Features of preeclampsia in patients with chronic kidney disease

Aims: to study the characteristics of preeclampsia (PE) in women with chronic kidney disease (CKD) compared to PE in the general population.

Method: a prospective observational study analyzed the course of PE in 24 women with a previously established diagnosis of CKD (Group 1) and 39 women in the general population (Group 2) without a complicating somatic history. In patients with CKD with a known pregestational creatinine level, the physiological response of the kidneys to pregnancy was assessed, defined as a decrease in serum creatinine by more than 10% in the first trimester. The angiogenic ratio (sFlt-1/PLGF) was studied in 13 patients with CKD.

Results: the two groups did not differ in age or parity. In the first group, 16 patients had CKD stage 1-2, 5 had CKD 3A, and one patient each had CKD 3B, 4 and 5 (the later receiving hemodialysis). Nineteen (79%) of women with CKD had hypertension, proteinuria (PU), renal impairment or a combination of these factors before conception. Only 3 out of 16 patients had a physiological renal response. Early PE developed in 58.3% of patients with CKD compared to 35.3% in second group (p = 0.082). The duration of PE inversely correlated with the stage of CKD (r = -0.630; p = 0.001). As pregnancy progressed in patients with CKD, PU increased, reaching nephrotic level in 54% of women by the time of PE. HELLP syndrome or isolated hematological signs of TMA were noted in 8 patients in the general population group, and in 1 in the CKD group. The average sFlt-1/PLGF value in patients with early stages of CKD (n = 9) was 81.0±24.0, with late stages (n = 4) it was 14±8.

Conclusion: the study identified the features of PE in CKD: early onset, increased PU reaching nephrotic level in half of the cases by the time PE is diagnosed, and the absence of a histological renal response to pregnancy in the 1st trimester. The lack of changes in the angiogenic coefficient in women with PE and late-stage CKD requires further study in a larger group of patients.

1. Kassebaum N. J., Barber R. M., Bhutta Z. A., et al. Global, regional, and national levels of maternal mortality, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. The Lancet. 2016. 388(10053): 1775-1812. doi: 10.1016/S0140-6736(16)31470-2

2. Rana S., Lemoine E. et al. Preeclampsia: Pathophysiology, Challenges, and Perspectives. Circulation Research. 2019. 124(7):1094-1112. doi: 10.1161/CIRCRESAHA.118.313276

3. Giorgione V., Ridder A., Kalafat E. et al. Incidence of postpartum hypertension within 2 years of a pregnancy complicated by pre-eclampsia: a systematic review and meta-analysis. BJOG. 2021. 128(3):495-503. doi: 10.1111/1471-0528.16545

4. Coutinho T., Lamai O., Nerenberg K.. Hypertensive disorders of pregnancy and cardiovascular diseases: current knowledge and future directions. Curr Treat Options Cardiovasc Med. 2018. 20(7):56. doi: 10.1007/s11936-018-0653-8

5. Tooher J., Thornton C., Makris A., et al. All hypertensive disorders of pregnancy increase the risk of future cardiovascular disease. Hypertension. 2017. 70(4):798-803. doi: 10.1161/HYPERTENSIONAHA.117.09246

6. Barrett P.M., McCarthy F.P., Evans M., et al. Hypertensive disorders of pregnancy and the risk of chronic kidney disease: A Swedish registry-based cohort study. PLoS Med. 2020. 17(8):e1003255. doi: 10.1371/journal.pmed.1003255

7. Vikse B. E., Irgens L. M., Leivestad T., et al. Preeclampsia and the Risk of End-Stage Renal Disease. N Engl JMed. 2008. 359(8):800-809. doi: 10.1056/NEJMoa0706790

8. Khashan A. S., Evans M., Kublickas M., et al. Preeclampsia and risk of end stage kidney disease: A Swedish nationwide cohort study. PLOS Medicine/ 2019. 16(7):e1002875. doi: 10.1371/journal.pmed.1002875

9. Zhang J.J., Ma X.X., Hao L., et al. A systematic review and meta-analysis of outcomes of pregnancy in CKD and CKD outcomes in pregnancy. Clin J Am Soc Nephrol. 2015. 10(11):1964-1978 doi: 10.2215/CJN.09250914

10. Cabiddu G., Castellino S., et al. A best practice position statement on pregnancy in chronic kidney disease: the Italian Study Group on Kidney and Pregnancy. J. Nephrol. 2016. 29(3):277-303. doi: 10.1007/s40620-016-0285-6

11. Clinical guidelines – Preeclampsia. Eclampsia. Edema, proteinuria and hypertensive disorders during pregnancy, childbirth and the postpartum period – 2021-2022-2023 (06.24.2021) – Approved by the Ministry of Health of the Russian Federation.

