Abstract
Healthy pregnancy produces dramatic changes in kidney function, including alterations in kidney hemodynamic, endocrine, and tubular function. This chapter discusses physiologic changes in the kidneys in pregnancy. We will outline an approach to acute kidney injury in pregnancy, with a focus on disorders unique to pregnancy such as preeclampsia and the HELLP ( H emolysis, E levated L iver enzymes, L ow P latelets) syndrome. The clinical presentation and management of pregnant women with preexisting kidney diseases, including lupus nephritis, diabetic nephropathy, end-stage renal disease, and kidney transplant recipients, will also be reviewed.
Keywords
pregnancy, hyperfiltration, preeclampsia, thrombotic microangiopathy, gestational hypertension, HELLP Syndrome, acute fatty liver of pregnancy, acute kidney injury, dialysis, kidney transplantation, nephrotic syndrome, kidney biopsy
Kidney Anatomy and Physiology During Normal Pregnancy
Pregnancy produces dramatic changes in systemic hemodynamics, leading to alterations in total circulating blood volume, cardiac output, and systemic vascular resistance. The kidney itself undergoes marked changes during gestation, including alterations in kidney size, renal plasma flow (RPF), glomerular hemodynamics, and tubular function. These adaptations are critical for favorable pregnancy outcomes. Although much of our knowledge of renal anatomic and physiologic changes in human pregnancy is extrapolated from animal models and small studies in healthy pregnant women, understanding the adaptive changes that occur during pregnancy is crucial for differentiating normal from compromised pregnancies.
Anatomic Changes During Gestation
Kidney size increases during pregnancy from a combination of increased kidney weight and dilatation of the urinary collecting system. In longitudinal studies of kidney size measured by ultrasound, kidney length increases by approximately 1 cm. Dilation of the collecting system is observed as early as the third month of pregnancy. The right renal pelvis is most often affected. Although traditionally believed to be the result of mechanical compression by the gravid uterus, dilatation occurs well before the uterus is large enough to cause obstruction, arguing for a hormonal contribution as well. Structural changes generally resolve by 12 weeks postpartum. Persistent hydronephrosis beyond 12 to 16 weeks postpartum suggests underlying mechanical obstruction that requires further investigation ( Box 49.1 ).
Structural Changes in the Kidney
Increase in kidney size by approximately 1 cm
Dilation of the urinary collecting system; more prominent on the right
Hormonal Changes
10- to 20-fold increase in aldosterone
Eightfold increase in renin
Fourfold increase in angiotensin
Resistance to pressor effect of angiotensin
Decreased set point for ADH release
Increased ANP release
Increased production of prostacyclin and nitric oxide
Systemic Hemodynamic Changes
Increased cardiac output by 40%–50%
Increased plasma volume by 40%–50%
Drop in SBP by ≈9 mm and DBP by 17 mm Hg (prominent in second trimester)
Renal Hemodynamic Changes
Increase in GFR and RPF by 50% above normal
Decrease in glomerular capillary oncotic pressure
Metabolic Changes
Decrease in BUN (to <13 mg/dL) and serum creatinine (to 0.4–0.5 mg/dL)
Increase in total body water by 6–8 L
Net retention of 900 mEq of sodium
Decrease in plasma osmolality by 10 mOsm/L
Decrease in serum sodium by 4–5 mEq/L
Mild respiratory alkalosis with compensatory metabolic acidosis (bicarb of 18–22 mEq/L)
Decrease in serum uric acid levels (to 2.5–4 mg/dL)
Glucosuria irrespective of blood glucose levels
ADH , Antidiuretic hormone; ANP, atrial natriuretic peptide; BUN , blood urea nitrogen; DBP , diastolic blood pressure; GFR , glomerular filtration rate; RPF , renal plasma flow; SBP, systolic blood pressure.
