Definition and Pathophysiology

Renal parenchymal disease consists of two general groups of disorders, glomerulopathies and tubulointerstitial disease. Glomerulopathies are further subdivided into disorders that involve inflammatory or necrotizing lesions—the nephritic syndromes —and disorders that involve abnormal permeability to protein and other macromolecules—the nephrotic syndromes. More than 20 specific glomerulopathies exist. The nomenclature for these glomerulopathies is complex, and specific diseases are not discussed in detail here.

Tubulointerstitial diseases are disorders characterized by abnormal tubular function. They result in abnormal urine composition and concentration but are not characterized by decreased GFR until late in the disease course. The disorders in this category include interstitial nephritis, acute tubular necrosis, multiple myeloma of the kidney, and functional tubular defects such as renal tubular acidosis.

Patients with renal parenchymal disorders may remain asymptomatic for years, and they may exhibit only proteinuria and microscopic hematuria, with little if any evidence of reduced renal function. Spontaneous recovery or improvement with treatment occurs with many glomerulopathies. However, other patients exhibit progressive nephropathy, hypertension, and renal insufficiency. The incidence of kidney disease in pregnancy is approximately 0.12%. In two-thirds of these patients, the disorder results from glomerulopathy, and in one-third, from tubulointerstitial disease.

Diagnosis

Women with preexisting disease may choose to become pregnant without the counsel of their nephrologist. When such patients become pregnant, the obstetrician and nephrologist seek to define the extent of renal involvement. Serial blood pressure measurements are obtained to define the severity of hypertension and the efficacy of current antihypertensive therapy. Creatinine clearance and the level of proteinuria should be determined. Urinalysis yields information about the presence of renal casts and bacteriuria. The determination of serum creatinine and BUN concentrations defines the extent of renal insufficiency. A serum creatinine concentration greater than 0.8 mg/dL, which may be normal in the nonpregnant woman, may represent significant renal insufficiency during pregnancy. Alternatively, the obstetrician may first detect renal dysfunction through routine prenatal screening tests since patients may otherwise be asymptomatic, as symptoms rarely develop until GFR decreases by 25%. If proteinuria, hematuria, or azotemia is detected, a complete biochemical evaluation should be performed.

Both preeclampsia and renal disease may manifest as hypertension, proteinuria, and edema. The distinction between the two disorders is often unclear, especially after 20 weeks’ gestation. Fisher et al. evaluated 176 renal biopsy specimens obtained from hypertensive women immediately postpartum, most of whom had a clinical diagnosis of preeclampsia. The clinicopathologic correlation was poor. Histologic evidence of preeclampsia (e.g., glomerular endotheliosis without hypercellularity) was present in only 65% of these hypertensive women. Primary renal disease was present in 20%, and hypertensive nephrosclerosis occurred in 11%. Nulliparous women (84%) were more likely to have a correct diagnosis of preeclampsia than parous women (38%), further demonstrating the difficulty in making the diagnosis in different patient populations.

Renal tissue biopsy is often used to establish a diagnosis in nonpregnant patients. The decision to perform a kidney biopsy in the parturient is complex, as the value of the clinical information obtained that may guide therapy must be balanced against the risks associated with the procedure. Studies reporting the safety of biopsies are small and heterogeneous. A recent meta-analysis by Piccoli et al. compared complication rates from 243 renal biopsies performed during pregnancy with 1236 performed in the postpartum period. Significant complications occurred in 7% of biopsies performed before delivery compared with 1% in the postpartum period. Most complications were minor and included groin pain as well as hematuria. The authors did report, however, that more serious complications (e.g., bleeding and loin pain) occurred the further along in pregnancy the biopsy was performed and seemed to peak around 25 weeks’ gestation. It should be noted that in 23 of the studies in the meta-analysis, kidney biopsies were performed as a means to characterize morphologies in preeclampsia, a practice that is no longer recommended and may have influenced the subject pool substantially. Given the apparent increase in risk associated with biopsy during pregnancy, it should only be performed in patients with a high likelihood of severe glomerular disease and when definitive diagnosis is critical to guide appropriate and immediate treatment.

Emerging research in the area of biomarkers may further guide treatment and management in this population as well as preclude the need for biopsy. When diagnosis is obtained through antineutrophil cytoplasmic antibodies or through double-stranded DNA antibodies, empiric treatment may begin with steroids, azathioprine, or calcineurin inhibitors in lieu of a kidney biopsy in a variety of the disorders, including lupus nephritis and glomerulonephritis. Novel biomarkers such as soluble urokinase plasminogen activator receptor (suPAR) for focal segmental glomeruloscleoris, M-type phospholipase A2 receptor (PLA2R) in membranous nephropathy, and others have been described in case reports and once further developed may change diagnosis and management.

