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Genetic, clinical, and pathological study of patients with severe hypertension-associated renal microangiopathy

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Abstract

Background

Severe hypertension may be a prominent manifestation of complement-mediated thrombotic microangiopathy. Furthermore, patients with severe hypertension-associated thrombotic microangiopathy may present with concurrent hematologic abnormalities that mimic complement-mediated thrombotic microangiopathy. Whether or not severe hypertension-associated thrombotic microangiopathy is associated with genetic susceptibility in complement- and/or coagulation-pathway genes remains unclear, and there is thus a need to identify clinicopathological clues to distinguish between these entities.

Methods

Forty-five patients with concomitant severe hypertension and thrombotic microangiopathy on kidney biopsy were identified retrospectively. Whole-exome sequencing was performed to identify rare variants in 29 complement- and coagulation-cascade genes. Clinicopathological features were compared between patients with severe hypertension-associated thrombotic microangiopathy and complement-mediated thrombotic microangiopathy with severe hypertension.

Results

Three patients with pathogenic variants diagnostic of complement-mediated thrombotic microangiopathy and two with anti-factor H antibody positivity were diagnosed with complement-mediated thrombotic microangiopathy with severe hypertension. Among the 40 patients with severe hypertension-associated thrombotic microangiopathy, 53 rare variants of uncertain significance were found in the analyzed genes in 34 (34/40, 85%) patients, of whom 12 patients harbored two or more variants. Compared with complement-mediated thrombotic microangiopathy patients with severe hypertension, patients with severe hypertension-associated thrombotic microangiopathy were more likely to have left ventricular wall thickening (p < 0.001), less-severe acute glomerular thrombotic microangiopathy lesions including mesangiolysis and subendothelial space widening (both p < 0.001), and less arteriolar thrombosis formation (p < 0.001).

Conclusions

Rare genetic variants involving complement and coagulation pathways can be found in patients with severe hypertension-associated thrombotic microangiopathy; their role needs further investigation. Cardiac remodeling and acute glomerular TMA lesions may help to differentiate between severe hypertension-associated thrombotic microangiopathy and complement-mediated thrombotic microangiopathy with severe hypertension.

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References

  1. George JN, Nester CM (2014) Syndromes of thrombotic microangiopathy. N Engl J Med 371(7):654–666. https://doi.org/10.1056/NEJMra1312353

    Article  CAS  PubMed  Google Scholar 

  2. Fakhouri F, Zuber J, Frémeaux-Bacchi V, Loirat C (2017) Haemolytic uraemic syndrome. Lancet 390(10095):681–696. https://doi.org/10.1016/s0140-6736(17)30062-4

    Article  PubMed  Google Scholar 

  3. Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, Bingham C, Cohen DJ, Delmas Y, Douglas K, Eitner F, Feldkamp T, Fouque D, Furman RR, Gaber O, Herthelius M, Hourmant M, Karpman D, Lebranchu Y, Mariat C, Menne J, Moulin B, Nürnberger J, Ogawa M, Remuzzi G, Richard T, Sberro-Soussan R, Severino B, Sheerin NS, Trivelli A, Zimmerhackl LB, Goodship T, Loirat C (2013) Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 368(23):2169–2181. https://doi.org/10.1056/NEJMoa1208981

    Article  CAS  PubMed  Google Scholar 

  4. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr, Williamson JD, Wright JT Jr (2018) 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 71(19):e127–e248. https://doi.org/10.1016/j.jacc.2017.11.006

    Article  PubMed  Google Scholar 

  5. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, Clement DL, Coca A, de Simone G, Dominiczak A, Kahan T, Mahfoud F, Redon J, Ruilope L, Zanchetti A, Kerins M, Kjeldsen SE, Kreutz R, Laurent S, Lip GYH, McManus R, Narkiewicz K, Ruschitzka F, Schmieder RE, Shlyakhto E, Tsioufis C, Aboyans V, Desormais I (2018) 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension. J Hypertens 36(10):1953–2041. https://doi.org/10.1097/hjh.0000000000001940

    Article  CAS  PubMed  Google Scholar 

  6. Cremer A, Amraoui F, Lip GY, Morales E, Rubin S, Segura J, Van den Born BJ, Gosse P (2016) From malignant hypertension to hypertension-MOD: a modern definition for an old but still dangerous emergency. J Hum Hypertens 30(8):463–466. https://doi.org/10.1038/jhh.2015.112

