Pregnancy Complicated by Renal Disorders
Denise Trigubo
Mercedes Negri Malbrán
Gustavo F. Leguizamón
Introduction
Kidney function is of utmost importance during pregnancy. Physiologic renal changes are cornerstone for adequate placental development, and even mildly impaired kidney function is associated with increased probability of adverse pregnancy outcomes. Furthermore, pregnancy can worsen the course of preexisting nephropathy or unmask an undiagnosed primary renal disease. In this chapter, we address the renal physiological adaptations of pregnancy, the impact of gestation on maternal and fetal outcomes, and the effects of pregnancy on preexisting renal disorders.
Renal Physiology in Pregnancy
Anatomical and functional changes in kidneys and the urinary tract start at approximately 6 weeks of gestation. These physiological modifications must be acknowledged in order to properly diagnose and manage renal disorders during pregnancy. Under normal conditions, these modifications regress to the nonpregnant state within one to one and a half months postpartum.1,2,3
Kidney growth and hydronephrosis are the most remarkable anatomical changes. An increase in renal size of 1 to 1.5 cm occurs as a result of proliferation in vascular and interstitial volume, rather than a variation in the number of nephrons.4,5,6 Furthermore, approximately 80% of pregnant women show a physiologic dilatation of the proximal ureter with a right-sided preponderance.4,7
Normal pregnancy is characterized by vasodilation resulting in reduction of peripheral vascular resistance, increased cardiac output, and decreased arterial blood pressure.8 These hemodynamic changes lead to enhancement of renal plasma flow (RPF). Furthermore, there is a 50% increase in the glomerular filtration rate (GFR), which is proportionally larger than the increase observed in the RPF. These proportionally different changes lead to an increase in the filtration fraction (FF) (GFR/RPF) and, therefore, to a decrease in serum creatinine as well as blood urea nitrogen (BUN). The glomerular hyperfiltration and the modifications in tubular reabsorption are also responsible for changes in serum levels of analytes that may challenge the interpretation of renal and metabolic conditions (Table 35.1).
The thresholds for thirst and antidiuretic hormone secretion are also modified, resulting in lower osmolality and serum sodium levels. Pregnant patients undergo a net gain of 1.1 to 1.6 liters due to a plasma volume expansion of 30% to 50% with subsequent hemodilution.4
Table 35.1 Normal Laboratory Values During Pregnancy | ||||||||||||||||||||||||||||||||||||
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Clinical Assessment of Renal Function in Pregnancy
There is a paucity of data on the accuracy of the available methods to determine GFR during pregnancy. Most studies have been conducted on nonpregnant and older subjects, and therefore, the conclusions must be interpreted with caution.9,10 In general, the assessment of GFR with current methods, such as the modification of diet in renal disease (MDRD), underestimates disease and should not be considered a reliable tool for clinical management.
Measuring serum creatinine and 24-hour urine collection for creatinine clearance are currently the most reliable surrogates of GFR and are the preferred methods to assess renal function during gestation in women with nephropathy.9 Because creatinine production remains stable throughout pregnancy, increased clearance results in decreased serum levels falling to an average of 0.4 mg/dL. In fact, a serum creatinine of 1.0 mg/dL, which is considered normal in nonpregnant subjects, may reflect renal impairment during gestation.11
Proteinuria is usually a sign of renal injury and if persistent may represent ongoing renal damage. Abnormal albuminuria reflects glomerular basement membrane permeability dysfunction or ineffective tubular reabsorption. Because dipstick determination lacks adequate accuracy in pregnancy, the 24-hour urine collection is the gold standard for quantification of proteinuria.11,12 In nonpregnant healthy subjects, normal 24-hour protein excretion is less than 200 mg. During normal pregnancy, urinary protein excretion rises, and values greater than 300 mg/24 h are considered abnormal.13
Chronic Kidney Disease and Pregnancy
The prevalence of chronic kidney disease (CKD) in women of childbearing age ranges from 0.1% to 3%.14 Because symptoms usually develop late in disease, it may be first diagnosed at the initial prenatal evaluation. Renal disease increases the risk of adverse pregnancy outcomes, and the gestation can accelerate the progression of this condition. The degree of renal insufficiency is considered a critical prognostic factor. Two different groups of women with CKD can be identified. Early disease is defined as serum creatinine below 1.4 mg/dL, creatinine clearance greater than 70 mL/min, or stages 1 to 2 CKD.15 On the other hand, advanced disease is characterized by serum creatinine greater than 1.4 mg/dL, creatinine clearence below 70 mL/min, and stages 3 to 5 CKD.15 Table 35.2 depicts CKD stages.
