors, which occur in many progressive renal diseases, pregnancy is a physiologic state of moderate renal vasodilatation without increased glomerular pressure or growth (9). Because direct assessment of many of these parameters is not possible in humans, animal models have been studied to determine the effect of pregnancy on the kidney and on pre-existing renal disease. As in humans, mild azotemia induced transiently by uninephrectomy did not have an adverse effect on pregnancy outcome. Although rat pups were born with glomeruli with larger volume, no long-term effect on glomerular growth or development was detected by 6 weeks after birth (230). Repeated normal pregnancy also showed no adverse effects on the kidney. In rats with hyperfiltration maintained by repeated pregnancies and lactation for 6 months, no adverse effects were seen on subsequent renal function, even with additional stimuli that increase hemodynamic load, such as high-protein diet and uninephrectomy (9). Glomerular pressures did not increase in these experimental settings despite the vasodilation of pregnancy, because of equal decrease in resistances of afferent and efferent arterioles (9).

When pregnancy was superimposed on experimental rat models of human membranous glomerulonephritis, anti-glomerular basement membrane disease, or focal segmental glomerulosclerosis, no additional deleterious effects on pregnancy, renal function, or sclerosis resulted (231,232,233,234,235). Even repeated pregnancies did not worsen sclerosis in the remnant kidney model of focal segmental glomerulosclerosis (234). Micropuncture studies showed decreased glomerular pressures with pregnancy in the remnant kidney model (233). Experimental membranous glomerulonephritis also led to decreased glomerular pressures in pregnant compared with nonpregnant rats, as a result of systemic decrease in blood pressure and glomerular vasoconstriction at both the afferent and efferent arterioles (231). These models do not mirror the human situation, in which pregnancy occasionally can lead to rapid and irreversible worsening of underlying renal disease. The next studies are of particular interest in this regard. In contrast to the foregoing models, rats with mild doxorubicin nephropathy, another model of focal segmental glomerulosclerosis, developed renal and systemic vasoconstriction, increased blood pressure, and proteinuria in response to pregnancy (235). These preeclamptic-like responses were partially corrected by L-arginine, which stimulates nitric oxide release. In normal rats, nitric oxide synthesis appears increased during pregnancy (). However, endogenous synthesis of nitric oxide could be inadequate when renal disease is superimposed on pregnancy, perhaps because of underlying endothelial dysfunction. Additional key vasoactive compounds, such as VEGF or PAI-1 (see preeclampsia discussion), which normally increase in pregnancy, could also be altered when there is underlying chronic kidney disease, with resulting endothelial and fibrotic/thrombotic injuries. Experimental evidence supports the hypothesis that decreased VEGF and increased PAI-1 are linked to accelerated kidney fibrosis (237,238,239).

Specific Renal Diseases and Pregnancy

Focal Segmental Glomerulosclerosis

In several series, focal segmental glomerulosclerosis was associated with the highest incidence of fetal and maternal complications (220,240,241). Impairment of renal function occurred in nearly 50% of pregnancies in this diagnostic group compared with only 5% among patients with non-IgA diffuse mesangial proliferative glomerulonephritis. Decreased renal function occurred in 15 of 31 pregnancies in 21 women with primary focal segmental glomerulosclerosis. In four patients, renal dysfunction was irreversible, and three of these patients progressed to end-stage renal disease. This series included patients who had focal and segmental hyalinosis and sclerosis, which may represent a group with worse prognosis and more advanced disease (242,243).

