1. What changes take place in the kidney during pregnancy?

The kidney undergoes anatomic and physiologic changes during normal pregnancy. The length of the kidney increases by 1 to 1.5 cm and there is hormonally mediated dilatation of the collecting system to a volume of about 300 cc. The resulting physiologic hydronephrosis makes it difficult to diagnose obstruction by ultrasound. The glomerular filtration rate increases by 50% during the first trimester so that the serum creatinine is expected to be 0.5 to 0.7 mg/dL. Pregnancy is also characterized by a reset osmotstat where the serum sodium is normally in the range of 134 mEq/L, but a water load can be excreted normally. Additionally, pregnancy is characterized by respiratory alkalosis with a compensatory drop in bicarbonate, making the normal bicarbonate in pregnancy 18 to 20 mEq/L.

2. How often do urinary tract infections occur during pregnancy?

Urinary stasis from the dilated collecting system predisposes to urinary tract infections. Asymptomatic bacteriuria occurs in 5% of pregnancies. Untreated, 30% of asymptomatic bacteriuria leads to pyelonephritis, which in pregnant women is frequently complicated by decreased kidney function/acute kidney injury, sepsis, and even acute respiratory distress syndrome (ARDS). Only 2% of healthy women with a negative urine culture on the first screening will develop a urinary tract infection (UTI) later in pregnancy, but women with preexisting kidney disease should be screened monthly.

3. What is the importance of preeclampsia?

Preeclampsia is the most common and important of the hypertensive disorders of pregnancy, affecting between 5% and 7% of pregnancies. Preeclampsia is a multisystem disease. The American College of Obstetrics and Gynecology does not require proteinuria if other end-organ disease is present. Severe preeclampsia is denoted by its most common symptoms, microangiopathic Hemolytic anemia, Elevated Liver enzymes and Low Platelets (HELLP syndrome). It can be accompanied by severe manifestations including acute kidney injury, stroke, blindness from vasoconstriction in the occipital lobe or retinal detachment, disseminated intravascular coagulation, hepatic rupture, or pulmonary edema. Preeclampsia may progress to seizures, a progression that changes the designation to eclampsia. The hypertension in preeclampsia is identified relative to prepregnancy blood pressure. A rise in systolic blood pressure of 30 mm Hg or a rise in diastolic blood pressure of 15 mm Hg raises the possibility of preeclampsia. The definitive treatment of preeclampsia is delivery of the baby and placenta, but depending on the severity of the preeclampsia, efforts may be made to postpone delivery if it occurs in the second trimester or early in the third trimester. Anticonvulsants, most commonly magnesium in the U.S., and antihypertensive drugs are usually required while getting the mother ready for delivery.

Over the last decade, long-term follow-up of large populations of women with preeclampsia has shown a subsequent increased risk of cardiovascular disease, kidney biopsy, and end-stage kidney disease (ESKD).

4. What is the pathophysiology of preeclampsia?

The initiating factor in preeclampsia is incomplete remodeling of uterine spiral arteries, which results in placental ischemia. The ischemic placenta produces high levels of the antiangiogenic factors, soluble Fms-like tyrosine kinase (sFlt1) and soluble endoglin which are released into the circulation. Levels of placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) are low. sFlt1 antagonizes the angiogenic activity of VEGF and PlGF, causing diffuse vasoconstriction and glomerular endothelial damage. Therapies targeting antiangiogenic factors to treat preeclampsia are an ongoing area of investigation. A different pathogenesis has been proposed for late-onset preeclampsia (more than 34 weeks gestation). In late preeclampsia, the problem may be maternal endothelial dysfunction in response to oxidative stress in the placenta.

5. What are the other hypertensive disorders of pregnancy?

The three other hypertensive disorders of pregnancy are chronic hypertension, chronic hypertension with superimposed preeclampsia, and gestational hypertension. Women with preexisting hypertension may become pregnant so that essential hypertension is seen during pregnancy. The diagnosis of essential hypertension is made by a blood pressure ≤140/90 before 20 weeks gestation with no other explanation or a diagnosis of essential hypertension before pregnancy. These women are at increased risk for preeclampsia, giving rise to essential hypertension with superimposed preeclampsia in 25%. Gestational hypertension is hypertension that occurs late in pregnancy and is not accompanied by proteinuria or other end-organ disease of preeclampsia. It resolves postpartum but is a predictor of future essential hypertension.

