Chapter 55. Pregnancy & Renal Disease

Anatomic Changes in Pregnancy

Kidney size increases by approximately 1 cm during pregnancy. The urinary collecting system (renal calyces, pelvis, and ureters) dilates. Hormonal and mechanical forces are thought to account for ureteral dilation as early as 6 weeks gestation. In the later stages of pregnancy, mechanical compression of the ureter against the pelvic brim may lead to hydroureter and hydronephrosis. Hydronephrosis occurs on the right in 90% of cases due to dextrorotation of the uterus by the sigmoid colon.

In rare instances this becomes a clinically significant cause of obstructive uropathy. The dilated collecting systems can hold up to 300 mL of urine and hence serve as a reservoir for bacteria. The dilated urinary tract also allows for urinary stasis and increases the risk of pyelonephritis in pregnant women with asymptomatic bacteriuria.

Physiologic Changes in Pregnancy

Renal physiologic changes are characterized by marked vasodilation, which leads to increases in glomerular filtration rate (GFR) and renal plasma flow (RPF). These changes occur early in the first trimester and peak increases in GFR and RPF to 50% above baseline are seen by the end of the first trimester. The filtration fraction (GFR/RPF) falls significantly, indicating a greater rise in effective RPF. Creatinine production is unchanged in pregnancy but creatinine clearance is increased, resulting in lower levels of serum creatinine; the normal creatinine value during pregnancy is <0.8 mg/dL (see Table 55–1).

Increased urinary excretion of protein, amino acids, uric acid, glucose, and calcium occurs as a result of the elevated GFR. Hence, proteinuria in pregnancy is considered abnormal when it exceeds 300 mg/day compared with an upper limit of normal of 150 mg/day in the nonpregnant population. Uric acid clearance also increases in pregnancy and serum uric acid levels in pregnant women usually do not exceed 4.5 mg/dL by the third trimester.

Electrolytes & Acid Base Changes

Pregnancy is associated with significant changes in water metabolism. Serum osmolality falls by 5–10 mOsmol/kg as a result of several forces. The serum osmostat is reset as suggested by normal responses to water loading and water deprivation despite a lower serum osmolality. There is a decrease in the osmotic thresholds for thirst and arginine vasopressin (AVP) release. Enhanced catabolism of AVP by release of placental vasopressinases leads to transient diabetes insipidus and in some women is severe enough to warrant treatment. Total body water increases by 6–8 L, most of which is extracellular. Plasma volume increases throughout pregnancy by 1.1–1.6 L, resulting in a plasma volume of 4.7–5.2 L, 30–50% above that in nonpregnant women. This is accompanied by the retention of 900–1000 mEq of sodium, which contributes to the mild edema seen in some pregnant women. Red blood cell mass increases 20–30% above baseline by the end of pregnancy. The proportionally greater increase in intravascular volume relative to red cell mass results in the dilutional or physiologic anemia of pregnancy.

Serum sodium falls by 5 mEq/L due to resetting of the osmostat (Table 55–1). Hyponatremia during pregnancy parallels the increased release of human chorionic gonadotropin (hCG), which appears to mediate these changes via the release of relaxin. Serum potassium levels are normal despite increased serum aldosterone, perhaps due to the potassium-sparing effects of elevated progesterone levels in pregnancy. Elevated progesterone levels stimulate hyperventilation and cause mild respiratory alkalosis, resulting in a slight increase in arterial pH and a fall in plasma bicarbonate concentrations by about 4 mEq/L. Total serum calcium levels fall in pregnancy but ionized calcium remains normal. Accelerated renal and placental production of calcitriol leads to increased gastrointestinal absorption of calcium and absorptive hypercalciuria with urine calcium as high as 300 mg/day. Serum parathyroid hormone (PTH) concentrations are lower than normal, partly in response to higher serum levels of calcitriol.

Hemodynamic Changes in Pregnancy

Profound changes in cardiovascular physiology and systemic hemodynamics are required to accommodate the increased metabolic demand of normal pregnancy. Pregnancy is accompanied by a rise in cardiac output and fall in mean arterial blood pressure and systemic vascular resistance (Figure 55–1). Cardiac output increases by 30–50% (1.8 L/minute) above prepregnancy values. Increased preload (due to increased blood volume), decreased afterload (due to decreased systemic vascular resistance), and the increase in maternal heart rate account for the rise in cardiac output. Cardiac output in pregnant women is affected significantly by changes in posture that compromise preload by compression of the inferior vena cava by a gravid uterus.

The fall in systemic vascular resistance (SVR) is manifested by a fall in blood pressure, which begins by the end of the first trimester. Blood pressure falls to 10 mm Hg below baseline by the second trimester, declining to a mean of 105/60 mm Hg. In the third trimester, the diastolic blood pressure gradually increases to nonpregnant values by term. Mechanisms underlying the fall in SVR and subsequent vasodilation include decreased vasopressor responsiveness to angiotensin II and norepinephrine, enhanced production of the vasodilatory factors prostacyclin and nitric oxide, and decreased aortic stiffness.

The renin–angiotensin–aldosterone system (RAS) is highly activated in normal human pregnancies. Plasma renin activity (PRA) increases 4-fold in the first trimester and continues to rise until approximately 20 weeks gestation. The increase in PRA stimulates increased secretion of aldosterone. The activation of the RAS is thought to be secondary, in response to vasodilation and a decrease in blood pressure.

Table 55–2 summarizes the two issues involved in chronic kidney disease/end-stage renal disease (ESRD) and pregnancy: the effects of kidney disease on pregnancy (course, complications, and outcome) and the effects of pregnancy on kidney disease.

Infertility

General Considerations

Pregnancy is not common in women on dialysis. Fertility rates in patients with ESRD are extremely low and are difficult to quantify accurately. Chronic kidney disease (CKD) is also associated with infertility.

Clinical Findings

The reproductive hormonal milieu in patients with ESRD remains an enigma. Elevated levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and low levels of free testosterone are common in men with ESRD.