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Lupus Nephritis

The risk of exacerbation of lupus nephritis with pregnancy varies widely, from 8% to 74% (244). In patients with mild systemic lupus erythematosus (SLE), pregnancy does not appear to affect the course of lupus, although pregnancy complications may be increased (245). Poor outcome is seen in patients with active proliferative lupus nephritis (World Health Organization or International Society of Nephrology/Renal Pathology Society class IV) before conception. In a comprehensive review by Hayslett (246), patients with disease activity at conception showed persistent or increased activity of SLE in 52%, compared with sustained remission in 65% of patients with quiescent SLE before conception. In a prospective series of patients with lupus nephritis from France (247), SLE exacerbation during pregnancy was increased in patients with a past history of fetal loss, proteinuria, or active SLE at the onset of pregnancy, hypertension, or absence of anti-SSA antibodies. Relapses of SLE during pregnancy occurred in 27 of 75 patients with inactive SLE before conception, and 7 additional patients had a relapse postpartum. Nearly half of the births were premature, and fetal loss occurred in 18 of 103 pregnancies (247). In a series reported by Packham et al (248), no progression to end-stage renal failure and no maternal deaths were seen, in contrast to a 3.4% death rate in a review by Cameron and Hicks (215249).

Differentiation of flares of lupus nephritis from preeclampsia may be difficult, and it is also critically important therapeutically, because high-dose prednisone is commonly used for SLE and may be contraindicated in preeclampsia (250). Previous studies have suggested the use of low C4 levels to distinguish SLE exacerbation from preeclampsia (251); however, low C3 or C4 levels may occur in preeclampsia (244,252).

Antiphospholipid Antibodies

249,253). In one series (254), only 2 of 23 pregnancies in 12 women with these antibodies were successful. Patients also have increased risk for chronic decreased renal function.

These antibodies may occur in patients with SLE also as part of the antiphospholipid syndrome. Patients with this syndrome have recurrent arterial or venous thrombosis, livedo reticularis, and recurrent fetal loss. Preeclampsia has also been linked to these antibodies. The prevalence of antiphospholipid antibodies among women with preeclampsia has been reported to be as high as 20% in some series (255,256,257,258). Postpartum renal disease has been reported in 12 cases with antiphospholipid antibodies, 8 after fetal death and 5 after preeclampsia (202,259).

Biopsy specimens taken during or soon after pregnancy in seven patients with antiphospholipid antibodies, one of whom also had lupus nephritis, showed acute fibrinoid lesions with fibrin thrombi in glomeruli, arterioles, and arteries. Glomeruli showed double contours of capillary walls, which persisted in later follow-up biopsies performed in five of these patients. Chronic vascular injury was also present in these late biopsies, with narrowing of arteries resulting from recanalizing thrombi and cellular intimal proliferation (254). Vasculitis involving medium-sized and smaller arteries with marked infiltration of the vascular wall by lymphocytes, neutrophils, and occasional eosinophils with focal fibrinoid necrosis was associated with antiphospholipid antibodies in a pregnancy with prolonged intrauterine fetal demise (259,260). Placental vascular lesions in one case of a patient with lupus anticoagulant were similar to those described in preeclampsia (261). Electron microscopic studies at the acute stage showed translucent glomerular subendothelial deposits and fibrin, typical of the acute phase of thrombotic microangiopathy. In biopsies performed 1 year or more after pregnancy, persistent double contours of glomerular capillaries with mesangial interposition were present.

Combined therapy with plasmapheresis and immunosuppression has been advocated for patients with antiphospholipid antibodies in pregnancy. Prolongation of pregnancy by steroids beyond the time at which spontaneous fetal loss would otherwise occur has been postulated to underlie the more severe vascular lesions (13).

IgA Nephropathy

IgA nephropathy and other mesangial diseases are associated with a moderately good prognosis for pregnancy outcome. In one large series (220) of patients with pregnancy and various glomerulonephritides, mesangial (non-IgA) glomerulonephritis was associated with the best prognosis. The incidence of normal delivery was 71% in patients

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with IgA nephropathy in one large series from Japan (216). Fetal loss or neonatal death occurred in 10% of pregnancies, and spontaneous abortion occurred in 3%.