    Article  CAS  PubMed  Google Scholar 

  7. Mishima E, Funayama Y, Suzuki T, Mishima F, Nitta F, Toyohara T, Kikuchi K, Kunikata H, Hashimoto J, Miyazaki M, Harigae H, Nakazawa T, Ito S, Abe T (2021) Concurrent analogous organ damage in the brain, eyes, and kidneys in malignant hypertension: reversible encephalopathy, serous retinal detachment, and proteinuria. Hypertens Res 44(1):88–97. https://doi.org/10.1038/s41440-020-0521-2

    Article  PubMed  Google Scholar 

  8. Shantsila A, Dwivedi G, Shantsila E, Butt M, Beevers DG, Lip GY (2011) Persistent macrovascular and microvascular dysfunction in patients with malignant hypertension. Hypertension 57(3):490–496. https://doi.org/10.1161/hypertensionaha.110.166314

    Article  CAS  PubMed  Google Scholar 

  9. Sallée M, Ismail K, Fakhouri F, Vacher-Coponat H, Moussi-Francés J, Frémaux-Bacchi V, Burtey S (2013) Thrombocytopenia is not mandatory to diagnose haemolytic and uremic syndrome. BMC Nephrol 14:3. https://doi.org/10.1186/1471-2369-14-3

    Article  PubMed  PubMed Central  Google Scholar 

  10. Cavero T, Arjona E, Soto K, Caravaca-Fontán F, Rabasco C, Bravo L, de la Cerda F, Martín N, Blasco M, Ávila A, Huerta A, Cabello V, Jarque A, Alcázar C, Fulladosa X, Carbayo J, Anaya S, Cobelo C, Ramos N, Iglesias E, Baltar J, Martínez-Gallardo R, Pérez L, Morales E, González R, Macía M, Draibe J, Pallardó L, Quintana LF, Espinosa M, Barros X, Pereira F, Cao M, Moreno JA, Rodríguez de Córdoba S, Praga M (2019) Severe and malignant hypertension are common in primary atypical hemolytic uremic syndrome. Kidney Int 96(4):995–1004. https://doi.org/10.1016/j.kint.2019.05.014

    Article  CAS  PubMed  Google Scholar 

  11. van den Born BJ, Honnebier UP, Koopmans RP, van Montfrans GA (2005) Microangiopathic hemolysis and renal failure in malignant hypertension. Hypertension 45(2):246–251. https://doi.org/10.1161/01.HYP.0000151620.17905.ee

    Article  CAS  PubMed  Google Scholar 

  12. Timmermans S, Abdul-Hamid MA, Vanderlocht J, Damoiseaux J, Reutelingsperger CP, van Paassen P (2017) Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities. Kidney Int 91(6):1420–1425. https://doi.org/10.1016/j.kint.2016.12.009

    Article  PubMed  Google Scholar 

  13. Timmermans S, Abdul-Hamid MA, Potjewijd J, Theunissen R, Damoiseaux J, Reutelingsperger CP, van Paassen P (2018) C5b9 formation on endothelial cells reflects complement defects among patients with renal thrombotic microangiopathy and severe hypertension. J Am Soc Nephrol 29(8):2234–2243. https://doi.org/10.1681/asn.2018020184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Timmermans S, Wérion A, Damoiseaux J, Morelle J, Reutelingsperger CP, van Paassen P (2020) Diagnostic and risk factors for complement defects in hypertensive emergency and thrombotic microangiopathy. Hypertension 75(2):422–430. https://doi.org/10.1161/hypertensionaha.119.13714

    Article  CAS  PubMed  Google Scholar 

  15. Zhang Y, Yang C, Zhou X, Hu R, Quan S, Zhou Y, Li Y, Xing G (2020) Association between thrombotic microangiopathy and activated alternative complement pathway in malignant nephrosclerosis. Nephrol Dial Transplant. https://doi.org/10.1093/ndt/gfaa280

    Article  PubMed  PubMed Central  Google Scholar 

  16. Larsen CP, Wilson JD, Best-Rocha A, Beggs ML, Hennigar RA (2018) Genetic testing of complement and coagulation pathways in patients with severe hypertension and renal microangiopathy. Mod Pathol 31(3):488–494. https://doi.org/10.1038/modpathol.2017.154

    Article  CAS  PubMed  Google Scholar 

  17. Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25(14):1754–1760. https://doi.org/10.1093/bioinformatics/btp324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tarasov A, Vilella AJ, Cuppen E, Nijman IJ, Prins P (2015) Sambamba: fast processing of NGS alignment formats. Bioinformatics 31(12):2032–2034. https://doi.org/10.1093/bioinformatics/btv098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38(16):e164. https://doi.org/10.1093/nar/gkq603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, Abecasis GR (2015) A global reference for human genetic variation. Nature 526(7571):68–74. https://doi.org/10.1038/nature15393

