|Year : 2016 | Volume
| Issue : 2 | Page : 48-52
Chronic Kidney Disease in Pregnancy
Aarti Malavade1, Praveen Malavade2, Mohan Biyani3, Swapnil Hiremath4, Ayub Akbari4
1 Gunasheela Surgical and Maternity Hospital, Department of Obstetrics and Gynecology, Bangalore, India
2 Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
3 Division of Nephrology, Department of Medicine, University of Ottawa; Kidney Research Centre, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
4 Division of Nephrology, Department of Medicine, University of Ottawa; Kidney Research Centre, Ottawa Hospital Research Institute; Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
|Date of Web Publication||26-Apr-2016|
The Ottawa Hospital, Riverside Campus, 1967 Riverside Drive, Ottawa, ON, K1H 7W9
Source of Support: None, Conflict of Interest: None
Pregnancy with chronic kidney disease carries substantial risk to the mother and the baby. Incidence of women becoming pregnant while having chronic kidney disease is increasing. The major risk to the mother is development of preeclampsia which may be hard to diagnose in patients with chronic kidney disease. Depending on the kidney function, women may also be at risk of decline in their kidney function. The major risk to baby is prematurity. The renal physiological changes that occur with pregnancy are quite profound and normal values of blood pressure, electrolytes and parameters to monitor kidney function are different then in non-pregnant state. Counselling these women about pregnancy and managing them through pregnancy remains a challenge. This review discusses the physiological changes that occur during pregnancy, risks of pregnancy with CKD and management of CKD during pregnancy.
Keywords: Chronic kidney disease, preeclampsia, pregnancy
|How to cite this article:|
Malavade A, Malavade P, Biyani M, Hiremath S, Akbari A. Chronic Kidney Disease in Pregnancy. J Integr Nephrol Androl 2016;3:48-52
| Introduction|| |
The prevalence of chronic kidney disease (CKD) is increasing, and women are delaying pregnancy. The combination of these two factors will result in more women with CKD becoming pregnant. Pregnancy with CKD may impact the mother as well as the baby. The major risk to the mother is decline in kidney function and the development of preeclampsia. The major risk to baby remains prematurity with its attendant consequences. In this review, we will discuss the physiological changes that occur during pregnancy, risks of pregnancy with CKD, and the management of CKD during pregnancy.
| Renal physiologic changes in pregnancy|| |
During pregnancy the kidney undergoes hypertrophy. Kidney volume increases and kidney size increases by about 1 cm. The renal collecting system dilates and involves the calyces, pelvis, and ureters. The cause of dilatation of the collecting system is thought to be hormonal (progesterone being implicated) as well as anatomical due to enlarging uterus pressing on the pelvic brim. , About 80-90% of women show an evidence of hydronephrosis. This hydronephrosis is more prominent on the right side.  The urinary stasis created by dilation of the collecting system increases the risk of pyelonephritis in pregnant women with bacteriuria.  A rare pregnancy related syndrome "overdistension syndrome" characterized by severe hydronephrosis, abdominal pain, decline in kidney function, and even elevation in blood pressure may occur. This syndrome may mimic pre-eclampsia and responds to lateral recumbency or may require stent placement. ,
| Systemic hemodynamics|| |
Normal pregnancy is a markedly vasodilated state. The vasculature of normal pregnant women is refractory to vasopressors including angiotensin 2. Cardiac output increases by about 50% due to increased heart rate and stroke volume. Blood pressure decreases soon after conception and nadirs at around 16-20 weeks of pregnancy and then gradually increases to prepregnant levels near term. Systolic blood pressure decreases by about 10 mmHg and diastolic by about 20 mmHg. , Anticipating this fall in blood pressure, clinicians should consider withholding antihypertensive medications in patients with mild to moderate hypertension and monitor blood pressure closely. Many of these women will need antihypertensive medications later in pregnancy. Antihypertensive medications found to be safe in pregnancy should be utilized when treating hypertension in pregnancy. These include alpha-methyldopa, labetalol, and nifedipine. Angiotensin receptor blockers, angiotensin converting enzyme inhibitors, and direct renin inhibitors are contraindicated in pregnancy. There is conflicting data on exposure of the fetus to angiotensin converting enzyme inhibitors in the first trimester. One study finding increased risk and the other attributing risk to hypertension. ,
| Glomerular filtration rate in pregnancy|| |
Glomerular filtration rate (GFR) starts to increase soon after conception. It is statistically higher than prepregnant levels quite early in gestation and GFR peaks at about 50% above prepregnant values by the end of the second trimester. It then remains stable until term. In a few studies, a decline at term has been shown. This response is quite robust, and it can be seen in a person with single kidney as well as in a single denervated kidney such as a renal transplant recipient. Even at this high GFR, the kidney does not seem to be working at its maximum as protein loading can further increase the GFR.  The hyperfiltration that a woman experiences during pregnancy is, however, not harmful to the normal kidney. In the normal kidney, hyperfiltration of pregnancy occurs without any change in intraglomerular pressure.  Rats subjected to multiple repetitive pregnancies show no evidence of any injury to the kidney. The GFR goes back to prepregnant values 6 days to 1 month postpartum.
