Clinical characteristics and genetic profile of complement system in renal thrombotic microangiopathy in patients with severe forms of arterial hypertension

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Abstract

Background. The spectrum of diseases characterized by the development of renal thrombotic microangiopathy (TMA) encompasses the malignant hypertension (MHT). TMA in MHT has conventionally been regarded as a variation of secondary TMA, the treatment of which is restricted to the stabilization of blood pressure levels, a measure that frequently fails to prevent the rapid progression to end-stage renal disease in patients. Nevertheless, there exists a rationale to suggest that, in certain instances, endothelial damage in MHT might be rooted in the dysregulation of the complement system (CS), thereby presenting potential opportunities for the implementation of complement-blocking therapy.

Aim. To study clinical manifestations and genetic profile of CS in patients with morphologically confirmed renal TMA combined with severe AH.

Materials and methods. 28 patients with morphologically verified renal TMA and severe AH were enrolled to the study. Patients with signs of microangiopathic hemolysis and thrombocytopenia were not included in the study due to possible compliance with the criteria for atypical hemolytic uremic syndrome (aHUS). The prevalence of rare genetic defects (GD) of the CS was assessed by molecular genetic analysis (search for mutations in the clinically significant part of the human genome – exome) by next-generation sequencing technology (NGS).

Results. GD of CS were detected in a quarter of patients. Rare genetic variants classified as “likely pathogenic” including defects in CFI, C3, CD46, CFHR4, CFHR5 genes were detected in five cases. Two patients were found to have chromosomal deletions containing CFH-related proteins genes (CFHR1, CFHR3).

Conclusion. Rare variants of CS genes linked to aHUS were found in 25% of patients with renal TMA, the genesis of which was originally thought to be secondary and attributed to MHT, with partial or complete absence of hematological manifestations of microangiopathic pathology. The key to confirming TMA associated with MHT, particularly in the absence of microangiopathic hemolysis and thrombocytopenia, elucidating its nature, and potentially effective complement-blocking therapy in patients with GD of CS, appears to be a genetic study of CS combined with a morphological study of a renal biopsy.

About the authors

Mariam I. Akaeva

Sechenov First Moscow State Medical University (Sechenov University); Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Author for correspondence.
Email: 0510_mary@mail.ru
ORCID iD: 0009-0002-0224-663X

аспирант каф. внутренних, профессиональных болезней и ревматологии Института клинической медицины им. Н.М. Склифосовского, врач-нефролог

Russian Federation, Moscow; Moscow

Natalia L. Kozlovskaya

Patrice Lumumba People’s Friendship University of Russia; Yeramishantsev City Clinical Hospital

Email: 0510_mary@mail.ru
ORCID iD: 0000-0002-4275-0315

д-р мед. наук, проф., проф. каф. внутренних болезней с курсом функциональной диагностики и кардиологии им. В.С. Моисеева, рук. Центра помощи беременным женщинам с патологией почек и мочевыводящих путей

Russian Federation, Moscow; Moscow

Larisa A. Bobrova

Sechenov First Moscow State Medical University (Sechenov University)

Email: 0510_mary@mail.ru
ORCID iD: 0000-0001-6265-4091

канд. мед. наук, ассистент каф. внутренних, профессиональных болезней и ревматологии Института клинической медицины им. Н.М. Склифосовского

Russian Federation, Moscow

Olga A. Vorobyeva

National Center for Clinical Morphological Diagnostics

Email: 0510_mary@mail.ru
ORCID iD: 0000-0002-6946-6816

канд. мед. наук, зав. отд-нием нефропатологии и сложного морфологического диагноза

Russian Federation, Saint Petersburg

Ekaterina S. Stoliarevich

Russian University of Medicine; City Clinical Hospital №52

Email: 0510_mary@mail.ru
ORCID iD: 0000-0002-0402-8348

д-р мед. наук, проф. каф. нефрологии, врач-нефролог высшей квалификационной категории, патологоанатом