Women with ESRD are usually amenorrheic or have irregular menstrual cycles. The frequency of menstruation in women of childbearing age with ESRD is variable, between 10% and 42%. Anovulatory cycles commonly occur even among menstruating women with ESRD. In contrast to women with ESRD, premenopausal women with normal kidney function have both tonic and cyclic components of gonadotropin secretion. The tonic component is regulated through basal gonadotropin secretion; the cyclic component is regulated through the midcycle surge of LH and its effects on the hypothalamus. The ovarian dysfunction in women on dialysis is characterized by the absence of cyclic gonadotropin release, presumably hypothalamic in origin. Menopause tends to occur earlier among women on dialysis.

Prolactin levels are elevated in both men and women on dialysis due to increased production and reduced renal clearance. Strikingly high numbers of women on hemodialysis (70–90%) and most peritoneal dialysis patients have hyperprolactinemia. Because of all of these factors, successful conception in dialysis patients is rare. Pregnancy is more common in kidney transplant recipients and in women with chronic kidney disease.

Fetal Outcomes

General Considerations

The difficulties of conception notwithstanding, successful pregnancies in dialysis-dependent patients are rare: of 115 pregnancies reported by the European Dialysis and Transplant Association, 23% carried to term. Fetal outcomes have improved over time: the percentage of pregnancies with surviving infants reported from the United States was 21% prior to 1990 and 52% from 1990 to 1991. The U.S. registry of pregnancy in dialysis patients reported that 42% of pregnancies resulted in a surviving infant, 7.5% in neonatal death, 6% in still birth, 32% in spontaneous abortion, and 10.5% in therapeutic abortion. Only 12% of the therapeutic abortions were performed due to pregnancy complications. Women who started dialysis during their pregnancy, conceived close to the point of requiring dialysis, or experienced a rapid decline in kidney function during their pregnancy have fairly good infant survival (73.6%) compared to that in women who conceived after starting dialysis (40% infant survival).

Complications

Prematurity

Prematurity and low-birth-weight babies are, unfortunately, the norm. Most deliveries in women who conceive on dialysis are premature (mean gestational age 32.4 weeks) and 36% of these infants weighed less than 1500 g at birth. Long-term medical and developmental problems are also common in these children and are due to prematurity and low birth weights rather than the azotemic intrauterine environment.

Polyhydramnios

Polyhydramnios, which can precipitate preterm labor and postpartum infant complications, is an important fetal complication in pregnancies in women with CKD. It is thought to be the result of increased fetal diuresis in response to high maternal blood urea nitrogen levels. The resulting fetal azotemia resolves rapidly after delivery but can lead to volume depletion and electrolyte imbalance from the ensuing osmotic diuresis.

Treatment

Obstetric management of these infants involves preventing preterm labor and appropriate fetal surveillance and timing of delivery. Strategies to prevent preterm labor include cautious use of magnesium or indomethacin in women with polyhydramnios. Magnesium levels must be closely monitored to avoid toxicity and consequent respiratory distress. Indomethacin can result in the loss of residual renal function and hyperkalemia, necessitating the initiation of dialysis or an increase in dialysis dose. Mid trimester losses may be prevented by monitoring dialysis patients for cervical shortening or cervical incompetence.

The timing of delivery is controversial. In most dialysis patients, preterm labor or an obstetric complication necessitates early delivery. Some obstetricians prefer delivery at 34–36 weeks if fetal lung maturity can be demonstrated. In transplant recipients and those with CKD, delivery is delayed until the onset of labor as long as maternal and fetal conditions remain optimal. A multidisciplinary team of health care providers including nephrologists, obstetricians, perinatologists, and dialysis providers is needed to ensure optimal care for the pregnant woman with CKD or ESRD.

General Considerations

Pregnancy may influence the course of kidney disease. Importantly, women with CKD do not have the normal pregnancy-associated increase in GFR. Overall, the pregnancy outcome is usually favorable in women with mild CKD, serum creatinine less than 1.4 mg/dL, and normal blood pressure early in pregnancy. Several case series suggest that women who conceive with a serum creatinine greater than 1.4 mg/dL experience a more rapid deterioration in kidney function than their nonpregnant counterparts with similar degrees of kidney function. In a study of 82 pregnancies in 67 women with a serum creatinine level of 1.4 mg/dL or greater at conception or in their first trimester, 20% of women had a decline in kidney function during pregnancy and 23% had a decline by the first 6 weeks postpartum. At 6 months postpartum, 8% of women recovered kidney function to their baseline values and an additional 10% had deterioration in kidney function. Women with a baseline creatinine exceeding 2.0 mg/dL experienced the greatest decrease in kidney function: 10% of this group had a rapid loss of kidney function and progressed to ESRD within 1 year of delivery. Women with pregnancy-associated deterioration in kidney function account for approximately 20% of women requiring dialysis in pregnancy. Obstetric complications include a high rate of preterm delivery (59%) and fetal growth retardation (37%). The infant survival rate was 93%.

Complications

Proteinuria usually increases in pregnant women with CKD. Hypertension occurs or is exacerbated in most women with underlying kidney disease and usually requires antihypertensive medications. The Registry of Pregnancy in Dialysis Patients reported that 79% of pregnant patients with ESRD were hypertensive and 48% experienced a blood pressure greater than 170/110 mm Hg during their pregnancy. In women with moderate to severe CKD, the frequency of hypertension rose from 28% at baseline to 48% in the third trimester. Maternal mortality, although rare, has certainly been reported.

Kidney disease that develops during pregnancy is usually due to new onset glomerulonephritis, lupus nephritis, interstitial nephritis, or acute renal failure. The evaluation of kidney disease during pregnancy includes the measurement of kidney function, serologic testing, and ultrasonography. Renal biopsy is rarely employed and is reserved for unexplained deterioration in renal function or severe nephritic syndrome. There is no role for a renal biopsy in pregnancy beyond 32 weeks.

Diabetic Nephropathy & Pregnancy

General Considerations & Complications

Pregnancy in women with diabetes mellitus is relatively common. The presence of diabetic nephropathy (urine albumin excretion >300 mg/day) at conception is a significant risk factor for perinatal morbidity and mortality. Preeclampsia superimposed upon diabetic nephropathy enhances the risk for preterm delivery and intrauterine growth retardation.

