Pregnancy and the Kidney

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Pregnancy and the Kidney CHUN LAM1 AND S. ANANTH KARUMANCHI2 1 2

Merck Research Laboratories, Rahway, NJ, USA Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

plasma concentration of creatinine and blood urea nitrogen (BUN). Average plasma creatinine during pregnancy is about 0.5 mg/dl and BUN 9 mg/dl, respectively, compared to pre-pregnancy average levels of approximately 0.8 and 13 mg/dl, respectively (Sims and Krantz, 1958). This increase in GFR can also lead to the appearance of microalbuminuria in normal pregnancies, while women with pre-existing proteinuric renal disease can expect to have a dramatic increase in proteinuria after the first trimester (Higby et al., 1994; Gordon et al., 1996). Accompanying the large rise in GFR is an increase in renal size by about 1 cm in length and 30% in volume, as well as dilation of the collecting systems (Bailey and Rolleston, 1971, Rasmussen and Nielsen, 1998). Physiologic hydronephrosis can be seen in up to 90% of pregnancies beginning in the first trimester and resolving after about 1 month postpartum (Peake et al., 1983). The etiology is attributed to the hormones that affect smooth muscle, such as progesterone, but primarily to mechanical compression by the gravid uterus, more pronounced on the right than the left because of dextrorotation of the uterus (Fainaru et al., 2002). Although typically asymptomatic, physiologic hydronephrosis can be a rare cause of acute renal failure in pregnancy that is characterized by abdominal pain and severe hydronephrosis resulting in obstruction (Khanna and Nguyen, 2001). More commonly, the physiologic dilation predisposes women to infection, which can range from asymptomatic bacteriuria to urosepsis (Puskar et al., 2001). Renal handling of electrolytes is also affected by the rise of GFR. The increase in urate clearance results in a decline of serum uric acid to as low as 2–3 mg/dl by the second trimester (Lind et al., 1984). In the third trimester, increased renal tubular absorption of urate accounts for the return to pre-pregnant serum uric acid concentrations by delivery. By week 8 of gestation, calcium excretion is found to be increased, likely from elevated circulating 1,25 dihydroxyvitamin D3, but this may be counteracted by a concomitant rise in excreted nephrocalcin, thought to be a crystalluria inhibitor (Heaney and Skillman, 1971; Davison et al., 1993). The overall incidence of nephrolithiasis is not increased compared to non-pregnant women of child-bearing

Contents I. II. III. IV. V.

Introduction Normal pregnancy Pre-eclampsia and HELLP syndrome Other hypertensive disorders of pregnancy Renal failure in pregnancy References

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I. INTRODUCTION The kidney and the placenta can both be viewed as endocrine organs. Pregnancy represents unique physiology which, in the context of kidney disease, presents challenges for the obstetrician, the nephrologist and the endocrinologist. This chapter will detail the major renal physiological changes during pregnancy, clinical features and pathogenesis of pre-eclampsia, other causes of hypertension in pregnancy and acute and chronic renal failure, as well as renal transplantation in pregnancy. The goal is to present relevant and recent developments in the understanding of mechanisms of renal disease and/or hypertension during pregnancy with the recognition of the multifaceted nature of these conditions.

II. NORMAL PREGNANCY A. Renal Adaptation Normal pregnancy is associated with increases in glomerular filtration rate (GFR) of 40–65% and renal plasma flow (RPF) of 50–85% above non-pregnant levels during the first half of gestation (Dunlop, 1981). These increases are a result of reductions in both afferent and efferent arteriolar resistances without glomerular pressure change that have been demonstrated in micropuncture studies (Baylis, 1980). Creatinine clearance has been found to be increased 25% by as early as the second week of gestation (Davison and Noble, 1981). In the final stages of pregnancy, RPF falls, while GFR is generally maintained throughout gestation (Conrad, 2004). The rise in GFR results in a corresponding reduction in Textbook of Nephro-Endocrinology. ISBN: 978-0-12-373870-7

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Copyright 2009, Elsevier Inc. All rights reserved.

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age, which might be attributable to the presence of a urinary inhibitory protein, physiologic dilation and higher urine flow (Gorton and Whitfield, 1997). Diminished serum bicarbonate levels in pregnant women are commonly seen. This is not caused by a metabolic acidosis, but rather represents compensation for respiratory alkalosis, which is also reflected by a decline in arterial pCO2. Once compensation is achieved and steady state is again reached, urine pH returns to its usual acidity (Lyons, 1976). Progesterone both increases the sensitivity of the respiratory center to CO2 and stimulates the respiratory drive directly. As a result, pCO2 drops to approximately 27–32 mmHg. This allows for a high-normal pO2 to be sustained despite the 20–33% increase in oxygen consumption in pregnancy (Mason et al., 2005). Women without diabetes may experience mild glycosuria and aminoaciduria in a normal pregnancy because of increased GFR and therefore load of glucose and amino acids, as well as the decreased glucose absorption capacity of the kidneys reabsorption (Buhling et al., 2004). During the first trimester, plasma osmolality falls as a result of lowering of the osmotic threshold for thirst and secretion of antidiuretic hormone (ADH), shown to be induced by human chorionic gonadotropic hormone (Davison et al., 1990). The ability to excrete a water load is otherwise normal. As a result, mild hyponatremia is frequently observed at levels of 4–5 mEq/L below non-pregnant levels. Studies in rats have more recently suggested that upregulation of aquaporin 2 in the renal papillae may also play a role in the water retention of pregnancy (Ohara et al., 1998). The kidney in pregnancy preserves the ability efficiently to excrete a sodium load (Chesley et al., 1958). However, sodium reabsorption is increased through activation of the renin–angiotensin–aldosterone system (RAAS), which offsets the additional renal loss of sodium from the rise in GFR and the natriuretic effect of other hormones, such as progesterone and atrial natriuretic peptide (ANP). This leads to a slow, gradual retention of sodium of about 900 mmol by term (Elsheikh et al., 2001). Total body water, distributed among the fetus and the maternal extracellular and interstitial space, increases by 6–8 liters (Davison, 1997). Because the increase in plasma volume is disproportionately greater than the increase in red cell mass, a physiologic fall in the hemoglobin concentration during pregnancy is commonly seen (Sifakis and Pharmakides, 2000).

B. Cardiac and Vascular Adaptation in Pregnancy One of the earliest physiological adaptations in pregnancy is decreased vascular resistance and increased arterial compliance (Poppas et al., 1997). By as early as 6 weeks of gestation, even before placentation is complete, many of the major hemodynamic changes associated with pregnancy are already well underway: systemic vascular resistance drops,

heart rate increases 15–20%, mean arterial blood pressure decreases by about 10 mmHg and cardiac output rises by approximately 20%, peaking at 50% above pre-conception level by the third trimester (Chapman et al., 1998; Desai et al., 2004). As delivery approaches, these changes begin to revert. The mechanisms underlying the significant hemodynamic changes in early pregnancy are incompletely understood, however, the fall in systemic vascular resistance that precedes full development of the fetal–placental unit appears to stem from the increase in not only uterine blood flow, but also in renal and other extrauterine blood flow. By the end of the first trimester, diminished response to the vasopressors angiotensin II, norepinephrine and vasopressin, as well as increased production of vasodilators such as prostacyclin have been noted. Other hormones that also likely play a role in the systemic decrease in vascular tone include estrogen and progesterone (Gant et al., 1974; Fitzgerald et al., 1987; Baker et al., 1992). In addition, during the first and second trimesters, as the placenta develops, ‘pseudovasculogenesis’ takes place, whereby cytotrophoblasts, transforming from an epithelial to endothelial phenotype in the process of invading uterine spiral arteries in order to remodel the pre-pregnancy high-resistance, low-capacitance maternal arteries into large-caliber, high-capacitance vessels in anticipation of the requirements of the developing fetus and placenta (Zhou et al., 2003). In the second and third trimesters, increasing uterine blood flow continues to play a part in persistent low systemic resistance. Placental vascular development is complex and remains incompletely understood. The impact of angiogenic factors, such as vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt1) and the angiopoietin receptors Tie-1 and Tie-2 (Kayisli et al., 2006), both systemically and on the development of the placenta have yet to be fully elucidated, but it seems clear that imbalance of these factors can lead to defective placental vascular development, most notably, pre-eclampsia. In contrast to other conditions of peripheral vasodilation, such as sepsis, cirrhosis and high-output congestive heart failure that are not characterized by any change in renal plasma flow, pregnancy is marked by decreased renal vascular resistance and significantly increased renal plasma flow. The expectation that activation of the RAAS during pregnancy should lead to renal vasoconstriction therefore suggests the presence of a more dominant direct renal vasodilating factor. It has been proposed that the ovarian hormone relaxin plays this role in pregnancy. Relaxin is a 6 kDa peptide hormone isolated in the 1920s initially from pregnant serum and shown to relax the pelvic ligaments (Sherwood, 2005). It is secreted by the corpus luteum of the ovary and its release is stimulated by human chorionic gonadotropin (hCG) (Conrad et al., 2005). Studies in pregnant rats have indicated that relaxin mediates the renal

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vasodilation, glomerular hyperfiltration and fall in plasma osmolality (Posm) of pregnancy (Novak et al., 2001). The mechanism is thought to be relaxin’s upregulation of matrix metalloproteinase 2 which, in turn, promotes cleavage of big endothelin (ET) into ET1-32. This then leads to nitric oxide (NO)-mediated vasodilation via endothelial ET-B receptors (Smith et al., 2006). More recently, relaxin infusions over 5 hours in men and non-pregnant women resulted in a 50% increase in renal plasma flow without affecting GFR or peripheral blood pressure. No fall in Posm was noted, however, scleroderma patients treated with relaxin over several weeks did exhibit a small, but significant drop in Posm.

III. PRE-ECLAMPSIA AND HELLP SYNDROME Pre-eclampsia is a pregnancy-associated hypertensive syndrome characterized by new-onset hypertension and proteinuria, often diagnosed in the third trimester, and is typically accompanied by edema and hyperuricemia. Clinical management still consists mainly of supportive measures, the only known definitive treatment being delivery of the fetus. The syndrome affects approximately 5% of pregnancies and continues to be a leading cause of maternal and neonatal morbidity and mortality, particularly in the developing world. The primary organs affected may be the liver (HELLP syndrome is the hemolysis, elevated liver enzymes and low platelet count syndrome), the brain (eclampsia) and the kidney (proteinuria and glomerular endotheliosis). In the USA, pre-eclampsia and eclampsia represent 20% of pregnancy-related maternal mortality (MacKay et al., 2001). Worldwide, pre-eclampsia and eclampsia account for 10–15% of the roughly 500 000 women who die annually in childbirth (Duley, 1992; Hill et al., 2001). The most common causes of maternal death are eclampsia, cerebral hemorrhage, renal failure, hepatic failure and the HELLP syndrome. Worldwide, pre-eclampsia is associated with a perinatal and neonatal mortality rate of 10% (Altman et al., 2002). Neonatal death is usually caused by iatrogenic prematurity as a result of early delivery to preserve the health of the mother. The earlier pre-eclampsia presents in gestation, the higher the risk of neonatal mortality. Impaired uteroplacental blood flow or placental infarction can lead to fetal growth restriction. Less frequently seen are oligohydramnios and placental abruption. Despite significant recent advances in the understanding of its pathogenetic mechanisms, the pathophysiology of pre-eclampsia remains incompletely understood.

A. Epidemiology and Risk Factors Pre-eclampsia has been described as a ‘disease of first pregnancies’ and its incidence is highest among nulliparous women, who account for roughly 75% of cases of

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pre-eclampsia (Sibai et al., 1995). Numerous risk factors for the development of pre-eclampsia have been identified. These include certain medical conditions, such as chronic hypertension, diabetes mellitus, renal disease and hypercoagulable states, as well as settings of increased placental mass, such as molar and multiple gestation pregnancies. Women with a prior history of pre-eclampsia are also at increased risk. Others that have been explored include genetic, nutritional and environmental risk factors. Although pre-eclampsia is more common in first pregnancies, multigravidas who are pregnant with a new partner are also at a similarly elevated risk (Tubbergen et al., 1999; Tuffnell et al., 2005). Once thought to be related to immunoprotection by exposure to paternal antigens, it is now recognized that interpregnancy interval is likely the determinant of increased risk in this group (Skjaerven et al., 2002). Most cases occur without a family history; however, women who do have a first-degree relative with pre-eclampsia are at fourfold increased risk of severe pre-eclampsia, pointing to the influence of genetic factors on a woman’s susceptibility to pre-eclampsia (Cincotta and Brennecke, 1998). Both men and women who were products of a pregnancy complicated by pre-eclampsia are also more likely to have a child whose in-utero course is complicated by pre-eclampsia (Esplin et al., 2001). Genome-wide scanning of Icelandic, Finnish and Dutch populations have revealed loci on chromosome 2p13, 2p25 and 12q, respectively, the last with a linkage to HELLP syndrome (Arngrimsson et al., 1999; Lachmeijer et al., 2001; Laivuori et al., 2003). A gene on chromosome 13 has also been suggested to raise susceptibility, since women with trisomy 13 fetuses have been found to have a higher incidence of pre-eclampsia (Tuohy and James, 1992). Two case-control studies have demonstrated higher incidence of pre-eclampsia in mothers who carry trisomy 13 fetuses, compared to other trisomies and control pregnant patients (Boyd et al., 1987; Tuohy and James, 1992). However, specific genetic mutations within these loci have not been identified. Still other suspected risk factors that continue to be debated include infectious etiologies, racial/ethnic factors, thrombophilia and teenage pregnancy. In women with earlyonset pre-eclampsia, anti-CMVand anti-chlamydia antibody (IgG) titers have been found to be increased relative to normal controls and women with late-onset pre-eclampsia (von Dadelszen et al., 2003). Parvovirus B19 infection has been reported in association with cases of pre-eclampsia (Yeh et al., 2004). Recently, it was suggested that perhaps periopathogenic bacteria may contribute to the pathogenesis of pre-eclampsia (Barak et al., 2007). On the other hand, certain other viruses have been associated with a lower incidence of pre-eclampsia (Trogstad et al., 2001). The true role of infectious agents in the pathogenesis of pre-eclampsia has not been established. Some studies have seen a racial disparity in the incidence of pre-eclampsia, namely, a higher rate of pre-eclampsia

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among Hispanics and African-Americans, although the greater incidence in the latter group has not been borne out by studies conducted in healthy, nulliparous women (Siba et al., 1993; Levine et al., 1997; Wolf et al., 2004). As hypertension is a risk factor for pre-eclampsia, it has been suggested that the higher incidence of pre-eclampsia in black women seen in some studies stems from the increased rate of chronic hypertension in this subgroup (Samadi et al., 1996). In general, African-American women have also been noted to have a higher case-mortality rate, which could be attributed to more severe disease or inadequate prenatal care (MacKay et al., 2001). Interestingly, Hispanic ethnicity, while associated with an increased risk of pre-eclampsia, appeared to have a decreased risk of gestational hypertension (Wolf et al., 2004). Overall, it is difficult to determine racial differences in the incidence and severity of pre-eclampsia because of invariable confounding by socioeconomic and cultural factors. Conflicting data currently exist on the association of pre-eclampsia with congenital or acquired thrombophilia (Roque et al., 2004; Rasmussen and Ravn, 2004; Stella et al., 2006). It is not surprising that data from the USA from 1979 to 1986 suggest that for every year past age 34, a woman’s risk for pre-eclampsia increases, but some studies have also pointed to teenage pregnancy as a risk factor for pre-eclampsia, however, a subsequent meta-analysis and systematic review did not support the latter (Duckitt and Harrington, 2005).