Chronic deterioration of renal function in IgA nephropathy rarely can be linked to gestation. Reversible decline in renal function is much more common, occurring in 24% (262). In a prospective study of 71 women with biopsy-proven IgA nephropathy, no difference in pregnancy outcome or renal function was seen between those who conceived and those who did not (263). Four of the pregnant patients and two of the nonpregnant patients reached end-stage renal disease during the 5-year follow-up. Entry biopsies in these patients already showed moderate to advanced diffuse proliferative glomerulonephritis with advanced tubular atrophy, interstitial fibrosis, and arteriosclerosis. Superimposed focal and segmental hyalinosis and sclerosis or diffuse mesangial proliferation were indicators of poor prognosis in another large series. Approximately one third of patients with these biopsy changes showed renal dysfunction, increased proteinuria, or increased blood pressure during pregnancy (220). The highest incidence of maternal complications was correlated with those biopsies with superimposed focal and segmental proliferative lesions (264). The presence of active crescents or more than 10% sclerosed glomeruli was not associated with statistical differences in fetal or maternal outcome. Because these features have been associated with poor outcome in nonpregnant patients, it is possible that the relatively small number of patients with these lesions prevented detection of a specific effect.

Membranous Glomerulonephritis

Membranous glomerulonephritis in general is associated with a favorable renal prognosis and an ability to carry pregnancy to term (215). Only 3 cases of irreversible decline in glomerular function were reported in series totaling 132 patients (265). Thirty of the 193 pregnancies (15.5%) in these women resulted in fetal loss. Nephrotic-range proteinuria during early pregnancy was associated with poor fetal outcome and irreversible hypertension or renal impairment. No correlation was found between stage of membranous glomerulonephritis (see Chapter XX) and outcome in this group.

Reflux Nephropathy

Combining published series of reflux nephropathy from Kincaid-Smith and Fairley (266), Jungers et al (54), and Arze et al (267) gives results from 772 pregnancies in 320 women. Overall, fetal deaths occurred in 15% of pregnancies, hypertension in 20%, and UTI in 29%. When only persistent vesicoureteric reflux was present, there was no increased fetal or maternal risk (55242). Patients with reflux who have increased serum creatinine are at increased risk for preeclampsia (54). This incidence is particularly high, 24%, in women with bilateral scars, compared with only 7% in patients with only unilateral scars (55,242).

Systemic and Genetic Diseases

Diabetes Mellitus

Prematurity and complications in neonates are well known to occur in diabetic patients, and they are particularly common in patients with impaired renal function during the first trimester. Diabetic patients without nephropathy have fewer fetal complications. Increased renal dysfunction during pregnancy, characterized by increased proteinuria and serum creatinine, is common in patients with diabetic nephropathy. More serious complications may also occur. In a study of 40 pregnancies in 33 women with diabetic nephropathy, 7 developed a preeclampsia-like syndrome, and decline in renal function was significantly greater in those patients with elevated serum creatinine at the beginning of pregnancy. However, the average rate of fall in creatinine clearance (0.65 mL/min/mo) in diabetic patients is only slightly higher than the range observed prospectively in studies of diabetic nephropathy treated with antihypertensive agents (268). Thus, a specific long-term effect of pregnancy on diabetic nephropathy has not been proven.

Autosomal Dominant Polycystic Kidney Disease

Preeclampsia occurs in increased frequency (9%) in pregnancies in patients with autosomal dominant polycystic kidney disease. When superimposed preeclampsia occurred, prematurity rates were significantly increased (269). The incidence was particularly high in patients who were hypertensive at the onset of pregnancy versus those who were normotensive (54% versus 8%). Of the 26 women who developed preeclampsia or eclampsia, 23 subsequently developed persistent hypertension.

Wegener's Granulomatosis and Microscopic Polyangiitis

Several reports suggest the possibility that pregnancy could have an adverse effect on Wegener's granulomatosis, as reviewed by Pauzner et al (270) and Habib et al (271). Relapse of kidney involvement occurred in five of eight pregnancies in women with known Wegener's granulomatosis (270). Fifteen pregnancies in 10 women with Wegener's granulomatosis were reviewed in one series, with diagnoses made during pregnancy or postpartum in 7 of these cases (270). Risk factors for relapse in pregnancy were not identified. One patient completed two normal pregnancies without relapse before a mild relapse occurred in a