12. Brown M.A., Laura M.A., Louise K.C., et al. The hypertensive disorders of pregnancy: ISSHP classification, diagnosis & management recommendations for international practice. Pregnancy Hypertension. 2018. 13:291-310. doi: 10.1016/j.preghy.2018.05.004

13. Piccoli G.B., Cabiddu G., Attini A.,et al. Risk of Adverse Pregnancy Outcomes in Women with CKD. Am Soc Nephrol. 2015. 26(8):2011-2022. doi: 10.1681/ASN.2014050459

14. Bramham K., Seed P.T., Lightstone L., et al. Diagnostic and predictive biomarkers for pre-eclampsia in patients with established hypertension and chronic kidney disease. Kidney International. 2016. 89(4):874-885. doi: 10.1016/j.kint.2015.10.012

15. Lokki A.I., Heikkinen-Eloranta J. Pregnancy induced TMA in severe preeclampsia results from complement-mediated thromboinflammation. Human Immunology. 2021. 82(5):371- 378. doi: 10.1016/j.humimm.2021.03.006

16. Wiles K., Bramham K., Seed P. T., et al. Diagnostic indicators of superimposed pre-eclampsia in women with chronic kidney disease. Kidney International Reports. 2019. 4(6):842-853. doi: 10.1016/j.ekir.2019.03.012

17. Morton A., Burke M. et al. Changes in proteinuria and diagnosing preeclampsia in CKD pregnancy. Pregnancy Hypertension. 2020. 20:92-95. doi: 10.1016/j.preghy.2020.03.005

18. Prakash J., Pant P., Prakash S. et al. Changing picture of acute kidney injury in pregnancy: Study of 259 cases over a period of 33 years. Indian J Nephrol. 2016.26(4):262-267. doi: 10.4103/0971-4065.202406

19. Stepan H., Herraiz I., Schlembach D. et al. Implementation of the sFlt-1/PlGF ratio for prediction and diagnosis of preeclampsia in singleton pregnancy: implications for clinical practice. Ultrasound in Obstetrics and Gynecology. 2015. 45(3):241-246. doi: 10.1002/uog.14799

20. Moghaddas S.H., Zununi V.S., Ardalan M. Preeclampsia: A close look at renal dysfunction. Biomedicine and Pharmacotherapy. 2019. 109:408-416. doi: 10.1016/j.biopha.2018.10.082

21. Karumanchi S.A., Maynard S.E., Stillman I.E. et al. Preeclampsia: A renal perspective. Kidney International. 2003. 67(6):2101-2113. doi: 10.1111/j.1523-1755.2005.00316.x

22. Piccoli G. B., Fassio F., Attini R. et al. Pregnancy in CKD: whom should we follow and why? Nephrology Dialysis Transplantation. 2012. 27(3):iii111-iii118. doi: 10.1093/ndt/gfs302

23. Wiles K., Webster P., Seed P. T. et al. The impact of chronic kidney disease Stages 3–5 on pregnancy outcomes. Nephrology Dialysis Transplantation. 2020. 36(11):2008-2017. doi: 10.1093/ndt/gfaa247

24. Piccoli G.B., Zakharova E., et al. Pregnancy in Chronic Kidney Disease: Need for Higher Awareness. A Pragmatic Review Focused on What Could Be Improved in the Different CKD Stages and Phases. J. Clin. Med. 2018. 7(11):415. doi: 10.3390/jcm7110415

