Renal Diseases in Pregnancy

Deepa Amberker

Will Ross

General Principles

Pregnancy is associated with predictable anatomic changes of the kidney and is characterized by physiologic changes of systemic and renal hemodynamics.
Hypertension and proteinuria should be considered pathologic, and the presence of these findings must lead to consideration of preeclampsia as well as other conditions.
Women with mild kidney disease have a slightly higher risk of maternal and fetal complications, but their pregnancies are generally successful.
More advanced kidney disease is associated with lower fertility rates and worse maternal and fetal outcomes.
Normal anatomic renal changes in pregnancy
- Kidney size increases by 1.0 to 1.5 cm in pregnancy. Kidney volume increases by 30% due to increased renal blood flow and increased interstitial volume.¹
- Renal histology and nephron numbers are unchanged.
- Dilation of the ureters (hydroureter) and renal pelvis/calyces (hydronephrosis) occurs due to the smooth muscle relaxing effect of progesterone and relaxin, causing reduced ureteral tone and peristalsis. These are physiologic findings and occur in about 80% of pregnant women, more prominent on the right side.
- Extrinsic compression of the ureters by the gravid uterus may cause mechanical obstruction as the pregnancy progresses, but this is usually of no clinical significance.
- The dilated collecting system can result in urinary stasis, leading to an increased risk for ascending infection of the urinary tract.

Normal hemodynamic changes in pregnancy

Systemic hemodynamics:
- There is reduction in systemic vascular resistance in early pregnancy, leading to a drop in mean arterial blood pressure by 10 mm Hg by the second trimester.
- The reduced systemic vascular resistance leads to increased sympathetic activity, resulting in 15% to 20% increase in heart rate.
- Cardiac output increases by 30% to 50% due to increased heart rate and stroke volume, and reduced afterload.
- Renin–angiotensin–aldosterone system is activated, leading to increased sodium and water reabsorption, resulting in retention of up to 900 mEq of extra sodium during the entire pregnancy and increase of total body water by 6 to 8 L. As a result, physiologic anemia and edema are common during normal pregnancy.

Renal hemodynamics:

Renal vascular resistance decreases during early pregnancy due to incompletely understood mechanisms, leading to a significant increase in renal blood flow.
Glomerular filtration rate (GFR) increases during early pregnancy by 50% because of both increased renal blood flow and increased cardiac output.²

The increase in GFR results in a decrease in serum creatinine (from 0.8 mg/dL to 0.4 to 0.5 mg/dL), serum blood urea nitrogen (from 13 mg/dL to 8 to 10 mg/dL), and serum uric acid levels (from 4 mg/dL to 2 to 3 mg/dL) (see Table 15-1).

TABLE 15-1 EXPECTED LABORATORY VALUES IN PREGNANCY

	Nonpregnant	Pregnant
Hematocrit (vol/dL)	41	33
Plasma creatinine (mg/dL)	0.7–0.8	0.4–0.5
Plasma osmolality (mOsm/kg)	285	275
Plasma sodium (mmol/L)	140	135
Arterial PCO₂ (mm Hg)	40	30
pH	7.40	7.44
Bicarbonate (mmol/L)	25	22
Uric acid (mg/dL)	4.0	3.0
Plasma protein (g/dL)	7.0	6.0

Creatinine-based formulas for estimating GFR are less reliable in pregnancy. It is important to remember that serum creatinine that is considered normal in a nonpregnant female might actually signify significant renal impairment in a pregnant patient.

Changes in water homeostasis
- Mild, asymptomatic hyponatremia is due to downward resetting of osmotic threshold for antidiuretic hormone (ADH) secretion and thirst (frequently known as the “reset osmostat”). This leads to a new steady-state plasma osmolality of 270 to 275 mOsm/kg and fall in serum sodium level by 5 mEq/L. Reset osmostat is thought to be mediated by human chorionic gonadotropin (hCG).
- During the second half of pregnancy, high levels of placental vasopressinase can lead to increased ADH catabolism. Rarely, diabetes insipidus (DI) can ensue but is usually transient.
- DI in pregnancy can be treated with desmopressin, a vasopressin analog that is resistant to the actions of vasopressinase.
Acid–base regulation: In pregnancy, there is increase in minute ventilation and mild chronic respiratory alkalosis (PCO₂ falls to 30 mm Hg, pH increases to 7.44, and serum bicarbonate level decreases to 20 to 22 mEq/L because of compensatory increase in renal bicarbonate excretion). This can occur even in the first trimester, as progesterone directly stimulates central respiratory receptors.
Other renal changes
- Urinary protein excretion increases during pregnancy, up to 200 mg/24 hrs. Proteinuria of >300 mg/24 hrs is pathologic.
- Owing to increased filtered load of glucose and amino acids, as well as less efficient tubular reabsorption, pregnant women may have mild glycosuria and aminoaciduria.

