Renal disease and pregnancy

11th Postgraduate Course for Training in Reproductive Medicine and Reproductive Biology

Marshall D. Lindheimer MD

Women with renal disease wishing to conceive or already pregnant, seek advice as to whether the pregnancy will be complicated, will the baby be healthy, and if gestation will further damage their kidneys. Similar queries come from renal allograft recipients. My response, to be defended during the lecture, is that most gestations succeed and there is little or no evidence that pregnancy adversely influences the natural history of the disease or transplant provided that renal function is preserved or but minimally decreased and hypertension absent. The presentation which follows starts with a synopsis of changes in the urinary tract occurring in normal gestation focusing on their relevance to clinical circumstance. The lecture then stresses gestation in women with chronic diseases of the kidney including those receiving renal replacement therapy. There are also brief discussions of acute renal failure and when to perform a renal biopsy during pregnancy.

I) Physiological changes in normal gestation: Kidney weight and size increase. Renal length, estimated radiologically or sonographically, increases by approximately 1 cm. The most striking morphological changes, however, occur in the collecting system, where dilation of renal calyces, pelves, and ureters may be observed in the initial trimester and persist to 3-4 months post partum. The causes of these alterations include both humoral and obstructive factors (e.g. estrogens, progesterone, or compression of the ureters by the enlarging uterus and the iliac arteries where the latter cross the pelvic brim). Relevance of these changes include, a) difficulty in obtaining reliable timed measurements of urinary volume, (which can be minimized by establishing high urine flow rates, and avoiding supine recumbency for 30 min before starting and ending a collection period). b) Urinary stasis may explain the propensity of gravidas with asymptomatic bacteriuria to develop frank pyelonephritis. c) A rare "over-distension syndrome" associated with abdominal pain and an increased P_creatinine, which can be treated by placement of ureteral stents may relate to obstruction at the pelvic brim.

Both glomerular filtration, effective renal plasma flow, and the fractional clearance of urate increase substantially during gestation. The relevance of these changes are that concentrations of serum creatinine, urea N, and uric acid of 0.9, 14, and 5.6 mg/dl, normal in nonpregnant subjects, are already suspiciously high in gravid women. The increased filtered loads, at any filtrance, may be responsible for an approximate doubling of urinary protein excretion, and contributes to the glycosuria and aminoaciduria of normal pregnancy. (The fate of albumin excretion is more complex and disputed).

Other physiological alterations include; the renal bicarbonate threshold and Pco₂ levels decrease, the result being a mild alkalemia with bicarbonate and Pco₂ values 4 mEq/l and 10 torr below those in nonpregnant women. (Thus, an asthmatic gravida with a Pco₂ of 40 torr already displays considerable CO₂ retention). The osmotic thresholds for thirst and AVP secretion decrease 10 mOsm/kg, resulting in mild hyponatremia and a P_osm ~10 mOsm/kg below those in nongravid populations (Thus suspect hypernatremia when P_Na levels are in the low 140s). Finally, there is a marked increment in the metabolic clearance of AVP, in part due to the high circulating levels of vasopressinase, which may account for a rare syndrome termed transient diabetes insipidus of pregnancy.

II) Pregnancy in women with preexisting renal disease:(Table 1). Counseling and managing women with chronic renal disease are based primarily on retrospective studies of over 1,000 patients whose kidney disease was diagnosed by renal biopsy. Most of the women surveyed had been normotensive with only minimal renal dysfunction. The following concepts have emerged: Fertility and the ability to sustain an uncomplicated gestation generally relate to the degree of functional impairment and whether hypertension is present or absent, rather than the nature of the underlying disorder. Patients are arbitrarily considered in three categories: those with 1) preserved or only mildly impaired function (serum creatinine #1.4 mg/dl) and no hypertension. 2) moderate renal insufficiency (serum creatinine 1.5-3 mg/dl [some use 2.5 mg/dl as the cutoff]); and 3) severe renal insufficiency (serum creatinine $3 mg/dl). Women in the first category usually have successful obstetric outcomes and gestation does not appear to affect adversely the underlying disease; perinatal mortality now less than 5%, while evidence of irreversible functional loss in the mother is even lower. This generalization, however, may not hold true for certain specific diseases. For instance patients with scleroderma and periarteritis nodosum, (disorders associated with hypertension) do poorly and conception in such women should be emphatically discouraged. Prognosis is somewhat poorer in lupus nephritis, especially when the disease has flared within six months of conception. There is controversy on whether pregnancy effects the natural history if IgA nephritis, focal glomerular sclerosis, membranoproliferative nephritis, and reflux nephropathy (a view for which there is little supporting evidence.)

