No abstract

Membranoproliferative GN (MPGN) was recently reclassified as alternative pathway complement-mediated C3 glomerulopathy (C3G) and immune complex-mediated membranoproliferative GN (IC-MPGN). However, genetic and acquired alternative pathway abnormalities are also observed in IC-MPGN. Here, we explored the presence of distinct disease entities characterized by specific pathophysiologic mechanisms. We performed unsupervised hierarchical clustering, a data-driven statistical approach, on histologic, genetic, and clinical data and data regarding serum/plasma complement parameters from 173 patients with C3G/IC-MPGN. This approach divided patients into four clusters, indicating the existence of four different pathogenetic patterns. Specifically, this analysis separated patients with fluid-phase complement activation (clusters 1-3) who had low serum C3 levels and a high prevalence of genetic and acquired alternative pathway abnormalities from patients with solid-phase complement activation (cluster 4) who had normal or mildly altered serum C3, late disease onset, and poor renal survival. In patients with fluid-phase complement activation, those in clusters 1 and 2 had massive activation of the alternative pathway, including activation of the terminal pathway, and the highest prevalence of subendothelial deposits, but those in cluster 2 had additional activation of the classic pathway and the highest prevalence of nephrotic syndrome at disease onset. Patients in cluster 3 had prevalent activation of C3 convertase and highly electron-dense intramembranous deposits. In addition, we provide a simple algorithm to assign patients with C3G/IC-MPGN to specific clusters. These distinct clusters may facilitate clarification of disease etiology, improve risk assessment for ESRD, and pave the way for personalized treatment.

Since the discovery that the enzyme catalyzing the synthesis of the most active natural vitamin D metabolite(calcitriol) and the vitamin D-specific receptor (VDR)were expressed in a wide range of tissues and organs, not only involved in the mineral metabolism (MM), there has been increasing interest on the putative ‘non classical’ roles of vitamin D metabolites, particularly on their possible effects on the cardiovascular (CV) system. These hypothetical CV effects of vitamin D gained particular interesting the nephrology field, given the high prevalence of CV disease in patients affected by either acute or chronic kidney diseases. However, notwithstanding a huge amount of experimental data suggesting a possible protective role of vitamin D on the CV system, the conclusions of two recent meta-analyses from the Cochrane group and a recent statement from the Institute of Medicine, based on a complete revision of the available data, concluded that there is no clear evidence for a role of vitamin D other than that strictly associated with bone health. However, a continuous and increasing flow of new studies still continues to add information on this topic. In the present review, we have tried to critically address the data added on this topicin the last 2 years, considering separately the experimental,observational, and intervention studies that have appeared in PubMed in the last 2 years, discussing the data providing proof, pro or contra, the involvement of vitamin D in CV disease, both in the absence or presence of kidney function impairment.