    Article  CAS  PubMed  Google Scholar 

  21. Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4(7):1073–1081. https://doi.org/10.1038/nprot.2009.86

    Article  CAS  PubMed  Google Scholar 

  22. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249. https://doi.org/10.1038/nmeth0410-248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schwarz JM, Rödelsperger C, Schuelke M, Seelow D (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7(8):575–576. https://doi.org/10.1038/nmeth0810-575

    Article  CAS  PubMed  Google Scholar 

  24. Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46(3):310–315. https://doi.org/10.1038/ng.2892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Muona M, Berkovic SF, Dibbens LM, Oliver KL, Maljevic S, Bayly MA, Joensuu T, Canafoglia L, Franceschetti S, Michelucci R, Markkinen S, Heron SE, Hildebrand MS, Andermann E, Andermann F, Gambardella A, Tinuper P, Licchetta L, Scheffer IE, Criscuolo C, Filla A, Ferlazzo E, Ahmad J, Ahmad A, Baykan B, Said E, Topcu M, Riguzzi P, King MD, Ozkara C, Andrade DM, Engelsen BA, Crespel A, Lindenau M, Lohmann E, Saletti V, Massano J, Privitera M, Espay AJ, Kauffmann B, Duchowny M, Møller RS, Straussberg R, Afawi Z, Ben-Zeev B, Samocha KE, Daly MJ, Petrou S, Lerche H, Palotie A, Lehesjoki AE (2015) A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet 47(1):39–46. https://doi.org/10.1038/ng.3144

    Article  CAS  PubMed  Google Scholar 

  26. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL (2015) 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 17(5):405–424. https://doi.org/10.1038/gim.2015.30

    Article  PubMed  PubMed Central  Google Scholar 

  27. Van Laecke S, Van Biesen W (2017) Severe hypertension with renal thrombotic microangiopathy: what happened to the usual suspect? Kidney Int 91(6):1271–1274. https://doi.org/10.1016/j.kint.2017.02.025

    Article  PubMed  Google Scholar 

  28. Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaimé F, Dragon-Durey MA, Ngo S, Moulin B, Servais A, Provot F, Rostaing L, Burtey S, Niaudet P, Deschênes G, Lebranchu Y, Zuber J, Loirat C (2013) Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol 8(4):554–562. https://doi.org/10.2215/cjn.04760512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Noris M, Remuzzi G (2009) Atypical hemolytic-uremic syndrome. N Engl J Med 361(17):1676–1687. https://doi.org/10.1056/NEJMra0902814

    Article  CAS  PubMed  Google Scholar 

  30. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, Daina E, Fenili C, Castelletti F, Sorosina A, Piras R, Donadelli R, Maranta R, van der Meer I, Conway EM, Zipfel PF, Goodship TH, Remuzzi G (2010) Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 5(10):1844–1859. https://doi.org/10.2215/cjn.02210310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bu F, Borsa NG, Jones MB, Takanami E, Nishimura C, Hauer JJ, Azaiez H, Black-Ziegelbein EA, Meyer NC, Kolbe DL, Li Y, Frees K, Schnieders MJ, Thomas C, Nester C, Smith RJ (2016) High-Throughput genetic testing for thrombotic microangiopathies and C3 glomerulopathies. J Am Soc Nephrol 27(4):1245–1253. https://doi.org/10.1681/asn.2015040385

    Article  CAS  PubMed  Google Scholar 

  32. Osborne AJ, Breno M, Borsa NG, Bu F, Frémeaux-Bacchi V, Gale DP, van den Heuvel LP, Kavanagh D, Noris M, Pinto S, Rallapalli PM, Remuzzi G, Rodríguez de Cordoba S, Ruiz A, Smith RJH, Vieira-Martins P, Volokhina E, Wilson V, Goodship THJ, Perkins SJ (2018) Statistical validation of rare complement variants provides insights into the molecular basis of atypical hemolytic uremic syndrome and C3 glomerulopathy. J Immunol 200(7):2464–2478. https://doi.org/10.4049/jimmunol.1701695

    Article  CAS  PubMed  Google Scholar 

  33. El Karoui K, Boudhabhay I, Petitprez F, Vieira-Martins P, Fakhouri F, Zuber J, Aulagnon F, Matignon M, Rondeau E, Mesnard L, Halimi JM, Frémeaux-Bacchi V (2019) Impact of hypertensive emergency and rare complement variants on the presentation and outcome of atypical hemolytic uremic syndrome. Haematologica 104(12):2501–2511. https://doi.org/10.3324/haematol.2019.216903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Schaefer F, Ardissino G, Ariceta G, Fakhouri F, Scully M, Isbel N, Lommelé Å, Kupelian V, Gasteyger C, Greenbaum LA, Johnson S, Ogawa M, Licht C, Vande Walle J, Frémeaux-Bacchi V (2018) Clinical and genetic predictors of atypical hemolytic uremic syndrome phenotype and outcome. Kidney Int 94(2):408–418. https://doi.org/10.1016/j.kint.2018.02.029

