A cyclical corticosteroid-cyclophosphamide regimen is recommended for patients with primary membranous nephropathy at high risk of progression. We hypothesized that sequential therapy with tacrolimus ...and rituximab is superior to cyclical alternating treatment with corticosteroids and cyclophosphamide in inducing persistent remission in these patients. This was tested in a randomized, open-label controlled trial of 86 patients with primary membranous nephropathy and persistent nephrotic syndrome after six-months observation and assigned 43 each to receive six-month cyclical treatment with corticosteroid and cyclophosphamide or sequential treatment with tacrolimus (full-dose for six months and tapering for another three months) and rituximab (one gram at month six). The primary outcome was complete or partial remission of nephrotic syndrome at 24 months. This composite outcome occurred in 36 patients (83.7%) in the corticosteroid-cyclophosphamide group and in 25 patients (58.1%) in the tacrolimus-rituximab group (relative risk 1.44; 95% confidence interval 1.08 to 1.92). Complete remission at 24 months occurred in 26 patients (60%) in the corticosteroid-cyclophosphamide group and in 11 patients (26%) in the tacrolimus-rituximab group (2.36; 1.34 to 4.16). Anti-PLA2R titers showed a significant decrease in both groups but the proportion of anti-PLA2R-positive patients who achieved immunological response (depletion of anti-PLA2R antibodies) was significantly higher at three and six months in the corticosteroid-cyclophosphamide group (77% and 92%, respectively), as compared to the tacrolimus-rituximab group (45% and 70%, respectively). Relapses occurred in one patient in the corticosteroid-cyclophosphamide group, and three patients in the tacrolimus-rituximab group. Serious adverse events were similar in both groups. Thus, treatment with corticosteroid-cyclophosphamide induced remission in a significantly greater number of patients with primary membranous nephropathy than tacrolimus-rituximab.
Display omitted
End-stage renal disease caused by lupus nephritis (LN) is an avoidable outcome yet there is considerable uncertainty and variability among nephrologists in their approaches to this disorder. This ...review discusses recent evidence relevant to the management of LN including recent consensus statements. Long-term results are encouraging compared with 30 years ago, but despite the use of the best available current therapies and achieving high levels of early clinical responses, the kidney often sustains long-term damage and nephritis relapses affect over 50%. Major hurdles to management include the complexity of the clinical presentation, histological features and serological tests, and the absence of reliable outcome predictors or markers of treatment response. The key serological and histopathological characteristics relevant to the practising nephrologist are reviewed, and the limitations of current disease activity markers discussed. There are many potential biomarkers under evaluation, and a framework for their validation is presented. Clinical trials of existing or newer agents for LN have typically been inconclusive and have raised problems of trial design and interpretation that are a barrier to new drug development. The major issues affecting clinical trial design and their potential solutions are summarized.
Refractory lupus nephritis indicates an inadequate response to lupus nephritis therapy. It implies persisting or worsening disease activity despite therapy, but the definition is complicated by the ...parameters of response, proteinuria and renal function, that do not discriminate clearly between activity and irreversible damage. Understanding the causes of refractory disease and developing treatment strategies is important because these patients are more likely to develop poor outcomes, especially end stage renal disease. This review explores current concepts and definitions of refractory disease and summarises treatment approaches that have been used in observational cohort studies and case series. We highlight the importance of optimising adherence to the prescribed immunosuppressive and supportive measures and avoidance of diagnostic delay. Treatment options include higher dose glucocorticoid, switching between cyclophosphamide and mycophenolate acid derivates, or addition of rituximab, the latter potentially in combination with belimumab. Less evidence supports extracorporeal treatment (plasma exchange or immunoadsorption), calcineurin inhibitors (cyclosporine A or tacrolimus), intravenous immunoglobulin and stem cell transplantation. Improvements in understanding what refractory disease is and how definitions can be integrated into treatment pathways has the potential to enhance lupus nephritis outcomes.
The phenotype of renal involvement in anti-neutrophil cytoplasmic antibodies (ANCA) vasculitis has a major influence on survival, and histological subgrouping of diagnostic renal biopsies has been ...proposed to aid in the prediction of renal outcome. We aimed to validate this histological subgrouping and to investigate the additional value of ANCA serotype in the prediction of renal outcome.
Data were retrospectively collected from the time of diagnosis by systematic review of medical records from 136 patients with renal biopsies recruited to cohorts from the UK and Spain, over 15 years. The end point, renal survival, was the composite of end-stage renal disease (ESRD) or death from any cause. The occurrence of ESRD, Stage 4 Kidney Disease Outcomes Quality Initiative-Chronic Kidney Disease, was assessed separately, in order to establish a severity index risk of chronic kidney disease.
Renal survival at 5 years was 96% in the focal, 86% in the crescentic, 81% in the mixed and 61% in the sclerotic subgroups (P = 0.03). Myeloperoxidase (MPO)-ANCA was associated with more severe disease when compared with PR3-ANCA, as demonstrated by a lower frequency of focal and higher frequency of sclerotic subgroups, by more advanced interstitial fibrotic change and by lower glomerular filtration rate at diagnosis and worse renal function at 1 and 2 years.
We have confirmed the predictive value for renal survival of the ANCA vasculitis histology classification in a multi-centre study. We found a worse renal outcome in patients with tubulointerstitial fibrosis and atrophy. MPO-ANCA positive patients had a worse renal prognosis due to more severe glomerular injury. These results contribute to patient stratification in renal vasculitis for therapeutic, epidemiological and basic research.
The Case | Persistent fever in a hemodialysis patient Rodríguez-Espinosa, Diana; Broseta, José Jesús; Garrote, Marta ...