Russian Federation, Moscow; Moscow

Petr A. Shatalov

National Medical Research Radiological Centre

Email: 0510_mary@mail.ru
ORCID iD: 0000-0001-5374-8547

канд. биол. наук, зав. отд. молекулярно-биологических исследований

Russian Federation, Obninsk

Tatiana V. Smirnova

Krasnov Research Institute of Eye Diseases

Email: 0510_mary@mail.ru
ORCID iD: 0000-0001-5137-6786

канд. мед. наук, врач-офтальмолог

Russian Federation, Moscow

Anastasiia O. Anan'eva

Mariinsky City Hospital

Email: 0510_mary@mail.ru

врач-нефролог

Russian Federation, Saint Petersburg

References

  1. Saba ES, Cambron JC, Go R, et al. Clinical Associations, Treatment, and Outcomes of Renal-Limited Thrombotic Microangiopathy. Blood. 2018;132(Suppl. 1):4978. doi: 10.1182/blood-2018-99-117723
  2. Genest DS, Patriquin CJ, Licht C, et al. Renal Thrombotic Microangiopathy: A Review. Am J Kidney Dis. 2023;81(5):591-605. doi: 10.1053/j.ajkd.2022.10.014
  3. De Serres SA, Isenring P. Renal thrombotic microangiopathy revisited: when a lesion is not a clinical finding. Saudi J Kidney Dis Transpl. 2010;21(3):411-6.
  4. Tsai HM. Atypical Hemolytic Uremic Syndrome May Present as Severe Hypertension without Hemolysis or Thrombocytopenia. Austin J Nephrol Hypertens. 2016;3(1):1055.
  5. Rifkin BS, Brewster UC. Thrombotic microangiopathy associated with malignant hypertension. Mayo Clin Proc. 2006;81(5):593. doi: 10.4065/81.5.593
  6. Lamia R, El Ati Z, Ben Fatma L, et al. Malignant hypertension-associated thrombotic microangiopathy following cocaine use. Saudi J Kidney Dis Transpl. 2016;27(1):153-6. doi: 10.4103/1319-2442.174195
  7. Timmermans SAMEG, Abdul-Hamid MA, Vanderlocht J, et al. Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities. Kidney Int. 2017;91(6):1420-5. doi: 10.1016/j.kint.2016.12.009
  8. Mathew RO, Nayer A, Asif A. The endothelium as the common denominator in malignant hypertension and thrombotic microangiopathy. J Am Soc Hypertens. 2016;10(4):352-9. doi: 10.1016/j.jash.2015.12.007
  9. Besbas N, Karpman D, Landau D, et al. A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders. Kidney Int. 2006;70(3):423-31. doi: 10.1038/sj.ki.5001581
  10. Palma LMP, Sridharan M, Sethi S. Complement in Secondary Thrombotic Microangiopathy. Kidney Int Rep. 2021;6(1):11-23. doi: 10.1016/j.ekir.2020.10.009
  11. Praga M, Rodríguez de Córdoba S. Secondary atypical hemolytic uremic syndromes in the era of complement blockade. Kidney Int. 2019;95(6):1298-300. doi: 10.1016/j.kint.2019.01.043
  12. Keith NM, Wagener HP, Kernohan JW. The syndrome of malignant hypertension. Arch Intern Med (Chic). 1928;41(2):141-88. doi: 10.1001/archinte.1928.00130140003001
  13. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021-104. doi: 10.1093/eurheartj/ehy339
  14. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-24. doi: 10.1038/gim.2015.30
  15. Zipfel PF, Edey M, Heinen S, et al. Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome. PLoS Genet. 2007;3(3):e41. doi: 10.1371/journal.pgen.0030041
  16. Moore I, Strain L, Pappworth I, et al. Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. Blood. 2010;115(2):379-87. doi: 10.1182/blood-2009-05-221549
  17. Welte T, Arnold F, Kappes J, et al. Treating C3 glomerulopathy with eculizumab. BMC Nephrol. 2018;19(1):7. doi: 10.1186/s12882-017-0802-4
  18. Maximiano C, Silva A, Duro I, et al. Genetic atypical hemolytic uremic syndrome in children: a 20-year experience from a tertiary center. J Bras Nefrol. 2021;43(3):311-7. doi: 10.1590/2175-8239-JBN-2020-0199
  19. Timmermans SAMEG, Wérion A, Damoiseaux JGMC, et al. Diagnostic and Risk Factors for Complement Defects in Hypertensive Emergency and Thrombotic Microangiopathy. Hypertension. 2020;75(2):422-30. doi: 10.1161/HYPERTENSIONAHA.119.13714