25. Nikolskaya I.G., Prokopenko E.I., Novikova S.V. et al., Complications and outcomes of pregnancy in chronic renal failure. Almanac of Clinical Medicine. 2015. 37:52-69. doi: 10.18786/2072-0505-2015-37-52-69

26. Odutayo A., Hladunewich M. Obstetric nephrology: renal hemodynamic and metabolic physiology in normal pregnancy. Clinical journal of the American Society of Nephrology. 2012. 7(12):2073-80. doi: 10.2215/CJN.00470112

27. Williams D., Davison J. Chronic kidney disease in pregnancy. British medical journal. 2008. 336(7637):211-215. doi: 10.1136/bmj.39406.652986.BE

28. Merkusheva L.I, Kozlovskaya N.L. Renal injury in preeclampsia: the view of nephrologist. (Literature review). Nephrology. 2018. 22(2):30-38. DOI: 10.24884/1561-6274-2018-22-2-30-38

29. Bello A.K., Levin A., Lunney M. et al. Status of care for end stage kidney disease in countries and regions worldwide: international cross sectional survey. BMJ. 2019. 367:l5873. doi: 10.1136/bmj.l5873

30. Webster P., Lightstone L. et al. Pregnancy in chronic kidney disease and kidney transplantation. Kidney International. 2017. 91(5):1047-1056. doi: 10.1016/j.kint.2016.10.045

31. Munkhaugen J., Lydersen S., Romundstad P.R. et al. Kidney function and future risk for adverse pregnancy outcomes: a population-based study from HUNT II, Norway. Nephrol Dial Transplant. 2009. 24(12):3744-3750. doi: 10.1093/ndt/gfp320

32. Jones D.C., Hayslett J.P. Outcome of pregnancy in women with moderate or severe renal insufficiency. N Engl JMed 1996. 335(4):226-32. doi: 10.1056/NEJM199607253350402

33. Williams D., Davison J. Chronic kidney disease in pregnancy. BMJ. 336(7637):211-215. doi: 10.1136/bmj.39406.652986.BE

34. Demographic Yearbook of Russia. Statistical Handbook 2021. Page 66.

35. Arkhangelsky V.N., Kalachikova O.N. Mother's age at the birth of the first child: dynamics, regional differences, determination. Economic and social changes: facts, trends, forecast. 2020. 13(5):200–217. doi: 10.15838/esc.2020.5.71.12

36. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases, translation into Russian. Bobkova I.N., Bulanov N.M., Zakharova E.V. et al. edited by E.V. Zakharova. Nephrologу and Dialуsis. 2022 24(4):577-874. doi: 10.28996/2618-9801-2022-4-577-874

37. Homer C.S., Brown M.A., Mangos G. et al. Non-proteinuric pre-eclampsia: a novel risk indicator in women with gestational hypertension. J. Hypertens. 2008. 26(2):295-302. doi: 10.1097/HJH.0b013e3282f1a953

38. Shalina R.I., Mikhalyova L.M., Simukhina M.A., et al. Modern features of the clinical course of severe forms of preeclampsia. Gynecology, Obstetrics and Perinatology. 2017. 16(6):16-23. DOI: 10.20953/1726-1678-2017-6-16-23

39. Roberts M., Lindheimer M.D., Davison J.M. Altered glomerular permselectivity to neutral dextrans and heteroporous membrane modeling in human pregnancy. Am J Physiol. 1996. 270(2 Pt):F338-F343. doi: 10.1152/ajprenal.1996.270.2.F338

40. Wiles K., Chappell L. C., Lightstone L. et al. Updates in Diagnosis and Management of Preeclampsia in Women with CKD. Clin J Am Soc Nephrol. 2020. 15(9):1371-1380. doi: 10.2215/CJN.15121219

41. Masini G., Foo L.F., Tay J. et al. Reply: preeclampsia has 2 phenotypes that require different treatment strategies. Am J Obstet Gynecol. 2021. 227(1):114-115. doi: 10.1016/j.ajog.2021.09.006

42. Terekhina V.Yu., Nikolaeva M.G.,Momot A.P. et al. Delayed endothelial dysfunction in patients with a history of early pre-eclampsia and features of pregravidary preparation. Bulletin of Medical Science. 2022. 3(27):65-73. doi 10.31684/25418475_2022_3_65

