In This Issue

in t hi s i s s u e

http://www.kidney-international.org © 2015 International Society of Nephrology Kidney International (2015) 88, 927. doi:10.1038/ki.2015.330

Highest cardiovascular risk occurs early after dialysis initiation Patients with end-stage renal disease have the highest risk of mortality soon after initiating hemodialysis (HD), but the causes of early mortality are not well understood. Eckardt and colleagues analyzed data from incident HD patients from more than 300 European dialysis centers to determine the incidence of cardiovascular events (CVEs) and their components (coronary artery, cerebrovascular, peripheral arterial, congestive heart failure, and sudden cardiac death) during the first 2 years after starting HD. The rate of CVEs during the first year on HD was 30.2 per 100 personyears and declined to 19.4 per 100 personyears during the second year. Rates for all CVE components except sudden cardiac death were highest during the first week of HD and remained elevated through the first 4 months on HD. Factors associated with increased CVEs during the high-risk period included higher or lower weekly dialysis dose, lower blood flow, and lower net ultrafiltration. These important data provide clinicians with valuable information regarding increased risk of CVEs after initiation of HD. See page 1117

Efficacy of mycophenolate mofetil in C3 glomerulonephritis C3 glomerulonephritis (C3GN) is a recently characterized disease defined by the presence of isolated or dominant C3 deposits as detected by immunofluorescence, and the optimal approach to treatment of C3GN remains poorly defined. In this issue, Rabasco et al. report clinical outcomes in 60 patients with C3GN who were followed for a median of 47 months. Twenty patients had not received immunosuppressive treatments. Of the remaining 40 patients, 22 had been treated with corticosteroids plus mycophenolate Kidney International (2015) 88

mofetil (MMF), and 18 were treated with corticosteroids with or without cyclophosphamide. No patients received eculizumab. Renal survival at 5 years and the proportion of patients achieving clinical remission were superior in patients treated with corticosteroids plus MMF as compared with patients treated with other immunosuppressive regimens and untreated patients. This study strongly suggests that immunosuppression, especially with regimens including MMF plus corticosteroids, can improve the prognosis of patients with C3GN. See page 1153

and tumor necrosis factor-a (TNF-a) expression in macrophages, and 25(OH) D3 and TNF-a together increased oxidative stress in tubular cells. These fascinating data provide novel insights into the mechanisms by which excessive 25(OH) D may promote renal injury and fibrosis. See page 1013

Role of intrarenal MPO in ANCA glomerulonephritis

25-OH-Vitamin D promotes macrophage-mediated kidney injury

There is a rapidly expanding literature describing the immunomodulatory effects of 25-OH-vitamin D (25(OH)D). Though most of these studies suggest a beneficial effect of 25(OH)D repletion, excessive treatment may have negative effects. Kusunoki and co-workers studied the effects of excessive 25(OH)D3 on the kidney using 25(OH)D-1a-hydroxylase (CYP27B1) knockout mice, which are unable to convert 25(OH)D3 to 1,25(OH) D3. Excessive doses of 25(OH)D3 worsened renal fibrosis and oxidative stress in mice subjected to unilateral ureteral obstruction, but moderate doses had no effect. These effects were reversed when vitamin D receptor knockout and macrophage-depleted CYP27B1–/– mice were used. Interestingly, excess 25(OH)D3 increased transforming growth factor-b



Myeloperoxidase (MPO) is one of two major autoantigens targeted by anti-neutrophil cytoplasmic antibodies (ANCAs) in patients with ANCA-associated vasculitis (AAV). MPO is not normally present in renal tissue but can be released by neutrophils accumulating in glomeruli after binding to ANCAs. O’Sullivan and co-workers examined MPO deposition in kidney biopsies from 47 patients with MPO-AAV. MPO was not detected in non-inflammatory glomerular diseases but was prominent in glomerular, periglomerular, and tubulointerstitial regions in MPO-AAV biopsies. Neutrophils were the major source of extracellular MPO, which was present in extracellular traps in glomeruli. Glomerular MPO-containing macrophages were also associated with extracellular trap-like structures, and MPO localized to endothelial cells and podocytes. The severity of glomerular lesions correlated with intraglomerular CD4+ cells and MPO+ macrophages. These novel and exciting results suggest that cellular and extracellular MPO contributes to the pathogenesis of MPOAAV. See page 1030 927