B. Clinical Features and Pathophysiology Pre-eclampsia is often a diagnostic challenge in the settings of proteinuric renal disease or chronic hypertension. It may be difficult to distinguish from other hypertensive disorders during pregnancy, such as gestational hypertension and chronic hypertension. Guidelines on the diagnosis of preeclampsia published by the American College of Obstetrics and Gynecology were last updated in 2002 (ACOG Practice Bulletin, 2002).

1. HYPERTENSION Hypertension, as one of the criteria for the diagnosis of preeclampsia, is defined by the American College of Obstetrics and Gynecology (ACOG) as a systolic blood pressure of 140 mmHg or higher or a diastolic blood pressure of 90 mmHg or higher in two separate measurements at least 2 h apart, in a previously normotensive woman after 20 weeks’ gestation (ACOG Practice Bulletin, 2002). Blood pressure elevation in pre-eclampsia can vary considerably from mild, which may be treatable by bed rest alone, to severe, which may be resistant to multiple anti-hypertensive agents. When severe hypertension is accompanied by headache and visual disturbances as well, urgent delivery is indicated, as it may portend eclampsia.

In contrast to normal pregnancies, where peripheral vascular resistance and blood pressure are decreased, preeclampsia is marked by increased peripheral vascular resistance, which is the primary cause of the hypertension (Wallenberg, 1998). The rises in peripheral vascular resistance and blood pressure seen in pre-eclampsia are thought to be mediated by a substantial increase in sympathetic vasoconstrictor activity (Schobel et al., 1996). Results from a recent study suggested that this sympathetic over-activity may not be a secondary phenomenon of pre-eclampsia, but rather, a precursor of it (Fischer et al., 2004). An exaggerated response to angiotensin II and other hypertensive stimuli has also been found in pre-eclamptic women (Strauss, 1937; Gant et al., 1973; Gallery and Brown, 1987). In an animal model, an imbalance of expression of AT1 relative to AT2 receptors has been observed (Anguiano-Robledo et al., 2007). The hypertension seen in pre-eclampsia is distinctively characterized by suppression, rather than activation, of the renin–angiotensin–aldosterone system (August et al., 1990). Total plasma volume, however, is generally believed to be somewhat decreased (Redman, 1984). This perceived increase in effective circulating blood volume then leads to suppression of renin and aldosterone, as well as brain natriuretic peptide (Tapia et al., 1972; Okuno et al., 1999). The perturbations of the balance of vasoactive substances are thought to reflect the contribution of endothelial dysfunction to the development of hypertension (reviewed later in the section on maternal endothelial function). Imbalances in these vasoactive substances that are predominantly synthesized by the vascular endothelium, including the vasoconstrictors norepinephrine, endothelin and potentially thromboxane and placental endothelin 1 (ET-1), as well as the vasodilators, such as prostacyclin and possibly nitric oxide, appear to be responsible for the prominent vasoconstriction seen in pre-eclampsia (Clark et al., 1992; Mills et al., 1999; Noris et al., 2004; Fiore et al., 2005). Prostaglandin I2 (PGI2, prostacyclin) is a circulating vasodilator produced chiefly by endothelial and smooth muscle cells and is increased in normal pregnancy (Goodman et al., 1982). In women with pre-eclampsia, but not pregnant women with chronic hypertension, production of PGI2 is reduced before the appearance of hypertension and proteinuria (Fitzgerald et al., 1987; Moutquin et al., 1997; Mills et al., 1999). Thromboxane A2 (TXA2) is a potent vasoconstrictor produced by endothelial cells, activated platelets and macrophages. Its metabolites have been reported to be increased in the urine of pre-eclamptics in some studies, though not all (Fitzgerald et al., 1990; Paarlberg et al., 1998; Mills et al., 1999). TXA2 synthesis was noted to be higher in patients with coagulopathy and marked platelet activation (Paarlberg et al., 1998). Studies examining the effect of aspirin on the incidence of pre-eclampsia via inhibition of platelet TXA2 production have generally yielded conflicting data (CLASP Collaborative Group, 1994; Caritis et al., 1998).

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Nitric oxide (NO) has generated interest because of its putative role in normal pregnancy as a vasodilator (Williams et al., 1996; Conrad et al., 1999). In pregnant rats, its inhibition by NG-nitro-L-arginine methyl ester (L-NAME), an exogenous nitric oxide synthase (NOS) inhibitor, induced some of the clinical characteristics of pre-eclampsia (Danielson et al., 1995). Supplementation of L-arginine reversed the hypertension and proteinuria caused by infusion of L-NAME and decreased the extent of glomerular injury (Helmbrecht et al., 1996). Data in humans have been inconsistent, with some studies demonstrating decreased nitric oxide production and others noting no change or an increase (Seligman et al., 1994; Davidge et al., 1996; Silver et al., 1996; Garmendia et al., 1997; Smarason et al., 1997; Ranta et al., 1999; Shaamash et al., 2000). Although levels of asymmetric dimethyl arginine, an endogenous inhibitor of NOS, are elevated in pre-eclampsia, its very low levels render it technically challenging to study and interpret. In addition, L-arginine supplementation has not been shown to be of significant benefit in pre-eclampsia (Holden et al., 1998; Staff et al., 2004). Data on ET-1, a potent vasoconstrictor released by vascular endothelial cells in response to injury, have also been conflicting in pre-eclampsia (Clark et al., 1992; Schiff et al., 1992; Battistini and Dussault, 1998; Paarlberg et al., 1998; Slowinski et al., 2002). Some studies have reported increased circulating levels, while others have not. Current evidence suggests that endothelin alterations in pre-eclampsia are a secondary phenomenon (Greenberg et al., 1997; Scalera et al., 2001; Karumanchi et al., 2005).

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or neonatal outcomes and, therefore, not by itself an indication for urgent delivery (Hall et al., 2002). The proteinuria of pre-eclampsia is ‘non-selective’ and thought to stem from loss of glomerular barrier charge selectivity (Moran et al., 2003). Postpartum, proteinuria generally resolves within 7–10 days, although it may persist for 3–6 months.

3. EDEMA Edema is often present in normal pregnancies and is not specific to pre-eclampsia, however, sudden weight gain, particularly with edema of the feet, hands and face, is a common presenting symptom of pre-eclampsia. Women with preeclampsia given an intravenous saline load have been found to excrete a much smaller percentage than do normal pregnant women (Gallery and Brown, 1987). Unlike the edema of hepatic cirrhosis, congestive heart failure and nephrotic syndrome, in which low effective plasma volume results in activation of the RAAS and renal retention of salt, as mentioned, a primary renal retention of salt and water occurs in pre-eclampsia with suppression of the RAAS. The edema of pre-eclampsia is accompanied by a fall in GFR that is disproportionate to the decline in real plasma flow and, therefore, resembles the ‘over-fill’ edema of acute glomerulonephritis or of acute ischemic renal failure with volume overload (Schrier, 1998). Other contributing factors to the edema may be generalized increase in capillary permeability and hypoalbuminemia, but they are not unique to pre-eclampsia. Increased endothelial permeability is also seen in non-pregnant patients with heart failure and nephrotic syndrome (Galatius et al., 2000; Rostoker et al., 2000).

2. PROTEINURIA Although the urine dipstick method is frequently used to screen for proteinuria in routine prenatal monitoring, it has a high rate of false positives and false negatives in comparison to 24-hour urine protein measurement. In the nonobstetric population, the urine-protein-to-creatinine ratio (in units of mg protein per mg creatinine) is commonly used to estimate 24-hour protein excretion. While the urine-proteinto-creatinine ratio is not widely used among obstetricians, a number of studies have also supported use of the urineprotein-to-creatinine ratio in pregnant women, given that it closely approximates the 24-hour urinary protein excretion (Rodriguez-Thompson and Lieberman, 2001; Neithardt et al., 2002; Yamasmit et al., 2004). In these studies, spot urine protein-to-creatinine ratios >0.2 mg/mg are highly (>90%) sensitive for detection of significant (>300 mg) proteinuria by 24 hour collection in pregnant women in the third trimester. Proteinuria in pre-eclampsia can vary widely, from minimal to nephrotic-range. Although proteinuria exceeding 5 g per day is defined as severe pre-eclampsia according to the ACOG practice guidelines, the degree of proteinuria is not considered an independent risk factor for adverse maternal

4. URIC ACID A serum uric acid level greater than 5.5 mg/dl is a strong indicator of pre-eclampsia. The elevation of uric acid is attributed chiefly to decreased renal clearance and often precedes the onset of proteinuria and fall in GFR (Gallery and Gyory, 1979). In humans given infusions of vasoconstrictors, similar declines in uric acid clearance have been observed (Ferris and Gorden, 1968). Lowering serum uric acid with probenecid, however, does not appear to have any effect on the blood pressure in women with pre-eclampsia (Schackis, 2004). The serum level of uric acid rises as preeclampsia progresses and correlates with its severity, as well as with adverse pregnancy outcome; a level greater than 7.8 mg/dl is associated with significant maternal morbidity (Martin et al., 1999; Thadhani et al., 2005). The degree of uric acid rise also correlates with the severity of proteinuria and renal pathological changes and with fetal demise (Martin et al., 1999). Because the serum uric acid level in women with gestational hypertension similarly correlates with severity of disease and poor pregnancy outcomes, it is of limited clinical utility in distinguishing pre-eclampsia from other hypertensive disorders of pregnancy and/or as a

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clinical predictor of adverse outcomes (Lim et al., 1998; Lam et al., 2005; Roberts et al., 2005). A recent meta-analysis of data from 18 studies including nearly 4000 women concluded that serum uric acid is a weak predictor of maternal and fetal complications in women with pre-eclampsia (Thangaratinam et al., 2006). Nevertheless, pre-eclampsia superimposed on chronic renal disease may be a clinical setting where serum uric acid could be useful, as the diagnostic criteria of new-onset hypertension and proteinuria may be difficult to apply. In such cases, a serum uric acid level that exceeds 5.5 mg/dl and stable renal function may suggest the diagnosis of pre-eclampsia. Still debated is whether uric acid plays a direct role in the pathogenesis of pre-eclampsia by inducing endothelial dysfunction (Khosla et al., 2005).

5. RENAL CHANGES AND PATHOLOGY In contrast to normal pregnancy, where GFR and renal plasma flow increase during early and mid-pregnancy, in pre-eclampsia, GFR and renal plasma flow are both decreased. Because of pregnancy’s overall effect of augmenting GFR, BUN and serum creatinine often remain in the normal, non-pregnant range in pre-eclampsia despite the latter’s significant GFR-lowering effect. Although acute renal failure can be seen in pre-eclampsia, it is more common for only proteinuria and renal sodium and water retention to manifest. Renal filtration fraction is lower in pre-eclamptics than in normal women in the 3rd trimester of pregnancy (Lafayette et al., 1998; Moran et al., 2003). The fall in renal

blood flow (RBF) is a consequence of high renal vascular resistance, chiefly from increased afferent arteriolar resistance. GFR declines because of the decreases in RBF and in the ultrafiltration coefficient (Kf), which is attributed to endotheliosis in the glomerular capillary (Moran et al., 2003). The urinary sediment of pre-eclamptics is usually ‘bland’, with no or few white and red blood cells, and cellular casts. Recent evidence reveals that ‘podocyturia’, the urinary excretion of glomerular visceral epithelial cells (podocytes) may be a novel way to distinguish women with pre-eclampsia from non-proteinuric, normotensive pregnant women (Garovic et al., 2007). As a diagnostic, though not necessarily a predictive, marker, this remains to be validated by larger studies. The unique appearance of glomerular endothelial cells in pre-eclampsia is termed ‘glomerular endotheliosis’ and describes narrowed glomerular capillary lumen that are typically ‘bloodless’, enlarged glomeruli with generalized swelling and vacuolization of endothelial cells (Figure 30.1). Glomerular cellularity may be slightly increased and mesangial interposition may occur in severe cases or in the healing stages (Spargo et al., 1959; Pollak and Nettles, 1960). Immunofluorescence may reveal deposits of fibrin and fibrinogen within the endothelial cells, particularly in biopsies done within 2 weeks postpartum (Morris et al., 1964). Electron microscopy shows loss of glomerular endothelial fenestrae, but with relative preservation of the podocyte foot processes. Glomerular subendothelial and occasional

FIGURE 30.1 Glomerular endotheliosis. (A) Normal human glomerulus, H & E. (B) Human pre-eclamptic glomerulus, H & E – 33-yearold woman with twin gestation and severe pre-eclampsia at 26 weeks’ gestation with urine protein/creatinine ratio of 26 at the time of biopsy. (C) Electron microscopy of glomerulus of the above patient described in (b). Note occlusion of capillary lumen cytoplasm and expansion of the subendothelial space with some electron-dense material. Podocyte cytoplasms show protein resorption droplets and relatively intact foot processes; original magnification 1500 . (D) Control rat glomerulus, H & E – note normal cellularity and open capillary loops. (E) sFlt-1 treated rat, H & E – note occlusion of capillary loops by swollen cytoplasm with minimal increase in cellularity. (F) Electon microscopy of sFlt1 treated rat – note occlusion of capillary loops by swollen cytoplasm with relative preservation of podocyte foot processes; original magnification 2500 . All light micrographs taken at identical original magnification of 40. This figure was reproduced with permission from Karumanchi et al. (2005). (See color plate section.)