Information on women with moderate or severe dysfunction who conceive is more limited. Fetal outcome is still good in the former group (after excluding first trimester abortions 80-90% of the pregnancies succeeds), but <40% of pregnancies in women undergoing dialysis are successful. The greatest concern, however, is maternal jeopardy. About one third of women with moderate renal dysfunction experience escalating, and at times life-threatening, hypertension, and one quarter of them suffer an accelerated decrease in GFR which may fail to reverse after delivery. These problems increase as function falls further. Thus it is primarily maternal risk in women with moderate insufficiency, and the added likelihood of a poor fetal outcome when function is severe, that leads me to discourage pregnancy in both these groups, especially in the latter.

Principals of management: Patients with known renal disease should be examined by their obstetricians at biweekly intervals until gestational week 32, and weekly thereafter. Routine antenatal testing and observations are supplemented with monthly assessment of renal function (timed [24h preferred]creatinine clearances and protein excretion (can do Protien/Creatinine ratios when timed collections difficult). The women should be preferably enrolled at a tertiary care center where the Maternal-Fetal-Medicine physician will monitor for early signs of superimposed preeclampsia (the incidence of which is increased in these patients), and will institute electronic monitoring of uterine activity and the fetal heart in the third trimester, usually during the 32d gestational week. Increases in blood pressure are treated aggressively. Whereas women with essential hypertension are often not treated until their diastolic levels reach 100 mm Hg, the goal for women with parenchymal renal disorders should be to maintain levels between 80-85 mm Hg .

Managing pregnant women undergoing dialysis: The following guidelines are suggested: a) Both hemo and peritoneal dialysis may be performed in pregnant women, though the amounts of dialysate infused into the peritoneum may have to be adjusted as the uterus increases in size. b) The frequency of hemodialysis, or the number of peritoneal cycles should be increased to maintain predialysis serum urea levels at or below 50 mg/dl. c) Heparin doses may have to be altered to avoid either bleeding (vaginally) and clotting, (pregnancy is a hypercoagulable state). c) The dialyzer should be familiar with the normal changes in acid base, electrolyte levels, body tonicity, and maternal as well as fetal volume alterations when assessing the appropriateness of "dry weights", etc. d) Gestation often aggravates the anemia of end-stage renal disease, while early experience with erythropoietin is favorable. e) There is increased absorption of calcium during gestation, and dialysis patients are prone to hypercalcemia; thus vitamin D doses may have to be decreased. f) Uterine contractions should be monitored electronically starting at midgestation, as premature contractions amenable to tocolytic therapy often occur during hemodialysis. g) The obstetrician should be aware of the high incidence of growth retardation associated with these pregnancies, and intervene accordingly.

Pregnancy in renal transplant recipients: Over 5,000 transplant recipients have conceived since 1958. Most treated with azathioprine and prednisone alone. There is also accruing data with cyclosporine, but experience with newer immunosuppresive agents is to fragmentary to comment on. Advice concerning conception, derived primarily from Registry data, small series, and case reports, generally parallels the optimistic views described for women who were not graft recipients, and had preserved or mildly impaired kidney function. There is also an increased incidence of premature and low birth infants but >90% of these gestations succeed. Whether the use of cyclosporine and the newer immunosuppresents will alter this favorable prognosis is under study, and as of 2001 there was two major Transplantation registries, one at the National Transplantation Pregnancy Registry (USA), housed at the Department of Surgery, Jefferson Medical College, Philadelphia (c/o Dr. Vincent Armenti); the second in the United Kingdom(c/o Dr John Davison, U of Newcastle).