Because of hyperfiltration (increased GFR), the serum creatinine concentration drops and usually the serum creatinine concentration is between 45 and 65 mmol/L.  Most experts regard creatinine concentration >80 mmol/L to be abnormal in pregnancy. Due to increased GFR, the protein excretion increases in pregnancy and the upper limit of normal is about 300 mg/day. Most of the protein excreted is of small molecular weight.
| Electrolytes in pregnancy|| |
Serum sodium (Na) concentration drops in pregnancy because of resetting of the osmostat. One study using ion specific electrodes reported a mean (standard deviation) of 139 ± 1.6 mEq/L as compared to 143 ± 1.6 mEq/L postpartum.  This normal decrease in Na should be kept in mind when treating pregnant patients with diabetes insipidus. There is an effect of posture on salt excretion. Upright posture decreases Na excretion and in the third trimester, merely turning the women from supine to lateral position increases Na excretion. In the rare patient with volume overload, consider prescription of posture before using a diuretic if a diuretic is not needed urgently. Anion gap in normal pregnancy is lower than the postpartum state. There is poor correlation of anion gap and albumin concentration in pregnancy. 
| Markers of glomerular filtration rate in pregnancy|| |
Inulin which is a small molecule freely filtered through the glomerulus and not modified, reabsorbed or secreted by the renal tubules is the gold standard for measuring GFR in pregnant and nonpregnant states. It is cumbersome and very expensive and not routinely available. Radio-isotope measurement of GFR is contraindicated in pregnancy because of the risk of radiation to the fetus. Twenty-four-hour creatinine clearance in pregnancy is a good marker of GFR if GFR is preserved and care is taken to obtain a complete collection. 
Creatinine-based estimating equations for GFR (Cockroft-Gault, Modification of Diet in Renal Disease [MDRD], and Chronic Kidney Disease Epidemiology Collaboration formulae) are routinely utilized in nonpregnant population to estimate GFR.  Quadri et al. reported a correlation coefficient of 0.87 between Cockroft-Gault formula (using prepregnancy weight) and 24 h creatinine clearance in pregnant women. The authors concluded that Cockroft-Gault calculated GFR can be used in pregnancy using the prepregnancy weight.  MDRD formula performs poorly in pregnant patients with one study reporting a bias of 27.3 mL/min in patients with renal disease. 
Cystatin C is a small molecule that is freely filtered by the glomeruli. It has shown to be a good marker of GFR in nonpregnant state, and its estimating equation has been endorsed by International Society of Nephrology for estimating GFR.  Unfortunately, in pregnancy, it is not reliable. Its concentration increases from the second trimester to the third trimester in spite of creatinine clearance remaining unchanged.  Similarly, another marker of GFR, beta-trace protein, was not found to reliably predict GFR in pregnancy.  Thus, estimating equations are not reliable in pregnancy and should not be utilized. If precise GFR measurement is truly necessary, clinically the easiest and most cost-effective method would be to do a 24 h urine creatinine clearance with attention to complete collection.
| Effects of chronic kidney disease on pregnancy|| |
Kidney disease is present in about 0.03-3% of women of childbearing age.  Fertility as well as ability to have a successful pregnancy depends on the degree of kidney dysfunction. Kidney disease because of systemic disease such as diabetes and systemic lupus erythematosus may have a different prognosis, than patients with primary kidney disease. In patients with primary kidney disease, pregnancy is well tolerated if hypertension is absent and kidney function is preserved (creatinine <124 mmol/L or creatinine clearance >70 mL/min), but still these are high-risk pregnancies. In one report  of 127 patients with Stage 1 CKD studied over 11 years, the rate of C-section was 46.4% versus 24.7% for controls (OR: 2.73; 95% CI: 1.72-4.33), and preterm delivery was 28.3% versus 4.9% in patients with Stage 1 CKD. In another report, women with CKD Stage 1 even without baseline hypertension, proteinuria, or systemic disease had higher risk (OR: 1.88; 95% CI: 1.27-2.79) of combined outcome of preterm delivery, neonatal intensive care unit stay, and small for gestational age baby. 