Table 35.2 Chronic Kidney Disease (CKD) Stages According to Estimated Glomerular Filtration Rate (GFR) | ||||||||||||||
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Impact of CKD on pregnancy outcomes
Patients with CKD have a greater risk of pregnancy complications. Although women with mild GFR decrease are more likely to experience a successful pregnancy, the frequency of complications is enhanced as women progress through each stage of renal disease.
Zhang et al14 reviewed the impact of CKD on the risk of pregnancy complications in 23 studies involving over half a million pregnancies. When compared with healthy controls, the authors observed a significantly increased risk for preeclampsia (PE) (odds ratio [OR] 10.3), preterm birth (OR 5.72), low birth weight (OR 4.85), cesarean delivery (OR 2.87), and perinatal death (OR 1.8) in women with CKD.14
Severe renal impairment, chronic hypertension, and proteinuria have been identified as risk factors that worsen perinatal outcomes among women with CKD.15,16 In fact, advanced CKD was associated with higher rates of cesarean delivery (70%), preterm delivery (89%), small for gestational age (50%), and admission to neonatal intensive care unit (70%).17 Furthermore, renal compromise in the context of a systemic condition, such as diabetes or systemic lupus erythematosus (SLE), presents an excess risk. Although women with stage 1 CKD without other risk factors have the best perinatal prognosis, this population presents higher perinatal risks than the general population. Therefore, these women also benefit from specialized care.17
Finally, with the exception of diabetic kidney disease and autosomal dominant polycystic kidney
disease, the frequency of fetal congenital malformations is not increased in pregnancies complicated with CKD.18
disease, the frequency of fetal congenital malformations is not increased in pregnancies complicated with CKD.18
Table 35.3 Obstetrical Outcomes Across the Spectrum of Chronic Kidney Disease (CKD) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Table 35.3 depicts the outcomes in CKD.
Impact of pregnancy on CKD
Current literature is still conflicting regarding the impact of pregnancy on progression of CKD. Piccoli et al17 evaluated the progression of renal impairment among 504 pregnancies in women with CKD. The authors observed that 7.6% of women with stage 1 CKD presented a shift in CKD stage. Furthermore, 20% of women with severe renal disease (stages 3-4) showed progression and an increasing trend in stage shift.17 Different investigators observed a strong association between advanced-stage CKD and progression of renal disease. Imbasciati et al reported that pregnancy in women with advanced CKD is associated to a 16% to 20% risk of worsening renal function throughout gestation and postpartum.16 Finally, renal function deterioration attributed to pregnancy was observed in 43% of women with moderate and severe CKD.19
Contradictory conclusions were reached in a large meta-analysis where investigators reported that pregnancy was not a risk factor for progression of renal disease in women with CKD before pregnancy.14 These discrepancies could be related to unequally distributed risk factors, such as hypertension and proteinuria, in the studied populations. In fact, there is evidence to believe that GFR ≤ 40 mL/min with proteinuria ≥ 1 g/24 h are risk factors for progression of renal dysfunction during or after pregnancy.16,19
In conclusion, in women with early CKD and preserved renal function in early pregnancy, a significant renal deterioration is unlikely, especially if high blood pressure and proteinuria are either absent or negligible. On the other hand, women with advanced renal failure at the beginning of gestation are more likely to suffer long-term renal deterioration.
Pregnancy in End-Stage Renal Disease
Hemodialysis in Pregnancy
Although fertility decreases throughout the spectrum of CKD stages,20 the incidence of pregnancy in women on dialysis has increased during the past decades.15 Previous reports showed considerable pregnancy complications, with rates of fetal loss over 50%.8 However, perinatal survival has improved significantly due to advances in dialytic treatment,15 and current live birth rates are between 70% and 90%.21 Although perinatal survival has consistently improved, maternal and fetal morbidity remains substantial. Worsening hypertension (50%-70%), polyhydramnios (40%), PE (18%-67%), intrauterine growth restriction (IUGR) (17%-77%), prematurity, and low birth weight (50%-100%) are significantly higher than in the general population.21
Two important protective factors have been identified. Women who initiate dialysis during pregnancy have a higher rate of live birth (91%) than those who conceive while on hemodialysis (HD) (63%).22 This probably reflects reserved renal functions enhanced by pregnancy. Second, an intensive HD regimen is a critical factor in improving pregnancy outcomes.