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mesangial electron-dense deposits can also be seen (Mautner et al., 1962; Lafayette et al., 1999). In contrast to other nephrotic diseases, where podocytes are damaged early in the disease, the primary focus of injury in pre-eclampsia is the endothelial cell. Other renal histological changes that have been described include atrophy of the macula densa and hyperplasia of the juxtaglomerular apparatus (Govan, 1954). It is now known that mild glomerular endotheliosis can be seen in non-pre-eclamptic pregnant women. Indeed, up to 50% of patients with non-proteinuric pregnancyinduced hypertension exhibit mild glomerular endotheliosis (Nochy et al., 1980; Fisher et al., 1981), perhaps suggesting that pregnancy-induced hypertension may represent an early or mild form of pre-eclampsia, or even a phenomenon that occurs at term in all pregnancies. The glomerular enlargement and endothelial swelling generally resolve within 8 weeks postpartum, along with resolution of the proteinuria and hypertension. However, persistent renal damage can follow pre-eclampsia in the form of focal segmental glomerulosclerosis (FSGS) in 50% or more of cases (Heaton and Turner, 1985; Gaber and Spargo, 1987).

6. SEVERE PRE-ECLAMPSIA AND ECLAMPSIA Severe pre-eclampsia should prompt a consideration to terminate pregnancy, given the potential life-threatening nature of maternal morbidity. The clinical and laboratory findings that indicate severe disease include: oliguria (less than 500 ml urine in 24 h, typically transient) and, uncommonly, acute renal failure. Pulmonary edema is seen in 2–3% of severe pre-eclampsia and can lead to respiratory failure (Tuffnell et al., 2005). Elevated liver enzymes can occur alone or as part of the HELLP syndrome and may be associated with epigastric or right upper quadrant pain. Persistent headache or visual disturbances can portend seizures (eclampsia), seen in roughly 2% of cases of pre-eclampsia in the USA (Saftlas et al., 1990). Typically, but not invariably, eclampsia occurs in the presence of hypertension and proteinuria. Late postpartum eclampsia is a diagnostic challenge, accounts for up to one-third of cases, occasionally days to weeks after delivery, and is frequently seen by nonobstetricians in the emergency room setting. Magnetic resonance imaging (MRI) or computed tomography (CT) of the head usually reveals vasogenic edema and infarctions in subcortical white matter and adjacent gray matter of the parieto-occipital lobes, however, radiological head imaging is not necessary if the diagnosis is otherwise clear (Sibai, 2005). The cerebral edema of eclampsia predominantly involves the posterior, parieto-occipital lobes and is similar to images described in reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome characterized by headache, altered mental status, convulsions and cortical blindness (Hinchey et al., 1996). Cerebral edema is thought to result primarily from endothelial dysfunction rather than from hypertension, as it appears to parallel markers of

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endothelial damage, rather than severity of hypertension (Schwartz et al., 2000). This is confirmed by autopsy findings of cerebral edema and intracerebral parenchymal hemorrhage in women who have died from eclampsia. Cerebral vasospasm, excitation of brain receptors, a hyperactive sympathetic nervous system and hypertensive encephalopathy from cerebral overperfusion have all been associated with eclamptic seizures (Belfort et al., 2006). Most of these women have been found to have cerebral overperfusion rather than ischemia (Belfort et al., 2001). Interestingly, RPLS can be precipitated by acute blood pressure rises and treatment with antiangiogenic agents such as bevacizumab, a monoclonal antibody against VEGF and its receptors (Hinchey et al., 1996; Ozcan et al., 2006). This appears to align with the accumulating evidence on the role of antiangiogenic factors in the pathophysiology of pre-eclampsia/ eclampsia.

7. HELLP SYNDROME AND HEMATOLOGICAL ABNORMALITIES Although it can occur in the absence of proteinuria, the HELLP syndrome is generally considered to be a severe variant of pre-eclampsia. It develops in approximately 10–20% of women with severe pre-eclampsia. The HELLP syndrome can be complicated by eclampsia (6% of cases), placental abruption (10%), acute renal failure (5%), disseminated intravascular coagulation (8%) and pulmonary edema (10%). Rarely, hepatic hemorrhage and rupture can occur, even after delivery of the fetus; associated maternal and perinatal mortality rates of 59 and 42%, respectively, have been reported (Haddad et al., 2000; Dessole et al., 2007). The HELLP syndrome is a consumptive coagulopathy and thrombotic microangiopathy that shares many clinical and biological features with thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) (Gando et al., 1995; Boehme et al., 1996; Rath et al., 2000; Mori et al., 2001). In normal pregnancy, coagulation is enhanced because the circulating levels of all coagulation factors are increased, including those made in the liver and in the vascular endothelium (Cadroy et al., 1993). In preeclampsia, however, only factors that are synthesized by the vascular endothelium are elevated (Friedman et al., 1995). These factors include prostacyclins (PGI2), thrombomodulin, cellular fibronectin, PAI-1 and von Willebrand factor (vWF) (Estelles et al., 1989; Taylor et al., 1991; Hsu et al., 1993; Friedman et al., 1995). Plasma concentrations of cellular fibronectin are increased weeks before the onset of hypertension (Chavarria et al., 2002). Exposure of cultured endothelial cells to serum from pre-eclamptic women results in greater cellular fibronectin and thrombomodulin release compared to serum from normotensive pregnant women (Taylor et al., 1991; Roberts et al., 1992; Kobayashi et al., 1998). Recently, it was shown that the large vWF multimers (normally cleaved by the metalloproteinase ADAMTS13)

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that are highly reactive with platelets may be increased in women with the HELLP syndrome because of both endothelial activation and, similar to TTP, decreased ADAMTS13 levels (Hulstein et al., 2006). Other markers of endothelial injury that have also been reported will be reviewed in the section on maternal endothelial function.

C. Long-Term Cardiovascular and Renal Outcomes Although the symptoms of pre-eclampsia appear to remit completely following delivery of the fetus, many of these women ultimately develop cardiovascular and renal morbidity later. Women with a history of pre-eclampsia continue to have impaired endothelial-dependent vasorelaxation, as measured by brachial artery flow-mediated dilatation up to 3 years postpartum, implying that changes in the maternal endothelium may be long-standing (Chambers et al., 2001; Agatisa et al., 2004). About 20% of women with preeclampsia are found to have hypertension or microalbuminuria on long-term follow-up (Nisell et al., 1995). One study observed that development of subsequent ischemic heart disease was increased by 1.7-fold and hypertension by 2.4fold in women with pre-eclampsia, which was confirmed by two large subsequent European studies (Hannaford et al., 1997; Irgens et al., 2001; Smith et al., 2001). Women with pre-eclampsia and gestational hypertension have a roughly twofold increase in cardiovascular and cerebrovascular risk compared to age-matched controls (Irgens et al., 2001; Ray et al., 2005). The rates of heart disease among women with pre-eclampsia complicated by pre-eclampsia with preterm birth or intrauterine growth restriction and among those with severe or recurrent pre-eclampsia were increased by up to

eightfold (Irgens et al., 2001; Smith et al., 2001). Risk of maternal renal morbidity requiring kidney biopsy has also been found to be increased in women with pre-eclampsia accompanied by low birth weight (Vikse et al., 2006). Because pre-eclampsia and cardiovascular disease share many common risk factors, such as obesity, chronic hypertension, diabetes mellitus, renal disease and the metabolic syndrome, it may well be the reason their risks are so closely linked. However, the increase in long-term cardiovascular mortality appears to be present even for women who develop pre-eclampsia without clear cardiovascular risk factors, raising the possibility that perhaps pre-eclampsia itself causes vascular damage and persistent endothelial dysfunction. Children who were products of pregnancies complicated by low birth weight with or without pre-eclampsia have been observed to have a higher incidence of subsequent hypertension, diabetes, cardiovascular disease and chronic kidney disease (Zandi-Nejad et al., 2006).

D. Pathogenesis of Pre-Eclampsia (Figure 30.2) 1. ABNORMAL PLACENTATION Accumulating evidence has pointed to the placenta’s pivotal role in the pathogenesis of pre-eclampsia. It is removal of the placenta, rather than the fetus, which leads to the amelioration of symptoms, as evident in cases of hyatidiform moles and extrauterine pregnancies, where delivery of the fetus is insufficient (Shembrey and Noble, 1995). Common pathological findings in pre-eclamptic placentas include atherosis, necrosis, sclerotic narrowing of arteries and arterioles, fibrin deposition, thrombosis, endothelial damage, atherosclerosis and infarcts, all consistent with placental hypoperfusion and ischemia, which appear to correlate to the severity of

FIGURE 30.2 Summary of the pathogenesis of pre-eclampsia.

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pre-eclampsia (Hertig, 1945; Salafia et al., 1998). Hypoxia has been implicated as a contributing factor because of the two- to four-fold increased incidence of pre-eclampsia in women living at high altitudes (Palmer et al., 1999). The finding of abnormal uterine artery Doppler ultrasound, suggesting decreased uteroplacental perfusion, typically precedes the onset of pre-eclampsia, although it is non-specific for pre-eclampsia (North et al., 1994; Lees et al., 2001; Frusca et al., 2003). In various species, constriction of uterine blood flow has reproduced hypertension, proteinuria and glomerular endotheliosis (Kumar, 1962; Combs et al., 1993; Podjarny et al., 1999). Finally, it has been suggested that a decrease in placental production of nitric oxide may contribute to placental ischemia (Noris et al., 2004). Based on this evidence, a causative role for placental ischemia may be likely, but other data have challenged ischemia as the sole cause of pre-eclampsia. Animal models of uterine hypoperfusion have not been able to reproduce the full clinical syndrome seen in humans, such as seizures and the hallmark renal pathological finding of glomerular endotheliosis. Based on the frequent finding of placental ischemia and infarction in women with sickle cell disease, it could be theorized that they might have a higher incidence of pre-eclampsia, however, thus far, the data have been inconsistent (Larrabee and Monga, 1997; Stamilio et al., 2003). It appears that, while ischemia may be an important trigger, it is not present in all cases of pre-eclampsia and the maternal response to placental ischemia is variable.

2. PLACENTAL VASCULAR DEVELOPMENT In the course of normal placental development, cytotrophoblasts attach to the uterine decidua by means of anchoring villi; a small percentage of cytotrophoblasts in the anchoring villi migrate into the endometrium. The process whereby these extravillous cytotrophoblasts invade the uterine spiral arteries of the decidua and myometrium peaks around the 12th week of gestation. By 18–20 weeks, the cytotrophoblasts have lined the endometrial and superficial myometrial portion of the spiral arteries and have converted the arteries from small resistance vessels to high-caliber capacitance vessels (Brosens et al., 1972; De Wolf et al., 1980). Vascular remodeling permits an increase in uterine blood flow that is essential to nourish the developing fetus throughout pregnancy. In addition, the process by which the invasive cytotrophoblasts transform from an epithelial to endothelial phenotype, termed ‘pseudovasculogenesis’ is required to take place in order for normal placental development to ensue. This process describes the downregulation of the expression of adhesion molecules typical of epithelial cells and switch to expression of endothelial cell surface molecules by the invasive fetal cells (Zhou et al., 1997). Defective placental vascular remodeling is thought to cause the placental ischemia seen in pre-eclampsia (Robertson et al., 1967). Pseudovasculogenesis fails to

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occur, which impedes normal invasion of the myometrial spiral arteries. This superficial invasion of the decidua results in narrow and undilated proximal segments of the spiral arteries, which ultimately leads to uterine hypoperfusion (Meekins et al., 1994; Zhou et al., 1997a, b). The abnormalities in cytotrophoblast differentiation found in the placentas of pre-eclamptics suggest that the mechanisms contributing to placental ischemia are set into motion very early in pregnancy, although their determinants have yet to be fully elucidated. Placentas from women with pre-eclampsia have been found to over-express the hypoxia-inducible transcription factor proteins, HIF-1a and -2a (Rajakumar et al., 2003). The HIF-1a protein over-expressed in pre-eclamptic placentas has been shown to be capable of binding to the DNA hypoxia response element in vitro and target genes regulated by the HIF pathway appear to be altered in preeclamptic placentas in vivo (Rajakumar et al., 2003). Placental sFlt-1 expression has been observed to be increased by both physiologically and pathologically low levels of oxygen in women living at high altitudes and those with pre-eclampsia, respectively, which appears to be mediated by HIF-1 (Nevo et al., 2006). Other HIF-1 target genes, such as transforming growth factor beta-3 (TGF-b3) may block cytotrophoblast invasion (Caniggia et al., 2000). Expression of a number of angiogenic factors and receptors that are regulated by HIF on invasive cytotrophoblasts has been found to be altered in pre-eclampsia, including VEGF, PlGF and VEGFR-1 (Zhou et al., 2002). Epidermal growth factor (EGF) receptors are expressed in both extra-villous and villous cytotrophoblasts, as well as syncytiotrophoblasts of first trimester placentas. EGF was recently shown to promote differentiation of isolated term trophoblasts and regulate invasion of extravillous trophoblasts. It has also been demonstrated to be decreased in pre-eclamptic cytotrophoblasts, however, its exact role in pseudovasculogenesis it unclear (Moll et al., 2007). In non-human primates with uteroplacental hypoperfusion induced by aortic constriction, proteinuria and hypertension, but not defective placental cytotrophoblast invasion, were induced (Zhou et al., 1993). Genetic studies of the STOX1 gene, which encodes a putative DNA binding protein involved in trophoblast differentiation, have thus far yielded conflicting data on whether maternally-inherited mutations in this gene within the 10q22 locus might account for matrilineal pre-eclampsia in Dutch women (van Dijk et al., 2005; Berends et al., 2007). Despite these recent advances in our knowledge of the mechanisms underlying the abnormalities in pseudovasculogenesis, the defects of placental cytotrophoblast invasion remain incompletely understood.