    Article  PubMed  Google Scholar 

  35. Fakhouri F, Frémeaux-Bacchi V (2021) Thrombotic microangiopathy in aHUS and beyond: clinical clues from complement genetics. Nat Rev Nephrol 17(8):543–553. https://doi.org/10.1038/s41581-021-00424-4

    Article  CAS  PubMed  Google Scholar 

  36. Zhang B, Xing C, Yu X, Sun B, Zhao X, Qian J (2008) Renal thrombotic microangiopathies induced by severe hypertension. Hypertens Res 31(3):479–483. https://doi.org/10.1291/hypres.31.479

    Article  PubMed  Google Scholar 

  37. Johnson W, Nguyen ML, Patel R (2012) Hypertension crisis in the emergency department. Cardiol Clin 30(4):533–543. https://doi.org/10.1016/j.ccl.2012.07.011

    Article  PubMed  Google Scholar 

  38. Rubin S, Cremer A, Boulestreau R, Rigothier C, Kuntz S, Gosse P (2019) Malignant hypertension: diagnosis, treatment and prognosis with experience from the Bordeaux cohort. J Hypertens 37(2):316–324. https://doi.org/10.1097/hjh.0000000000001913

    Article  CAS  PubMed  Google Scholar 

  39. Lane DA, Lip GY, Beevers DG (2009) Improving survival of malignant hypertension patients over 40 years. Am J Hypertens 22(11):1199–1204. https://doi.org/10.1038/ajh.2009.153

    Article  PubMed  Google Scholar 

  40. Polgreen LA, Suneja M, Tang F, Carter BL, Polgreen PM (2015) Increasing trend in admissions for malignant hypertension and hypertensive encephalopathy in the United States. Hypertension 65(5):1002–1007. https://doi.org/10.1161/hypertensionaha.115.05241

    Article  CAS  PubMed  Google Scholar 

  41. Shantsila A, Shantsila E, Beevers DG, Lip GYH (2017) Predictors of 5-year outcomes in malignant phase hypertension: the West Birmingham Malignant Hypertension Registry. J Hypertens 35(11):2310–2314. https://doi.org/10.1097/hjh.0000000000001446

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Richard Robins, PhD, and Susan Furness, PhD, from Liwen Bianji (Edanz) (www.liwenbianji.cn) for editing the English text of a draft of this manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81770671 and 82090021).

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Author notes

  1. Xuejing Chen and Xu Zhang have contributed equally to the work.

Authors and Affiliations

  1. Renal Division, Department of Medicine, Peking University First Hospital, No. 8 Xishiku St., Xicheng District, Beijing, 100034, China

    Xuejing Chen, Yu Wang & Minghui Zhao

  2. Institute of Nephrology, Peking University, Beijing, China

    Xuejing Chen, Yu Wang & Minghui Zhao

  3. Key Laboratory of Renal Disease, National Health and Family Planning Commission of the People’s Republic of China, Beijing, China

    Xuejing Chen, Yu Wang & Minghui Zhao

  4. Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, China

    Xuejing Chen, Yu Wang & Minghui Zhao

  5. Laboratory of Electron Microscopy, Pathological Centre, Peking University First Hospital, Beijing, China

    Xu Zhang & Suxia Wang

  6. Peking-Tsinghua Center for Life Sciences, Beijing, China

    Minghui Zhao

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  1. Xuejing Chen
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  2. Xu Zhang
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Contributions

YW conceived and designed research; XC collected and analyzed data, prepared figures and drafted manuscripts; XZ and SW reviewed kidney biopsy; MZ edited and revised manuscript; all authors approved final version.

Corresponding author

Correspondence to Yu Wang.

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This study adhered to the principles outlined in the Declaration of Helsinki for all human experimental investigations. Animal experiments were not involved and this study was approved by the Committee on Research Ethics of Peking University First Hospital (2017[1280]).

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Chen, X., Zhang, X., Wang, Y. et al. Genetic, clinical, and pathological study of patients with severe hypertension-associated renal microangiopathy. J Nephrol 36, 2477–2490 (2023). https://doi.org/10.1007/s40620-023-01644-6

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