Effect of Pregnancy on Preexisting Kidney Disease

The extent to which pregnancy affects preexisting renal disease depends on the level of renal insufficiency before pregnancy. Among women with mild antenatal renal insufficiency, pregnancy does not substantially alter the natural course of renal disease. Jungers et al. evaluated the effect of pregnancy on renal function among 360 women with primary glomerulonephritis. During the study period, 171 (48%) women became pregnant. All study subjects had normal renal function at the time of entry into the study, and all patients who became pregnant had normal renal function at conception. In the case-control analysis of the study, pregnancy was not identified as a risk factor for progression to end-stage renal failure. Limardo et al. evaluated 223 women with biopsy-documented IgA nephropathy who had a serum creatinine level greater than 1.2 mg/dL, 136 of whom became pregnant. Women were observed for a minimum of 5 years (median, 10 years), and pregnancy did not seem to affect long-term outcome of kidney disease or the onset of proteinuria or hypertension.

In contrast, Jones and Hayslett analyzed the outcome of 82 pregnancies in 67 women with preexisting moderate or severe renal insufficiency (i.e., serum creatinine level greater than 1.4 mg/dL before pregnancy or at the first antepartum visit). The mean ± standard deviation serum creatinine concentration increased from 1.9 ± 0.8 mg/dL in early pregnancy to 2.5 ± 1.3 mg/dL in the third trimester. The prevalence of hypertension rose from 28% at baseline to 48% during late pregnancy. Pregnancy-related deterioration of maternal renal function occurred in 43% of cases. Purdy et al. also found that greater than 40% of women with moderate to severe kidney disease had deterioration in renal function caused by pregnancy. Women with a serum creatinine concentration greater than 2.0 mg/dL who became pregnant had a one in three chance of developing dialysis-dependent end-stage renal disease during or shortly after pregnancy. In summary, the preponderance of evidence seems to demonstrate that while pregnancy exacerbates renal disease, it appears to have a greater effect on those who present with moderate to severe levels of renal dysfunction before pregnancy.

The pathophysiology by which pregnancy exacerbates renal disease is unknown. One hypothesis is that increased glomerular perfusion, which normally accompanies pregnancy, paradoxically causes further injury to the kidneys in patients with preexisting impairment of function. However, this hypothesis is unsupported by published data, which demonstrate no evidence of hyperfiltration (i.e., an initial decline in serum creatinine concentration) during early pregnancy in patients with renal disease. An alternative hypothesis is that preexisting renal disease may induce a cascade of platelet aggregation, microvascular fibrin thrombus formation, and endothelial dysfunction that leads to microvascular injury in the already tenuous kidneys. In addition to general changes to renal mechanics discussed earlier, exacerbation or improvement of the initial disease process during pregnancy could also alter the long-term course of renal dysfunction.

Effect on the Mother and Fetus

Pregnant women with chronic kidney disease (CKD) are at an increased risk for maternal and fetal complications. Nevis et al. systematically reviewed all published observational studies of women with CKD that included a control group for comparison, excluding retrospective studies. They identified 13 studies between 1966 and 2010 that included at least five women. Maternal complications included gestational hypertension, preeclampsia/eclampsia, and maternal mortality. Adverse fetal outcomes included preterm births, fetal growth restriction (also known as intrauterine growth restriction), small-for-gestational-age infants, neonatal mortality, stillbirths, and low birth weight. Adverse maternal outcomes were found in 12 studies, and when examined in aggregate, their incidence was five times greater than in women without kidney disease. Adverse fetal outcomes were identified in nine studies, and when examined in aggregate, the incidence was two times greater than in the otherwise healthy women. There was no analysis of the variance of magnitude of the effect by specific outcome.

The incidence of obstetric complications is proportional to the extent of preexisting maternal renal disease and preexisting hypertension. Bar et al. evaluated maternal and neonatal outcomes in 38 women (46 pregnancies) with primary renal disease. They did not have a control group of women without renal disease. They observed that most women (98%) had a successful pregnancy, but many had complications including superimposed preeclampsia (22%), preterm delivery (22%), fetal growth restriction (13%), and cesarean delivery (24%) ( Fig. 51.1 ). In a logistic regression model, only preexisting hypertension and an elevated preconception serum uric acid level were independent predictors of poor outcome. Other factors (e.g., degree of preexisting renal impairment) were not found to be significant predictors, but because 90% of the cohort had mild disease the study may have been underpowered to detect an association. In a study of women with moderate to severe renal disease, Jones and Hayslett found the complication rate was much higher. The incidence of preterm birth was 59%, the incidence of fetal growth restriction was 37%, and the cesarean delivery rate was 59%. The largest literature review on the topic by Lindheimer and Davison supports the results of prior studies, demonstrating good outcomes for patients with mild renal disease (serum creatinine less than or equal to 1.4 mg/dL) in which over 95% of patients had live births (75% were size appropriate for gestational age). Outcomes worsened substantially as renal dysfunction increased, with patients suffering from severe dysfunction (serum creatinine greater than or equal to 2.0 mg/dL) having a successful obstetric outcome only 78% of the time and with 40% of patients developing end-stage renal failure within 1 year postpartum.