Physiologic Changes During Gestation
Systemic Hemodynamic Changes
Systemic adaptations to normal pregnancy begin soon after conception, with the development of a low-resistance placental circulation. Changes in maternal systemic vascular resistance and cardiac output can be detected as early as 6 weeks’ gestation. Pregnancy leads to systemic vasodilation, increased cardiac output, and plasma volume expansion. Despite the increase in blood volume and cardiac output, systemic blood pressure (BP) decreases over the first half of gestation and reaches a nadir between 18 and 24 weeks gestation. The mechanisms leading to systemic vasodilation in healthy human pregnancy are not fully understood but likely reflect a balance between vasodilation and vasoconstriction mediators, such as the corpus luteal hormone, relaxin, nitric oxide (NO), and alterations of the renin-angiotensin-aldosterone system (RAAS). Systemic vasodilation results in venous pooling that triggers volume restorative responses, including increased RAAS activity and a lowered set point for antidiuretic hormone (ADH) release, leading to progressive volume expansion throughout gestation. It is interesting to note that, despite increases in RAAS activity by 2- to 10-fold, systemic BP declines.
Renal Hemodynamic Changes
Similar to the systemic hemodynamic changes seen in healthy pregnancies, renal vascular resistance falls, leading to increased RPF and glomerular filtration rate (GFR). Existing studies in human pregnancy physiology are challenging to interpret because of variations in GFR measurement techniques. In general, GFR and RPF increase by approximately 40%. Increased GFR is noted as early as 4 weeks’ gestation, reaches peak level during the first half of pregnancy, and remains elevated until term ( Fig. 49.1 ). The key factors that contribute to GFR are represented by the following equation:
GFR = K f × ( Δ P ⋅ π GC )
π GC = glomerular intracapillary oncotic pressure
K f = measure of surface area available for filtration and the glomerular permeability
In micropuncture studies in rats, pregnancy produces a 30% increase in single glomerular plasma flow and a 30% increase in the single nephron GFR. These single nephron measurements were proportional to whole kidney GFR and RPF measurements. Despite this increased GFR, there was no increase in ΔP due to proportional dilation of the afferent and efferent arterioles. Thus it appears that the glomerular hyperfiltration in normal pregnancy is accompanied by other hemodynamic adaptations that prevent interglomerular hypertension and potential glomerular damage during this period of hyperfiltration. It is not clear how applicable these physiologic changes are to a healthy human pregnancy.
Volume Regulation and Electrolyte Changes
Total body water increases during pregnancy by 6 to 8 L, of which 4 to 6 L are extracellular. Changes in central osmostat regulation result in lower plasma osmolality (10 mOsm/L below normal), represented by a decrease in serum sodium by 4 to 5 mEq/L. Despite decreased plasma sodium concentrations, healthy pregnant women are in positive sodium balance, with a net gain of 3 to 4 mEq/day. Although normal pregnancy results in increased basal metabolic rate and acid generation, plasma pH is more alkaline because of a respiratory alkalosis mediated by elevated progesterone levels. This is accompanied by an appropriate renal metabolic adaptation with reduced serum HCO 3 levels (18 to 22 mmol/L).
Tubular Changes
In the nonpregnant state, kidneys efficiently reabsorb glucose and amino acids. In a small study of euglycemic women who displayed glycosuria, the maximal tubular reabsorption capacity for glucose was significantly decreased. The precise incidence of glycosuria in pregnancy is unclear, with extensive variability noted both between women and within individual women at different times during pregnancy. There does not appear to be a relationship between glycosuria and clinical diabetes, and the majority of women with glycosuria have normal glucose screening in pregnancy. Uric acid levels drop to 2.5 to 4 mg/dL from the combined effects of increased filtration and decreased tubular reabsorption. Uric acid levels nadir in the second trimester and gradually increase as pregnancy progresses toward term. High renal clearance of uric acid is believed to be necessary to clear the increased production that occurs with fetal growth.
Assessment of Kidney Function
Glomerular Filtration Rate
Serum creatinine-based formulas are not accurate for calculating estimated GFR in pregnancy, with both the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology (CKD-EPI) underestimating GFR measured by inulin clearance by approximately 40%. Creatinine clearance (CrCl) measured in a 24-hour urine collection remains one method to estimate GFR during pregnancy, although complete collection can be difficult because of urinary retention. Cystatin C levels have been studied in a variety of clinical settings; however, their use in pregnancy is not established, as cystatin C may be released by the placenta in response to ischemia. Gestational hyperfiltration and subsequent increased GFR result in decreased blood urea nitrogen (BUN) and serum creatinine levels. A BUN greater than 13 mg/dL or serum creatinine of 0.7 to 0.8 mg/dL or higher is of concern in normal pregnancy and should be further investigated.