3. MATERNAL ENDOTHELIAL FUNCTION Because pre-eclampsia appears to originate in defective placentation and progress to widespread endothelial dysfunction manifesting as vasoconstriction and end-organ

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damage, circulating factors derived from the placenta have been suspected as the culprits for the clinical syndrome (Roberts et al., 1989; Ferris, 1991). The search for these circulating factors has revealed numerous potential serum markers of endothelial dysfunction, such as von Willebrand antigen, cellular fibronectin, soluble tissue factor, soluble E-selectin, platelet-derived growth factor, endothelin, tumor necrosis factor-a (TNF-a), interleukin (IL)-6, IL-1, Fas ligand, neurokinin B, asymmetric dimethy L-arginine (ADMA), C-reactive protein and leptin (Roberts et al., 1989; Page et al., 2000; Roberts, 2000; Walker, 2000; Roberts and Cooper, 2001; Chappell et al., 2002; Savvidou et al., 2003; Qiu et al., 2004). Production of PGI2, an endothelial-derived prostaglandin, is also diminished prior to the onset of clinical symptoms (Mills et al., 1999). Markers of endothelial injury, including the adhesion molecules soluble P-selectin, soluble E-selectin, and soluble vascular cell adhesion molecule-1 (VCAM-1) have been noted to be elevated in pre-eclampsia (Chaiworapongsa et al., 2002). That a number of these endothelial biomarkers of interest are altered before the onset of symptoms again points to the pivotal role of endothelial dysfunction in pre-eclampsia. Recent data suggest that increased syncytiotrophoblast microfragment shedding occurs as a result of placental apoptosis (Sargent et al., 2003). The syncytiotrophoblast microparticles have been found to circulate in bound (to monocytes) and unbound forms in pregnancy, but are substantially increased in the unbound form in the circulation of pre-eclamptics. This placental ‘debris’ appears to lead to greater stimulation of inflammatory cytokine production in vitro and has therefore been hypothesized to contribute to generalized endothelial dysfunction, although no in vivo data exist to support this (Cockell et al., 1997; Germain et al., 2007). There has been recent interest in p57Kip2, a cell-cycle inhibitor and paternally-imprinted gene in mice and humans. Pregnant mice that were heterozygous for p57Kip2 deficiency appeared to exhibit the full pre-eclamptic syndrome, including abnormal placentation, hypertension, proteinuria, glomerular endotheliosis thrombocytopenia and increased endothelin levels in late pregnancy, in addition to trophoblastic hyperplasia (Kanayama et al., 2002). These findings, however, were not fully replicated in a subsequent study, which suggested that perhaps this is a model in which placental abnormalities cause pre-eclampsia only in the setting of specific environmental variables (Knox and Baker, 2007).

4. IMMUNOLOGIC MALADAPTATION As mentioned previously, because pre-eclampsia is more common in first pregnancies, with a change in partners and with long inter-pregnancy interval, immunological intolerance to paternal fetal antigens has been invoked as a cause, although it remains unproven (Tubbergen et al., 1999; Skjaerven et al., 2002). In general, decreased exposure to a

partner’s sperm has been observed to increase the incidence of pre-eclampsia. These include contraceptive methods that reduce exposure to sperm and conception by intracytoplasmic sperm injection (ICSI) (Klonoff-Cohen et al., 1989; Wang et al., 2002). Prior exposure to paternal antigens, conversely, such as by co-habitation or oral tolerization, leads to lower risk of pre-eclampsia (Robillard et al., 1993; Koelman et al., 2000). Expression of HLA-G is typically found on invasive extravillous cytotrophoblasts and has been reported to be abnormally low or absent in pre-eclampsia, indicating a possible role in determining immune tolerance and possibly trophoblast invasion at the maternal–fetal interface. Natural killer (NK) cells in the maternal–fetal interface, which are thought to play an important role in innate immunity, have been recently noted to play an important role during normal placental vascular remodeling. Moreover, genetic studies suggest that the susceptibility to pre-eclampsia may be influenced by polymorphic HLA-C ligands and the killer cell receptors (KIR) present on NK cells. Analysis of various human populations revealed a strong association between the lack of KIR AA and the presence of HLA-C2 haplotypes (that appear to favor unfavorable trophoblast invasion) and the occurrence of pre-eclampsia (Hiby et al., 2004). Based on these observations, a hypothesis was formulated indicating that, in normal pregnancies, dNK cells activation through interaction with HLA-C on extravilous trophoblasts would promote placental development and maternal decidual spiral artery modifications by extra-villous cytotrophoblasts. Insufficient dNK cell activation would halt this process prematurely resulting in poor decidual artery remodeling, increasing the risk of pre-eclampsia (Hiby et al., 2004; Parham, 2004).

5. OXIDATIVE STRESS Accumulating evidence indicates that oxidative stress plays a role in human placental pathologies, such as pre-eclampsia and intrauterine growth restriction. Some studies have shown elevation of markers of oxidative stress in women with preeclampsia, although not all studies have confirmed this (Hubel, 1999; Regan et al., 2001). Superoxides and free radicals generated during maternal oxidative stress could attack cell membranes, proteins and nucleic acids, resulting in placental damage, and initiating maternal endothelial dysfunction and leukocyte activation (Hubel, 1999). The production of superoxide by neutrophils appears to differ for pregnant women with essential hypertension, in whom neutrophil activation remains unchanged postpartum, and for pre-eclamptics, in whom neutrophilic superoxide generation abates after delivery, prompting the suggestion of the presence of a neutrophil-activating serum factor in preeclampsia (Tsukimori et al., 2007). Some clinical and in vitro evidence has indicated that antioxidant supplementation may decrease the incidence of pre-eclampsia, including inhibition of monocyte adhesion by N-acetylcysteine,

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vitamin C and vitamin E to human umbilical vascular endothelial cells (HUVEC) in the presence of pre-eclamptic, but not normal pregnant serum (Ryu et al., 2007). Subsequent large trials, however, have not validated these findings (Chappell et al., 1999; Roberts and Speer, 2004; Poston et al., 2006; Rumbold et al., 2006). Given that dietary intake of food rich in antioxidants is more effective than vitamin E and C supplementation in preventing atherosclerotic vascular disease, it may well be that the focus in pre-eclampsia should be on different antioxidants. Nevertheless, this may also be consistent with the role of oxidative stress as a secondary phenomenon, rather than as a primary causative factor in the pathogenesis of pre-eclampsia, which remains to be proven.

6. ANGIOGENIC FACTORS Using gene expression profiling to identify the factor(s) produced by the placenta in pre-eclampsia, placental sFlt-1 mRNA was found to be upregulated (Maynard et al., 2003). sFlt-1 is a splice variant of vascular endothelial growth factor (VEGF) receptor Flt-1 that lacks the transmembrane and cytoplasmic domains and is produced and released by the placenta into maternal circulation (Kendall and Thomas, 1993; Clark et al., 1998; Zhou et al., 2002). It then binds to circulating VEGF and PlGF (Banks et al., 1998). In rats, sFlt-1 reproduced the maternal syndrome of hypertension, proteinuria and glomerular endotheliosis (see Figure 30.1). In vitro angiogenesis assays revealed that the anti-angiogenic effects of pre-eclamptic serum can be reversed by exogenous VEGF and PlGF (Maynard et al., 2003). In women with preeclampsia, circulating levels of sFlt-1 were found to be increased (Maynard et al., 2003; Koga et al., 2003; Tsatsaris et al., 2003; Chaiworapongsa et al., 2004). Correspondingly, levels of free VEGF and PlGF are decreased in pre-eclamptics, both before and during disease (Polliotti et al., 2003; Taylor et al., 2003). Beginning at about 5–6 weeks prior to the onset of the clinical syndrome, sFlt-1 concentrations rise dramatically and free VEGF and PlGF fall, correlating with earlier onset and severity of disease, as well as the risk of having a small-for-gestational-age infant (Hertig et al., 2004; Levine et al., 2004). In women who develop pre-eclampsia, a modest, but significant decrease in serum PlGF levels is seen as early as the 1st trimester, however, the concentration of free PlGF in plasma drops dramatically when sFlt-1 levels begin to rise in mid-pregnancy. Unbound PlGF is also freely filtered into the urine and, consistent with decreased serum concentrations of unbound PlGF, mid-gestation diminished levels of free PlGF in the urine are also predictive of development of pre-eclampsia (Buhimschi et al., 2005; Levine et al., 2005). These data suggest that sFlt-1 potentially plays a central role in the pathogenesis of pre-eclampsia. VEGF promotes angiogenesis and plays a critical role in preserving glomerular endothelial cell health, as evidenced by proteinuria and glomerular endotheliosis in its absence

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(Ostendorf et al., 1999; Masuda et al., 2001; Eremina et al., 2003; Sugimoto et al., 2003). In the kidneys, it is constitutively expressed and serves to maintain the fenestrated endothelia; antagonism by sFlt-1 results in the expected glomerular injury that is seen in pre-eclampsia (Esser et al., 1998; Eremina et al., 2003). In addition, VEGF induces nitric oxide and vasodilatory prostacyclins in endothelial cells, which decrease vascular tone and blood pressure (He et al., 1999). Symptoms of headaches, hypertension, proteinuria and coagulopathy have been reported in reaction to neutralizing antibodies to VEGF used in oncology trials (Kuenen et al., 2002; Kabbinavar et al., 2003; Yang et al., 2003). Current evidence points to the fact that angiogenic factors are very likely to be important in the regulation of placental vasculogenesis. The mechanism by which placental dysfunction influences sFlt-1 production has yet to be elucidated, however, evidence exists in in vitro primary cytotrophoblast cultures pointing to the possible role of placental hypoxia in upregulating sFlt-1 production (Nagamatsu et al., 2004). Recently, it was reported that isolated decidual cells express sFlt-1 mRNA, suggesting that they can synthesize sFlt-1 and that these mRNA levels in 1st trimester, but not term decidual cells were increased by thrombin. Based on this, it was hypothesized that thrombin could be influencing decidual cells to interfere with placental pseudovasculogenesis (Lockwood et al., 2007). In vitro, sFlt-1 decreases cytotrophoblast invasiveness (Zhou et al., 2002). Placental tissue has high expression of VEGF ligands and receptors in the first trimester (Yancopoulos et al., 2000). Early in pregnancy, sFlt-1 levels are relatively low, but begin to rise in the 3rd trimester. The theory behind this timing is that placental vascular development relies on the balance between pro- and anti-angiogenic factors. An excess of the latter (e.g. sFlt-1) early in pregnancy might lead to defective cytotrophoblast invasion. In late gestation, high levels of sFlt-1 could be considered physiologic and represent completion of the vasculogenic phase of placental development and, therefore, a shift in angiogenic balance. Certain patterns of elevated circulating sFlt-1 have been observed in various groups: higher sFlt-1 levels have been found in first versus second pregnancies, in twin versus singleton pregnancies (Maynard et al., 2005; Wolf et al., 2005; Bdolah et al., 2006) and in non-smokers versus smokers, the latter of whom have also been noted to have a lower incidence of pre-eclampsia, possibly explained by the lower circulating sFlt-1 levels (Belgore et al., 2000; Lain et al., 2003; Levine et al., 2006). Another placental anti-angiogenic protein, soluble endoglin (sEng), was recently reported to be high in preeclamptics. Endoglin (Eng or CD105) is an angiogenic receptor that is expressed on the surface of endothelial cells and placental syncytiotrophoblasts and acts as a co-receptor for TGF-b3, a potent proangiogenic molecule. Eng mRNA has been shown to be upregulated in the pre-eclamptic placenta (Venkatesha et al., 2006). Soluble endoglin (sEng)

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is the extracellular 65-kDa proteolytically cleaved form of endoglin that is released into the circulation and was recently found to be elevated in women with pre-eclampsia. In rats, sEng appeared to augment the vascular injury of sFlt-1, with a resultant severe pre-eclampsia-like syndrome similar to the HELLP syndrome. In explant cultures of trophoblasts from gestational week 5–8, mAb to Eng and antisense Eng oligonucleotides stimulated trophoblast outgrowth and migration (Caniggia et al., 1997). TGF-b1 and/or TGF-b3 inhibition of the migration and invasion appeared to be mediated by sEng, leading to the hypothesis that production of sEng by the placenta may be a compensatory mechanism to limit the effects of Eng. Subsequently, sEng was observed to be elevated in the serum of pre-eclamptic women 8–12 weeks before the clinical onset of the disease (Levine et al., 2006). Elevations in sEng were most marked and likely most useful for prediction in women who developed preterm pre-eclampsia or pre-eclampsia with a small-for-gestational-age fetus. Multivariate analysis indicated that sEng, sFlt-1 and PlGF were independently and significantly associated with pre-eclampsia, although the pattern of sEng concentration throughout pregnancy tended to parallel that of the sFlt-1/ PlGF ratio. In this study, combining all three was even more strongly predictive of pre-eclampsia than the individual biomarkers. Recent in vitro data demonstrated that adenoviral overexpression of heme oxygenase-1 (HO-1) in endothelial cells resulted in decreased sFlt-1 and sEng production, while HO-1 small interfering RNA (siRNA) knockdown and pharmacological inhibition of HO-1 activity in placental villous explants potentiated endothelial sFlt-1 and sEng release (Cudmore et al., 2007). How exactly sEng might interact with sFlt-1 to produce this clinical picture in humans requires further investigation. Other angiogenic molecules have also been identified. Endostatin is another antiangiogenic factor that is modestly raised in pre-eclampsia (Hirtenlehner et al., 2003). In preeclamptic placenta, the soluble form of Flk (VEGFR-2) has been found, although its function in placental vasculogenesis is unclear (Ebos et al., 2004). Insulin resistance is common among women who develop pre-eclampsia and conversely, women with pre- or gestational diabetes mellitus are at greater risk of developing pre-eclampsia (Wolf et al., 2002; Duckitt and Harrington, 2005). Women with previous pre-eclampsia or gestational hypertension exhibit signs of altered angiogenesis and insulin resistance within the first decade postpartum. Therefore, insulin resistance and defective angiogenesis may represent the link between hypertensive diseases of pregnancy and long-term cardiovascular risk in this population (Thadhani et al., 2004; Wolf et al., 2004; Girouard et al., 2007).