Kidney international,
January 2022, 2022-Jan, 2022-01-00, 20220101, Letnik:
101, Številka:
1
Journal Article
•End stage renal disease by ANCA vasculitis affects 40% of the patients.•Major hurdles are the complex balance between treatment toxicity and recurrence.•New data indicate that C5 and C5aR are ...therapeutic targets in ANCA renal vasculitis.•The way is open for clinical use of this complement target therapy in the near future.
ANCA associated vasculitis is a serious, very often recurrent disease that despite the current standard treatment with high-dose glucocorticoids and either cyclophosphamide or rituximab, patients have a nine-fold increased mortality risk in the first year compared with healthy controls, attributed to infections, vasculitis activity, and renal disease.
During the last few years, novel findings have suggested that activation of the complement system, in particular the alternative complement system, has a significant role in ANCA associated vasculitis pathogenesis. Detection of several components of this system in the circulation and urine reflects disease activity, and thus may be useful for clinical prognosis and to set up personalised treatments. In fact, some components of the complement system, such as C5a, might be potential targets for therapy.
In this Review an update on clinical evidence for the role of complement activation in AAV is provided and subsequently we discuss potential therapeutic strategies that target complement components and open the way for clinical use of this target therapy in the near future.
Malignant hypertension is listed among the causes of secondary thrombotic microangiopathy, but pathogenic mutations in complement genes have been reported in patients with hypertension-induced ...thrombotic microangiopathy. Here we investigated the frequency and severity of hypertension in 55 patients with primary atypical hemolytic uremic syndrome (aHUS). A genetic analysis was performed in all patients, and funduscopic examination was performed in all the patients with Grades 2 and 3 hypertension. A cohort of 110 patients with malignant hypertension caused by diseases other than aHUS served as control. Thirty-six patients with aHUS presented Grade 2 or Grade 3 hypertension and funduscopic examination showed malignant hypertension in 19. Genetic abnormalities in complement were found in 19 patients (37% among patients with malignant hypertension). Plasmapheresis was performed in 46 patients and 26 received eculizumab. Renal and hematological responses were significantly lower after plasmapheresis (24%) than after eculizumab (81%). Renal survival was significantly higher in patients treated with eculizumab (85% at one, three and five years) compared to patients who did not receive this treatment (54%, 46% and 41%), respectively. Response to eculizumab was independent of hypertension severity and the presence of complement genetic abnormalities. Among patients with malignant hypertension caused by other diseases the prevalence of thrombotic microangiopathy was very low (5%). Thus, severe and malignant hypertension are common among patients with aHUS and eculizumab treatment leads to a higher renal survival when compared to plasmapheresis. However, thrombotic microangiopathy is uncommon among patients presenting with malignant hypertension caused by diseases other than aHUS.
Display omitted
Secretory phospholipase A2 receptor (PLA2R) is the target antigen of the auto-antibodies produced in most (∼ 70%) patients with primary membranous nephropathy (pMN). The applicability of anti-PLA2R1 ...antibody monitoring for the prediction of MN recurrence in kidney transplant recipients still is a matter of debate.
We sought to characterize the presence and concentration of anti-PLA2R antibodies by enzyme-linked immunosorbent assay (ELISA) in a cohort of 21 patients with pMN before and after transplantation to evaluate whether anti-PLA2R concentrations could predict pMN recurrence.
The presence of pMN recurrence was significantly correlated with the existence of a positive ELISA assay at graft biopsy or with high level of anti-PLA2R1 activity before transplantation (P = 0.03). In the receiver operating characteristic analysis, anti-PLA2R levels (cut-off of 45 U/mL) during the pretransplantation period accurately predicted pMN recurrence, with a sensitivity of 85.3%, specificity of 85.1%, negative predictive value of 92%, and an area under the curve of 90.8%. This finding supports the hypothesis that anti-PLA2R cause pMN recurrence in humans and indicates the need to prove in an experimental model. Furthermore, 6 of 7 patients with recurrence were carriers of HLA DQA1* 05:01/05 and DQB1* 02:01, confirming these DQ alleles as those associated with higher anti-PLA2R levels.
This study is the first to demonstrate pretransplantation circulating anti-PLA2R antibodies in a cohort of renal transplant recipients who prospectively developed recurrent disease. Currently, anti-PLA2R levels measured by ELISA may be a rational tool to establish the risk of MN recurrence in renal allograft recipients.
Acute kidney injury (AKI) increases early mortality in allogeneic hematopoietic cell transplant (allo-HCT) recipients and may accelerate chronic kidney disease (CKD) development. We analyzed ...prospective variables related to AKI and CKD in 422 allo-HCT recipients to establish risk factors of severe acute renal failure and CKD. Renal function and creatinine were periodically assessed from baseline till the last follow-up. Sixty-three patients (14%) developed severe AKI (AKI-3) at 100 days post transplant and 15% at 12 months. Variables associated with AKI-3 were age above 55 years hazard ratio (HR): 2.4; p = 0.019, total body irradiation (TBI) (HR: 1.8; p = 0.044), high-risk cytomegalovirus reactivation (HR: 1.8; p = 0.041), and methotrexate as GVHD prophylaxis (HR: 2.1; p = 0.024). AKI-3 increased the mortality risk (HR: 2.5, 95% confidence interval: 1.9-3.4). The CKD prevalence in 161 living patients was 10.2% at the last follow-up and in most, CKD developed 1 year post HCT, independent of AKI. The CKD at 1 year post HCT was associated with increased mortality (HR: 3.54; p < 0.001). Interestingly, pretransplant CKD was associated with early mortality (HR: 5.6; p < 0.001). In fact, pre- and posttransplant CKD had independent unfavorable long-term outcomes. These pretransplant factors can potentially be targeted to improve allo-HCT outcomes.
PDF
