Recent years have brought notable progress in the field of IgA nephropathy. Here, we highlight important new directions and latest developments, including successful discovery of several genetic ...susceptibility loci, formulation of the multihit pathogenesis model, introduction of the Oxford pathology scoring system, and formalization of the Kidney Disease Improving Global Outcomes (KDIGO) consensus treatment guidelines. We focus on the latest genetic findings that confirm a strong contribution of inherited factors and explain some of the geoethnic disparities in disease susceptibility. Most IgA nephropathy susceptibility loci discovered to date encode genes involved in the maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The concerted pattern of interpopulation allelic differentiation across all genetic loci parallels the disease prevalence and correlates with variation in local pathogens, suggesting that multilocus adaptation might have shaped the present-day landscape of IgA nephropathy. Importantly, the ‘Intestinal Immune Network for IgA Production’ emerged as one of the new targets for potential therapeutic intervention. We place these findings in the context of the multihit pathogenesis model and existing knowledge of IgA immunobiology. Lastly, we provide our perspective on the existing treatment options, discuss areas of clinical uncertainty, and outline ongoing clinical trials and translational studies.
Membranous nephropathy (MN) is either primary or associated with various etiologies, each with unique glomerular antigens. The discovery of the phospholipase A2 receptor (PLA2R) antigen in primary MN ...revolutionized our understanding of MN and led to major clinical progress. Other recently discovered antigens in MN include the THSD7A antigen and exostosin. Sethi et al. have now identified a new antigen, NELL-1, in primary MN, again decreasing the number of patients whose antigen remains unknown.
In this double-blind, randomized trial, mycophenolate mofetil was superior to azathioprine for maintaining a renal response and preventing relapse in patients with lupus nephritis who had had a ...response to induction therapy.
Systemic lupus erythematosus is an autoimmune disorder often characterized by the development of glomerulonephritis.
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Renal involvement remains the strongest predictor of morbidity and mortality among patients with lupus,
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and despite improvements in the management of lupus, the incidence of end-stage renal disease has not declined.
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Management of lupus nephritis consists of induction therapy to achieve remission and long-term maintenance therapy to prevent relapse, progression to end-stage renal disease, and death.
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However, the options for long-term therapy remain controversial. Treatment options include glucocorticoids and the immunosuppressive agents cyclophosphamide, azathioprine, and mycophenolate mofetil. These drugs have considerable toxicity and are not effective . . .
Updates on the Treatment of Lupus Nephritis BOMBACK, Andrew S; APPEL, Gerald B
Journal of the American Society of Nephrology,
12/2010, Letnik:
21, Številka:
12
Journal Article
Recenzirano
Odprti dostop
The treatment of lupus nephritis has changed significantly over the past decade in large part because of data from well-conducted randomized clinical trials. The concept of two phases of ...therapy-induction and maintenance-is widely accepted. The histopathologic classification of lupus nephritis continues to guide therapy, and treatment for all major classes of lupus nephritis has seen some shift in management during this time. New regimens using lower doses and shorter treatment durations of intravenous cyclophosphamide have been advanced to reduce toxicity without sacrificing efficacy of therapy. Mycophenolate mofetil has emerged as a viable alternative to cyclophosphamide for induction therapy of both proliferative and membranous lupus nephritis. Combination induction treatment with multiple agents has also been successful. Large controlled trials using mycophenolate mofetil and azathioprine for maintenance therapy have been performed. Here, we review recent additions to the growing body of literature on how to most effectively treat lupus nephritis with the least amount of toxicity. We discuss new treatment strategies currently being explored in clinical trials.
Chronic changes represent an important component of native kidney biopsy evaluation and have a major bearing on predicting prognosis and guiding treatment. We propose here a uniform, semiquantitative ...approach to assessing such changes, which include glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis, and we report these findings as an overall chronicity grade.
Precise immunofluorescence criteria for C3 glomerulopathy remain to be defined. Here we tested hierarchical immunofluorescence criteria with varying stringency for C3 glomerulopathy in a cohort with ...dense deposit disease as the gold standard and then applied these criteria to analyze the incidence of C3 glomerulopathy in membranoproliferative glomerulonephritis (MPGN) types 1 and 3. Among 319 archived cases of primary MPGN types 1–3, immunofluorescence reports were retrospectively coded as glomerular deposits of the following: C3 only; C3 dominant with trace or 1+ immunoglobulin (Ig)M only; and C3 dominant and at least two orders of intensity stronger than any combination of IgG, IgM, IgA, and C1q. The most restrictive criteria of ‘C3 only’ captured only half of the cases with dense deposit disease (compared with 8% of type 1 and 10% of type 3). Adding the most liberal definition identified 88% of those with dense deposit disease (compared with 31% of type 1 and 39% of type 3). The unaccounted 12% had stronger intensity of Ig staining, but it never exceeded the intensity of C3. Among MPGN type 3, 90% of C3 glomerulopathy cases were the Strife and Anders variant. Repeat biopsies in C3 glomerulopathy revealed a change in immunofluorescence pattern in 10 of 23 biopsies. The prevalence of low serum C3 and/or low C4 did not significantly differ among the three immunofluorescence criteria. Thus, ‘C3 only’ is an impractical definition of C3 glomerulopathy, and we propose a definition of C3 dominant and at least two orders of magnitude more intense than any other immune reactant, which requires validation by alternative pathway evaluation. These criteria provide a framework for identifying patients most likely to benefit from investigations of alternative complement pathway dysregulation.