Among women with gestational diabetes, the prevalence of preeclampsia is 10–20%. The frequency of preeclampsia is higher with increasing severity of diabetes and in those with proteinuria at conception. Preterm delivery may be as high as 30% in women with preeclampsia. Diabetic women with microalbuminuria (urine albumin excretion of 30–300 mg/day) are also likely to develop preeclampsia, a risk similar to that of women with diabetic nephropathy. Preeclampsia also substantially increases the prevalence of their preterm delivery.

Early reports suggested pregnancy had little effect on the long-term progression of diabetic nephropathy, but recent reports contradict this. The progression of kidney disease is accelerated in 45% of pregnant women with diabetic nephropathy. A significant elevation in maternal blood pressure and proteinuria with nephrotic syndrome develops in most (71%) of these pregnancies. Infant birth weight correlates with gestational age and maternal kidney function: 71% of infants are appropriate for gestational age, 16% are small for gestational age, and 13% are large for gestational age. A prepregnancy history of tight glycemic control, a urine albumin excretion of less than 500 mg/day, and angiotensin-converting enzyme inhibitor (ACEI) therapy have been linked to a prolonged protective effect on maternal kidney function and more favorable pregnancy outcomes.

Pregnancy & Antiphospholipid Antibody Syndrome

General Considerations

Systemic lupus erythematosus (SLE) is a disease often seen in women of childbearing age. Signs of active SLE early in pregnancy herald a hazardous course. As with other nephropathies, the presence of hypertension and elevated creatinine level increases the risk of complications. Antiphospholipid syndrome (APS) can be primary or secondary. Secondary APS is associated with SLE, other collagen vascular diseases, and malignancy. APS is associated with arterial and/or venous thrombosis and recurrent fetal loss, particularly in the second trimester, and is usually accompanied by mild to moderate thrombocytopenia and elevated titers of antiphospholipid antibodies (aPLs). aPLs, either anticardiolipin antibodies of the IgG or IgM serotype or the lupus anticoagulant, link the seemingly disparate syndromes of recurrent pregnancy loss with spontaneous thrombosis and suggest that the placenta and systemic blood vessels may in some way be targets of autoantibodies with similar phospholipid specificity. Preliminary classification criteria for APS are described in Table 55–3. This classification of pregnancy loss recognizes that a preterm live birth accompanied by severe preeclampsia or severe placental insufficiency is comparable to fetal loss late in pregnancy.

Prevention

Preconception counseling and close maternal–fetal monitoring are recommended during all pregnancies of aPL-positive women. Recommendations for pharmacologic treatment are controversial and specific to a woman's clinical and obstetric history. Combination aspirin and heparin therapy has been recommended. Warfarin is contraindicated during pregnancy (Table 55–4) but can be used in the postpartum period. Both heparin and warfarin are safe for nursing mothers. Primary aPL syndrome and aPL syndrome with SLE are treated similarly.

Complications

Maternal complications include arterial and venous thrombosis, thrombotic microangiopathy, and increased risk of preeclampsia (18–50%). An association between severe preeclampsia and aPL has been reported. The presence of lupus anticoagulant is a strong predictor of a pregnancy-associated thrombotic event; anticardiolipin antibody was less predictive. A past thrombotic event posed a strong risk and a past history of intrauterine growth retardation (IUGR) or fetal death predicted IUGR in the current pregnancy. Survival rates of neonates born to aPL-positive women are 62–84%. High rates of prematurity (37–43%), fetal distress (50%), and IUGR (30%) have been reported.

Prevention

Preconception counseling is important in patients with CKD, after kidney transplantation, and while on dialysis. ACEIs and angiotensin receptor blockers (ARBs) are contraindicated in pregnancy (Table 55–4). ACEIs and ARBs disrupt fetal vascular perfusion and renal function and are associated with oligohydramnios, severe fetal renal dysfunction, fetal growth retardation, pulmonary hypoplasia, limb contractures, and calvarial hypoplasia mediated via the suppression of the fetal renin–angiotensin system. Studies have shown no adverse effects from exposure to ACEIs/ARBs in the first trimester of pregnancy. Thus, inadvertent exposure to ACEIs/ARBs in the first trimester may not warrant termination of pregnancy. Also, women with CKD who are on ACEIs/ARBs need not be advised to terminate the medication prior to planned conception as long as there is some assurance that pregnancy can be diagnosed promptly and ACEIs/ARBs stopped at that time.

Dialysis & Pregnancy

General Considerations

Diagnosing pregnancy can be difficult in dialysis patients. Results of urine pregnancy tests are not reliable, even if patients are not anuric. hCG levels may be mildly elevated even in nonpregnant patients on dialysis, hence, pregnancy may need to be confirmed by ultrasound.

There is no evidence to suggest that fetal or maternal outcomes are influenced by dialysis modality. The usual methods of selecting a dialysis modality can be employed if dialysis is started during pregnancy. Peritoneal dialysis has the theoretical advantage of gradual ultrafiltration and solute clearance, but peritoneal dialysis may be relatively contraindicated in patients with gestational diabetes due to the possibility of dialysate-induced hyperglycemia.

Treatment

Dialysis Prescription

The dialysis dose is an important consideration in pregnant patients because intensive dialysis results in a prolonged period of gestation, improved infant survival, and fewer maternal complications. A cumulative weekly dialysis dose exceeding 20 hours per week is recommended. The Registry for Pregnancy in Dialysis Patients reported improved pregnancy outcome in patients who conceived before dialysis therapy was initiated, suggesting that residual renal function and increased clearance of uremic toxins contribute to better outcomes. These women had lower rates of premature birth, low birth weight, and perinatal mortality than those who conceived after starting dialysis. They also had a lower incidence of polyhydramnios and a reduced risk for intradialytic hypotension.

