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A comprehensive supportive therapy approach constitutes the mainstay treatment of IgA nephropathy (IgAN) patients. In our recent Supportive versus immunosuppressive Therapy Of Progressive IgA Nephropathy (STOP-IgAN) trial, we systematically selected for patients at high risk of a progressive disease course and evaluated the effect of immunosuppression, combined with supportive care, on renal end points in these patients. There was a higher rate of full clinical remission and transient proteinuria reduction in immunosuppressed patients. However, deterioration of renal function (i.e. number of patients with an estimated glomerular filtration rate (eGFR) decrease of at least 15 mL/min over the 3-year trial phase) was remarkably slow in both groups, compared with previous studies, and was not slowed further by adding immunosuppression to supportive care. Here, we address several concerns raised on the design and interpretation of our trial. In our randomized patients, we confirmed a lower baseline proteinuria to be predictive of clinical remission in IgAN. However, the observed transient drop in proteinuria in the immunosuppressed patients did not translate into an improved overall renal outcome in these patients. Although longer follow-up would be desirable, there was not even a trend for the eGFR course to diverge between our two treatment arms during the trial phase. Finally, it is important to note that we excluded specific infrequent patient groups during our run-in phase. Therefore, IgAN patients with a rapidly progressing course and those with persistent proteinuria >3.5 g/day would require further evaluation regarding potential benefits of immunosuppressive therapies., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Platelet-derived growth factors (PDGF)-AA and -CC mediate renal fibroblast proliferation and/or renal fibrosis. Whereas PDGF-CC binds to both the PDGF receptors (PDGFRs)-αα- and -αβ, PDGF-AA binds more selectively to the αα-receptor, suggesting potential differences in the biological activities., Methods: We compared signal transduction, gene expression as well as changes in the proteome induced by PDGF-AA and -CC in rat renal fibroblasts, which express both PDGFR subunits. The growth factor concentrations used were chosen based on their equipotency in inducing rat renal fibroblast proliferation., Results: Both PDGF-AA and PDGF-CC induced phosphorylation and activation of extracellular signal-regulated kinase 1 (ERK1) and ERK2. Renal fibroblast proliferation induced by either PDGF-AA or -CC could be blocked by signal transduction inhibitors of the mitogen-activated protein kinase (MAPK)-, Janus-kinase (JAK)/signal transducers and activators of transcription (STAT) and phosphatidyl-inositol-3-kinase (PI3K) pathway, pointing to the involvement of all the three pathways. However, quantitative differences between both the stimulations were minor. Additive or synergistic effects by stimulating simultaneously with PDGF-AA and -CC were not observed. Using a proteomic approach we found eleven differentially expressed proteins, which were quantitatively altered after treatment with either PDGF-AA or PDGF-CC. The regulation of calreticulin and inorganic pyrophosphatase 1 could be verified by western blotting., Conclusions: PDGF-AA and -CC exhibit almost identical biological effects on signal transduction and proteome in cultured renal fibroblasts, suggesting that the ligands exert their activity essentially through the commonly bound PDGFR-αα. Nonetheless, two differentially expressed proteins were identified which might be involved in the development of renal failure.

Background: Chronic kidney disease (CKD) is increasingly recognized as a global health problem. The conditions leading to CKD, the health impact of CKD and the prognosis differ markedly between affected individuals. In particular, renal failure and cardiovascular mortality are competing risks for CKD patients. Opportunities for targeted intervention are very limited so far and require an improved understanding of the natural course of CKD, of the risk factors associated with various clinical end points and co-morbidities as well as of the underlying pathogenic mechanisms., Methods: The German Chronic Kidney Disease (GCKD) study is a prospective observational national cohort study. It aims to enrol a total of 5000 patients with CKD of various aetiologies, who are under nephrological care, and to follow them for up to 10 years. At the time of enrolment, male and female patients have an estimated glomerular filtration rate (eGFR) of 30-60 mL/min×1.73 m2 or overt proteinuria in the presence of an eGFR>60 mL/min×1.73 m2. Standardized collection of biomaterials, including DNA, serum, plasma and urine will allow identification and validation of biomarkers associated with CKD, CKD progression and related complications using hypothesis-driven and hypothesis-free approaches. Patient recruitment and follow-up is organized through a network of academic nephrology centres collaborating with practising nephrologists throughout the country., Conclusions: The GCKD study will establish one of the largest cohorts to date of CKD patients not requiring renal replacement therapy. Similarities in its design with other observational CKD studies, including cohorts that have already been established in the USA and Japan, will allow comparative and joint analyses to identify important ethnic and geographic differences and to enhance opportunities for identification of relevant risk factors and markers.