| Moderate to severe chronic kidney disease and pregnancy|| |
Patients with moderate kidney disease (creatinine 124-220 mmol/L), are at high risk with approximately 50% having pregnancy-related decline in kidney function and are also at increased risk of preeclampsia and preterm delivery. About 25% of these patients, renal function decline persists or progresses postpartum. In patients with severe kidney disease (creatinine >220 mmol/L) approximately 70% have preterm delivery, 40% develop preeclampsia, and 40% may progress to dialysis. Thus, consideration should be given to discourage pregnancy in this setting. ,,,
| Proteinuria in pregnancy|| |
Proteinuria may occur de novo or markedly increase in pregnancy in patients with underlying kidney disease. Rising proteinuria in isolation in the third trimester is quite common and does not necessarily imply preeclampsia.  In a study by Imbasciati et al., estimated GFR of <40 mL/min and proteinuria >1 g/day was associated with accelerated decline in kidney function.  Angiogenic factors may be helpful in predicting preeclampsia in patients with CKD. 
| End stage renal disease and pregnancy|| |
Pregnancy on dialysis is relatively rare. It is an extremely high-risk pregnancy with prematurity, low birth weight and intrauterine growth retardation (IUGR) being common. Infant survival has ranged from 42% to 60%, but recent data suggests intensive dialysis may improve survival and outcome for the babies. Intensive dialysis, in a Canadian study involving 22 pregnancies, was associated with 86.4% live birth rate, and 50% of babies had normal birth weight. Patients who start dialysis during pregnancy do better than patients who get pregnant on established dialysis.  Intensive dialysis, about 40 h per week should be considered in pregnant patients who require renal replacement therapy.
| Renal transplant recipient and pregnancy|| |
Renal transplantation offers a much better risk profile for mother and child than becoming pregnant on dialysis. In a majority of women with renal transplant, pregnancy is successful. The major risks to the mother are hypertension and preeclampsia. Fetal risks include preterm birth and intrauterine growth retardation. , Prednisone in a dose of 15 mg/day or less is safe, as is Imuran, cyclosporine, and tacrolimus. Mycophenolate mofetil use is associated with congenital malformation and should be stopped at least 6 weeks before conception. , If kidney function is preserved, long-term follow-up suggests that pregnancy probably does not have a deleterious effect on the graft.  The best outcomes are in patients with stable renal function with the serum creatinine being <133 mmol/L, proteinuria <500 mg/day, and normal or well-controlled blood pressure on medications that are safe in pregnancy.  Women should be advised that this is high-risk pregnancy. That they may develop diabetes and high blood pressure in pregnancy and if they already have hypertension, more medications may be needed to control blood pressure. They should also be informed of the risk of preeclampsia, preterm birth, IUGR, and infection. Close follow-up and coordinated care with high-risk obstetrician and transplant nephrologist are essential.
| Conclusion|| |
All pregnancies with kidney disease should be regarded as high-risk and managed in conjunction with a nephrologist. Adverse outcomes are common, and patients should be counseled on what to expect. When hypertension is absent, and kidney function is preserved, most mothers and baby do well. With moderate to severe kidney disease, there is substantial mortality and morbidity. Patients with end-stage renal disease are at high-risk, and at a minimum hemodialysis should be done 6 days a week for 4 h. Intensive dialysis 42 ± 7 h per week may improve fetal outcomes. Patients with end-stage renal disease should strongly consider kidney transplantation before considering pregnancy.
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| References|| |
Christensen T, Klebe JG, Bertelsen V, Hansen HE. Changes in renal volume during normal pregnancy. Acta Obstet Gynecol Scand 1989;68:541-3.
Bailey RR, Rolleston GL. Kidney length and ureteric dilatation in the puerperium. J Obstet Gynaecol Br Commonw 1971;78:55-61.
Rasmussen PE, Nielsen FR. Hydronephrosis during pregnancy: A literature survey. Eur J Obstet Gynecol Reprod Biol 1988;27:249-59.
Weissenbacher ER, Reisenberger K. Uncomplicated urinary tract infections in pregnant and non-pregnant women. Curr Opin Obstet Gynecol 1993;5:513-6.
Meyers SJ, Lee RV, Munschauer RW. Dilatation and nontraumatic rupture of the urinary tract during pregnancy: A review. Obstet Gynecol 1985;66:809-15.
Nielsen FR, Rasmussen PE. Hydronephrosis during pregnancy: Four cases of hydronephrosis causing symptoms during pregnancy. Eur J Obstet Gynecol Reprod Biol 1988;27:245-8.
MacGillivray I, Rose GA, Rowe B. Blood pressure survey in pregnancy. Clin Sci 1969;37:395-407.
Sturgiss SN, Dunlop W, Davison JM. Renal haemodynamics and tubular function in human pregnancy. Baillieres Clin Obstet Gynaecol 1994;8:209-34.
Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, et al.
Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006;354:2443-51.
Li DK, Yang C, Andrade S, Tavares V, Ferber JR. Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: A retrospective cohort study. BMJ 2011;343:d5931.
Lindheimer M, Katz A. Renal physiology and disease in pregnancy. In: Seldin DW, Giebisch G, editors. The Kidney: Physiology and Pathophysiology. New York: Raven Press; 1992. p. 3371-431.
Baylis C, Reckelhoff JF. Renal hemodynamics in normal and hypertensive pregnancy: Lessons from micropuncture. Am J Kidney Dis 1991;17:98-104.
Girling JC. Re-evaluation of plasma creatinine concentration in normal pregnancy. J Obstet Gynaecol 2000;20:128-31.
Akbari A, Wilkes P, Lindheimer M, Lepage N, Filler G. Reference intervals for anion gap and strong ion difference in pregnancy: A pilot study. Hypertens Pregnancy 2007;26:111-9.
White CA, Akbari A. The estimation, measurement, and relevance of the glomerular filtration rate in stage 5 chronic kidney disease. Semin Dial 2011;24:540-9.
Quadri KH, Bernardini J, Greenberg A, Laifer S, Syed A, Holley JL. Assessment of renal function during pregnancy using a random urine protein to creatinine ratio and Cockcroft-Gault formula. Am J Kidney Dis 1994;24:416-20.
Smith MC, Moran P, Ward MK, Davison JM. Assessment of glomerular filtration rate during pregnancy using the MDRD formula. BJOG 2008;115:109-12.
Akbari A, Lepage N, Keely E, Clark HD, Jaffey J, MacKinnon M, et al.
Cystatin-C and beta trace protein as markers of renal function in pregnancy. BJOG 2005;112:575-8.
Hladunewich M, Hercz AE, Keunen J, Chan C, Pierratos A. Pregnancy in end stage renal disease. Semin Dial 2011;24:634-9.
Piccoli GB, Fassio F, Attini R, Parisi S, Biolcati M, Ferraresi M, et al.
Pregnancy in CKD: Whom should we follow and why? Nephrol Dial Transplant 2012;27 Suppl 3:iii111-8.
Piccoli GB, Cabiddu G, Attini R, Vigotti FN, Maxia S, Lepori N, et al.
Risk of adverse pregnancy outcomes in women with CKD. J Am Soc Nephrol 2015;26:2011-22.
Chopra S, Suri V, Aggarwal N, Rohilla M, Keepanasseril A, Kohli HS. Pregnancy in chronic renal insufficiency: Single centre experience from North India. Arch Gynecol Obstet 2009;279:691-5.
Imbasciati E, Ponticelli C. Pregnancy and renal disease: Predictors for fetal and maternal outcome. Am J Nephrol 1991;11:353-62.
Jones DC, Hayslett JP. Outcome of pregnancy in women with moderate or severe renal insufficiency. N Engl J Med 1996;335:226-32.
Khoury JC, Miodovnik M, LeMasters G, Sibai B. Pregnancy outcome and progression of diabetic nephropathy. What's next? J Matern Fetal Neonatal Med 2002;11:238-44.
Katz AI, Davison JM, Hayslett JP, Singson E, Lindheimer MD. Pregnancy in women with kidney disease. Kidney Int 1980;18:192-206.
Imbasciati E, Gregorini G, Cabiddu G, Gammaro L, Ambroso G, Del Giudice A, et al.
Pregnancy in CKD stages 3 to 5: Fetal and maternal outcomes. Am J Kidney Dis 2007;49:753-62.
Rolfo A, Attini R, Nuzzo AM, Piazzese A, Parisi S, Ferraresi M, et al.
Chronic kidney disease may be differentially diagnosed from preeclampsia by serum biomarkers. Kidney Int 2013;83:177-81.
Bramham K, Nelson-Piercy C, Gao H, Pierce M, Bush N, Spark P, et al.
Pregnancy in renal transplant recipients: A UK national cohort study. Clin J Am Soc Nephrol 2013;8:290-8.
Deshpande NA, James NT, Kucirka LM, Boyarsky BJ, Garonzik-Wang JM, Montgomery RA, et al.
Pregnancy outcomes in kidney transplant recipients: A systematic review and meta-analysis. Am J Transplant 2011;11:2388-404.
Anderka MT, Lin AE, Abuelo DN, Mitchell AA, Rasmussen SA. Reviewing the evidence for mycophenolate mofetil as a new teratogen: Case report and review of the literature. Am J Med Genet A 2009;149A:1241-8.
Nevis IF, Garg AX; Donor Nephrectomy Outcomes Research (DONOR) Network. Maternal and fetal outcomes after living kidney donation. Am J Transplant 2009;9:661-8.