Intensive hemodialysis may be achieved by daily dialysis or nocturnal hemodialysis. Appropriate modifications include a high potassium, low calcium, and low bicarbonate dialysis bath. Daily dialysis treatments (5–6 days/week) will also allow gentle ultrafiltration and avoid rapid hemodynamic changes during the treatment. Patients with hypertension may require intensive ultrafiltration, which may contribute to intradialytic hypotension. Because of the expected increase in plasma volume with pregnancy, vigilant attention must be paid to the changing dry weight of the pregnant dialysis patient. Patients on peritoneal dialysis who cannot tolerate large volume exchanges may need more frequent exchanges. A combination of daytime continuous ambulatory peritoneal dialysis (CAPD) and nighttime continuous cycling peritoneal dialysis (CCPD) may be necessary to achieve dialysis adequacy. Heparin can be used safely for anticoagulation during hemodialysis as it does not cross the placenta and hence is not teratogenic (Table 55–4).

Anemia

The anemia of kidney disease is likely to worsen in hemodialysis patients during gestation. Hemoglobin below 8 g/dL poses a significant risk to the fetus. Erythropoietin is safe during pregnancy; there are no reports of teratogenicity. Erythropoietin requirements increase by 50–100% during pregnancy in patients on hemodialysis. Iron deficiency is also common in pregnancy and supplemental oral iron is often prescribed. Intravenous iron can cause acute iron toxicity in the fetus, hence small doses are recommended if there is a poor response to oral agents.

Nutrition

Protein intake must be increased to meet the needs of pregnancy. Achieving adequate protein intake may be particularly difficult in patients on peritoneal dialysis. Potassium intake will also need to be increased, especially if dialysis is performed 5–6 days per week. Water-soluble vitamins such as folic acid should be dosed to meet increased demand and loss during dialysis.

Pregnancy after Kidney Transplantation

General Considerations

Fertility is usually restored following kidney transplantation. The incidence of pregnancy can be as high as 12% in transplant recipients of childbearing age; 90% of these pregnancies succeed once they pass the first trimester if the preconception creatinine is ≤1.5 mg/dL.

Women with good allograft function usually experience a physiologic increase in GFR during pregnancy. Short-term effects of glomerular hyperfiltration may manifest as proteinuria, but urinary protein excretion usually returns to baseline values by 3 months postpartum. However, proteinuria in the first trimester of pregnancy indicates underlying kidney disease that may worsen during pregnancy, especially in the setting of uncontrolled hypertension. From an immunologic standpoint, the risk of acute rejection during pregnancy is no different than that expected for nonpregnant controls. Acute rejection rates of 3–9% have been reported.

Clinical Findings

Blood Pressure in Pregnant Transplanted Women

In pregnant kidney transplant recipients, blood pressure tends to increase after 20 weeks gestation, making it difficult to distinguish between accelerated hypertension and preecclampsia. Calcineurin inhibitors promote hyperuricemia, making elevated uric acid levels a poor marker of preecclampsia in women taking cyclosporine or tacrolimus. Hypertension and preecclampsia have been reported in 25–40% of pregnancies and the incidence of preecclampsia is four times greater in kidney transplant recipients than in the general population. If hypertension is present at conception, a 5-fold greater risk of worsening hypertension or superimposed preecclampsia exists.

Effects of Pregnancy on Allograft Function

The effects of pregnancy on graft function are controversial. Some case–control studies suggest that pregnancy has no adverse effect on allograft function. One controlled study reported poor graft survival: 69% at 10-year follow-up compared to 100% in the control group. The National Transplantation Pregnancy Registry (NTPR) reports a rejection rate of 11% and a 7.5% rate of graft loss at 2 years in patients treated with cyclosporine. Most studies suggest that the two criteria most strongly affecting long-term kidney function are serum creatinine at the time of conception and the interval between transplant and conception. Patients with a serum creatinine of less than 1.5 mg/dL did not have any adverse renal outcome.

Complications

Infectious complications pose a significant problem for pregnant renal transplant recipients. Bacterial infections occur with increased incidence; 40% of patients have urinary tract infections. Pregnant transplant patients should therefore have monthly urine cultures. Opportunistic infections may also pose risks to the fetus. Reactivation of cytomegalovirus (CMV) in pregnancy may cause infection in the fetus. Up to 10% of infants with congenital CMV infection have microcephaly, mental retardation, or perinatal death; 5–15% may have late manifestations such as deafness and learning disabilities. The efficacy of treatment to prevent CMV disease in the fetus has not been established and treatment is reserved for serious maternal infections.

Herpes simplex infection during pregnancy is problematic only when the infection occurs close to the onset of labor. Acyclovir can be safely used in this situation. Toxoplasmosis in the mother may result in neonatal infection in 25–65% of cases and should be treated with sulfadiazine and pyrimethamine or spiromicin, even if the mother is not seriously ill. Hepatitis B can be transmitted vertically to the fetus and 80% of infants born to hepatitis B carriers become carriers themselves. Hepatitis B immune globulin and vaccination are effective in preventing 95% of infections in the neonate. Hepatitis C is a relatively common problem in dialysis patients and in those with kidney transplants. Vertical transmission is thought to be low, but there are no good approaches to prevention.

Treatment

The effects of immunosuppressive drugs on infants of pregnant kidney transplant recipients have not been studied long-term and it is not known whether the risk for childhood cancer or infertility is increased (Table 55–4). Prednisone crosses the placenta in the form of prednisolone and may cause adrenal insufficiency or thymic hypoplasia in infants. These side effects appear minimal when the dose of prednisone is less than 15 mg/day. Azathioprine has been associated with small-for-gestational age babies and myelosuppression in the fetus. Calcineurin inhibitors have not been linked to congenital abnormalities but have been associated with increased risk of small-for-gestational age and very-low-birth weight infants. Tacrolimus, in particular, has been associated with neonatal anuria and hyperkalemia (Table 55–4). There are no data on the use of mycophenolate mofetil in pregnancy. The effects of polyclonal antibodies on the fetus are also unknown. Pregnancy in women with kidney disease requires a multidisciplinary team approach involving nephrologic, obstetric, and pediatric health care providers to maximize the likelihood of good maternal and fetal outcomes.

Essentials of Diagnosis

• Rising blood urea nitrogen (BUN) and creatinine levels.
• Elements of history that suggest a specific cause.
• Will need a complete blood count (CBC) and platelet count and liver function tests.
• Urine analysis, especially urine protein.