Rate of short-term pregnancy outcome in women with primary renal disease. NICU, neonatal intensive care unit.

(From Bar J, Orvieto R, Shalev Y, et al. Pregnancy outcome in women with primary renal disease. Isr Med Assoc J. 2000;2:178–181.)

Medical and Obstetric Management

During pregnancy, the nephrologist and the obstetrician monitor maternal renal function, blood pressure, and fetal development at frequent intervals. Monthly determination of serum creatinine concentration, creatinine clearance, and proteinuria allows the recognition of renal deterioration and establishes a baseline for the patient, which may be useful in diagnosing superimposed preeclampsia if it occurs. An antepartum consultation with the anesthesia provider should also be considered to address issues such as peripartum medication and fluid management, and to perform an overall risk assessment to discuss and develop potential plans for anesthetic technique and monitoring.

Some glomerulopathies respond to corticosteroids, and corticosteroid therapy should be continued during pregnancy. Rapid deterioration of renal function that occurs before 28 weeks’ gestation may require renal biopsy to exclude rapidly progressive glomerulopathies that require treatment, as discussed earlier. Antihypertensive therapy should be instituted as needed (see Chapter 35 ). As in patients with iron deficiency anemia or patients who refuse blood products, recombinant human erythropoietin has been used successfully to improve maternal anemia in patients with CKD. Because of its large molecular weight, recombinant erythropoietin does not appear to cross the placenta or have an adverse impact on the fetus. In the non-CKD population, doses of 4000 units subcutaneously 3 times per week for 4 weeks in the third trimester for the treatment of iron deficiency anemia caused a gain of 1.9 ± 1.0 g/dL of hemoglobin at delivery, although the optimal dose range and timing in pregnancy are unknown. Data in the CKD population are limited to case reports and small case series. In patients who are treated with erythropoietin, a decreased response to the current dose may actually be the first sign that the patient is pregnant. As in the non-CKD population, no optimal regimen is known; however, it should be noted that doses may need to be changed during varying stages of the pregnancy to keep the hemoglobin target within the range of 11 to 12 g/dL, as recommended by the National Kidney Foundation for the pregnant patient. Efficacy has been shown in pregnant patients with CKD and end-stage renal disease on hemodialysis, as well as renal transplant recipients; however, the efficacy and doses are highly variable, and the number of cases reported is very small. Protein restriction places the fetus at risk for growth restriction and is not used. Deterioration of maternal renal function, the onset of preeclampsia, or evidence of fetal compromise may necessitate urgent delivery.

Hemodialysis and Long-Term Ambulatory Peritoneal Dialysis

When renal disease has progressed to end-stage renal failure (i.e., GFR less than 5 mL/min), fertility is suppressed and conception and pregnancy are rare. Less than 10% of premenopausal patients undergoing dialysis have regular menses. Luteinizing hormone and follicle-stimulating hormone concentrations assume an anovulatory pattern, which causes 40% of affected women to be amenorrheic. One-half of all female patients undergoing dialysis exhibit hyperprolactinemia because of reduced clearance and hypothalamic disturbances. Toma et al. surveyed 2504 dialysis units in Japan and reported only 172 pregnancies among 38,889 women who were undergoing dialysis.

When pregnancy does occur, there are several important management considerations necessary to maximize the probability of a successful outcome. There are two modalities of dialysis: extracorporeal hemodialysis and intracorporeal peritoneal dialysis. Hemodialysis necessitates vascular access and the need for anticoagulation of the extracorporeal circuit and may be complicated by cardiovascular instability, large fluid and electrolyte shifts, and the risk for hepatitis. Hypotension may compromise uteroplacental perfusion and cause fetal compromise. Even when hypotension and major fluid shifts are avoided, Doppler ultrasonographic examination of uterine and umbilical artery flow during hemodialysis suggests the occurrence of a redistribution of arterial flow away from the uteroplacental vascular bed. Fetal heart rate monitoring is recommended during dialysis. Rapid removal of maternal solutes and reduced oncotic pressure with attendant free-water diffusion into the amniotic cavity may lead to polyhydramnios. Hemodynamic consequences are minimized by more frequent but shorter dialysis runs. Long-term ambulatory peritoneal dialysis allows less hemodynamic trespass, a more stable fetal environment, and the freedom to undergo dialysis at home. However, peritoneal dialysis may not be associated with greater fetal survival. Complications of this modality include peritonitis and catheter difficulties.