Proteinuria
Routine prenatal care includes dipstick urine protein assessment at each prenatal visit. While inexpensive, the urine dipstick has high false-positive and false-negative rates. Twenty-four-hour urine protein excretion remains the gold standard for measurement of proteinuria in pregnancy, although again it can be difficult to obtain complete collections because of incomplete bladder emptying and urinary stasis. Assessment of the urine protein-to-creatinine ratio (UPCR) or albumin-to-creatinine ratio in spot urine specimens is probably the most practical way to follow protein excretion in pregnancy.
Urinary protein excretion remains below 200 mg/24 hours in normal pregnancy despite glomerular hyperfiltration. Most obstetric guidelines define significant protein excretion as greater than 300 mg in a 24-hour period; however, this cutoff is based on small studies. In one of the largest studies, the mean 24-hour protein excretion was near 100 mg, significantly lower than the established cutoff. As such, even low levels of proteinuria should not be attributed to gestational hyperfiltration and should prompt further evaluation.
Hypertensive Disorders of Pregnancy
Hypertension in pregnancy is defined as BP ≥140/90 mm Hg, measured on at least two separate occasions. Hypertensive disorders complicate up to 10% of pregnancies and are a major cause of maternal morbidity and mortality. Hypertensive disorders in pregnancy are classified into four categories: chronic hypertension, gestational hypertension, preeclampsia, and superimposed preeclampsia. Management of hypertension in pregnancy requires the clinician to balance the effects of treatment on both the mother and developing fetus.
Chronic Hypertension
The diagnosis of chronic hypertension is most often based on essential hypertension diagnosed before pregnancy or a BP greater than 140/90 mm Hg diagnosed before 20 weeks of gestation that does not resolve after delivery. The prevalence of chronic hypertension in pregnancy appears to be increasing because of higher pregnancy rates in women of advanced maternal age and higher rates of maternal obesity. Chronic hypertension is associated with increased risk for preeclampsia (25%), intrauterine growth restriction (IUGR; 17%), and perinatal mortality (4%), compared with the general population.
Management of Hypertension in Pregnancy
The primary management of chronic hypertension in pregnancy includes treatment of high BP and monitoring for superimposed preeclampsia. Nonpharmacologic strategies for hypertension management in nonpregnant populations, including aerobic exercise, weight loss, and dietary sodium restriction, have not been thoroughly evaluated in pregnant women. When hypertension is severe (>160/105 mm Hg), drug therapy is clearly indicated. Until recently, data on specific BP targets in mild to moderate hypertension in pregnancy were sparse. The Control of Hypertension in Pregnancy Study (CHIPS) was a recent multicenter randomized trial of women with mild to moderate nonproteinuric gestational or chronic hypertension in pregnancy. CHIPS showed no difference in adverse maternal or fetal outcomes in women with chronic hypertension treated to tight (diastolic blood pressure [DBP] target 85 mm Hg) versus less tight (DBP target 100 mm Hg) BP control during pregnancy. Women in the tight control arm did have fewer episodes of severe hypertension during pregnancy. Thus, it appears safe for the fetus to treat women with chronic or gestational hypertension to lower DBP (goal DBP 85 mm Hg), and this may prevent the acceleration of mild/moderate hypertension to severe hypertension during pregnancy. Whether tighter control of BP during pregnancy has a long-term benefit on maternal cardiovascular outcomes is unknown.
Recommended agents used to treat hypertension in pregnancy are summarized in Table 49.1 . Medications used for treatment of hypertension in pregnancy include β-blockers, calcium channel blockers, methyldopa, and hydralazine. Exposure to angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in the second trimester is associated with fetal renal dysplasia, oligohydramnios, and pulmonary hypoplasia. ACE inhibitors and ARBs cannot be used during pregnancy. Diuretics are not first-line agents for chronic hypertension in pregnancy, but can be used if necessary to treat volume overload. They should not be used in states like preeclampsia.
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