General Considerations

Acute renal failure in pregnancy is uncommon but can be severe, requiring dialysis. Any of the causes of acute renal failure occurring in the nonpregnant population may also occur during pregnancy, but there are some specific causes of acute renal failure during pregnancy that must be considered. Determining the type of acute renal failure in a pregnant woman will depend on the history, especially the timing of the acute renal failure in terms of the pregnancy (eg, in the first, second, or third trimester or postpartum), the presence or absence of preeclampsia, findings on urine analysis (especially proteinuria, white blood cells, red blood cells), and associated laboratory abnormalities, especially anemia, platelet count, liver transaminases and bilirubin, and tests of coagulation (prothrombin time and partial thromboplastin time).

Because plasma volume is increased in normal pregnancy, normal BUN and creatinine levels are lower in pregnancy than in the nonpregnant state (Table 55–1). Thus, during pregnancy, a creatinine >0.8 mg/dL and a BUN >14 mg/dL are abnormal and consistent with kidney disease (either acute or chronic).

Prerenal or Hemodynamic Causes of Acute Renal Failure in Pregnancy

Essentials of Diagnosis

• Rising BUN and creatinine.
• History, physical examination, and laboratory data consistent with volume depletion, sepsis, or hemorrhage.

General Considerations

Hyperemesis gravidarum and hemorrhage may cause acute renal failure in pregnancy as a result of volume depletion. Sepsis-induced acute renal failure in pregnancy is most often associated with abortion, especially in the developing world and in areas where therapeutic abortion is illegal. Most cases of prerenal acute renal failure in pregnancy occur early in the pregnancy. As in the nonpregnant state, prerenal causes of acute renal failure in pregnancy may progress to acute tubular necrosis (ATN). Prerenal acute renal failure must be distinguished from postrenal (obstruction) and intrinsic acute renal failure.

Clinical Findings

Symptoms and Signs

The history and physical examination will suggest volume depletion and/or hemodynamic compromise. Abruptio placentae may precede hemorrhage and is also associated with cortical necrosis.

Laboratory Findings

Evidence of intact kidney tubular function (low urine sodium, low urine fractional excretion of sodium and fractional excretion of urea) may often accompany prerenal acute renal failure. An elevated BUN:creatinine ratio may also be seen.

Treatment & Prognosis

Treatment of prerenal acute renal failure in pregnancy is to correct the underlying cause, ie, replete lost volume or blood and treat sepsis. With timely and appropriate treatment, progressive acute renal failure (ATN) may be avoided with an excellent chance of complete recovery of kidney function.

Postrenal Acute Renal Failure in Pregnancy

Essentials of Diagnosis

• Rising BUN and creatinine in a pregnant woman.
• Obstruction of the urinary tract.

General Considerations

Moderate dilation of the urinary collecting system is usual during pregnancy. This “functional” hydronephrosis is commonly more prominent on the right side, usually with preservation of normal kidney function. In rare cases, acute renal failure can occur if the degree of obstruction is great. In such cases, kidney function often normalizes if the woman is placed in the lateral recumbent position (relieving uterine pressure on the ureters), thereby confirming the diagnosis. In some cases, urologic intervention or delivery is needed to relieve the obstruction and resolve the acute renal failure.

Intrinsic Acute Renal Failure in Pregnancy

Essentials of Diagnosis

• Rising BUN and creatinine.
• Exclusion of prerenal and postrenal causes of acute renal failure.

General Considerations

Although most cases of pyelonephritis during pregnancy do not result in acute renal failure, acute pyelonephritis can cause acute renal failure during pregnancy. As in the nonpregnant population, ATN, acute interstitial nephritis, and acute glomerulonephritis may also cause acute renal failure in a pregnant woman. In such cases, the history, physical examination, and urine analysis will usually lead to these diagnoses. However, there are some specific causes of acute renal failure that are seen only during pregnancy or are associated primarily with pregnancy. These include the acute renal failure seen with preeclampsia/eclampsia, acute fatty liver of pregnancy (AFLP), thrombotic microangiopathies [hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), and HELLP syndrome (hemolysis with a microangiopathic blood smear, elevated liver enzymes, and a low platelet count)], and cortical necrosis.

Preeclampsia/Eclampsia-Associated Acute Renal Failure

Essentials of Diagnosis

• Typically develops late in the third trimester.
• Preeclampsia does not occur before 20 weeks of gestation.
• Preeclampsia = hypertension, edema, and proteinuria.

General Considerations

Kidney function is usually normal or near normal in women with preeclampsia unless hemodynamic instability develops with excessive bleeding or disseminated intravascular coagulation (DIC) occurs. Mild degrees of kidney dysfunction may be seen with preeclampsia, likely because of reduced glomerular permeability. Delivery of the fetus usually results in resolution of the preeclampsia in 24–48 hours. Severe preeclampsia may also present with thrombotic microangiopathic acute renal failure (see below and the section on eclampsia/preeclampsia).

Thrombotic Microangiopathies

Essentials of Diagnosis

• Thrombocytopenia.
• Microangiopathic anemia.
• Normal prothrombin time.
• Abnormal kidney function.
• Usually occurs late in pregnancy or early postpartum.

General Considerations

It can be difficult to make a specific diagnosis when acute renal failure associated with thrombocytopenia and microangiopathic hemolytic anemia occurs late in pregnancy. In addition to TTP and HUS, severe preeclampsia and HELLP (hemolysis with a microangiopathic blood smear, elevated liver enzymes, and a low platelet count) can cause acute renal failure as a result of thrombotic microangiopathy. Although TTP and HUS are considered distinct entities, because their clinical presentations are often indistinguishable, they are best considered as part of a spectrum of disease. Differentiating severe preeclampsia or HELLP from TTP-HUS is important for both therapeutic and prognostic reasons. The most useful distinguishing features are the timing of the onset of acute renal failure and the blood pressure and urine protein during the pregnancy.