Background: Haemodialysis patients are at high risk for developing healthcare-associated infections as well as acquiring multidrug-resistant microorganisms. Hand hygiene is considered to be the single most effective tool to prevent healthcare-associated infections. The number of indications and the extent of indication-specific compliance with hand rubs in the haemodialysis setting are currently unknown., Methods: We conducted a prospective, three-phase, observational intervention study on hand hygiene during haemodialysis treatments. Optimized hand hygiene standard operating procedures (SOPs) for dialysis connections (Intervention I) and disconnections (Intervention II) were compiled and implemented during two predefined intervention periods., Results: A total of 8897 indications for hand rubs were observed throughout this study. In the course of the study, we identified an increase in the number of hand rubs performed (6-9, mean number per dialysis procedure), parallelled by a decrease in the indications for hand rubs (21-15), resulting in a significant increase of overall hand rub compliance (30-62%). The greatest improvement was seen before aseptic tasks (21-52%), the indication with the greatest impact on preventing healthcare-associated infections. There was no difference between haemodialysis via central venous catheter access or arterio-venous (AV) fistulas., Conclusions: This study provides the first detailed data on the number of and indications for hand rubs during dialysis. An >100% increase in overall hand hygiene compliance could be achieved by a comparably moderate increase in hand rubs performed in combination with optimized hand hygiene SOPs.

Background: Renoprotective actions of angiotensin receptor blockers are not well established in normotensive, low-grade proteinuric glomerular diseases. We examined the effect of low-dose telmisartan (LT) and high-dose telmisartan (HT) versus conventional antihypertensive therapy in the rat anti-Thy1.1 model of glomerulonephritis., Methods: Rats were randomized on Day 4 after disease induction to no treatment (CT, control), LT or HT or hydrochlorothiazide + hydralazine (HCT + H)., Results: All rats remained normotensive: HT and HCT + H reduced blood pressure by 15-20%. LT, HT and HCT + H reduced glomerular endothelial cell proliferation and glomerular and interstitial matrix deposition on Day 14. Only HT reduced podocyte damage and tubular cell dedifferentiation on Day 9 and mesangial cell activation on Day 14. By gene expression analysis arrays, we identified discs-large homolog 1 and angiopoietin-like 4 as potential mediators of the HT effects. In addition, we identified several pathways possibly related to the pleiotropic effects of HT, including growth factor signalling, mammalian target of rapamycin signalling, protein ubiquitination, the Wnt-beta catenin pathway and hypoxia signaling., Conclusions: In summary, treatment with HT, initiated after the induction of disease, ameliorates glomerular and tubulointerstitial damage. We provide the first comprehensive insight into the mechanisms underlying the renoprotective effect of high-dose angiotensin II receptor blockers (ARBs). Our study lays the basis for future investigations on novel pathways affected by ARBs in renal disease.

