Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis

Familial microscopic hematuria (FMH) is associated with a genetically heterogeneous group of conditions including the collagen-IV nephropathies, the heritable C3/CFHR5 nephropathy and the glomerulopathy with fibronectin deposits. The clinical course varies widely, ranging from isolated benign familial hematuria to end-stage renal disease (ESRD) later in life. We investigated 24 families using Next Generation Sequencing (NGS) for five genes: COL4A3, COL4A4, COL4A5, CFHR5 and FN1. In 17 families (71%), we found 15 pathogenic mutations in COL4A3/A4/A5, nine of them novel. In five families patients inherited classical AS with hemizygous X-linked COL4A5 mutations. Even more patients developed later-onset Alport-related nephropathy having inherited heterozygous COL4A3/A4 mutations that cause thin basement membranes. Amongst 62 heterozygous or hemizygous patients, eight (13%) reached ESRD, while 25% of patients with heterozygous COL4A3/A4 mutations, aged >50-yrs, reached ESRD. In conclusion, COL4A mutations comprise a frequent cause of FMH. Heterozygous COL4A3/A4 mutations predispose to renal function impairment, supporting that thin basement membrane nephropathy is not always benign. The molecular diagnosis is essential for differentiating the X-linked from the autosomal recessive and dominant inheritance. Finally, NGS technology is established as the gold standard for the diagnosis of FMH and associated collagen-IV glomerulopathies, frequently averting the need for invasive renal biopsies

Erythropoietic response to oral iron in patients with nondialysis-dependent chronic kidney disease in the FIND-CKD trial

Aims: To evaluate erythropoietic response rates to oral iron over time in iron-deficient anemic patients with nondialysis- dependent chronic kidney disease (NDCKD). Materials and methods: FIND-CKD was a 1-year, randomized, multicenter trial of iron therapy in patients with ND-CKD, anemia, and iron deficiency, without erythropoiesis- stimulating agent (ESA) therapy. Patients with active infection or C-reactive protein > 20 mg/L were excluded. In this post-hoc analysis, response was defined as 65 1 g/dL increase in hemoglobin (Hb) from baseline, before initiation of alternative anemia therapy (i.e., ESA, transfusion, or intravenous iron). Results: 308 patients received oral iron (200 mg elemental iron/day). Mean (SD) Hb at baseline was 10.4 (0.7) g/dL. At week 4, Hb data were available from 292 patients without alternative anemia therapy: 63/292 (21.6%) showed a response. Among the 229 nonresponders at week 4, 48.8% showed a cumulative response on 651 occasion by week 52 (11.1%, 19.9%, 25.9%, and 28.7% had a response at weeks 8, 12, 24, and 52, respectively), and 27.9% had received alternative iron therapy by week 52. Baseline levels of Hb, ferritin, and transferrin saturation were lower in responders than in nonresponders. Neither concomitant medication nor adherence (as assessed by medication count) was substantially different between early responders and nonresponders. Conclusion: Four weeks after starting oral iron therapy, only 21.6% of anemic patients with ND-CKD and iron deficiency showed an Hb increase of at least 1 g/dL. Among early nonresponders, < 30% responded at any subsequent time point. Earlier consideration of alternative therapy could improve anemia management in this population