Renal adaptations during pregnancy

A fundamental appreciation of maternal renal and cardiovascular adaptations is a prerequisite to complete understanding, proper diagnosis, and management of kidney disease during pregnancy. Physiologic changes occur as early as the first trimester and include anatomic, hemodynamic, substrate handling and acid‐base alterations [4, 5]. (See reference [5] for a detailed review on the topic.)

Anatomic changes: The size and volume of the kidneys increase due to the increase in blood volume and capacity of the collecting system. Dilation of the collecting system with hydronephrosis and hydroureter occurs in 80% of women by mid‐pregnancy, likely secondary to hormonal effects resulting in smooth muscle relaxation [6, 7]. Right‐sided ureteral dilation is greater than the left because of compression by the enlarged and dextro‐rotated uterus as well as the ovarian vascular plexus at the level of the pelvic brim.

Hemodynamic adaptations: The increase in renal blood flow and glomerular filtration rate (GFR) is one of the earliest and most dramatic changes in pregnancy. By the third trimester, renal plasma flow is 50–85% above non‐pregnant levels with a slight decline toward the very end of gestation. Secondarily, GFR also increases by 40–65%. In addition, there is marked reduction of systemic vascular resistance as well as an increase in cardiac output and plasma volume by approximately 50% and 40% above the non‐pregnant baseline, respectively [4]. Progesterone, relaxin, and other luteal/placental hormones are likely responsible for these hemodynamic changes. These renal adaptations affect the normal ranges for standard laboratory parameters and have practical implications for the care of the pregnant woman (Table 27.1). For example, a serum creatinine of 0.9–1.0 mg dl⁻¹ considered to be normal for an adult would be abnormal in a healthy pregnant woman.

Substrate handling: Some degree of proteinuria (<300 mg per 24 hours) is normal in advancing gestation and generally does not indicate renal compromise. This is likely due to increased GFR along with reduced resorption at the level of the proximal tubule [4]. Alteration in the glomerular membrane charge also allows for membrane permeability to negatively charged proteins. Women with baseline proteinuria generally have a progressive increase in total protein excretion with advancing gestation; however, the precise amount is inconsistent. Glucosuria is also not uncommon in pregnancy and does not necessarily indicate diabetes. Normally, glucose is freely filtered at the glomerulus and reabsorbed in the proximal tubule. The increased GFR and reduced proximal tubular reabsorption often results in glucose in the urine. Despite this marked increase in GFR, there is net sodium retention of 900–950 mEq over the course of pregnancy due to tubular reabsorption and total body water increases by 6–8 l.

Acid‐base homeostasis: The kidney also plays an important role in acid‐base homeostasis. Increased minute ventilation of pregnancy results in a respiratory alkalosis (pCO₂ is reduced by ∼10 mmHg). A partial compensatory metabolic acidosis occurs via increased renal bicarbonate excretion. The resulting increase in CO₂ gradient across the placenta facilitates gas exchange and is beneficial for the fetus; however, it reduces the maternal capacity to buffer acids. These physiologic acid‐base changes are important in the care of the pregnant woman, particularly in the Intensive care unit (ICU) setting [5].

Chronic kidney disease and pregnancy

As with other medical disorders of pregnancy, major considerations are (i) the effect of renal disease on pregnancy outcomes; and (ii) the impact of pregnancy on the course of renal disease. In taking an evidence‐based approach to this topic, it is critical to understand the limitations of the published literature. Most studies have small numbers and are retrospective, often based in a single institution and lacking a comparison group. Importantly, preconception counseling, antenatal care, and follow‐up are not standardized. With larger studies often spanning many years, changes in perinatal care such as administration of steroids for prematurity have improved but confounded comparison of outcomes. Furthermore, classification of kidney disease as well as the definition of outcomes has been inconsistent across the published literature. For example, premature delivery may be defined as less than 34 weeks’ in some studies and less than 37 weeks’ in others.

