Histologic Features Associated with Kidney Survival in Scleroderma Renal Crisis

Key Points Kidney pathology in scleroderma renal crisis was heterogeneous, with three histologic patterns of kidney injury identified by hierarchical cluster analysis. Creatinine, acute arteriolar thrombotic microangiopathy, and onion skinning in small arteries were associated with a higher risk of kidney failure. Complement system was activated in these injured vessels. Background Scleroderma renal crisis (SRC) is a severe complication of systemic sclerosis that is associated with higher morbidity and mortality. However, limited data are currently available regarding the factors affecting kidney outcome during SRC. The objective of this study was to describe kidney histopathology in SRC and to evaluate its association with kidney failure. Methods We performed a French multicenter retrospective study that included 65 patients who underwent a kidney biopsy in the context of SRC between 2006 and 2020. Nonsupervised hierarchical cluster analysis was used to identify histologic patterns. Cox model was performed to estimate the hazard ratios associated with histologic parameters for kidney failure, defined as the need for long-term dialysis therapy or eGFR <15 ml/min per 1.73 m 2 at the last follow-up. Multiplexed sequential immunofluorescence and proximity ligation assay was used in kidney biopsies to analyze complement system activation. Results Kidney pathology in SRC was more heterogeneous than expected, with three histologic patterns of kidney injury identified by cluster analysis. Multivariable analysis showed that together with creatinine at presentation, acute arteriolar thrombotic microangiopathy and onion skinning in small arteries were independently associated with the risk of kidney failure. Multiplex immunofluorescence identified fractions from the complement classical pathway in arterioles and arteries in SRC, while proximity ligation experiments confirmed the in situ activation of classical pathway C3 convertase. Complement terminal pathway fraction C5b-9 was localized in injured arteries. Conclusions This study shows that the clinical definition of SRC encompasses heterogeneity in the patterns of kidney injury. Acute arteriolar thrombotic microangiopathy and onion skinning were associated with kidney failure. Complement system was activated in these injured vessels.