7. RENIN–ANGIOTENSIN SYSTEM As noted previously, vascular responsiveness to angiotensin II and other vasoconstrictive agents is heightened in preeclamptic compared to normal pregnancies. Plasma renin

levels are also suppressed in pre-eclamptics compared to normotensive pregnant women as a response to systemic vasoconstriction and hypertension. Antiogensin-1 receptor (AT1) agonistic autoantibodies have been identified in malignant renovascular hypertension and in transplant patients with vascular rejection, as well as in women with preeclampsia and have been hypothesized to account for the increased sensitivity to angiotensin II seen in pre-eclamptics (Wallukat et al., 1999; Fu et al., 2000). These AT1 activating antibodies (AT1-AA) were then shown to activate endothelial cells to produce tissue factor, an early marker of endothelial dysfunction (Dechend et al., 2000). Subsequently, AT1-AAs were found to increase PAI-1 production and lower invasiveness of human trophoblasts in vitro, suggesting that they may contribute to defective placental pseudovasculogenesis (Xia et al., 2003). It was recently shown that significantly more women with a history of pre-eclampsia had persistently detectable AT1-AAs even at 18 months’ postpartum, compared to women who had normal pregnancies (Hubel, 1999). The autoantibody-positive women also had significantly increased sFlt-1, reduced free VEGF and higher insulin resistance homeostasis model assessment values compared with autoantibody-negative women. This raises the question of the long-term cardiovascular impact of AT1-AAs. However, the autoantibodies may be non-specific for placental hypoperfusion, since they have also been found in women with abnormal second trimester uterine artery Doppler studies who later had normal pregnancies or intrauterine growth retardation (Walther et al., 2005). The finding of heterodimerization of AT1 with bradykinin 2 receptors has been thought to explain sensitization to the vasopressor response of angiotensin II in pre-eclampsia (AbdAlla et al., 2001). In hypertensive rats, specific inhibition of these AT(1)/B-2 receptor heterodimers have revealed that they appear to mediate increased endothelin-1 secretion and enhanced angiotensin II-stimulated G alpha(q/11) activation in mesangial cells. Thus, AT(1)/B-2 receptor heterodimerization contributes to angiotensin II hyper-responsiveness of mesangial cells in experimental hypertension (AbdAlla et al., 2005).

E. Screening and Treatment 1. SCREENING Despite the lack of effective treatment or prevention of preeclampsia, monitoring and supportive care is still beneficial to the patient and fetus, as evidenced by the poor outcomes seen with inadequate antenatal care (Abi-Said et al., 1995). Nulliparous women with any risk factors should be evaluated every 2–3 weeks after 20 weeks of gestation to monitor for the development of hypertension, proteinuria, headache, visual disturbances or epigastric pain. Screening for preeclampsia using uterine artery Doppler is not considered standard practice in the USA, however, the utility of combining uterine artery Doppler with serum markers remains to

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be seen (Parra et al., 2005). Biomarkers for pre-eclampsia that have shown promise have included cellular fibronectin (Chavarria et al., 2002), plasma neurokinin-B (Page et al., 2000) and, more recently, serum sFlt-1, PlGF and sEng, as well as urinary PlGF (Levine et al., 2004, 2005, 2006). Maternal sFlt-1 levels increase approximately 5–8 weeks before onset of pre-eclampsia. Serum PlGF concentrations are conversely lower starting in the 1st or early 2nd trimester and urinary PlGF may be significantly reduced starting in late 2nd trimester, although the latter is not borne out by all studies (Livingston et al., 2001). Recently, a placental protein-13, a member of the galectin family, was found to be depressed as early as the 1st trimester in patients who are at risk for developing pre-eclampsia (Chafetz et al., 2007). Numerous approaches have been used in studies for the prevention of pre-eclampsia, including antiplatelet agents, calcium and antioxidants. Despite early trials showing aspirin’s apparent benefit, it was not subsequently borne out in most trials to be effective in lowering the incidence of pre-eclampsia, except perhaps in those at highest risk, in whom the modest benefits would still need to be weighed against the risks (Salmela et al., 1993; Askie et al., 2007). In those at low risk for pre-eclampsia, it is thought that the benefit is minimal (Subtil et al., 2003). Calcium supplementation is recommended for women who have a low baseline dietary calcium intake (<600 mg/day) and for those who are at high risk of gestational hypertension. In a large, randomized, placebo-controlled trial, calcium did not lower the incidence of pre-eclampsia, but it did diminish the rate of eclampsia, gestational hypertension, complications of pre-eclampsia and neonatal mortality (Villar et al., 2006). As mentioned, antioxidants have been studied in pre-eclamptics, based on the theory that oxidative stress may play a central role in the pathogenesis of pre-eclampsia. Once again, large trials have failed to demonstrate that antioxidant supplementation reduces pre-eclampsia (Poston et al., 2006; Rumbold et al., 2006). Nutritional interventions, such as protein, salt and calorie restriction in obese pregnant women, have also not been shown to lower the incidence of pre-eclampsia (Villar et al., 2004). Although methods of prevention have been the focus of numerous studies, none has been identified to date to be of clear benefit.

2. MANAGEMENT AND TREATMENT Perinatal and neonatal mortality are extremely high (>80%) prior to 24–26 weeks of gestation and maternal complications are common. The presence of non-reassuring fetal testing, suspected abruption placentae, thrombocytopenia, rising liver enzymes and/or creatinine and symptoms suggestive of impending eclampsia or HELLP syndrome are generally considered indications for urgent delivery or possibly termination of pregnancy, particularly if the patient presents in the 2nd trimester.

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Onset of pre-eclampsia from 24 to 34 weeks of gestation without signs and symptoms suspicious for severe preeclampsia may be managed by postponing delivery in the hope of improving neonatal outcome. However, the potential fetal benefit from delaying delivery must be balanced against the possibility of increased maternal morbidity. Most studies have supported the approach of postponing delivery to minimize fetal complications, provided that careful maternal and neonatal monitoring can be achieved (Odendaal et al., 1990; Sibai et al., 1994). The goal of blood pressure management in the pre-eclamptic patient is to minimize maternal and fetal morbidity. Caution must be applied to avoid aggressive treatment of hypertension that compromises placental blood flow and fetal growth. Indeed, treatment of mild-to-moderate hypertension in pregnancy has not been shown to improve outcomes and has even been associated with an increased risk of small-for-gestational-age infants (Abalos et al., 2001; von Dadelszen et al., 2003). Acute and dramatic blood pressure reduction can potentially result in fetal distress or demise, particularly in the setting of preexisting inadequate placental perfusion. Thus, the ACOG recommends that only blood pressure elevation greater than 150–160 mmHg systolic or 100–110 mmHg diastolic, where the risk of cerebral hemorrhage is significant, should be treated with anti-hypertensive agents (ACOG Practice Bulletin, 2002). Magnesium has been shown to be superior to other agents for the management and prevention of eclampsia (Collaborative Eclampsia Trial, 1995; Lucas et al., 1995). It is generally given intravenously as a bolus, followed by a continuous infusion. Women receiving continuous infusions of magnesium must be monitored carefully for signs of neuromuscular toxicity, particularly in women with impaired magnesium excretion as a result of renal insufficiency.

3. MANAGEMENT OF THE HELLP SYNDROME For women in weeks 24–34 of gestation who have a reassuring fetal status and appear to be relatively stable, expectant management is an acceptable alternative to delivery. However, it should be noted that sudden and unpredictable deterioration is not uncommon in the clinical course of the HELLP syndrome and, therefore, some recommend urgent delivery upon confirmation of the diagnosis. Although intravenous steroids have been given based on retrospective and uncontrolled data, a recent randomized, controlled trial showed no benefit to high-dose dexamethasone treatment in HELLP syndrome (Fonseca et al., 2005). Based on the recent advances in the understanding of the pathogenesis of pre-eclampsia, sFlt-1 may represent a promising target for therapeutic intervention (Li et al., 2007).

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IV. OTHER HYPERTENSIVE DISORDERS OF PREGNANCY A. Chronic Hypertension Chronic essential hypertension in pregnancy is generally diagnosed prior to pregnancy or by the finding of a blood pressure >140/90 before 20 weeks of gestation. It is seen in 3–5% of pregnancies and is more prevalent with advanced maternal age, obesity and black race (Sibai, 1996; Magee et al., 1999). Pregnant women with chronic essential hypertension are at a higher risk of experiencing pre-eclampsia (21–25%), premature delivery (33–35%), IUGR (10–15%), placental abruption (1–3%) and perinatal mortality (4.5%) (Sibai et al., 1998; ACOG Practice Bulletin, 2001). The duration and the severity of hypertension correlate with neonatal morbidity and risk of pre-eclampsia (McCowan et al., 1996; August et al., 2004). Pre-existing proteinuria raises the risk of preterm delivery and IUGR, but not preeclampsia (Sibai et al., 1998). Most of these adverse outcomes, however, are seen in women with severe hypertension (diastolic blood pressure >110 mmHg) and pre-existing cardiovascular or renal disease. Pregnant women with mild, chronic hypertension can expect to have outcomes comparable to the general obstetric population (Sibai, 1996). The physiologic fall in blood pressure in the 2nd trimester also occurs in women with chronic essential hypertension and may mask underlying chronic hypertension. When this occurs, the chronic hypertension may be misdiagnosed as gestational hypertension when the blood pressure subsequently rises in the 3rd trimester. In women without underlying proteinuric renal disease, new-onset proteinuria >300 mg/day accompanied by worsening hypertension likely indicates superimposed pre-eclampsia (ACOG Practice Bulletin, 2002). Diagnosing superimposed pre-eclampsia in women with chronic essential hypertension and pre-existing proteinuria, however, can be challenging. In this case, the diagnosis would require significant exacerbation of hypertension of at least 30 mmHg over baseline levels, along with other signs and symptoms suggestive of pre-eclampsia, such as headache, visual changes, epigastric pain and laboratory abnormalities of hemoconcentration, elevated liver enzymes and elevated uric acid. Pre-eclampsia can occasionally present before 20 weeks of gestation, thus, it should also be considered in women presenting with new hypertension and proteinuria in mid-gestation.

B. Gestational Hypertension Gestational hypertension is new-onset hypertension without proteinuria after 20 weeks’ gestation, which then resolves postpartum. Some women diagnosed with gestational hypertension in fact have pre-existing, undiagnosed essential hypertension. In these cases, a woman may be mistakenly presumed to be previously normotensive if she presents

during the physiologic 2nd-trimester nadir in blood pressure. The diagnosis of chronic hypertension may not be made until after delivery, when blood pressure fails to normalize. In approximately 10–25% of cases, gestational hypertension progresses to pre-eclampsia (Saudan et al., 1998). In cases of severe gestational hypertension, the risk for adverse outcomes are similar to those of pre-eclampsia (Buchbinder et al., 2002). Interestingly, a renal biopsy study found a substantial percentage of gestational hypertensives to have renal glomerular endothelial damage, suggesting that gestational hypertension may share certain pathophysiologic mechanisms with pre-eclampsia (Fisher et al., 1981; Strevens et al., 2003). In another subset of women with gestational hypertension, it may be a transient unmasking of an underlying predisposition toward chronic hypertension. These women often have a strong family history of chronic hypertension and tend to develop hypertension in the 3rd trimester without hyperuricemia or proteinuria. Although gestational hypertension typically resolves after delivery, the women are at risk for development of hypertension later in life (Marin et al., 2000).