Rates of successful pregnancy in women undergoing dialysis vary by study but range between 50% and 70%. A meta-analysis and systematic review by Piccoli et al. reviewed almost 550 pregnancies in patients undergoing both hemodialysis and peritoneal dialysis and reported a low maternal/perinatal mortality rate (0.4%), with a malformation rate of approximately 2%, which is in line with the risk in the general population. Fetal complications are most often seen in the form of respiratory distress, sepsis, and retinopathy and are likely a result of the higher incidence of preterm birth rather than related specifically to dialysis. The optimal dialysis schedule is an area of active research, with a trend toward more favorable outcomes with longer and more frequent dialysis sessions. BUN levels should be kept below 50 mg/dL before dialysis and below 30 mg/dL after dialysis. At birth, azotemia in the newborn is similar to that in the mother, but this quickly corrects because the newborn has normal kidney function. The long-term effects of intrauterine azotemia on newborn cognitive development are unknown; however, it appears that if the neonate survives the complications from preterm delivery, further development may be normal.

Patients undergoing hemodialysis have a high rate of viral hepatitis, a greater frequency of active tuberculosis, and a higher rate of infection with vancomycin-resistant enterococci, human immunodeficiency virus (HIV), and methicillin-resistant Staphylococcus aureus . The risk for hepatitis C virus (HCV) infection is particularly of concern, with reported rates as high as 36%. However, with improvement in aseptic technique and more attention to handwashing, the decline in the reuse of dialysis equipment, and the use of dedicated isolated dialysis machines for HCV-seropositive patients, the rates of infection and seroconversion can be markedly reduced.

Anesthetic Management

Anesthetic management is influenced by the extent of renal dysfunction and hypertension. The parturient with stable renal disease, mild to moderate renal insufficiency, well-controlled hypertension, and euvolemia requires minimal special consideration. In contrast, the dialysis patient with end-stage renal failure presents many anesthetic challenges because renal disease may affect almost every organ system ( Box 51.1 ). Poorly controlled hypertension leads to left ventricular hypertrophy and dysfunction. Symptoms of cardiovascular compromise should prompt a cardiac workup including echocardiography to evaluate ventricular function. An intra-arterial catheter also may aid the management of the parturient with poorly controlled hypertension, especially when multiple agents are required to control blood pressure or when the continuous infusion of antihypertensive agents is required. Uremic pericarditis, cardiomyopathy, and accelerated atherosclerosis are rarely seen until advanced uremia has been present for several years.

Box 51.1

Chronic Renal Failure: Abnormalities That May Affect Anesthetic Management

Cardiovascular

• •
  

  Hypertension

  
  
• •
  

  Fluid overload

  
  
• •
  

  Ventricular hypertrophy

  
  
• •
  

  Accelerated atherosclerosis

  
  
• •
  

  Uremic pericarditis

  
  
• •
  

  Uremic cardiomyopathy

Pulmonary

• •
  

  Increased risk for difficult airway

  
  
• •
  

  Recurrent pulmonary infections

  
  
• •
  

  Pleural effusion

Metabolic and Endocrine

• •
  

  Hyperkalemia

  
  
• •
  

  Metabolic acidosis

  
  
• •
  

  Hyponatremia

  
  
• •
  

  Hypocalcemia

  
  
• •
  

  Hypermagnesemia

  
  
• •
  

  Decreased protein binding of drugs

  
  
• •
  

  Hypoglycemia

Hematologic

• •
  

  Anemia

  
  
• •
  

  Platelet dysfunction

  
  
• •
  

  Decreased coagulation factors

  
  
• •
  

  Leukocyte dysfunction

Neurologic

• •
  

  Autonomic neuropathy

  
  
• •
  

  Mental status changes

  
  
• •
  

  Peripheral neuropathy

  
  
• •
  

  Restless legs syndrome

  
  
• •
  

  Seizure disorder

Gastrointestinal

• •
  

  Delayed gastric emptying

  
  
• •
  

  Increased gastric acidity

  
  
• •
  

  Hepatic venous congestion

  
  
• •
  

  Hepatitis (viral or drug-induced)

  
  
• •
  

  Malnutrition

Neurologic

• •
  

  Autonomic neuropathy

  
  
• •
  

  Peripheral neuropathy

  
  
• •
  

  Cerebrovascular insufficiency

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