C3 Glomerulopathy and Thrombotic Microangiopathy: A “Hybrid” Phenotype

C3 glomerulopathy (C3G) with morphologic features of thrombotic microangiopathy (TMA) has recently been acknowledged; the phenotype resembles either C3G or TMA.1Ravindran A. Pereira Palma L.M. Fervenza F.C. Sethi S. Overlap of C3 glomerulopathy and thrombotic microangiopathy: a case series.Kidney Int Rep. Forthcoming. 2022; https://doi.org/10.1016/j.ekir.2022.12.009Abstract Full Text Full Text PDF Scopus (1) Google Scholar Here, we studied kidney biopsies from 73 consecutive patients with TMA who had been included in the Limburg Renal Registry for morphologic features of C3G; 1 of 73 patients (1%) with TMA presented with coexisting C3G. The patient, a 73-year-old woman with no relevant medical history, presented with mild hypertension, generalized edema, acute kidney injury (creatinine, 166 μmol/l), nephrotic-range proteinuria, and glomerular hematuria. Nonhemolytic normocytic anemia was present, with platelet count at 311,000/μl. Kidney biopsy showed a diffuse endocapillary proliferative glomerulonephritis, with mesangiolysis and segmental double contours (Figure 1a), and arteriolar thrombosis. C3c deposits, but no other immunoreactants, were found along segments of the glomerular basement membrane (Figure 1b). Marked widening of the glomerular basement membrane due to electron lucent fluff was present; electron-dense deposits were found along segments of the glomerular basement membrane (Figure 1c). Therefore, C3G with morphologic features of TMA was diagnosed. The autoimmune workup, including factor H autoantibodies and C3 nephritic factor, was unremarkable; C4 and C3 were 0.08 g/l (LLN, 0.10 g/l) and 0.51 g/l (LLN, 0.90 g/l), respectively. No monoclonal protein was detected. The patient was treated with prednisolone and mycophenolate mofetil (1000 mg BID). After 1 month, she presented with altered mental status, worsening kidney function (creatinine, 348 μmol/l), Coombs negative microangiopathic hemolytic anemia, and platelet count at 91,000/μl. ADAMTS13’s enzymatic activity was 61%, and secondary etiologies2Timmermans S. Damoiseaux J. Werion A. et al.Functional and genetic landscape of complement dysregulation along the spectrum of thrombotic microangiopathy and its potential implications on clinical outcomes.Kidney Int Rep. 2021; 6: 1099-1109https://doi.org/10.1016/j.ekir.2021.01.034Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar,3Timmermans S. van Paassen P. The syndromes of thrombotic microangiopathy: a critical appraisal on complement dysregulation.J Clin Med. 2021; 10: 3034https://doi.org/10.3390/jcm10143034Crossref PubMed Scopus (12) Google Scholar were excluded. Rare variants in complement genes (i.e., CFH, CFI, CD46, CFB, C3, CFHR1-5, C2, and CFP) were not found, but the patient carried the MCPggaac at-risk haplotype. Mycophenolate mofetil was switched to cyclophosphamide IV (500 mg fortnightly) and add-on eculizumab for 3 months, followed by azathioprine (150 mg OD). A hematologic remission and partial kidney remission were achieved within 1 and 4 weeks, respectively. The patient’s kidney function improved (creatinine, 124 μmol/l; estimated glomerular filtration rate, 37.0 ml/min per 1.73 m2), with proteinuria <1 g/d, during the 6-month follow-up period. Altogether, we demonstrate the “hybrid” phenotype of a patient with C3G with morphologic features of TMA. Therefore, patients should be monitored for complications of both diseases and treated accordingly. M. Christiaans, E. Duijnhoven, T. Fung, M. Gelens, M. Hemmelder, J. Kooman, E. Litjens, and F. van der Sande (Maastricht University Medical Center); S. Boorsma, J. Huitema, B. Sars, and J. Wirtz (Laurentius Hospital); L. Frenken, S. Gaertner, F. de Heer, M. Krekels, F. Stifft, N. Ter Braak, G. Verseput, and L. Vossen (Zuyderland Medical Center).