Classification : The standardized classification of CKD includes five stages based on progressively worsening GFR. Stage 1 CKD represents renal damage with normal to increased GFR and stage 5 is end‐stage renal disease (ESRD) including dialysis (Table 27.2) [8]. Preconception classification is ideal, since standard formulas for GFR such as the Modification of Diet in Renal Disease equation may not accurately represent renal function in pregnancy [9]. If pre‐pregnancy staging is not available, first trimester serum creatinine is most commonly used for classification. Earlier publications used a three‐tiered classification system during pregnancy with mild (serum creatinine less than 1.4 mg dl⁻¹), moderate (serum creatinine 1.4–2.4 mg dl⁻¹), and severe (serum creatinine greater than or equal to 2.5 mg dl⁻¹) renal disease. Stages 3–5 CKD correspond to moderate and severe renal disease. Based on the existing data, pre‐pregnancy renal function and hypertension have consistently emerged as the best predictors of adverse perinatal outcomes; thus, appropriate classification impacts counseling.

Impact of CKD on pregnancy outcomes: Adverse pregnancy outcomes associated with CKD include pre‐eclampsia, fetal growth restriction, indicated preterm delivery, and perinatal death. With mild renal impairment, the frequency of livebirths is greater than 90–95% [10–14]. Pregnancy outcomes are progressively worse with higher stages of CKD and hypertension. In Table 27.3a, we provide evidence‐based estimates of adverse outcomes by degree of CKD adapted from reviews [1, 2, 4, 10, 15–18] and including a number of original studies [14, 19–26]. Pre‐eclampsia is the most common adverse maternal outcome in women with pre‐existing renal disease. In a 2011 systematic review of 13 cohort studies, women with CKD were more likely to develop gestational hypertension, pre‐eclampsia, eclampsia or to die compared to women without CKD (12% versus 2%) [17]. In a recent systematic review, the odds ratio of pre‐eclampsia in women with CKD (stages 1–3) was 10.36 (95% confidence interval, 6.28–17.09) compared to women without CKD [18]. Both reviews are limited by the quality of the individual studies, many of which had a small sample of CKD cases. Importantly, diagnosing pre‐eclampsia is particularly challenging in women with baseline proteinuria and/or pre‐existing hypertension associated with CKD since progression of proteinuria and higher blood pressures are not uncommon in the third trimester. A sudden escalation of blood pressure or proteinuria, new onset of pre‐eclampsia symptoms (headache, visual changes, right upper quadrant, or epigastric pain), or other evidence end‐organ dysfunction (thrombocytopenia or elevated liver transaminases) supports the diagnosis of pre‐eclampsia. Renal biopsy is not indicated for the diagnosis of pre‐eclampsia. Emerging data indicate that circulating angiogenic factors may be used to differentiate between pre‐eclampsia and the benign third trimester progression of hypertension and/or proteinuria with CKD. Soluble Flt‐1 (sFlt‐1), a soluble receptor for vascular endothelial growth factor and placental growth factor (PlGF), is elevated weeks prior to and during pre‐eclampsia. Conversely, PlGF is reduced [27]. These alterations are more pronounced when pre‐eclampsia is of early‐onset, severe, or associated with fetal growth restriction [28]. The PlGF as well as the ratio of sFlt‐1/PlGF has been shown to predict pre‐eclampsia in a number of studies [28]. A few studies, albeit with small numbers, indicate that PlGF, and/or the sFlt/PlGF ratio may be helpful in the differential diagnosis of pre‐eclampsia and other high risk conditions including worsening CKD [29–34].

Adverse fetal/neonatal outcomes are also higher in pregnancies complicated by CKD (Table 27.3a). In the 2011 systematic review, preterm birth was significantly higher 13% compared to 6%; while higher but nonsignificant rates were noted for fetal growth restriction (5% vs 0%), small for gestational age (14% versus 8%), and stillbirth (5% versus 2%) [17]. Higher odds of preterm birth (5.7, 95% confidence interval of 3.3–10.0) and small for gestational age/low birth weight infants (4.9; CI, 3.0–7.8) were reported in the more recent systematic review [18]. As acknowledged by the both sets of authors, the quality of the primary studies inherently limits some of the conclusions and many had very small sample size. The incidence of fetal growth restriction is higher in women with CKD even in the absence of pre‐eclampsia. Preterm delivery associated with CKD is most often indicated based on pre‐eclampsia, fetal growth restriction, or progression of renal disease. Unfortunately, there is marked variability in the criteria for delivery and patient management such that comparison across studies is problematic. High risk obstetricians and neonatologists should be involved in the decision‐making regarding timing of delivery and optimization of fetal/newborn care. (See Section 27.4).