C. Secondary Causes of Hypertension in Pregnancy The major forms of secondary hypertension seen in pregnant women are renal artery stenosis, primary hyperaldosteronism, Cushing’s syndrome, pheochromocytoma and chronic renal failure from any cause. Hypertension that is severe and resistant to therapy in the 1st and 2nd trimesters of pregnancy should alert the clinician to the possibility of a secondary cause of hypertension. The prevalence of renal artery stenosis varies from 0.5 to 2% of the total hypertensive population, with higher rates among patients with severe hypertension (Davis et al., 1979). Atherosclerosis is more common in men with late-onset hypertension, but 80% of patients with fibromuscular dysplasia are women of child-bearing age (Simon et al., 1972). The characteristic upper abdominal bruit of renal artery stenosis, even if present, will likely be masked in mid-gestation by the presence of a placental murmur. Angioplasty and stent placement in the 2nd and 3rd trimesters of pregnancy after diagnosis by magnetic resonance angiography (MRA) have been described (Hayashida et al., 2005). Primary hyperaldosteronism is characterized by hypertension and hyperkalemic alkalosis. Plasma renin activity is low and plasma and urinary aldosterone levels are high. The prevalence is 0.5–1% of the hypertensive population (Gallery, 1999). Most reported cases have been hypokalemic, with suppressed plasma renin activity unresponsive to sodium deprivation (Hammond et al., 1982). Functional adrenal adenomas may be managed either medically or surgically, but as long as serum potassium and blood pressure are corrected, definitive therapy may be postponed until after delivery. Aldosterone antagonists, such as spironolactone,

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should be avoided, given the theoretical risks to the fetus (Gallery, 1999). Cushing’s syndrome may be diagnosed by measuring plasma cortisol and dexamethasone suppression testing. Fewer than 70 cases of Cushing’s syndrome have been reported. Cortisol levels increase progressively throughout pregnancy and, by the 2nd trimester, reach levels that are two- to threefold greater than pre-pregnancy values, as a result of an increase in cortisol-binding globulin levels under the influence of estrogen. Low dose dexamethasone suppression tests can therefore give false negatives in pregnancy, but a high dose dexamethasone test that fails to suppress serum cortisol would be helpful in diagnosing an adrenal tumor causing Cushing’s syndrome (Anjali et al., 2004). Cushing’s syndrome in pregnancy may be complicated by hypertension in 54% and diabetes and pre-eclampsia in 13%. Adverse fetal outcomes include increased rates of spontaneous abortion and perinatal mortality (>10%) (Check et al., 1979). Pheochromocytoma is a catecholamine-secreting tumor that is a rare cause of hypertension (<0.5%), but can be life-threatening for both mother and fetus. It is occasionally unmasked during labor and delivery, when fatal hypertensive crisis is precipitated by vaginal delivery, uterine contractions, and anesthesia (Del Giudice et al., 1998). Screening of hypertensive pregnant women can be achieved by measurement of 24-hour urinary catecholamine excretion prior to conception, though it may also be done during gestation, since catecholamine excretion is unchanged in normal pregnancy (Schenker and Chowers, 1971). If at all possible, surgical intervention should be postponed until the postpartum period. A rare form of hypertension in pregnant women is caused by an activating mineralocorticoid receptor mutation, which is exacerbated by pregnancy. The result is inappropriate receptor activation by progesterone, which leads to a marked exacerbation of hypertension in pregnancy, but no proteinuria or other features of pre-eclampsia (Geller et al., 2000).

D. Management of Chronic Hypertension in Pregnancy Prior to conception, women with chronic hypertension should be counseled on the risks of adverse pregnancy outcomes and blood pressure management should be optimized. During pregnancy, they should be monitored closely for development of pre-eclampsia. Anti-hypertensive therapy is indicated for the prevention of stroke and cardiovascular complications in severe hypertension (DBP >100 mmHg) (Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy, 2000). Treatment of less severe hypertension has not, however, shown clear maternal or fetal benefit. In three meta-analyses, no beneficial effect on the development of pre-eclampsia, neonatal death, preterm birth, small-for-gestational-age babies or other adverse

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outcomes was demonstrated with treatment of mild-tomoderate hypertension, although it did reduce the women’s risk of developing severe hypertension (Magee et al., 1999; Ferrer et al., 2000; Abalos et al., 2001). Aggressive treatment of mild-to-moderate hypertension in pregnancy may impair fetal growth. Indeed, reduction of mean arterial pressure effected by anti-hypertensive treatment was associated with lower birth weight and fetal growth restriction, possible as a result of diminished uteroplacental perfusion (von Dadelszen et al., 2000). Therefore, practice guidelines recommend that anti-hypertensive treatment should be administered to newly-diagnosed chronic hypertensives only if evidence of end-organ injury (e.g. proteinuria or cardiomyopathy) is seen, or if SBP is greater than 150–160 mmHg, or DBP exceeds 100–110 mmHg. It is also advised that tapering or discontinuing therapy to meet these goal blood pressures be considered for women previously on antihypertensive treatment (ACOG Practice Bulletin, 2002). Methyldopa, a centrally acting alpha-2 adrenergic agonist, is the first-line oral agent for the management of hypertension in pregnancy, although it is usually not used outside of pregnancy. Although it has the most extensive safety data and has no apparent adverse fetal effects, its main disadvantages are a short half-life, sedating effects and, rarely, elevated liver enzymes and hemolytic anemia. Less data are available on clonidine, but its mechanism and safety profile are largely comparable to those of methyldopa. With the exception of atenolol (fetal growth restriction), beta-adrenergic antagonists are non-teratogenic and used effectively and extensively in pregnancy (Magee and Duley, 2003). Labetalol is also effective and widely used and may have the advantage of better preservation of uteroplacental blood flow due to its alpha inhibition (Podymow et al., 2004). Calcium channel blockers, including long-acting nifedipine and non-dihydropyridines, appear to be safe in pregnancy, although there has been somewhat less experience with this class of anti-hypertensives (Bortolus et al., 2000; Podymow et al., 2004). Diuretics may be appropriate and effective in the setting of pulmonary edema, however, they are not firstline agents, given that plasma volume is normal in pregnancy and low in pre-eclampsia, in which case they are avoided altogether. Nevertheless, there is no evidence that diuretics are associated with adverse fetal or maternal outcomes. ACE-inhibitors and angiotensin receptor blockers (ARBs) are contraindicated in the 2nd and 3rd trimesters of pregnancy because of their known adverse effects on fetal kidneys, including renal dysgenesis, fetal oliguria, oligohydramnios and neonatal anuric ARF leading to death (Podymow et al., 2004). The limited data on ARBs indicate that their impact on the fetus is similar to that of ACE-Is (Serreau et al., 2005). Intravenous medications used for urgent control of severe hypertension are classified as pregnancy class C (no controlled studies in humans). However, there is broad clinical

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experience with several, which has thus far yielded no evidence of adverse effects. These include, in order of known safety, labetalol, calcium channel blockers such as nicardipine, and hydralazine. Nitroprusside is generally avoided, given that it can cause fetal cyanide poisoning if used for more than 4 hours.

oligo-anuria, although it can also affect the entire renal cortex and result in irreversible renal failure. Other than prompt administration of antibiotics, management of ATN in this setting is chiefly supportive, e.g. volume resuscitation, or possibly delivery if late enough in the pregnancy.

3. THROMBOTIC MICROANGIOPATHY V. RENAL FAILURE IN PREGNANCY A. Acute Renal Failure Over the past 40 years, the incidence of acute renal failure (ARF) in pregnancy in the developed world has decreased considerably (Selcuk et al., 1998). This decline is felt to stem from improved prenatal care and better availability of safe and legal abortion. In this series, the primary etiologies of ARF were abortion (30%), HELLP syndrome and pre-eclampsia (14%), pre-eclampsia or eclampsia (12%), postpartum hemorrhage (15%), fetal death (12%), abruptio placentae (6%) and placentae previa (1%). In general, the differential diagnosis of ARF in pregnancy includes: prerenal causes, such as hyperemesis gravidarum and uterine hemorrhage; infectious etiologies, such as acute pyelonephritis and septic abortion; renal cortical necrosis; those conditions unique to pregnancy, including severe pre-eclampsia, acute fatty liver of pregnancy and idiopathic postpartum acute renal failure; and obstructive causes, e.g. obstructive uropathy, rarely (Krane, 1988).

1. ACUTE TUBULAR NECROSIS Acute tubular necrosis (ATN) in pregnancy can be the result of a number of factors. Hyperemesis gravidarum or uterine hemorrhage from placental abruption or previa, failure of the postpartum uterus to contract or uterine lacerations and perforations can lead to severe prerenal azotemia and subsequent ATN. ARF may also be precipitated by intraamniotic saline administration, amniotic fluid embolism and other factors unrelated to pregnancy.

2. CORTICAL NECROSIS Placental abruption and septic abortion are associated with bilateral cortical necrosis, which is often severe and irreversible. Septic abortion is infection, usually polymicrobial, of the uterus and surrounding tissues usually after a non-sterile (illegal) abortion, but can occur after any abortion. In countries where abortion is inaccessible or illegal, it remains a serious problem, although it has become rare in countries with more liberalized abortion laws. The typical presentation is vaginal bleeding, abdominal pain and fever, which may progress to shock, with renal failure occurring in up to 73% of cases, commonly accompanied by gross hematuria, flank pain and oligo-anuria (Finkielman et al., 2004). Placenta abruption in the 3rd trimester of pregnancy can also cause bilateral patchy cortical necrosis characterized by

ARF in the context of thrombotic microangiopathy and pregnancy encompasses five pregnancy syndromes, which can be challenging to distinguish from each other: pre-eclampsia/ HELLP, TTP/HUS, acute fatty liver of pregnancy, systemic lupus erythematosus (SLE) with the antiphospholipid antibody syndrome, and disseminated intravascular coagulation (DIC). ARF is rare in pre-eclampsia, but when present, requires urgent delivery and is often accompanied by coagulopathy, hepatic rupture, liver failure or is superimposed on pre-existing renal disease. Acute fatty liver of pregnancy (AFLP) occurs after mid-gestation, most often near term (Fesenmeier et al., 2005) and is rare, affecting about 1 in 10 000 pregnancies, but potentially life-threatening, with a 10% case fatality rate (Pereira et al., 1997). It is characterized by jaundice and liver dysfunction and, in about half of cases, also complicated by pre-eclampsia. Hemolysis and thrombocytopenia, however, are usually absent, and their presence would be more indicative of HUS/TTP or the HELLP syndrome. The exact mechanism of renal failure is unknown, as renal lesions are both mild and non-specific and appear to be completely reversible. A defect in mitochondrial fatty acid oxidation due to mutations in the long-chain 3-hydroxyacyl CoA dehydrogenase deficiency has been proposed as a risk factor for the development of AFLP (Ibdah et al., 1999). Urgent delivery is necessary in the management of AFLP. Pregnancy confers a higher risk of HUS/TTP, which is characterized by thrombocytopenia, hemolysis and ARF (or other organ dysfunction) (Vesely et al., 2004). TTP is associated more with the presence of neurological symptoms and HUS with renal failure. Occurrence of TTP is usually prior to 24 weeks and of HUS, typically near term or postpartum (George, 2003). Although relapse is a concern in women with a history of TTP, the data are too limited to determine risk of recurrence (Sibai, 2007). In non-pregnant states, the pathogenesis of TTP has been attributed to the deficiency of the von Willebrand factor cleaving protease, ADAMTS13, the levels of which decline in the 2nd and 3rd trimester. In distinguishing HUS/TTP from pre-eclampsia/HELLP syndrome, a history of preceding proteinuria, hypertension and severe liver injury is more suggestive of the HELLP syndrome, whereas the presence of renal failure and severe hemolytic anemia is more typical of HUS/TTP. The level of ADAMTS13 may also be helpful, as it is expected to remain detectable (albeit lower than in normal pregnant women) in HELLP syndrome, in contrast to its absence in TTP (Lattuada et al., 2003). Plasmapheresis has been reported

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in uncontrolled studies to be effective and safe (Sibai, 2007). In contrast to the HELLP syndrome, unless the neonate is compromised, the pregnancy may be continued in women with HUS/TTP.

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and mortality (Smaill, 2001). Pyelonephritis is frequently treated more aggressively with hospitalization and intravenous antibiotics.

B. Chronic Kidney Disease 4. OBSTRUCTION In rare cases, ARF from ureteral obstruction by renal calculi can occur. Hypercalciuria during pregnancy is likely a result of a rise in circulating levels of 1, 25 dihydroxyvitamin D3 and higher intestinal calcium absorption (Kumar et al., 1980). However, the incidence of urolithiasis in pregnancy is no higher than that in non-pregnant women of child-bearing age, which is roughly 0.026–0.531%, or 1 in 200 to 1 in 2000 pregnancies (Coe et al., 1978; Drago et al., 1982; Gorton and Whitfield, 1997). The risk may be offset by increases in filtered citrate, magnesium and urinary glycosaminoglycans, which inhibit urinary lithogenesis, as well as possibly by an increase in urine flow and physiological dilation of the urinary tract (Kashyap et al., 2006). The vast majority of women who do develop urolithiasis in pregnancy do so after the 1st trimester (Horowitz and Schmidt, 1985). As in the general population, most stones formed during pregnancy are calcium oxalate and calcium phosphate. Infection risk is increased and severe pain from nephrolithiasis can contribute to premature labor (Hendricks et al., 1991). Treatment includes initial conservative management with hydration, analgesics and anti-emetics, with antibiotics in the case of complication by a urinary tract infection and ureteral catheterization and ureteral stent, if necessary. Lithotripsy, although contraindicated during pregnancy because of adverse fetal effects, has been reported to be used before 12 weeks of gestation without apparent adverse impact on the fetus (Cormier et al., 2006). Thiazide diuretics and allopurinol are contraindicated in pregnancy. If infection is present, antibiotics should be administered for 3–5 weeks, with continued suppressive treatment after delivery, since the stone may still serve as a nidus of infection. Urinary tract infections (UTI) are the most frequent renal problem during pregnancy (Millar and Cox, 1997). The prevalence (2–10%) of asymptomatic bacteriuria is similar to that in non-pregnant populations, however, in pregnancy, it needs to be managed more aggressively for a number of reasons. Asymptomatic bacteriuria is associated with increased risk of premature delivery and low birth weight (Schieve et al., 1994). Pregnant women are susceptible to ascending pyelonephritis because of physiologic hydronephrosis. Untreated asymptomatic bacteriuria can progress to cystitis or acute pyelonephritis in up to 40% of pregnant women (Hill et al., 2005). Commonly presenting between 20 and 28 weeks of gestation as fevers, loin pain and dysuria, acute pyelonephritis can progress to sepsis, endotoxic shock, disseminated intravascular coagulation and ARF. Treatment of asymptomatic bacteriuria has been shown to reduce the risk of these complications and improve perinatal morbidity

Pregnancy in renal disease is recognized to be at higher risk for adverse maternal and fetal outcomes. Pre-eclampsia and maternal renal function deterioration, as well as prematurity, IUGR and neonatal death are common (Jones and Hayslett, 1996; Fischer et al., 2004). Compared to women without chronic renal disease, one study reported a near doubling of the frequency of fetal complications and a tripling of the rate of maternal adverse outcomes (Jones and Hayslett, 1996; Fischer et al., 2004). Chronic kidney disease may be exacerbated by the additional stress of increased renal blood flow during pregnancy, as evidenced by the frequent finding of worsening of pre-existing hypertension and proteinuria (Sanders and Lucas, 2001). Not surprisingly, maternal and fetal outcome correlates with the severity of pre-existing renal disease, proteinuria and hypertension. Most authors, however, agree that women with well-controlled blood pressure, serum creatinine 1.4 mg/dl, and no proteinuria can generally expect favorable maternal and neonatal outcomes and are at low risk for permanent renal function deterioration (Jungers et al., 1995; Hou, 1999). A >30% risk of accelerated progression to end-stage renal disease during and after pregnancy is seen when creatinine is >2.0 mg/dl (Jones and Hayslett, 1996). When serum creatinine exceeds 2.5 mg/dl, >70% of the pregnancies end with preterm delivery and >40% are complicated by pre-eclampsia (Jones and Hayslett, 1996; Sanders and Lucas, 2001). Several specific conditions, such as diabetic nephropathy and lupus nephritis may present additional challenges when encountered in the setting of pregnancy and chronic kidney disease.