Achievement of successful pregnancy in women on HD requires thorough consideration in the management of dialysis adequacy, volume management, blood pressure control, treatment of anemia, and nutritional adjustments.
Dialysis Adequacy
There is a remarkable correlation between BUN levels and pregnancy-associated risks. In fact, the proportion of fetal demise, preterm delivery, and low birth weight seem to increase with BUN levels ≥50 mg/dL.23,24 Polyhydramnios is also associated with high BUN levels and/or inadequate ultrafiltration. An enhanced clearance of urea can be achieved by increasing the intensity of dialysis. Recent data have demonstrated that pregnancy outcomes significantly improve when the patient undergoes HD for at least 36 h/wk.25 Intensified HD regimes are consistently associated with improved pregnancy outcomes. Hlanudewich et al25 compared pregnancy outcomes in women with intensified and conventional HD. The intensified group had higher live birth rates (85% vs 61.4%) and longer median durations of pregnancy (36 vs 27 weeks). Furthermore, a dose response between dialysis intensity and pregnancy outcomes was observed. Women dialyzed for either ≤20 or >36 hours a week had 48% and 85% live birth rates, respectively. Finally, the intensified group had greater infant birth weights.25 The association between intensity of dialysis (hours/week) and pregnancy outcomes follows a continuous correlation with no identifiable threshold.26 Therefore, intensified HD regimes (>36 h/wk) are strongly recommended.27
Volume Management
Because precise determination of dry weight in pregnancy is difficult, volume management during HD is challenging. Frequent clinical evaluations of volume status are recommended. As a general rule, it can be considered that the normal dry weight increase during the second and third trimesters of pregnancy is 0.5 kg/wk. Attempts should be made to minimize large fluid shifts during HD because these can be associated with hypertension as well as hypotension, which lead to enhanced fetal risks. Ideally, during and after dialysis, blood pressure should not be lower than 120/70 mm Hg and should not exceed 140/90 mm Hg.8,28
If no other conditions, such as diabetes, are present, no dietary restrictions are made, and nutritional advice should be offered to guarantee proper protein intake (approximately 1.5-1.8 mg/kg/d). Supplements of 5 mg/d of folic acid and prenatal vitamins should be prescribed.28,29
Monitoring and treatment of anemia is an important consideration among pregnant women undergoing HD. To achieve a target hemoglobin level of 10 to 11 g/dL, a significant increase of the erythropoietin (EPO) dose is required. Furthermore, oral and/or intravenous iron sucrose should be supplemented as required to maintain adequate iron stores.28
Available data to guide the appropriate timing for renal replacement therapy (RRT) initiation in pregnant women with advanced CKD are not definitive. Hladunewich et al suggested that dialysis should be prescribed before any life-threatening indications occur due to changes in fluid, electrolytes, and acid-base balance.27,28 The authors recommend RRT in pregnant patients with a creatinine clearance < 20 mL/min or with ongoing progressive kidney function loss, in which urea (BUN) consistently exceeds 20 mmol/L (56 mg/dL).28
Renal Transplantation
Following successful renal transplantation, fertility is restored and pregnancy outcomes are better than those in women with advanced stages of CKD.20 A 2019 meta-analysis showed that although the live birth rate in pregnant women who underwent a prior renal transplant is close to 73%, maternal and fetal adverse events remain higher than the general population.30 In fact, the rate of PE has increased sixfold (21.5% vs 3.8%), and the risk of preterm birth is 43.1%, with a mean gestational age at delivery of 35 weeks and a mean birth weight of 2470 g.30 Neonatal mortality and stillbirth are also significantly higher (3.8% vs 0.4% and 5.1% vs 0.6%, respectively).30 On the other hand, the overall acute rejection rate during gestation is comparable to the general population (9.4% vs 9.1%). Thus, for patients with advanced CKD and those receiving RRT who wish to conceive, it is advisable to attempt to defer pregnancy until after kidney transplantation. At the time of this publication, there is no consent regarding the optimal timing of conception after renal transplant, but the American Society of Transplantation recommends postponing pregnancy for 1 to 2 years after transplantation.30
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