Until recently, membranoproliferative glomerulonephritis (MPGN) was clinically classified as either primary, idiopathic MPGN or as secondary MPGN when an underlying aetiology was identifiable. ...Primary MPGN was further classified into three types--type I, type II, and type III--based principally on the ultrastructural appearance and location of electron-dense deposits. Both the clinical and histopathologic schemes presented problems, however, as neither was based on disease pathogenesis. An improved understanding of the role of complement in the pathogenesis of MPGN has led to a proposed reclassification into immunoglobulin-mediated disease (driven by the classical complement pathway) and non-immunoglobulin-mediated disease (driven by the alternative complement pathway). This reclassification has led to improved diagnostic clinical algorithms and the emergence of a new grouping of diseases known as the C3 glomerulopathies, best represented by dense deposit disease and C3 glomerulonephritis. In this Review, we re-examine the previous and current classification schemes of MPGN, focusing on the role of complement. We survey current data about the pathogenesis of the C3 glomerulopathies, including familial studies and patient cohorts from the USA and Europe. In addition, we discuss the diagnosis, treatment, and prognosis of the C3 glomerulopathies.
Background The role of change in proteinuria as a surrogate end point for randomized trials in immunoglobulin A nephropathy (IgAN) has previously not been thoroughly evaluated. Study Design ...Individual patient–level meta-analysis. Setting & Population Individual-patient data for 830 patients from 11 randomized trials evaluating 4 intervention types (renin-angiotensin system RAS blockade, fish oil, immunosuppression, and steroids) examining associations between changes in urine protein and clinical end points at the individual and trial levels. Selection Criteria for Studies Randomized controlled trials of IgAN with measurements of proteinuria at baseline and a median of 9 (range, 5-12) months follow-up, with at least 1 further year of follow-up for the clinical outcome. Predictor 9-month change in proteinuria. Outcome Doubling of serum creatinine level, end-stage renal disease, or death. Results Early decline in proteinuria at 9 months was associated with lower risk for the clinical outcome (HR per 50% reduction in proteinuria, 0.40; 95% CI, 0.32-0.48) and was consistent across studies. Proportions of treatment effect on the clinical outcome explained by early decline in proteinuria were estimated at 11% (95% CI, −19% to 41%) for RAS blockade and 29% (95% CI, 6% to 53%) for steroid therapy. The direction of the pooled treatment effect on early change in proteinuria was in accord with the direction of the treatment effect on the clinical outcome for steroids and RAS blockade. Trial-level analyses estimated that the slope for the regression line for the association of treatment effects on the clinical end points and for the treatment effect on proteinuria was 2.15 (95% Bayesian credible interval, 0.10-4.32). Limitations Study population restricted to 11 trials, all having fewer than 200 patients each with a limited number of clinical events. Conclusions Results of this analysis offer novel evidence supporting the use of an early reduction in proteinuria as a surrogate end point for clinical end points in IgAN in selected settings.
This 24-week randomized, open-label, noninferiority trial compared oral mycophenolate mofetil with monthly intravenous cyclophosphamide as induction therapy for active lupus nephritis. Mycophenolate ...mofetil appeared more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis, with a more favorable safety profile.
Mycophenolate mofetil appeared to be more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis, with a more favorable safety profile.
Intravenous cyclophosphamide has been the standard of care for treating severe lupus glomerulonephritis
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; however, its use is limited by potentially severe toxic effects including bone marrow suppression, hemorrhagic cystitis, opportunistic infections, malignant diseases, and premature gonadal failure.
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Clinical trials of treatment with intermittent intravenous cyclophosphamide combined with corticosteroids show greater long-term renal survival but not overall survival, as compared with treatment with corticosteroids alone.
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Furthermore, failure to achieve remission, which is associated with an increased rate of progression to renal failure, is reported in 18 to 57 percent of patients who received cyclophosphamide.
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Mycophenolate mofetil, an immunosuppressive . . .
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