6. What antihypertensive drugs can be used to treat hypertension in pregnancy?

Use of angiotensin converting enzyme inhibitor (ACEi) in the second and third trimester is associated with renal dysplasia, oligohydramnios, and neonatal death from hypoplastic lungs. Using ACEis in the first trimester may cause cardiac anomalies in the neonate. There are less data on angiotensin receptor blockers (ARBs), but they are avoided because of concern that their effects will be similar to those of ACEis. Direct renin inhibitors, such as aliskiren, should also be avoided.

Alpha methyldopa has been used for more than 50 years to treat hypertension in pregnant women and careful follow-up on children support its safety. Labetalol, hydralazine, and calcium channel blockers are safe. Calcium channel blockers may cause severe hypotension when used with magnesium. Hydralazine is ineffective as a single oral agent, but may be effective when used with a sympatholytic drug. Beta blockers, particularly atenolol, have been reported to have adverse effects on fetal growth and labetalol can usually be used as an alternative. They are not considered contraindicated. Diuretics have been associated with less than normal expansion of plasma volume but may be necessary in women with underlying kidney disease. Intravenous hydralazine and labetalol are the drugs most commonly used for hypertensive emergencies.

7. What are the causes of acute kidney injury in pregnancy?

In underdeveloped countries, sepsis from illegal abortion and preeclampsia are the most common causes of acute kidney injury. With improved health care systems, pregnancy-associated acute kidney injury is rare, on the order of 1 in 10,000 to 20,000 pregnancies. Preeclampsia is occasionally associated with acute kidney injury, especially in the setting of the HELLP syndrome. Pregnancy can be complicated by hemolytic uremic syndrome, which presents in a manner similar to hemolytic uremic syndrome (HUS) in other settings. It can be distinguished from preeclampsia by the elevated transaminases and abnormal clotting parameters seen in preeclampsia. Acute kidney injury can complicate acute fatty liver of pregnancy. Despite the rarity of acute kidney injury in pregnancy, pregnancy makes the kidney more susceptible to cortical necrosis. When acute kidney injury occurs in the setting of an obstetric catastrophe such as abruptio placentae, amniotic fluid embolus, or hemorrhage from other causes, there may be residual kidney dysfunction after recovery.

8. What is the effect of chronic kidney disease (CKD) on fertility and pregnancy?

Fertility is decreased in women with preexisting kidney disease. Since the denominator (number of women with kidney disease trying to become pregnant) is not known, it is impossible to know how much fertility is decreased, but it is unusual to see a pregnancy in a woman with a serum creatinine >2.5 mg/dL. In women with kidney disease and preserved glomerular filtration rate (GFR), pregnancy carries an increased risk of hypertension and premature delivery. If proteinuria is present, it is likely to increase during pregnancy. It can be difficult to distinguish between hypertension associated with kidney disease and preeclampsia, since increased proteinuria, increased uric acid, and increased creatinine may be seen in both. One complication of pregnancy in a woman with kidney disease is worsening kidney function. The likelihood of worsening kidney function depends on the level of kidney function before conception. Most studies rely on serum creatinine to assess kidney function. The risk of worsening kidney function increases when the serum creatinine is >1.4 mg/dL. If the serum creatinine is >2 mg/dL, the risk of worsening kidney function is 30% to 50%. Imbasciati et al. used eGFR and proteinuria in assessing kidney disease. Worsening kidney function was seen only in women with both a GFR of <40 cc/min and at least 1 g of proteinuria in 24 hours. The formulas used to calculate GFR have not been validated in pregnancy.

9. Is successful pregnancy possible in patients on renal replacement therapy?

Fertility is markedly decreased in dialysis patients with frequency of conception ranging from 0.3% to 1.5% per dialysis patient per year. One exception is a 15% conception rate among women treated with nocturnal dialysis. There are no data on whether or not women were trying to become pregnant. Outcomes are better with increased dialysis hours. In women with less than 20 hours of dialysis per week, infant survival is about 50%. Infant survival increases to 75% with 20 or more hours of dialysis. The most encouraging outcomes originate from women receiving nocturnal dialysis (48 h/week) where 84.6% of infants survived. Prematurity is decreased in the pregnancies of nocturnal dialysis patients with a mean gestational age of 36 weeks. Life-threatening hypertension can occur up to 6 weeks postpartum in dialysis patients. There are no data on the ideal time to start dialysis in pregnant women, but fetal loss appears to increase when the serum creatinine is between 3 and 4 mg/dL.

For pregnancies in women with kidney insufficiency severe enough to require starting dialysis during pregnancy, infants survival is around 75%. With lesser degrees of kidney insufficiency, infant survival is above 80%. There are two studies in women with serum creatinine over 2 mg/dL where fetal survival was 100%.