Background: Pneumocystis jiroveci pneumonia (PcP) is a potentially life-threatening complication in renal transplant recipients with increased reports during the past few years. Individual risk factors for susceptibility to PcP are incompletely understood., Methods: We retrospectively analysed 60 cases of confirmed PcP, diagnosed in six German transplant centres between 2004 and 2008, as well as 60 matched controls., Results: Compared with controls, PcP cases revealed the following significant differences: PcP cases had a poorer renal function (eGFR 31 vs. 42 mL/min in controls), more biopsy-proven rejections (18 vs. 5 patients), more frequent treatment with mycophenolate mofetil (53 vs. 44 patients) and less frequent treatment with interleukin-2 receptor antagonist (20 vs. 32 patients). According to centre policy, in those years, none of the patients or controls had received PcP prophylaxis after transplantation. Of the 60 patients with PcP, 30% developed the disease after the currently recommended duration of prophylactic treatment, 27% died in the course of the disease and 45% required treatment in the ICU., Conclusions: Our case-control study reveals a novel risk profile for PcP. Renal transplant recipients with more pronounced renal insufficiency following rejection episodes and treated with intensified immunosuppression are at particular risk for PcP.

Background: Platelet-derived growth factor (PDGF) is a central mediator of mesangioproliferative glomerulonephritis (GN). In experimental mesangioproliferative GN, PDGF-DD serum levels, unlike PDGF-BB, increased up to 1000-fold., Methods: We assessed disease activity in 72 patients with GN, established a novel PDGF-D ELISA and then determined their PDGF-DD levels. In parallel, we studied renal PDGF-DD mRNA expression by RT-PCR., Results: PDGF-DD serum levels in patients with IgA nephropathy (IgAN) were significantly higher (1.67 +/- 0.45 ng/ml) and in patients with lupus nephritis significantly lower (0.66 +/- 0.86 ng/ml) compared to healthy controls (1.17 +/- 0.46 ng/ml), while patients with focal segmental glomerulosclerosis, membranous GN and ANCA-positive vasculitis did not differ from controls. The subgroup of IgAN patients with elevated PDGF-DD levels (27% of samples) did not differ in their clinical features from those with normal PDGF-DD levels. In IgAN patients with repetitive PDGF-DD determinations, most exhibited only minor fluctuations of serum levels over time. Intrarenal PDGF-DD mRNA expression did not differ between controls and patients, suggesting an extrarenal source of the elevated PDGF-DD in IgAN., Conclusions: Serum PDGF-DD levels were specifically elevated in patients with IgAN, in particular in those with early disease, i.e. preserved renal function. Our data support the rationale for anti-PDGF-DD therapy in mesangioproliferative GN.

Background: Altered IgA1 galactosylation is involved in the pathogenesis of IgA nephropathy (IgAN). The galactosyltransferase core-1 beta3-galactosyltransferase-1 (C1GALT1) and its chaperone cosmc are specifically required for O-galactosylation of the IgA1 hinge region. Mutations in the cosmc gene result in a secondary loss of function of C1GALT1 with subsequent undergalactosylation of glycoproteins. Mosaic mutations of cosmc have been shown to result in autoimmune disease. We hypothesized that cosmc mutations might contribute to the altered IgA1 galactosylation in IgAN patients., Methods: We studied cosmc gene sequences in genomic DNA obtained from male patients with biopsy-proven sporadic (n = 33) and familial IgAN (n = 6 patients from different families). To account for a potential mosaicism we sequenced cosmc in 10 different peripheral blood mononuclear cell DNA clones of every patient. To specifically assess potential mosaic mutations in IgA-producing cells, cosmc mutations were also analysed in DNA isolated from CD20+ B-lymphocytes from three male IgAN patients., Results: Despite our extensive genomic analysis, the data revealed no functionally relevant cosmc gene variants in sporadic or familial IgAN cases. A cosmc gene polymorphism, rs17261572, was identified in these IgAN patients in a similar frequency as previously reported in healthy adults. A functional consequence of this polymorphism has not yet been determined., Conclusion: Although decreased C1GALT1 activity has been implicated in the IgAN pathogenesis and cosmc chaperone mutations can cause autoimmune disease, our data provide no evidence for a relevant role of cosmc gene mutations in European patients with sporadic or familial IgAN.