III: Acute renal failure: Acute renal failure (ARF) severe enough to require dialysis estimated at between 1 in 5,000 gestations before 1970 is now less than 1 in 20,000 pregnancies. Likewise cortical necrosis, once observed mainly in obstetric populations occurs <1 in 80,000 deliveries. These trends, attributed to the increased ability of women to obtain sterile pregnancy terminations, has not been shared in the poorer and less industrialized nations where ARF continues to be an important cause of maternal mortality. There are ARF syndromes peculiar to pregnancy associated primarily with microangiopathic processes which have been given a variety of labels, most often idiopathic postpartum renal failure or postpartum hemolytic-uremic syndrome. These are often irreversible and are associated with substantial mortality.

Suggested Reading

Armenti VT, Moritz MJ, Davison JM: Medical management of the pregnant transplant recipient.5:14-23, 1998. Review of the USA National Pregnancy Transplant Registry as well as management guidelines.
Conrad KP, Lindheimer MD: Renal and cardiovascular alterations. In Lindheimer MD, Roberts JM, Cunningham FG (eds) Chesley’s Hypertension in Pregnancy, 2d ed, Appleton & Lange, Stamford CT, 1999, pp 263-326. Detailed review of studies delineating normal renal function in pregnancy
Hou S: Pregnancy in chronic renal unsufficiency and end-stage renal disease. Am J Kidney Dis 33:235-252, 1999. Review of the literature concerning outcomes, as well as guidelines for managing gravidas undergoing dialysis who conceive. (See also Hou S, Frequency and outcome of pregnancy in women on Dialysis. Am J Kidney Dis 23:60-3, 1994, and update of her registry Okundaye et al., Am J Kidney Dis, spring 1998).
Hayslett JP: The effect of systemic lupus erythematosus on pregnancy and pregnancy outcome. Am J Reprod Immun 28:199-204, 1992. Focuses on gravidas with lupus nephropathy.
Jones D, Hayslett JP: Outcome of pregnancy in women with moderate and severe renal insufficiency. N Eng J Med 335:226-32, 1995. Largest series and most up-to-date review of the renal prognosis, and outcome of pregnancy in women with moderate and severe renal insufficiency (see also editorial same issue).
Jungers P, Huiller P, Forget D, et al.: Influence of pregnancy on the course of primary glomerulonephritis. Lancet 346:1122-24, 1995. A study of 171 women with renal disease, but with minimal dysfunction, who conceived, comparing their long term renal prognosis with that of 171 women with similar diseases and dysfunction who never became pregnant.
Junger P, Chauveau D: Pregnancy and Kidney Disease. Kidney Int 52:871-5,1997. Comprehensive review.
Lindheime MD, Grunfeld J-P, Davison JM: Renal Disorders, In Barron WM, Lindheimer MD (eds), Medical Disorders During Pregnancy, 3d ed, Mosby Inc, St Louis, 2000 pp 39-70. Chapter in text focusing on management of pregnant women with acute and chronic renal disorders including sections on dialysis and transplantation (210 selected references)
Lindheimer MD, Katz AI: Renal physiology and disease in pregnancy. in The Kidney: Physiology and Pathophysiology, DW Seldin, G Giebisch (eds) Lippincott, Williams, & Wilkins, New York, 2000, pp 2597-2644. In depth discussions of physiological changes affecting the kidney in pregnancy as well as the management of gravidas with kidney disorders and/or hypertension. Contains over 500 references.
Lindheimer MD, Katz AI: The normal and diseased kidney in pregnancy. In Schrier RW, Gottschalk CW, (eds) Diseases of the Kidney, 6th edition, Boston, Little Brown & Co, 1977, pp 2063-97. Most of the above in a single chapter. (7^th edition in press fall 2001)
Pedler SJ, Orr KE: Bacterial, fungal, and parasitic infections. In Barron WM, Lindheimer MD (eds), Medical Disorders During Pregnancy, 3d ed, Mosby Inc, St Louis, 2000, pp 411-465. Management of pregnant women with urinary tract infections (not stressed in lecture). Contains FDA safty category for all antibiotics discussed.
Schmidt RJ, Holley JL: Fertility and conception in endstage renal disease. Adv Renal Repl Ther 5:38-44, 1998 Update of literature on endocrine problems associated with end-stage renal disease.