Clinical Findings

Symptoms and Signs

Severe preeclampsia is more common than TTP-HUS and usually presents with proteinuria, hypertension, and edema late in pregnancy. TTP-HUS often occurs postpartum without an antecendent history of pregnancy-associated hypertension or proteinuria. When TTP-HUS occurs antepartum, it often presents early in the second or even during the first trimester. Importantly, unlike TTP-HUS, acute renal failure with preeclampsia and HELLP usually resolves with delivery.

Laboratory Findings

Thrombocytopenia and microangiopathic anemia are the cardinal findings. Elevated liver enzymes may occur with TTP-HUS, but if they are extremely high, it should suggest HELLP (Figure 55–2). Patients with TTP generally have very low levels of plasma ADAMTS13 while HELLP is associated with only mildly to moderately low ADAMTS13 levels.

Differential Diagnosis

In addition to severe preeclampsia and HELLP, acute renal failure occurring late in pregnancy may also be associated with AFLP, disseminated intravascular coagulation with sepsis, hemorrhage, or obstetric catastrophe (eg, abruptio placentae). The differential diagnosis may also include severe ATN and cortical necrosis. In most cases, the clinical history and laboratory findings will narrow the diagnostic possibilities.

Treatment

The optimal treatment of TTP-HUS in pregnancy is the same as in the nonpregnant population. Plasma infusion with or without plasma exchange is the mainstay of treatment and has significantly improved mortality. Renal replacement therapy may be required depending on the clinical circumstances. The treatment of HELLP is more controversial, although delivery is clearly indicated. Some of the abnormal laboratory results may transiently worsen after delivery, but usually normalize within postpartum week one.

Prognosis

Before the use of plasma exchange, the mortality of pregnancy-associated TTP-HUS approached 90%. Today, with appropriate treatment, mortality has improved, although a significant proportion of women may be left with CKD or, less often, ESRD requiring dialysis.

Acute Fatty Liver of Pregnancy

Essentials of Diagnosis

• Jaundice and liver dysfunction.
• Occurs at the end of pregnancy or in early puerperium.
• Usually simultaneous coagulation disorders.
• Liver biopsy is diagnostic.

General Considerations

AFLP is characterized by microvesicular fatty infiltration of hepatocytes without necrosis or inflammation. This disorder is unique to human pregnancy and is relatively uncommon, occurring in one in 7000–16,000 deliveries. It usually occurs late in pregnancy, close to term. Some patients may present after delivery.

Pathogenesis

As with Reye's syndrome, microvesicular fatty infiltration is seen histologically with AFLP. Affected women may have an inherited enzyme deficiency in β-oxidation of fatty acids that predisposes them to AFLP. The accumulation of long-chain 3-hydroxyacyl metabolites produced by the fetus or the placenta is toxic to the maternal liver and may be the cause of the disease.

Clinical Findings

Symptoms and Signs

Women with AFLP often present with nausea and vomiting, abdominal pain, lethargy, jaundice, headache, bleeding, or altered mental status due to hepatic encephalopathy. However, in some patients incidentally elevated liver test results lead to the diagnosis.

Laboratory Findings

See Figure 55–2. Abnormal liver function tests occur with modest to severe elevations of aminotransferase. The platelet count is normal unless progression to DIC has occurred. In such cases, antithrombin III levels will be low. In severe cases of AFLP, elevations of ammonia may occur as well as profound hypoglycemia. Acute renal failure occurs in up to 60% of cases.

Imaging Studies

Imaging studies are primarily used to exclude hepatic infarct or hematoma. Fat may be seen on ultrasound or computed tomography (CT) of the liver but is rarely diagnostic.

Special Tests

Liver biopsy is diagnostic and shows pericentral pallor with lobular disarray and vacuolization of the centrizonal hepatocytes. Special stains should be done to identify the microvesicular fat. Because of the coagulopathy accompanying AFLP, liver biopsy caries a high risk of bleeding and is reserved for cases in which the diagnosis is in doubt and/or treatment is being delayed.

Differential Diagnosis

Acute renal failure associated with severe preeclampsia, HELLP, and thrombotic microangiopathies comprises the diagnostic possibilities (Figure 55–2). Hepatic infarction or hematoma and other causes of acute liver failure should be excluded.

Treatment

Treatment is delivery after stabilization. Supportive therapy is usually required and may include monitoring in an intensive care unit. Glucose infusion and reversal of the associated coagulopathy are usually required.

Prognosis

Today most women recover without sequelae, but a mortality rate of 10% has been reported. AFLP can recur in subsequent pregnancies. One out of four infants born to women with AFLP will have an inherited disorder of long-chain 3-hydroxyacyl CoA dehydrogenase deficiency (LCHAD). When stressed, such infants are at risk of fatal nonketotic hypoglycemia. Additionally, some forms of LCHAD deficiency are associated with neonatal dilated cardiomyopathy or progressive neuromyopathy.

Cortical Necrosis

Essentials of Diagnosis

• Seen with complications of pregnancy, eg, abruptio placentae, placenta previa, amniotic fluid embolism, prolonged intrauterine death.
• Usually associated with severe renal ischemia and/or DIC.
• Abrupt onset of oliguria or anuria.
• Often a triad of anuria, gross hematuria, and flank pain.

General Considerations

Bilateral cortical necrosis is an unusual cause of acute renal failure, but when seen it often occurs in the obstetric setting. It usually follows a complication of pregnancy and is associated with DIC and/or severely impaired renal blood flow. Cortical necrosis is usually diagnosed clinically and confirmed radiologically by finding hypoechoic or hypodense areas of renal cortex on ultrasound or CT scan. Renal calcification on plain film may be seen 1–2 months after the event. There is no specific treatment for cortical necrosis and many women require chronic dialysis; 20–40% may have some recovery of kidney function and be left with CKD. Most women with acute renal failure from cortical necrosis will remain dialysis dependent.

Essentials of Diagnosis

• A systolic blood pressure exceeding 140 mm Hg or a diastolic blood pressure exceeding 90 mm Hg.
• Proteinuria that may be in the nephrotic range.
• Eclampsia = grand mal seizure activity in a pregnant woman with preeclampsia.

