Clinicopathological Spectrum and Treatment Outcomes of Cryofibrinogen-Associated Nephropathies.

Introduction: Cryofibrinogen-associated nephropathy (CFN) is a very rare disease. Only few data are available about the clinicopathological presentation and treatment outcomes. Methods: Patients with cryofibrinogenemia (CF) diagnosed in French expert laboratories, and kidney biopsy findings suggestive of CFN (pauci-immune membranoproliferative glomerulonephritis [MPGN], thrombotic microangiopathy [TMA] and/or indirect signs of ischemia) were retrospectively included. Estimated glomerular filtration rate (eGFR), urinary protein-to-creatinine ratio (UPCR), and specific treatments were collected. Renal response (RR) was defined as a reduction of UPCR to < 0.5 g/g (or decrease > 50% if > 3 g/g at baseline) and an improvement of eGFR > 30% (if < 60 ml/min per 1.73 m2 and acute kidney injury (AKI) at baseline). Results: Among 2545 patients with CF, 232 (9%) underwent kidney biopsy, and only 28 (1%) had histological findings suggestive of CFN. Ten patients (36%) were female, and median age was 62 (interquartile range [IQR]: 49-71) years. eGFR at diagnosis was 21 (14-44) ml/min per 1.73 m2. Median UPCR was 3.30 (IQR: 1.52-4.85) g/g. AKI (78%) and nephrotic syndrome (41%) were frequent. Nine patients had an essential form, whereas 19 had a secondary form. MPGN was the most frequent pattern, with double contours (57%), nodular mesangial sclerosis (30%), mesangial (41%), endocapillary (56%) and extracapillary (11%) hypercellularity, and interstitial immune infiltration (41%). Thrombi were found in 43% of cases. Strikingly, 58% of the secondary forms were associated with a monoclonal gammopathy (MG). Patients with MG had more frequent skin manifestations (P = 0.002), endocapillary (P = 0.002), interstitial (P = 0.041) infiltration, and capillary thrombi (P = 0.012), and tended to have more frequent complement activation (P = 0.14). Sixty percent of patients were treated with various regimens of immunosuppressants (IS). After a mean follow-up of 476 (± 92) days, 65% of patients had an RR. Higher baseline eGFR (P = 0.04) and use of IS (P = 0.03) were predictive of RR. B-cell or plasma-cell depletion was effective in most cases associated with MG (80%). Conclusion: Our study, to the best of our knowledge, described for the first time the prevalence and the clinicopathological spectrum of CFN, which might be a very rare and underrecognized form of MG of renal significance presenting with pauci-immune MPGN ot TMA. IS are effective in most cases.