1. DIABETIC NEPHROPATHY Although diabetes mellitus is less common among women of child-bearing age, the number of diabetic women entering pregnancy is increasing, along with the general rise in incidence and prevalence of diabetes and diabetic nephropathy in the world (Dunne, 2005). In general, women with diabetes, with or without nephropathy are at an increased risk of adverse maternal and neonatal outcomes, relative to nondiabetics (Sibai et al., 2000; Dunne et al., 2003; Clausen et al., 2005). The risk of pre-eclampsia in women with pre-existing diabetes is more than twice that of non-diabetic women (Sibai et al., 2000). The presence of nephropathy further increases the risk of preterm delivery and pre-eclampsia. Suboptimal glycemic control has also been associated with higher risk of fetal malformations and pre-eclampsia (Hiilesmaa et al., 2000; Suhonen et al., 2000). Pregnancy alone does not appear to cause progression of renal disease, as long as kidney function is normal or only

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very mildly impaired (Hawthorne, 2005). Women with more severe renal impairment are more likely to have irreversible renal damage postpartum, which is evident as early as a few months after delivery (Biesenbach et al., 1999). Although aggressive treatment of hypertension before, throughout and after pregnancy in these women may mitigate the decline in renal function, disease progression is largely unavoidable (Rossing et al., 2002). As a result, women with moderateto-severe renal impairment are often counseled to postpone pregnancy until after renal transplantation, given that it improves fertility and neonatal outcome and has no impact on kidney function as long as graft function is normal. It has been hypothesized that the children of diabetic mothers have inadequate nephrogenesis and lower nephron mass because of intrauterine diabetes exposure, leading to a higher risk of development of renal disease and hypertension later in life (Nelson et al., 1998; Biesenbach et al., 2000).

2. LUPUS NEPHRITIS As with other types of chronic kidney disease, maternal renal disease is a strong predictor of adverse fetal outcome (Rahman et al., 1998). Women with SLE alone are already at higher risk for preterm birth, IUGR, pre-eclampsia and spontaneous abortions. With lupus nephritis, hypertension, or proteinuria, these risks are further increased (Khamashta and Hughes, 1996; Soubassi et al., 2004; Dhar et al., 2005; Moroni and Ponticelli, 2005). Women with SLE and antiphospholipid antibodies are at highest risk of developing pre-eclampsia, thrombosis and experiencing fetal death (Ruiz-Irastorza and Khamashta, 2005). Those with proliferative (WHO class III or IV) or membranous lupus nephritis (WHO class V) incur the greatest risk for pre-eclampsia and low birth weight (Carmona et al., 2005). In addition, lupus flares have been reported to occur at a rate of 48–62% when conception has taken place during active lupus nephritis. Conception during remission corresponds to flare rates of 7–32% (Tandon et al., 2004). Prophylactic steroid therapy does not appear to prevent lupus flares during pregnancy (Khamashta et al., 1997). In general, women with lupus are advised to delay pregnancy until lupus activity is quiescent and immunosuppressants can be minimized (Moroni and Ponticelli, 2005). A diagnostic challenge arises when a pregnant woman with a history of lupus nephritis presents with worsening proteinuria and hypertension. Distinguishing between preeclampsia and lupus flare, however, is critical for women presenting before 37 weeks of gestation because the treatments differ markedly. Lupus nephritis flares are managed by steroids and azathioprine and continuation of the pregnancy but, for pre-eclampsia, delivery is the only definitive treatment. Low complement levels and the presence of hematuria are typically not sensitive or specific enough to differentiate, although an active urinary sediment is often seen in lupus nephritis, while that of pre-eclampsia is bland.

Whether the measurement of angiogenic proteins such as sFlt-1 will help differentiate superimposed pre-eclampsia from lupus nephritis remains unknown (Williams et al., 2005). Nevertheless, a renal biopsy is frequently necessary, in the absence of diagnostic serologic tests, which have yet to be developed.

C. End-Stage Renal Disease and Dialysis Pregnancy is rare in women undergoing hemodialysis (HD) or peritoneal dialysis. Most women with end-stage renal disease (ESRD) have severe hypothalamic-pituitary-gonadal abnormalities that result in menstrual irregularities, anovulation and infertility (Leavey and Weitzel, 2002), which is reversed by transplantation but not by dialysis. It is thought that uremia leads to abnormal neuroendocrine regulation of hypothalamic GnRH secretion resulting in diminished fertility (Handelsman and Dong, 1993). Nonetheless, successful pregnancy has been reported in women with ESRD on renal replacement. Data on fertility rates in women on chronic dialysis derive from surveys and large retrospective studies. These studies, including the RPDP study, revealed a pregnancy rate of roughly 2% in women of child-bearing age on chronic dialysis over 2–4 years (about 2% of the pregnancy rate in women of similar age in the general population), with approximately 40–60% of pregnancies producing a live infant, though the prematurity rate is extremely high (>80%) (Hou, 1994; Bagon et al., 1998; Okundaye et al., 1998). The most common adverse outcomes were spontaneous miscarriage, pregnancy-induced hypertension, preterm labor, premature rupture of membranes, polyhydramnios and IUGR. Increasing dialysis dose, rather than frequency, appears to improve fetal outcome. The current practice guidelines recommend augmenting the weekly dialysis dose to 20 h. In the RPDP study, 90% of the 10 surviving infants had a gestational age >32 weeks and 57% had birth weights >2.5 kg in the group of women dialyzed for >20 h/week. Among women receiving <14 h/ week of dialysis, only 50% of the six surviving infants had a gestational age of >32 weeks and none had birth weight >2.5 kg (Okundaye et al., 1998). Data from a number of other studies have also provided evidence that increased dialysis correlates with greater birth weight and longer gestational age (Souqiyyeh et al., 1992; Bagon et al., 1998). Nocturnal hemodialysis (NHD) has been reported potentially to be the ideal modality to increase dialysis dose in pregnancy, given that it may allow for improved management of volume and blood pressure by minimizing fluctuations in extracellular fluid volume (Gangji et al., 2004). Peritoneal dialysis has also been used during pregnancy, however, increasing abdominal girth requires reductions in dwell volume and an increased number of exchanges to achieve adequate clearance, which may be difficult to maintain (Holley and Reddy, 2003). Finally, dosing of erythropoietin needs to be adjusted to maintain the physiologic anemia of

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pregnancy, as a high hematocrit can lead to adverse fetal outcomes.

D. Renal Transplant in Pregnancy As mentioned, successful kidney transplantation normalizes hormonal function and can restore fertility within 6 months in about 90% of women of child-bearing age (LessanPezeshki et al., 2004). Since 1958, more than 14 000 pregnancies in renal allograft recipients have been documented (McKay et al., 2005). Pregnancy following kidney transplantation is successful in >90%, with good maternal and fetal outcomes, however, these pregnancies require the involvement of and close monitoring by transplant nephrologists and obstetricians experienced in taking care of women with kidney disease (Hou, 2003; McKay and Josephson, 2006; Abbud-Filho et al., 2007).

1. MATERNAL, FETAL AND GRAFT OUTCOMES The outcome of the pregnancy is generally determined by maternal kidney function and blood pressure. Approximately 15–20% of pregnancies in kidney transplant patients end in elective termination and 10–15% in miscarriage. Women with serum creatinine <1.5 mg/dl are expected to deliver a live baby in >90% of pregnancies if it continues beyond the 1st trimester, while 75% of those with creatinine >1.5 mg/dl will have a live delivery (Abbud-Filho et al., 2007). There is, however, a high incidence of low birth weight (25–50%) and/or preterm delivery (30–50%) (Armenti et al., 2004; Gutierrez et al., 2005). Pregnancy does not appear adversely to affect graft function in transplant recipients, as long as baseline graft function is normal and significant hypertension is not present (Armenti et al., 2004). On a background of moderate renal insufficiency (creatinine >1.5–1.7 mg/dl), higher risks of developing pre-eclampsia and progressive renal impairment, and of having a small-for-gestationalage infant are incurred (Thompson et al., 2003; Galdo et al., 2005). The rejection rate (3–4%) is similar to that in non-pregnant controls when pregnancy occurs 1–2 years after transplantation (Armenti et al., 2004). The most common adverse outcomes include hypertension (50–70%), pre-eclampsia (30%), intrauterine growth retardation (IUGR; 20%) and preterm birth (50%), in addition to anemia, urinary tract infection and diabetes (5–10%) (Abbud-Filho et al., 2007). Hypertension typically stems from underlying medical conditions and the use of calcineurin inhibitors. The American Society of Transplantation recommends aggressive treatment of hypertension in pregnant renal transplant recipients, with target blood pressure close to normal, which is lower than the goal blood pressure of pregnant, non-transplanted women with hypertension (Podymow et al., 2004; McKay et al., 2005). The most commonly used anti-hypertensive agents are methyldopa, non-selective beta-adrenergic antagonists (e.g. labetalol)

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and calcium channel blockers. ACE inhibitors are contraindicated in the 2nd and 3rd trimesters, but should generally be avoided in pregnancy. Transplant recipients are at risk for infections that may have implications for the fetus, including cytomegalovirus, herpes simplex and toxoplasmosis. The rate of bacterial urinary tract infections is also increased (13–40%), but these are usually treatable and uncomplicated (Galdo et al., 2005). Typically, women have been advised to wait 2 years after transplantation before conceiving. Pregnancy within the first 6–12 months after transplantation is not recommended because of a higher risk of acute rejection in this period, higher doses of immunosuppressive agents and an increased risk of infection (European best practice guidelines for renal transplantation, 2002; McKay et al., 2005). However, this needs to be weighed against the downside of age-related decreases in fertility, as many women who undergo renal transplantation are already of advanced maternal age. More recently, the American Society of Transplantation has suggested that in women on stable, low doses of immunosuppressive agents with normal renal function and with no prior rejection episodes, conception could be safely considered as early as 1 year post-transplant (McKay et al., 2005). Current data conflict on whether pregnancy decreases overall graft survival (Salmela et al., 1993; Sturgiss and Davison, 1995).

2. IMMUNOSUPPRESSIVE THERAPY Cyclosporine or tacrolimus and steroids, with or without azathioprine, form the basis of immunosuppression during pregnancy. Low-dose corticosteroids are considered safe for use in pregnancy. Stress-dose steroids are needed at the time of and for 24–48 h after delivery. Azathioprine is safe at low doses, although doses >2 mg/kg/day should be avoided, since they have been associated with congenital anomalies and intrauterine growth retardation (European best practice guidelines for renal transplantation, 2002). Although high doses of cyclosporine and tacrolimus are associated with fetal resorption in animal studies, animal and human data indicate that lower doses of calcineurin inhibitors are safe in pregnancy (Danesi and Del Tacca, 2004; Garcia-Donaire et al., 2005). Thus far, clinical data have shown a possibly higher incidence of low birth weight, but not of congenital malformations (Danesi and Del Tacca, 2004). Cautious monitoring of cyclosporine and tacrolimus levels is necessary in pregnancy because of decreased GI absorption, increased volume of distribution and increased GFR, which can result in substantial fluctuations, with a concomitant risk of acute rejection (Garcia-Donaire et al., 2005). Sirolimus is teratogenic in rats at clinical doses and is therefore contraindicated in pregnancy. Mycophenolate mofetil (MMF), like sirolimus, is contraindicated in pregnancy, given its association with developmental toxicity, malformations and intrauterine death in animal studies at therapeutic dosages. Limited human data suggest it may also be associated with spontaneous

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abortions and major fetal malformations (Le Ray et al., 2004).

3. ACUTE REJECTION Acute rejection during pregnancy should be considered if fever, oliguria, graft tenderness or deterioration in renal function is present. The incidence of acute rejection in pregnancy is similar to that in the non-pregnant population (European best practice guidelines for renal transplantation, 2002; Armenti et al., 2004). Confirmation by renal biopsy should be made before instituting treatment, which is administration of high-dose steroids, despite their association with fetal malformations (European best practice guidelines for renal transplantation, 2002; Mastrobattista and Katz, 2004). Limited data are available on the safety of OKT3, antithymocyte globulin, daclizumab and basiliximab in pregnancy (Danesi and Del Tacca, 2004).