General Considerations

Preeclampsia is defined as the development of new onset hypertension and proteinuria in a pregnant woman after 20 weeks gestation. A significant increase in blood pressure in a previously normotensive woman during pregnancy should raise suspicion for the diagnosis. Proteinuria in excess of 300 mg in a 24-hour period is abnormal during pregnancy and should raise the possibility of preeclampsia.

Preeclampsia occurs in 3–14% of pregnancies. Most cases are mild and very few occur in pregnant women less than 34 weeks gestation. For unclear reasons, primigravid women less than 20 years of age are at highest risk for developing preeclampsia. Many factors are recognized as risks for preeclampsia, including higher blood pressure at the start of pregnancy, large maternal body size, preexisting hypertension, antiphospholipid syndrome, advanced maternal age (exceeding 35–40 years), preexisting diabetes, multiple pregnancies, and vascular or rheumatologic disease. A family history of preeclampsia raises the risk 2- to 5-fold and recent studies suggest that a paternal genetic factor might also contribute to defective placentation and the subsequent evolution of preeclampsia.

Eclampsia is recognized by the new onset of grand mal seizures in a pregnant woman with preeclampsia. Eclampsia develops in 2% and 0.5% of severe and mild preeclamptic women, respectively, and is more common in nonwhite nulliparous women of low socioeconomic status. Eclamptic seizures are typically short lived and do not result in neurologic deficit. The cause of eclamptic seizures is not known.

Pathogenesis

Abnormal placentation, placental ischemia, and endothelial dysfunction play supportive and integrated roles in the pathogenesis of preeclampsia. Abnormal trophoblastic invasion of the endothelium and maternal spiral arteries and the impaired trophoblast differentiation that follows preclude formation of the low resistance highly capacitant uteroplacental circulation. Placental ischemia is thought to elaborate circulating factors that culminate in maternal endothelial dysfunction, extreme renal vasoconstriction, and the clinical correlates of hypertension, arteriole thrombosis, and multiorgan failure. Genetic predisposition may pose a risk as well and both maternal and paternal contributions may be operative.

Prevention

Several agents have been studied to prevent preeclampsia but none has definitively been shown to reduce the risk. These include aspirin, calcium, fish oil, and vitamins C and E, the latter two for their purported antioxidant effect. A preventive role for the selective serotonin-2 receptor antagonist ketaserin has been suggested, but further study of its potential to mitigate endothelial cell vasoconstriction via serotonin blockade is needed.

Only aspirin has been confirmed to be safe, but its efficacy in preventing preeclampsia remains unclear. Aspirin may modestly reduce the risk in moderate to high-risk pregnant women but is not recommended for use in low-risk pregnancies. In addition, aspirin has not been shown to be of benefit when pregnancy-induced hypertension has developed. Aspirin also does not prevent progression of preeclampsia to HELLP. The risk of bleeding diathesis in the latter increases the risks associated with aspirin.

Clinical Findings

Symptoms and Signs

Symptoms and signs include the gradual development of hypertension, proteinuria, and edema, which all typically manifest in the late third trimester. Preeclampsia rarely presents before 20 weeks gestation, but symptoms can begin as early as 24 weeks (the late second trimester) or as late as immediately before delivery or even early postpartum. Primigravidas with hypertension, edema, and proteinuria most likely have preeclampsia and can be definitively diagnosed by the presence of two or more criteria. A rise in blood pressure from baseline, even to a level considered within normal range, constitutes risk and should be considered a clue to preeclampsia. While blood pressure increases usually occur in the second trimester, hypertension per se does not usually manifest until late in the third trimester. The diagnosis is confirmed by finding increased blood pressure on two occasions at least 6 hours, but no more than 7 days, apart. Edema is typical of normotensive pregnancy but may be abrupt and severe in preeclampsia and occurs in the face of decreased intravascular volume. Neurologic manifestations of preeclampsia include headache, blurred vision, scotoma, and cortical blindness. The latter is rare and signifies severe preeclampsia.

All signs and symptoms of preeclampsia generally resolve within 2–6 weeks after delivery.

Laboratory Findings

Urinary dipstick-positive proteinuria is an important clue, although not all preeclamptic women present with proteinuria. The 24-hour urine measurement for total protein remains the gold standard for quantifying proteinuria. However, a random or spot urine protein-to-creatinine ratio from nontimed specimens can be helpful in identifying significant proteinuria. Routine urinalysis (dipstick for protein) alone is not sensitive enough to rule out significant proteinuria. Proteinuria in preeclampsia typically evolves gradually and may reach a nephrotic range; hence, its absence should not be cause for excluding preeclampsia from the differential diagnosis of hypertension in pregnancy.

In addition to proteinuria, preeclamptic women may have thrombocytopenia (secondary to increased platelet turnover), hyperuricemia, hypocalcemia, and microangiopathic hemolytic anemia. The presence of hemolysis may not be obvious if the hemoconcentration is significant enough to mask anemia. Hemolysis in the presence of elevated liver enzymes suggests the evolution of the HELLP syndrome. Hemoconcentration, proteinuria, and hyperuricemia suggest preeclampsia, and although liver enzymes may be elevated in mild or moderate preeclampsia, severe elevations (greater than 2-fold), in conjunction with proteinuria >5 g/24 hours, increased creatinine, and thrombocytopenia suggest severe preelampsia. Elevated lactate dehydrogenase and a smear indicative of hemolysis support the diagnosis of HELLP.

Imaging Studies

Imaging of the uterine artery by Doppler flow can be used to assess risk. Reductions in flow within uterine and/or umbilical arteries suggest risk for impending preeclampsia. Diastolic notching of the arcuate vessels of the uterus and high resistive indices have been used as predictive tests. However, neither has adequate positive predictive value to warrant their routine use even in high-risk patients.

Special Tests

Urinary placental growth factor (PlGF) may be useful in predicting the future development of preeclampsia. PlGF appears to rise normally in women destined to have preeclampsia but nadirs at a level lower than in women without preeclampsia. Placental peptide measurements may be employed in the future to assess for preeclamptic risk, although studies of their potential use are currently experimental.

