Recurrence of primary membranous nephropathy after transplantation occurs in up to 44% of patients and is driven by PLA2R antibody. Here, we asked whether genetic determinants could improve risk prediction. First, we sequenced PLA2R1 and HLA-D loci in 248 patients with primary membranous nephropathy and identified two independent single nucleotide polymorphisms (SNPs) at risk for primary membranous nephropathy at each locus. These were rs9271188 (intergenic between HLA-DRB1 and HLA-DQA1,) and rs9275086 (intergenic between HLA-DQB1 and HLA-DQA2) at the HLA-D locus along with rs6726925 and rs13018963 at the PLA2R1 locus. Then we investigated whether primary membranous nephropathy at-risk variants were associated with recurrence in a retrospective cohort of 105 donor-recipient pairs and a replication cohort of 40 pairs. Seven SNPs located between HLA-DRB1 and HLA-DQA1 in linkage disequilibrium with rs9271188, and three SNPs in the PLA2R1 region predicted recurrence when presented by the donor, but not when presented by the recipient. The two SNPs in the HLA-D region most strongly associated with recurrence (rs9271705 and rs9271550) were confirmed in the replication cohort. A genetic risk score based on the two best predictors at each locus (rs9271705, rs9271550, rs17830558, and rs3828323) identified a group of patients with high risk of recurrence. Thus, our results suggest that the graft contributes to recurrence of primary membranous nephropathy through the disease susceptibility HLA-D and PLA2R1 SNPs in an autoimmune milieu. Further studies are needed before implementation of genetic testing for these in donor selection.

• MeSH
• alely MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• membranózní glomerulonefritida * diagnóza   genetika   MeSH
• receptory pro fosfolipasy A2 genetika   MeSH
• retrospektivní studie MeSH
• transplantace ledvin * škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Publikační typ
• tisková chyba MeSH

Membranous nephropathy (MN) is the most common cause of primary nephrotic syndrome among adults. The identification of phospholipase A2 receptor (PLA2R) as target antigen in most patients changed the management of MN dramatically, and provided a rationale for B-cell depleting agents such as rituximab. The efficacy of rituximab in inducing remission has been investigated in several studies, including 3 randomized controlled trials, in which complete and partial remission of proteinuria was achieved in approximately two-thirds of treated patients. Due to its favorable safety profile, rituximab is now considered a first-line treatment option for MN, especially in patients at moderate and high risk of deterioration in kidney function. However, questions remain about how to best use rituximab, including the optimal dosing regimen, a potential need for maintenance therapy, and assessment of long-term safety and efficacy outcomes. In this review, we provide an overview of the current literature and discuss both strengths and limitations of "the new standard."

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Primary forms of minimal change disease and focal segmental glomerulosclerosis are rare podocytopathies and clinically characterized by nephrotic syndrome. Glucocorticoids are the cornerstone of the initial immunosuppressive treatment in these two entities. Especially among adults with minimal change disease or focal segmental glomerulosclerosis, relapses, steroid dependence or resistance are common and necessitate re-initiation of steroids and other immunosuppressants. Effective steroid-sparing therapies and introduction of less toxic immunosuppressive agents are urgently needed to reduce undesirable side effects, in particular for patients whose disease course is complex. Rituximab, a B cell depleting monoclonal antibody, is increasingly used off-label in these circumstances, despite a low level of evidence for adult patients. Hence, critical questions concerning drug-safety, long-term efficacy and the optimal regimen for rituximab-treatment remain unanswered. Evidence in the form of large, multicenter studies and randomized controlled trials are urgently needed to overcome these limitations.

• MeSH
• dospělí MeSH
• fokálně segmentální glomeruloskleróza * farmakoterapie   MeSH
• imunologické faktory terapeutické užití   MeSH
• imunosupresiva škodlivé účinky   MeSH
• lidé MeSH
• lipoidní nefróza * farmakoterapie   MeSH
• nefrotický syndrom MeSH
• recidiva MeSH
• rituximab terapeutické užití   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: The differential diagnosis of thrombotic microangiopathy (TMA) is complex however the rapid diagnosis of the underlying condition is vital to inform urgent treatment decisions. A survey was devised with the objective of understanding current practices across Europe and the Middle East, and of challenges when diagnosing the cause of TMA. METHODS: Over 450 clinicians, from 16 countries were invited to complete an online survey. RESULTS: Of 254 respondents, the majority were nephrologists, had >10 years' experience in their specialty, and had diagnosed a patient with TMA. The triad of thrombocytopenia, haemolytic anaemia and acute kidney injury are the main diagnostic criteria used. Responses indicate that a differential diagnosis of TMA is usually made within 1-2 (53%) or 3-4 days (26%) of presentation. Similarly, therapy is usually initiated within the first 4 days (74%), however 13% report treatment initiation >1-week post-presentation. Extrarenal symptoms and a panoply of other conditions are considered when assessing the differential diagnosis of TMA. While 70 and 78% of respondents stated they always request complement protein levels and ADAMTS13 activity, respectively. Diagnostic considerations of paediatric and adult nephrologists varied. A greater proportion of paediatric than adult nephrologists consider extrarenal manifestations clinically related to a diagnosis of TMA; pulmonary (45% vs. 18%), gastrointestinal (67% vs. 50%), CNS (96% vs. 84%) and cardiovascular (54% vs. 42%), respectively. Variability in the availability of guidelines and extent of family history taken was also evident. CONCLUSIONS: This survey reveals the variability of current practices and the need for increased urgency among physicians in the differential diagnosis of TMA, despite their experience. Above all, the survey highlights the need for international clinical guidelines to provide systematically developed recommendations for understanding the relevance of complement protein levels, complement abnormalities and ADAMTS13 testing, in making a differential diagnosis of TMA. Such clinical guidelines would enable physicians to make a more rapid and informed diagnosis of TMA, therefore initiate effective treatment earlier, with a consequent improvement in patient outcomes.