Impact of pregnancy on CKD: High glomerular pressure and hyperfiltration contribute to progressive decline in GFR [35]. However, the precise effect of pregnancy‐induced hyperfiltration on underlying CKD is incompletely understood. Using animal models, Baylis and colleagues demonstrated that glomerular capillary pressure is not increased during pregnancy [36, 37]. Extrapolating from these data, hyperfiltration of pregnancy is likely secondary to increased renal blood flow along with vasodilation of both efferent and afferent arterioles; thus, without marked increase in intra‐glomerular pressure. This supports the lack of progressive, long‐term decline of renal function in healthy women due to pregnancy. In pregnant women with CKD, however, it is common to observe worsening proteinuria (approximately 50%) and the development or worsening of hypertension (approximately 25%) which have potential to further damage the kidney [15]. In most cases, these changes resolve after delivery. Therefore, it is important to differentiate between temporary changes and long‐term renal decline secondary to pregnancy.

Among women with mild CKD (stages 1 and 2), permanent decline in renal function occurs in 0–10% due to pregnancy which is comparable to the non‐pregnant population. Jungers et al. studied 360 women with glomerulonephritis of whom 171 conceived and observed no difference in long‐term renal function over 25 years in women who became pregnant compared to those who did not conceive [38]. A consistent and reassuring finding across this and a number of other studies is that women with mild CKD do not have long‐term, permanent renal decline due to pregnancy (Table 27.3b) [11, 38–40]. With moderate and severe CKD, the findings are more complex. Early, small studies reported that greater than 50% of women with moderate CKD had permanent renal decline after pregnancy. In 1986, Imbasciati et al. reported that progression of renal disease was lower than earlier reports and found that one third of women with moderate CKD prior to pregnancy had long‐term had decline in their renal function [20]. In a landmark paper on the topic, Jones and Hayslett reported on 82 pregnancies in 67 women with moderate to severe renal disease [21]. Among women with a baseline serum creatinine of 1.5–1.9 mg dl⁻¹, 40% had a decline of renal function during pregnancy and 2% had accelerated decline in GFR within six months post‐delivery. If serum creatinine was greater than 2.0 mg dl⁻¹, 65% of women had decline in renal function in the third trimester and 33% had accelerated decline in renal function by six months postpartum. Eight women from the entire group progressed to end‐stage renal failure within one year of pregnancy. A more recent study of women with stage 3–5 CKD assessed progression of renal disease before, during, and after pregnancy [22]. Women with a pre‐pregnancy GFR of less than 40 ml min⁻¹/1.73 m² and 24‐hour protein excretion of greater than 1 g, but not either factor alone, had accelerated decline in renal function after pregnancy compared to before pregnancy. Together, these data may allow for more nuanced counseling in women with moderate CKD. With severe renal impairment (serum creatinine >3 mg dl⁻¹), women are less likely to ovulate, conceive spontaneously, and carry a pregnancy to full term [1]. Thus, the data are fewer in this group. However, it is likely that the same principle applies, that the higher stage of renal impairment the worse the outcomes.

Decline in renal function
Pre‐pregnancy serum creatinine	During pregnancy (%)	Persisting post‐delivery up to 6 weeks (%)	Accelerated renal dysfunction at 6–12 months (%)
< 1.4 mg dl−1	2	0	0
1.4–2.0	40	20	2
>2.0	65	50	33

^a Modified and updated from refs [5, 15

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

1. 8: Endometriosis and adenomyosis
2. 29: Thyroid disease
3. 48: Hydrops fetalis
4. 42: Disorders of amniotic fluid volume

Stay updated, free articles. Join our Telegram channel

Join