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third pregnancy (270). Relapse did not occur in a patient with kidney transplant who was maintained on immunosuppression (270). Relapse affected the liver in one patient with stable renal function before pregnancy, and it resulted in fibrinoid necrosis of hepatic parenchyma and fetal loss (272). In a more recent survey of the literature, 28 pregnancies in patients with Wegener's granulomatosis were identified (273). The diagnosis of Wegener's granulomatosis was made during pregnancy in eight. Nineteen of 27 cases with outcomes recorded resulted in live births, seven pregnancies terminated in abortions and two maternal deaths occurred. Microscopic polyangiitis has only very rarely been reported in pregnancy (274), perhaps reflecting its lesser propensity to relapse than Wegener's granulomatosis. A single case demonstrated the transmission of myeloperoxidase-specific antineutrophil cytoplasmic antibodies (MPO-ANCA) across the placenta from a mother with microscopic polyangiitis, resulting in pulmonary hemorrhage and renal abnormalities developing shortly after delivery in the baby. The cord blood showed the presence of the same MPO-ANCA as in the mother's serum. The baby showed an excellent clinical response to exchange transfusion and immunosuppression, and the mother also responded to therapy (275).

Anti-Glomerular Basement Membrane Antibody Disease

In contrast to the experience in most kidney diseases, several case reports suggest that pregnancy may temporarily ameliorate activity of anti-glomerular basement membrane antibody disease. Detailed studies were performed in a patient who developed renal disease during pregnancy, with marked deterioration of renal function after delivery at 35 weeks' gestation. A renal biopsy performed 11 days postpartum revealed crescentic glomerulonephritis with anti-glomerular basement membrane antibodies. Studies of the patient's serum documented that her anti-glomerular basement membrane antibodies could bind to placental membranes. The infant showed no evidence of renal disease, and the infant's serum did not contain anti-glomerular basement membrane antibodies. The rapid decline of renal function postpartum was postulated to have been due in part to removal of the ameliorating influence of the placenta (276). An additional case of rapid decline in renal function postpartum has been described, although further studies were not performed in this case (277).

Other Systemic Diseases

In a review of effects of pregnancy on scleroderma, no significant effect of pregnancy could be established (278). Although individual case reports have described renal crisis during pregnancy, this condition does not appear to occur at an increased frequency during pregnancy (278,279). In amyloidosis, as in other renal diseases, more severely compromised renal function at conception was associated with deterioration of renal function during pregnancy (280).

Kidney Transplant

281) showed 69% graft survival at 10 years in renal transplant recipients who had become pregnant versus 100% in control transplant patients. This apparent adverse effect has not been found in other series (282,283). No adverse effects of pregnancy on graft function were detected in a series of 113 pregnancies in 73 transplanted women (284). Premature delivery occurred in 64% of the pregnancies, with no congenital defects or renal functional defects, hypertension, or proteinuria observed in these babies, followed on average till age 52 months (285286). Although creatinine clearance decreased late in pregnancy in renal transplant patients to a greater extent than in healthy women, permanent impairment of renal function was not typical. Proteinuria was also increased slightly during pregnancy, to approximately 200 mg/24 hours, versus 150 mg/24 hours in normal subjects at comparable time of pregnancy. By the third trimester, proteinuria in renal transplant patients was three times that of nonpregnant levels, returning to prepregnancy levels by 2 to 3 months after delivery (8). In an additional case-control study, no significant difference was found in plasma creatinine levels after 15 years of follow-up (287).

Patients with decreased renal function who also are receiving immunosuppression have decreased fertility. When renal transplant patients do conceive, spontaneous abortions are increased if significant renal insufficiency is present, whereas a good pregnancy outcome is associated with intact renal function (286).

Renal Cancer

The apparent increase in the number of cases of renal cancer in pregnancy reflects increased incidental detection during pregnancy because of the routine use of ultrasound. Forty-four cases of renal cell carcinoma discovered during pregnancy were reported in one review (288). Formerly, palpable flank masses were the most common presentation, in contrast to early detection of smaller lesions with the use of high-resolution ultrasound. Presenting symptoms, when present, are usually suggestive of recurrent UTI (288).

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