Hypertensive Disorders in Pregnancy

Absolute blood pressure ≥140/90 mm Hg, taken on two separate occasions 6 hours apart, is considered abnormal.
Chronic hypertension (or pre-existing hypertension): Hypertension diagnosed prior to 20th week of gestation, or persisting longer than 12 weeks postpartum.
Gestational hypertension: De novo hypertension occurring after 20th week of gestation and resolving within 12 weeks postpartum.
Preeclampsia: New-onset hypertension and proteinuria (>300 mg/24 hrs) occurring after 20th week of gestation. Diagnosis is changed to eclampsia with development of seizures. Preeclampsia may be superimposed on chronic hypertension.

Chronic Hypertension in Pregnancy

General Principles

Chronic hypertension occurs in 3% to 5% of all pregnancies and contributes significantly to maternal and fetal morbidity and mortality.
Pregnancies complicated by hypertension have an increased risk of preeclampsia, intrauterine growth retardation, placental abruption, preterm delivery, and fetal loss.
Chronic hypertension can be masked in early pregnancy because of the physiologic decrease in blood pressure.
Tight blood pressure control does not improve neonatal outcome or prevent superimposed preeclampsia and can compromise fetal growth because of decreased placental perfusion.
Target blood pressure is ill defined. Most experts recommend a goal of 140 to 150/90 mm Hg. Kidney Disease: Improving Global Outcomes (KDIGO) recommends that women with CKD without proteinuria should aim for a blood pressure <140/90 mm Hg. KDIGO also recommends this level for patients with an albumin to creatinine ratio >30 mg/mmol.

Treatment

Pharmacologic treatment is recommended when blood pressure is >150/100 mm Hg to prevent maternal end-organ damage.³ Please see Table 15-2 for medications.
Severe hypertension (≥170/110 mm Hg) can be managed using intravenous labetalol, hydralazine, or nicardipine, as these have been extensively used during pregnancy.
Oral agents that are used to treat elevated blood pressure in pregnancy include methyldopa, labetalol, long-acting nifedipine, and hydralazine.
Diuretics are generally not recommended during pregnancy because of the risk of volume depletion in the fetus.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are CONTRAINDICATED because of extremely high risk of teratogenicity. Other inhibitors of the renin–angiotensin–aldosterone axis also fall into this category.

TABLE 15-2 DRUG OPTIONS FOR HYPERTENSION IN PREGNANCY

Subacute Antihypertensive Therapy	Acute Antihypertensive Therapy
Methyldopa: 250 mg PO bid or tid; usual dose, 1.0–1.5 g/day; maximum dose, 3 g/day	Labetalol: 20 mg IV; can be repeated at 10–15-min intervals (with escalating doses, i.e., 40 mg, 60 mg, and so forth) to a total cumulative dose of 300 mg
Nifedipine, long acting: 30 mg/day PO; maximum dose 120 mg/day	Hydralazine: 5–10 mg IV; can be repeated at 15-min intervals to a maximum cumulative dose of 30 mg
Labetalol: 100 mg PO bid or tid; maximum dose, 1200 mg/day	—

Preeclampsia

General Principles

Preeclampsia affects about 5% of all pregnancies and remains the leading cause of maternal and fetal mortality in the world.⁴
Risk factors for preeclampsia are listed in Table 15-3.
Initiating events in preeclampsia are poorly understood, but the origin appears to be the placenta and the target is the maternal endothelium.
In normal pregnancy, cytotrophoblasts invade the uterine spiral arterioles, converting them from small-caliber vessels to large-caliber capacitance vessels capable of carrying larger amount of blood through the placenta.
In preeclampsia, this process of cytotrophoblast invasion is defective and there is deficient transformation of the spiral arterioles, leading to reduced placental perfusion.
The diseased placenta secretes an increased amount of antiangiogenic factor (soluble fms-like tyrosine kinase-1), which antagonizes the proangiogenic effects of vascular endothelial growth factor and placental growth factor, resulting in systemic vascular endothelial dysfunction characteristic of preeclampsia.⁵
Maternal endothelial dysfunction causes increased production of reactive oxygen species, thromboxane, and endothelin-1. Also, there is increased vascular sensitivity to angiotensin II and decreased nitric oxide and prostacyclin bioavailability.
The end result is potent vasoconstriction and end-organ damage.