43. Soto E., Romero R., Kusanovic J.P. et al. Late-onset preeclampsia is associated with an imbalance of angiogenic and antiangiogenic factors in patients with and without placental lesions consistent with maternal underperfusion. J Matern Fetal Neonatal Med. 2015. 25(5):498-507. doi: 10.3109/14767058.2011.591461

44. Kozlovskaya NL, Merkusheva LI, Kirsanova TV, Bobkova IN, Bobrova LA, Runikhina NK. Angiogenesis placental factors imbalance and clinical features of «early» and «late» preeclampsia. Archive of obstetrics and gynecology them V.F. Snigereva. 2014. 1(1):13-21 https://archivog.com/2313-8726/article/view/35458

45. Myatt L., Roberts J.M. Preeclampsia: syndrome or disease? Curr Hypertens Rep. 2015.17(11):83. doi: 10.1007/s11906-015-0595-4

46. Jena M.K., Sharma N.R., Petitt M. et al. Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta. Biomolecules. 2020. 10(6):953. doi: 10.3390/biom10060953

47. Vaisbuch E., Mazaki-Tovi S. Preeclampsia, portliness, and perturbation of adipose tissue function-are we beginning to connect the Dots? Am J Hypertens. 2017. 30(6):559-560. doi: 10.1093/ajh/hpx040

48. Roberts J.M., Catov J.M. Preeclampsia more than 1 disease: or is it? Hypertension. 2008. 51(4):989-990. doi: 10.1161/HYPERTENSIONAHA.107.100248

49. Cote A.M., Sauve N. The management challenges of nonpreeclampsia-related nephrotic syndrome in pregnancy. Obstetric Medicine. 2011. 4:133-139 doi: 10.1258/om.2011.110001

50. Rolfo A., Attini R., Nuzzo A.M. et al. Chronic kidney disease may be differentially diagnosed from preeclampsia by serum biomarkers. Kidney Int. 2013. 83(1):177-181. doi: 10.1038/ki.2012.348

51. Temirbulatov R.R., Bezhenar V.F., Smirnov A.V. Differential diagnostics of preeclampsia in patients with chronic kidney disease. Nephrology (Saint-Petersburg) 2019; 23(1):45-50. doi: 10.24884/1561-6274-2019-23-1-45-50

52. Morisawa H., Hirashima C., Sano M. et al. Difficulty of predicting early-onset super-imposed preeclampsia in pregnant women with hemodialysis due to diabetic nephropathy by serum levels of sFlt-1, PlGF, and sEng. Case Reports. 2019. 9(2):101- 105. doi: 10.1007/s13730-019-00435-y

53. Sibai B.M., Stella C.L. Diagnosis and management of atypical preeclampsia-eclampsia. American journal of obstetrics and gynecology. 2009. 200(5):481-487. doi: 10.1016/j.ajog.2008.07.048

54. Stevens A.B., Brasuell D.M., Higdon R.N. Atypical preeclampsia – Gestational proteinuria. Journal of family medicine and primary care. 2017. 6(3):669-671. doi: 10.4103/2249-4863.222029

55. Stella C.L., Malik K.M., Sibai B.M. HELLP syndrome: an atypical presentation. American Journal of Obstetrics and Gynecology. 2008. 198(5):e6-e8. doi: 10.1016/j.ajog.2007.12.034

56. Zeeman G.G. Neurologic complications of pre-eclampsia. Semin Perinatol. 2009. 33(3):166-72. doi: 10.1053/j.semperi.2009.02.003

57. Rolnik D.L., Wright D., Poon L.C.Y. et al. ASPRE trial: performance of screening for preterm pre-eclampsia. Ultrasound in Obstetrics and Gynecology. 2017. 50(4):492-495. doi: 10.1002/uog.18816

58. Roberge S., Bujold E., Nicolaides K.H. Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol. 2018. 218(3): 287-293. e1. doi: 10.1016/j.ajog.2017.11.561

59. Duley L., Meher S., Hunter K.E. et al. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev. 2019. 10:CD004659. doi: 10.1002/14651858.CD004659.pub3