Clinical Kidney Journal, 2021, vol. 14, no. 2, 707–709 doi: 10.1093/ckj/sfaa004 Advance Access Publication Date: 17 March 2020 Exceptional Case EXCEPTIONAL CASE Low factor H-related 5 levels contribute to infection-triggered haemolytic uraemic syndrome and membranoproliferative glomerulonephritis Irene Gómez Delgado1, Josué Gutiérrez-Tenorio2, Gloria M. Fraga Rodrı́guez3, Teresa Cavero4, Emilia Arjona5,6 and Pilar Sánchez-Corral 1,6 1 Complement Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain, 2Department of Immunology, Complutense University and Research Institute Hospital 12 de Octubre, Complutense University of Madrid, Madrid, Spain, 3Department of Paediatric Nephrology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain, 4 Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain, 5Department of Molecular Biomedicine, Centre for Biological Research, Madrid, Spain and 6Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain Correspondence to: Pilar Sánchez-Corral; E-mail: pilar.sanchez-corral@idipaz.es ABSTRACT Dysregulation of the alternative complement pathway is a major pathogenic mechanism in two rare renal diseases: atypical haemolytic uraemic syndrome (aHUS) and membranoproliferative glomerulonephritis (MPGN). We report on a 66-year-old male with chronic hepatitis C virus (HCV) infection and a combined liver–kidney transplant that was diagnosed with MPGN at the age of 63 years and a 5-year-old boy who presented with aHUS at the age of 21 months following a Streptococcus pneumoniae infection. Both patients carried similar frameshift variants in the complement CFHR5 gene that segregate with reduced levels of factor H–related 5 (FHR-5). We conclude that low FHR-5 levels may predispose to viral and bacterial infections that then trigger different renal phenotypes. Keywords: CFHR5, complement, HCV, HUS, MPGN, Streptococcus, pneumoniae BACKGROUND CASE REPORTS Pathogenic variants in complement genes that cause dysregula- Patient GN172 tion of the alternative complement pathway are associated In 1997, a 45-year-old male with cirrhosis secondary to chronic hep- with several renal diseases. We describe two patients carrying atitis C virus (HCV) infection received his first orthotopic liver trans- similar frameshift variants in complement CFHR5 who devel- plantation (OLT). In 2002 he presented with acute renal failure, mild oped haemolytic uraemic syndrome (HUS) or membranoproli- proteinuria and microhaematuria. A renal biopsy was contraindi- ferative glomerulonephritis (MPGN). cated because of thrombocytopaenia and coagulopathy and the Received: 5.6.2019; Editorial decision: 31.12.2019 C The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 707 708 | I. Gómez Delgado et al. FIGURE 1: Genetic variants and protein levels in patients GN172 and HUS619. (A) Two genetic variants in CFHR5 exon 4 (c.486_487insA; p.Glu163Argfs*35) and CFHR5 exon 5 (c.622T>C; p.Cys208Arg) that segregated in the same allele were observed in patient GN172 and his two brothers, but in none of his children. Carriers of the dou- ble-mutated CFHR5 allele have lower FHR-5 levels, as determined by Western blot and enzyme-linked immunosorbent assay. FHR-5 levels in the patient GN172 are higher than in his two brothers because he has a liver transplant. (B) Patient HUS619, who developed HUS in the context of an Streptococcus pneumoniae infection, has a similar variant in the CFHR5 exon 4 (c.486_487insAA; p.Glu163Lysfs*10) that was inherited from his father, and that determines lower FHR-5 levels. Patients GN172 and HUS619 did not present mutations in the CFH, CFI, MCP, C3,CFB, CFHR1-4, THBD or DGKE genes. patient was started on haemodialysis. In 2003 he required a second activation of the alternative complement pathway. Two heterozy- OLT but the transplant failed acutely because of an arterial thrombo- gous changes in the CFHR5 gene determining low plasma factor H– sis. Subsequently the patient received his third OLT and his first kid- related 5 (FHR-5) levels were detected (Figure 1A). After a second kid- ney transplant. The patient progressed satisfactorily while receiving ney transplant in 2017 with pre-emptive eculizumab for 6 months, tacrolimus and prednisone. A further HCV recurrence on the liver the patient has remained stable while receiving the standard immu- graft was treated successfully with ribavirin and interferon. In 2015 nosupression and there have been no signs of disease recurrence. the patient presented with oedema and hypertension. Laboratory tests revealed acute renal failure, hypoalbuminaemia, nephrotic pro- Patient HUS619 teinuria and microhaematuria. Anti-nuclear antibody, anti-neutro- A 21-month-old boy not vaccinated against pneumococcus pre- phil cytoplasmic antibodies, anti-DNA, anti-glomerular basement sented with pneumonia complicated by pleural empyaema, and membrane, anti–human leucocyte antigen antibodies, cryoglobulins antibiotic treatment was started (Supplementary data, Figure and HCV viraemia were all negative. A renal biopsy showed thicken- S2). Polymerase chain reaction was positive for influenza B vi- ing of the