• MeSH
• biologické markery krev   MeSH
• diferenciální diagnóza MeSH
• lidé MeSH
• nefrologie metody   normy   MeSH
• nefrologové * normy   MeSH
• průzkumy a dotazníky * normy   MeSH
• trombotické mikroangiopatie krev   diagnóza   epidemiologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH
• Střední východ epidemiologie   MeSH

BACKGROUND: There is a need for early identification of children with immunoglobulin A nephropathy (IgAN) at risk of progression of kidney disease. METHODS: Data on 261 young patients [age <23 years; mean follow-up of 4.9 (range 2.5-8.1) years] enrolled in VALIGA, a study designed to validate the Oxford Classification of IgAN, were assessed. Renal biopsies were scored for the presence of mesangial hypercellularity (M1), endocapillary hypercellularity (E1), segmental glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis (T1-2) (MEST score) and crescents (C1). Progression was assessed as end stage renal disease and/or a 50 % loss of estimated glomerular filtration rate (eGFR) (combined endpoint) as well as the rate of renal function decline (slope of eGFR). Cox regression and tree classification binary models were used and compared. RESULTS: In this cohort of 261 subjects aged <23 years, Cox analysis validated the MEST M, S and T scores for predicting survival to the combined endpoint but failed to prove that these scores had predictive value in the sub-group of 174 children aged <18 years. The regression tree classification indicated that patients with M1 were at risk of developing higher time-averaged proteinuria (p < 0.0001) and the combined endpoint (p < 0.001). An initial proteinuria of ≥0.4 g/day/1.73 m2and an eGFR of <90 ml/min/1.73 m2were determined to be risk factors in subjects with M0. Children aged <16 years with M0 and well-preserved eGFR (>90 ml/min/1.73 m2) at presentation had a significantly high probability of proteinuria remission during follow-up and a higher remission rate following treatment with corticosteroid and/or immunosuppressive therapy. CONCLUSION: This new statistical approach has identified clinical and histological risk factors associated with outcome in children and young adults with IgAN.

• MeSH
• analýza přežití MeSH
• biopsie MeSH
• chronické selhání ledvin epidemiologie   patologie   MeSH
• dítě MeSH
• hodnoty glomerulární filtrace MeSH
• hormony kůry nadledvin terapeutické užití   MeSH
• IgA nefropatie farmakoterapie   epidemiologie   patologie   MeSH
• imunosupresiva MeSH
• kohortové studie MeSH
• kojenec MeSH
• ledviny patologie   MeSH
• lidé MeSH
• předškolní dítě MeSH
• progrese nemoci MeSH
• proteinurie epidemiologie   patologie   MeSH
• retrospektivní studie MeSH
• rizikové faktory MeSH
• sexuální faktory MeSH
• stanovení cílového parametru MeSH
• věkové faktory MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH

BACKGROUND: Patients with primary membranous nephropathy (MN) and persistent nephrotic syndrome have a high risk of progression to end-stage renal disease. The Ponticelli protocol (steroids with alkylating agents) is the most effective immunosuppressive therapy for this condition, but it has severe adverse effects. Tacrolimus and rituximab have demonstrated efficacy for remission of nephrotic syndrome in MN with a safer profile. However, the published evidence is largely based on small or short-term observational studies, historical cohorts, comparisons with conservative therapy or clinical trials without appropriate control groups, and there is no head-to-head comparison with the Ponticelli protocol. METHODS: The STARMEN randomized clinical trial will compare the efficacy of sequential tacrolimus-rituximab therapy with a modified Ponticelli protocol (steroids plus cyclophosphamide). The trial will also evaluate the role of antibodies against the M-type phospholipase A2 receptor (anti-PLA2R) and other antibodies as markers of response to treatment and long-term prognosis. RESULTS: The trial has already started with 23 patients having been enrolled as of 1 April 2015, an estimated 21.7% of the estimated sample.

• Publikační typ
• časopisecké články MeSH