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Ryu, S., Huppmann, A. R., Sambangi, N., Takacs, P., and Kauma, S. W. (2007). Increased leukocyte adhesion to vascular endothelium in pre-eclampsia is inhibited by antioxidants. Am J Obstet Gynecol 196(400): e1–7; discussion e7–e8. Saftlas, A. F., Olson, D. R., Franks, A. L., Atrash, H. K., and Pokras, R. (1990). Epidemiology of pre-eclampsia and eclampsia in the United States, 1979–1986. Am J Obstet Gynecol 163: 460–465. Salafia, C. M., Pezzullo, J. C., Ghidini, A., Lopez-Zeno, J. A., and Whittington, S. S. (1998). Clinical correlations of patterns of placental pathology in preterm pre-eclampsia. Placenta 19: 67–72. Salmela, K. T., Kyllonen, L. E., Holmberg, C., and GronhagenRiska, C. (1993). Impaired renal function after pregnancy in renal transplant recipients. Transplantation 56: 1372–1375. Samadi, A. R., Mayberry, R. M., Zaidi, A. A., Pleasant, J. C., McGhee, N., and Rice, R. J. (1996). Maternal hypertension and associated pregnancy complications among African-American and other women in the United States. Obstet Gynecol 87: 557–563. Sanders, C. L., and Lucas, M. J. (2001). Renal disease in pregnancy. Obstet Gynecol Clin North Am 28: 593–600 vii. Sargent, I. L., Germain, S. J., Sacks, G. P., Kumar, S., and Redman, C. W. (2003). Trophoblast deportation and the maternal inflammatory response in pre-eclampsia. J Reprod Immunol 59: 153–160. Saudan, P., Brown, M. A., Buddle, M. L., and Jones, M. (1998). Does gestational hypertension become pre-eclampsia? Br J Obstet Gynaecol 105: 1177–1184. Savvidou, M. D., Hingorani, A. D., Tsikas, D., Frolich, J. C., Vallance, P., and Nicolaides, K. H. (2003). Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia. Lancet 361: 1511–1517. Scalera, F., Schlembach, D., and Beinder, E. (2001). Production of vasoactive substances by human umbilical vein endothelial cells after incubation with serum from preeclamptic patients. Eur J Obstet Gynecol Reprod Biol 99: 172–178. Schackis, R. C. (2004). Hyperuricaemia and preeclampsia: is there a pathogenic link? Med Hypotheses 63: 239–244. Schenker, J. G., and Chowers, I. (1971). Pheochromocytoma and pregnancy. Review of 89 cases. Obstet Gynecol Surv 26: 739–747. Schieve, L. A., Handler, A., Hershow, R., Persky, V., and Davis, F. (1994). Urinary tract infection during pregnancy: its association with maternal morbidity and perinatal outcome. Am J Public Hlth 84: 405–410. Schiff, E., Ben-Baruch, G., Peleg, E. et al. (1992). Immunoreactive circulating endothelin-1 in normal and hypertensive pregnancies. Am J Obstet Gynecol 166: 624–628. Schobel, H. P., Fischer, T., Heuszer, K., Geiger, H., and Schmieder, R. E. (1996). Pre-eclampsia – a state of sympathetic overactivity. N Engl J Med 335: 1480–1485. Schwartz, R. B., Feske, S. K., Polak, J. F. et al. (2000). Preeclampsia-eclampsia: clinical and neuroradiographic correlates and insights into the pathogenesis of hypertensive encephalopathy. Radiology 217: 371–376. Selcuk, N. Y., Tonbul, H. Z., San, A., and Odabas, A. R. (1998). Changes in frequency and etiology of acute renal failure in pregnancy (1980-1997). Ren Fail 20: 513–517.

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CHAPTER 30
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Taylor, R. N., Grimwood, J., Taylor, R. S., McMaster, M. T., Fisher, S. J., and North, R. A. (2003). Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathologic pregnancies. Am J Obstet Gynecol 188: 177–182. Thadhani, R., Ecker, J. L., Mutter, W. P. et al. (2004). Insulin resistance and alterations in angiogenesis: additive insults that may lead to preeclampsia. Hypertension 43: 988–992. Thadhani, R. I., Johnson, R. J., and Karumanchi, S. A. (2005). Hypertension during pregnancy: a disorder begging for pathophysiological support. Hypertension 46: 1250–1251. Thangaratinam, S., Ismail, K. M., Sharp, S., Coomarasamy, A., and Khan, K. S. (2006). Accuracy of serum uric acid in predicting complications of pre-eclampsia: a systematic review. Br J Obstet Gynaecol 113: 369–378. Thompson, B. C., Kingdon, E. J., Tuck, S. M., Fernando, O. N., and Sweny, P. (2003). Pregnancy in renal transplant recipients: the Royal Free Hospital experience. Q J Med 96: 837–844. Trogstad, L. I., Eskild, A., Bruu, A. L., Jeansson, S., and Jenum, P. A. (2001). Is pre-eclampsia an infectious disease? Acta Obstet Gynecol Scand 80: 1036–1038. Tsatsaris, V., Goffin, F., Munaut, C. et al. (2003). Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. J Clin Endocrinol Metab 88: 5555–5563. Tsukimori, K., Nakano, H., and Wake, N. (2007). Difference in neutrophil superoxide generation during pregnancy between pre-eclampsia and essential hypertension. Hypertension 49: 1436–1441. Tubbergen, P., Lachmeijer, A. M., Althuisius, S. M., Vlak, M. E., van Geijn, H. P., and Dekker, G. A. (1999). Change in paternity: a risk factor for pre-eclampsia in multiparous women? J Reprod Immunol 45: 81–88. Tuffnell, D. J., Jankowicz, D., Lindow, S. W. et al. (2005). Outcomes of severe pre-eclampsia/eclampsia in Yorkshire 1999/ 2003. Br J Obstet Gynaecol 112: 875–880. Tuohy, J. F., and James, D. K. (1992). Pre-eclampsia and trisomy 13. Br J Obstet Gynaecol 99: 891–894. van Dijk, M., Mulders, J., Poutsma, A. et al. (2005). Maternal segregation of the Dutch pre-eclampsia locus at 10q22 with a new member of the winged helix gene family. Nat Genet 37: 514–519. Venkatesha, S., Toporsian, M., Lam, C. et al. (2006). Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 12: 642–649. Vesely, S. K., Li, X., McMinn, J. R., Terrell, D. R., and George, J. N. (2004). Pregnancy outcomes after recovery from thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Transfusion 44: 1149–1158. Vikse, B. E., Irgens, L. M., Bostad, L., and Iversen, B. M. (2006). Adverse perinatal outcome and later kidney biopsy in the mother. J Am Soc Nephrol 17: 837–845. Villar, J., Abalos, E., Nardin, J. M., Merialdi, M., and Carroli, G. (2004). Strategies to prevent and treat preeclampsia: evidence from randomized controlled trials. Semin Nephrol 24: 607–615. Villar, J., Abdel-Aleem, H., Merialdi, M. et al. (2006). World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women. Am J Obstet Gynecol 194: 639–649.

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PART II
SECTION VII
Endocrine Disorders in Renal Failure

von Dadelszen, P., Ornstein, M. P., Bull, S. B., Logan, A. G., Koren, G., and Magee, L. A. (2000). Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis. Lancet 355: 87–92. von Dadelszen, P., Magee, L. A., Krajden, M. et al. (2003). Levels of antibodies against cytomegalovirus and Chlamydophila pneumoniae are increased in early onset pre-eclampsia. Br J Obstet Gynaecol 110: 725–730. Walker, J. J. (2000). Pre-eclampsia. Lancet 356: 1260–1265. Wallenberg, HCS. (ed.) (1998). Handbook of Hypertension, Elsevier Science, New York. Wallukat, G., Homuth, V., Fischer, T. et al. (1999). Patients with pre-eclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J Clin Invest 103: 945–952. Walther, T., Wallukat, G., Jank, A. et al. (2005). Angiotensin II type 1 receptor agonistic antibodies reflect fundamental alterations in the uteroplacental vasculature. Hypertension 46: 1275–1279. Wang, J. X., Knottnerus, A. M., Schuit, G., Norman, R. J., Chan, A., and Dekker, G. A. (2002). Surgically obtained sperm, and risk of gestational hypertension and pre-eclampsia. Lancet 359: 673–674. Williams, D. J., Vallance, P. J., Neild, G. H., Spencer, J. A., and Imms, F. J. (1996). Nitric oxide-mediated vasodilation in human pregnancy. Am J Physiol 272: H748–H752. Williams, W. W., Ecker, J. L., Thadhani, R. I., and Rahemtullah, A. (2005). Case records of the Massachusetts General Hospital. Case 38-2005. A 29-year-old pregnant woman with the nephrotic syndrome and hypertension. N Engl J Med 353: 2590–2600. Wolf, M., Sandler, L., Munoz, K., Hsu, K., Ecker, J. L., and Thadhani, R. (2002). First trimester insulin resistance and subsequent preeclampsia: a prospective study. J Clin Endocrinol Metab 87: 1563–1568. Wolf, M., Shah, A., Jimenez-Kimble, R., Sauk, J., Ecker, J. L., and Thadhani, R. (2004). Differential risk of hypertensive disorders of pregnancy among Hispanic women. J Am Soc Nephrol 15: 1330–1338. Wolf, M., Shah, A., Lam, C. et al. (2005). Circulating levels of the antiangiogenic marker sFLT-1 are increased in first versus second pregnancies. Am J Obstet Gynecol 193: 16–22. Xia, Y., Wen, H., Bobst, S., Day, M. C., and Kellems, R. E. (2003). Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human trophoblast cells. J Soc Gynecol Investig 10: 82–93. Yamasmit, W., Chaithongwongwatthana, S., Charoenvidhya, D., Uerpairojkit, B., and Tolosa, J. (2004). Random urinary protein-to-creatinine ratio for prediction of significant proteinuria in women with preeclampsia. J Matern Fetal Neonatal Med 16: 275–279. Yancopoulos, G. D., Davis, S., Gale, N. W., Rudge, J. S., Wiegand, S. J., and Holash, J. (2000). Vascular-specific growth factors and blood vessel formation. Nature 407: 242–248. Yang, J. C., Haworth, L., Sherry, R. M. et al. (2003). A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349: 427–434. Yeh, S. P., Chiu, C. F., Lee, C. C., Peng, C. T., Kuan, C. Y., and Chow, K. C. (2004). Evidence of parvovirus B19 infection in patients of pre-eclampsia and eclampsia with dyserythropoietic anaemia. Br J Haematol 126: 428–433.

Zandi-Nejad, K., Luyckx, V. A., and Brenner, B. M. (2006). Adult hypertension and kidney disease: the role of fetal programming. Hypertension 47: 502–508. Zhou, Y., Chiu, K., Brescia, R. J. et al. (1993). Increased depth of trophoblast invasion after chronic constriction of the lower aorta in rhesus monkeys. Am J Obstet Gynecol 169: 224–229. Zhou, Y., Fisher, S. J., Janatpour, M. et al. (1997). Human cytotrophoblasts adopt a vascular phenotype as they differentiate. A strategy for successful endovascular invasion? J Clin Invest 99: 2139–2151. Zhou, Y., Damsky, C. H., and Fisher, S. J. (1997). Pre-eclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? J Clin Invest 99: 2152–2164. Zhou, Y., McMaster, M., Woo, K. et al. (2002). Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe pre-eclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol 160: 1405–1423. Zhou, Y., Genbacev, O., and Fisher, S. J. (2003). The human placenta remodels the uterus by using a combination of molecules that govern vasculogenesis or leukocyte extravasation. Ann NY Acad Sci 995: 73–83.

Further reading Conrad, K. P., Jeyabalan, A., Danielson, L. A., Kerchner, L. J., and Novak, J. (2005). Role of relaxin in maternal renal vasodilation of pregnancy. Ann NY Acad Sci 1041: 147–154. Danielson, L. A., and Conrad, K. P. (1995). Acute blockade of nitric oxide synthase inhibits renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats. J Clin Invest 96: 482–490. Fischer, M. J., Lehnerz, S. D., Hebert, J. R., and Parikh, C. R. (2004). Kidney disease is an independent risk factor for adverse fetal and maternal outcomes in pregnancy. Am J Kidney Dis 43: 415–423. Fischer, T., Schobel, H. P., Frank, H., Andreae, M., Schneider, K. T., and Heusser, K. (2004). Pregnancy-induced sympathetic overactivity: a precursor of preeclampsia. Eur J Clin Invest 34: 443–448. Rajakumar, A., Brandon, H. M., Daftary, A., Ness, R., and Conrad, K. P. (2004). Evidence for the functional activity of hypoxiainducible transcription factors overexpressed in preeclamptic placentae. Placenta 25: 763–769. Schrier, R. W. (1988). Pathogenesis of sodium and water retention in high-output and low-output cardiac failure, nephrotic syndrome, cirrhosis, and pregnancy (2). N Engl J Med 319: 1127–1134. Sibai, B. M., Caritis, S. N., Thom, E. et al. (1993). Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 329: 1213–1218. The Eclampsia Trial Collaborative Group (1995). Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial Lancet 345: 1455–1463.

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Pregnancy and the Kidney Taylor, R. N., Crombleholme, W. R., Friedman, S. A., Jones, L. A., Casal, D. C., and Roberts, J. M. (1991). High plasma cellular fibronectin levels correlate with biochemical and clinical features of pre-eclampsia but cannot be attributed to hypertension alone. Am J Obstet Gynecol 165: 895–901.

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Taylor, R. N., Casal, D. C., Jones, L. A., Varma, M., Martin, J. N., and Roberts, J. M. (1991). Selective effects of preeclamptic sera on human endothelial cell procoagulant protein expression. Am J Obstet Gynecol 165: 1705–1710.