capillary walls and mesangial matrix proliferation, with rus. Two days later he needed to be intubated and required me- immunoglobulins, light chains and complement deposits suggesting chanical ventilation; infusions of red blood cells, platelets and immune complex–mediatedMPGN (Supplementary data, Figure S1). plasma, as well as vasoactive amines and continuous veno- Despite 6-methylprednisone and rituximab treatment, the patient fi- venous haemofiltration (CVVH) were also necessary. Analytical nally required dialysis. C3 nephritic factor and anti-factor H antibod- data were haemoglobin 6.4 g/dL, platelets 30 000/mL, ADAMTS13 ies were negative, but low C3 with normal C4 levels suggested 54%, schistocytes 9%, haptoglobin <0.06 g/L, creatinine FHR-5 deficiency and renal pathology | 709 119 mmol/L, estimated glomerular filtration rate 30 mL/min/ ACKNOWLEDGEMENTS 1.73 m2, cystatin C 1.62 mg/L, lactic dehydrogenase 4290 UI/L, di- We appreciate the technical assistance of César Vélez rect Coombs test negative, erythrocyte poly-agglutination T test positive, CH50 <16.47 UI/mL, C3 46.4 mg/dL and C4 10.80 mg/dL. Casanova in the management of biological samples of Serum analyses for cytomegalovirus, Epstein–Barr virus, patients and controls. We also thank Dr Sonia Brio human herpes virus type 6, hepatitis B virus, HCV, human im- Sanagustin and Dr Marina Alonso for providing clinical data munodeficiency virus types 1 and 2, blood culture and entero- and Dr Elena Goicoechea de Jorge for helpful suggestions haemorraghic Escherichia coli were negative, but pneumococcal and critical reading of the manuscript. antigen was detected in urine and pleural fluid and the patient was diagnosed with S. pneumoniae HUS (SP-HUS). Urinalysis FUNDING showed microhaematuria and proteinuria (29.20 g/L, protein/ creatinine 33450 mg/mmol) and renal ultrasound revealed in- This study was funded by the Spanish ‘Instituto de Salud creased bilateral echogenicity. The patient became hyperten- Carlos III’ (ISCIII) and the European Regional Development sive and needed CVVH for 13 days. On Day 30, a blood sample Fund from the European Union (grant PI16/00723 to P.S.-C.). was drawn for genetic studies. A variant in the CFHR5 gene was I.G.D. is supported by the Autonomous Region of Madrid found to be heterozygous and shown to determine low FHR-5 (Complement II-CM network; B2017/BMD-3673) and by the levels (Figure 1B). The patient progressed well and was dis- Spanish Fundación Senefro (http://www.senefro.org/). J.G.- charged on Day 52, remaining stable 3 years later. T. is supported by the Spanish ‘Ministerio de Economı́a y Competitividad’ (SAF2014-52339P, BES-2015-073833). E.A. is supported by the Autonomous Region of Madrid DISCUSSION (Complement II-CM network; B2017/BMD-3673). Genetic and/or acquired factors that result in dysregulation of the alternative complement pathway are present in many atyp- ical haemolytic uraemic syndrome (aHUS) and immune com- AUTHORS’ CONTRIBUTIONS plex–mediated membranoproliferative glomerulonephritis I.G.D. performed genetic studies and Western blot analyses (IC-MPGN) patients. A role for complement in the pathogenesis and prepared figures. J.G.-T. carried out Western blot and en- of HUS occurring after SP-HUS has been previously suggested zyme-linked immunosorbent assay studies. G.M.F.R. and T.C. [1], but only a few paediatric Streptococcus pneumoniae–associated gathered and described clinical data and prepared figures. E.A. HUS (SP-HUS) cases having complement genetic variants have collected biological samples and searched the Spanish aHUS/ been reported [2]. We describe a paediatric SP-HUS patient who C3G database (www.ahusc3g.es). P.S.-C. designed the study, had not been vaccinated against pneumococcus and an adult prepared figures and wrote the first draft of the manuscript. patient with chronic HCV infection status who developed IC- All the authors revised the data and contributed to the final MPGN after liver–kidney transplant. The two patients presented version of the manuscript. with similar variants in the complement CFHR5 gene that gener- ate premature stop codons and result in reduced plasma levels of FHR-5. The CFHR5 variant present in patient GN172 had been CONFLICT OF INTEREST STATEMENT previously observed in a post-streptococcal MPGN case and sug- None declared. P.S.-C. and G.M.F.R. have received speaking gested a predisposition to chronic kidney disease [3]. fees from Alexion Pharmaceuticals. FHR-5 is a 65-kDa plasma protein that may locally enhance The results presented in this article have not been pub- complement activation by different mechanisms, including lished previously in whole or part, except in abstract format binding to the extracellular matrix and to the acute phase pro- (Abstracts from the 27th International Complement tein pentraxin 3 [4]. Abnormal FHR-5 proteins that increase Workshop. Mol Immunol 2018; 102: 155). complement activation have been described in familial cases of C3 glomerulopathies, as initially reported in a large Cypriot ped- igree [5]. 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