Differential Diagnosis

Preeclampsia is a clinical diagnosis. The differential diagnosis includes chronic hypertension, gestational hypertension, new onset essential hypertension, and acute exacerbation of underlying kidney disease. Other diseases that can present with various combinations of hypertension, coagulopathy, and liver and renal dysfunction include primary liver disease, TTP-HUS, pancreatitis, diseases characterized by thrombocytopenia such as lupus, or even gestational thrombocytopenia.

The presence of liver enzyme abnormalities, hemoconcentration, and perhaps hemolysis is not typical in chronic hypertension and should prompt suspicion for preeclampsia. Further, chronic hypertension will not resolve postpartum as can be expected with preeclampsia.

Gestational hypertension may present with mild proteinuria late in the third trimester. However, both the increase in blood pressure and the elevated urinary protein excretion resolve shortly after delivery and typically without complications. Gestational hypertension that occurs earlier in gestation is more likely to evolve into preeclampsia and should be treated as such. Similarly, gestational hypertension with symptoms of severe preeclampsia, headache, growth restriction, or features suggestive of HELLP should be treated as preeclampsia.

New onset hypertension may be difficult to distinguish from preeclampsia, particularly in young, nulliparous women. The development of hypertension in a pregnant woman prior to 20 weeks gestation favors a diagnosis of new onset essential hypertension. The normal physiologic fall in blood pressure that occurs in the early stages of pregnancy may mask the presence of underlying but as yet undiagnosed hypertension.

Complications

Eclampsia is the major complication of untreated or unsuccessfully treated preeclampsia. Eclampsia occurs in 0.5% of mild and 2% of severe preeclampsia. Eclamptic seizures are indistinguishable from tonic–clonic seizures of other etiologies and are treated differently (see the section on treatment). In the 15–20% of preeclamptic women who do not have proteinuria, seizures may help retrospectively distinguish preeclampsia from chronic or new onset hypertension.

The timing of eclampsia is variable with approximately 50% of cases occurring prior to term, one-third at term, 25% postpartum, and less than 10% at 31 weeks. The pathogenesis of eclampsia is unclear, although cerebral hemorrhage and edema are thought to play a central role.

HELLP is likely a form of severe preeclampsia, but its classification in this regard remains controversial. HELLP develops in 10–20% of women with preeclampsia/eclampsia. Importantly, HELLP is an indication for delivery to avoid hepatic complications, such as rupture, infarct, and hemorrhage. Signs and symptoms include abdominal pain, commonly occurring in the right upper quadrant or epigastrium, nausea, vomiting, and elevated blood pressure. Proteinuria less commonly accompanies symptoms, occurring in 15–20% of cases.

The diagnostic criteria for HELLP include signs of microangiopathic hemolytic anemia (peripheral blood smear with schistocytes, hyperbilirubinemia or elevated lactate dehydrogenase, and decreased haptoglobin), thrombocytopenia, and elevated liver enzymes (Figure 55–2). The latter can be increased in preeclampsia, but in the presence of the other laboratory abnormalities noted above, HELLP should be considered. Delivery is indicated for women with HELLP who are past 34 weeks gestation and who exhibit signs and symptoms of multiorgan failure, DIC, renal failure, abruptio placentae, liver failure, or hemorrhage.

Treatment

Preeclampsia

Expectant treatment of preeclampsia includes close fetal and maternal monitoring and treatment of moderate to severe hypertension. Medical intervention is considered appropriate when the systolic blood pressure reaches 170 mm Hg or the diastolic blood pressure reaches 104 mm Hg with an ultimate target of 140–150 mm Hg systolic and 90–105 mm Hg diastolic. α-Methyldopa is the antihypertensive medication of choice because it has a long history of use in pregnancy without complications (Figure 55–2). Diuretics and β-blockers are generally avoided, but calcium channel blockers and, acutely, hydralazine and labetalol may be used (Figure 55–2). Severe preeclampsia is an indication for delivery and should prompt consideration of magnesium sulfate therapy, the drug of choice for primary prevention of eclampsia in women with severe preeclampsia. Gestational hypertension, when severe, should be treated as preeclampsia.

Eclampsia

This obstetric emergency poses significant risk of death or neurologic sequelae. In addition to general stabilization measures, intravenous magnesium sulfate is the drug of choice for treating eclamptic seizures. Calcium gluconate may be needed if symptoms of hypocalcemia evolve. Anticonvulsant agents such as phenytoin may be used, but in general are less effective than magnesium sulfate in preventing recurrent seizures. Moderate to severe hypertension (systolic pressure greater than 160 mm Hg and diastolic pressure greater than 105 mm Hg) should be treated with labetalol or hydralazine. No benefit of treating mild hypertension has been shown.

HELLP

As with eclampsia, management of HELLP syndrome includes maternal and fetal stabilization, therapy for hypertension to a target of less than 160/105 mm Hg, consideration of magnesium sulfate, and timely delivery for women after 34 weeks gestation. Corticosteroids are administered for pregnancies less than 34 weeks to optimize fetal lung maturation.

Prognosis

Preeclampsia

Multiparous women with a history of preeclampsia have a 3-fold increased risk of recurrent preeclampsia in subsequent pregnancies. Mild preeclampsia occurring near term in primagravid women is associated with a good outcome, rapid fall in blood pressure, and a 5–7% recurrence rate. Both severe preeclampsia and preeclampsia occurring early in pregnancy are associated with an increased risk of recurrence as well as an increased risk of developing chronic hypertension.

Women with a history of preeclampsia are at increased risk for cardiovascular disease and as many as 78% develop chronic hypertension. Risk of stroke is increased 3-fold in women with a history of preeclampsia.

HELLP

There is currently no therapy known to prevent recurrent HELLP. Prognosis for mothers with HELLP is generally good with only 1% maternal mortality. There is a 2–19% risk of recurrence and a 20% risk of preeclampsia in subsequent pregnancies.

Eclampsia

One-third of eclampsia is not preventable. Those with the earliest symptoms of preeclampsia are at highest risk of recurrence and/or a bad outcome. Maternal death occurs at a rate of 0–13.9% and is highest in women with early onset of eclampsia (eg, prior to 28 weeks). Complications of eclampsia occur in a large number of women (70%).