  20. El Karoui K, Boudhabhay I, Petitprez F, et al. Impact of hypertensive emergency and rare complement variants on the presentation and outcome of atypical hemolytic uremic syndrome. Haematologica. 2019;104(12):2501-11. doi: 10.3324/haematol.2019.216903
  21. Vyse TJ, Morley BJ, Bartok I, et al. The molecular basis of hereditary complement factor I deficiency. J Clin Invest. 1996;97(4):925-33. doi: 10.1172/JCI118515
  22. de Jong S, Volokhina EB, de Breuk A, et al. Effect of rare coding variants in the CFI gene on Factor I expression levels. Hum Mol Genet. 2020;29(14):2313-24. doi: 10.1093/hmg/ddaa114
  23. Diep J, Potter D, Mai J, Hsu D. Atypical haemolytic uremic syndrome with refractory multiorgan involvement and heterozygous CFHR1/CFHR3 gene deletion. BMC Nephrol. 2023;24(1):127. doi: 10.1186/s12882-023-03153-x
  24. Zhang Y, Goodfellow RX, Ghiringhelli Borsa N, et al. Complement Factor I Variants in Complement-Mediated Renal Diseases. Front Immunol. 2022;13:866330. doi: 10.3389/fimmu.2022.866330
  25. Cavero T, Arjona E, Soto K, et al. Severe and malignant hypertension are common in primary atypical hemolytic uremic syndrome. Kidney Int. 2019;96(4):995-1004. doi: 10.1016/j.kint.2019.05.014
  26. Totina A, Iorember F, El-Dahr SS, Yosypiv IV. Atypical hemolytic-uremic syndrome in a child presenting with malignant hypertension. Clin Pediatr (Phila). 2013;52(2):183-6. doi: 10.1177/0009922811412942
  27. Omiya C, Koga K, Nishioka K, et al. A case of malignant hypertension as a presentation of atypical hemolytic uremic syndrome. Clin Nephrol Case Stud. 2023;11:72-8. doi: 10.5414/CNCS110901
  28. Cavero T, Auñón P, Caravaca-Fontán F, et al. Thrombotic microangiopathy in patients with malignant hypertension. Nephrol Dial Transplant. 2023;38(5):1217-26. doi: 10.1093/ndt/gfac248
  29. De Serres SA, Isenring P. Athrombocytopenic thrombotic microangiopathy, a condition that could be overlooked based on current diagnostic criteria. Nephrol Dial Transplant. 2009;24(3):1048-50. doi: 10.1093/ndt/gfn687
  30. Kwak SH, Shah CV. A brief review of renal-limited thrombotic microangiopathy associated with immune checkpoint inhibitors. J Onco-Nephrol. 2023;7(2):105-10. doi: 10.1177/23993693221147769
  31. Козловская Н.Л., Демьянова К.А., Кузнецов Д.В., и др. «Субклиническая» тромботическая микроангиопатия при атипичном гемолитико-уремическом синдроме: единичный случай или закономерность? Нефрология и диализ. 2014;16(2):280-7 [Kozlovskaya NL, Demyanova KA, Kuznetsov DV, et al. Atypical haemolytic uremic syndrome with ”subclinical” thrombotic microangiopathy: a single case or regularity? Nephrology and Dialysis=Nefrologiia i dializ. 2014;16(2):280-7 (in Russian)].
  32. Козловская Н.Л., Акаева М.И., Столяревич Е.С., и др. Тромботическая микроангиопатия, ассоциированная со злокачественной артериальной гипертензией. Клиническая нефрология. 2017;1:49-56 [Kozlovskaya NL, Akaeva MI, Stolyarevich ES, et al. Thrombotic microangiopathy associated with malignant hypertension. Klinicheskaya nefrologiya. 2017;1:49-56 (in Russian)].
  33. Saleem M, Shaikh S, Hu Z, et al. Post-Transplant Thrombotic Microangiopathy due to a Pathogenic Mutation in Complement Factor I in a Patient With Membranous Nephropathy: Case Report and Review of Literature. Front Immunol. 2022;13:909503. doi: 10.3389/fimmu.2022.909503
  34. Von Tokarski F, Fillon A, Maisons V, et al. Thrombotic microangiopathies af er kidney transplantation in modern era: nosology based on chronology. BMC Nephrol. 2023;24(1):278. doi: 10.1186/s12882-023-03326-8

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