PURPOSE OF REVIEWImmunoglobulin A (IgA) nephropathy (IgAN) is a heterogeneous disease, and predicting individual patient risk of renal progression is challenging. Recent studies provide new evidence ...regarding the use of clinical, histologic, and biomarker predictors of renal outcome in IgAN.
RECENT FINDINGSA meta-analysis of clinical trials demonstrated that early change in proteinuria is a valid surrogate outcome measure for longer term decline in renal function, which supports the use of proteinuria to dynamically re-evaluate patient prognosis over time. The MEST histologic classification has been further validated in a large European cohort. An international multiethnic observational study demonstrated that crescents are independently associated with renal outcome, and as a result a crescent score (<25% versus >25% of glomeruli) has been added to MEST. Proteinuria, estimated glomerular filtration rate (GFR), and blood pressure at the time of biopsy can be used to accurately predict prognosis when combined with MEST, instead of using 2 years of follow-up data. Currently, no available risk prediction model that combines clinical and histologic predictors has been sufficiently validated for routine use. There are multiple biomarkers that have been studied in IgAN, however none have been externally validated and shown to improve prediction beyond clinical and histologic risk factors.
SUMMARYProteinuria, estimated GFR, blood pressure, and the MEST-C score are the most readily available risk factors to predict renal prognosis in IgAN. Future research is required to develop and validate methods of integrating these risk factors together to accurately risk stratify individual patients, and provide the framework for evaluating biomarkers capable of further improving risk prediction.
The use of corticosteroids to treat IgA nephropathy (IgAN) has been limited by many controversies related to uncertain benefit and safety concerns. Recent trials have tried to address these ...limitations.
After being paused because of an excess of adverse events in the full-dose steroid arm, the TESTING trial compared a reduced dose of methylprednisolone to placebo in patients with IgAN after optimization of supportive therapy. Steroid treatment was associated with a significant reduction in the risk of a 40% decline in estimated glomerular filtration rate (eGFR), kidney failure and kidney death as well as a sustained decrease in proteinuria compared with placebo. Serious adverse events were more frequent with the full dose regimen but less common in the reduced dose regimen. A phase III trial evaluating a new formulation of targeted-release budesonide showed a significant reduction in short-term proteinuria and has resulted in accelerated FDA approval for use in the United States. In a subgroup analysis of DAPA-CKD trial, sodium-glucose transport protein 2 inhibitors reduced the risk of kidney function decline in patients who have completed or are not eligible for immunosuppression.
Both reduced-dose corticosteroids and targeted-release budesonide are new therapeutic options that can be used in patients with high-risk disease. More novel-targeted therapies with a better safety profile are currently under investigations.
Controlled macrophage differentiation and activation in the initiation and resolution of inflammation is crucial for averting progression to chronic inflammatory and autoimmune diseases. Here we show ...a negative feedback mechanism for proinflammatory IFN-γ activation of macrophages driven by macrophage-associated matrix metalloproteinase 12 (MMP12). Through C-terminal truncation of IFN-γ at 135Glu↓Leu136 the IFN-γ receptor-binding site was efficiently removed thereby reducing JAK-STAT1 signaling and IFN-γ activation of proinflammatory macrophages. In acute peritonitis this signature was absent in Mmp12
mice and recapitulated in Mmp12
mice treated with a MMP12-specific inhibitor. Similarly, loss-of-MMP12 increases IFN-γ-dependent proinflammatory markers and iNOS
/MHC class II
macrophage accumulation with worse lymphadenopathy, arthritic synovitis and lupus glomerulonephritis. In active human systemic lupus erythematosus, MMP12 levels were lower and IFN-γ higher compared to treated patients or healthy individuals. Hence, macrophage proteolytic truncation of IFN-γ attenuates classical activation of macrophages as a prelude for resolving inflammation.
Identification of earlier surrogate markers of beneficial treatment effect—proteinuria reduction and rate of kidney function decline—has improved trial feasibility and contributed to unprecedented ...industry interest in drug development in IgA nephropathy.2–4 The PROTECT study was designed to address a need for targeted, non-toxic therapies to improve the outcome of patients with IgA nephropathy, a leading cause of kidney failure.5 The PROTECT study is a double-blind, randomised, phase 3 study comparing the impact of sparsentan, a novel dual endothelin-1 and angiotensin II receptor antagonist (n=202), to treatment with the angiotensin II receptor antagonist irbesartan (n=202). The results of the PROTECT trial are eagerly anticipated by the kidney community because a prespecified interim analysis of the primary outcome of the trial (change in proteinuria at week 36) showed impressive relative reduction in proteinuria with sparsentan (−49·8% vs −15·1%).5 This finding was sufficient for accelerated approval of sparsentan by the US Food and Drug Administration for treatment of adults with IgA nephropathy at risk of rapid disease progression.6 Full approval from US and European regulatory and funding agencies would require additional evidence of an impact on the rate of kidney function decline. Importantly, no patients had to stop treatment as a result of oedema or heart failure,7 which are complications seen with other endothelin receptor antagonists.8 The marked proteinuria reduction observed with sparsentan compared with irbesartan was disproportionate to the relatively modest difference in loss of kidney function.7 Similar disconnect has been observed in a study of immunosuppression in IgA nephropathy and when sparsentan was studied in focal segmental glomerulosclerosis, another glomerular disease.9,10 Further research is required to elucidate the reasons for this disconnect, underscoring the need for better early biomarkers of treatment effect and the importance of validation of the surrogate indices of treatment effect with evidence of impact on kidney function decline.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Although case reports have described relapses of glomerular disease after COVID-19 vaccination, evidence of a true association is lacking. In this population-level analysis, we sought to determine ...relative and absolute risks of glomerular disease relapse after COVID-19 vaccination.
In this retrospective population-level cohort study, we used a centralized clinical and pathology registry (2000-2020) to identify 1105 adult patients in British Columbia, Canada, with biopsy-proven glomerular disease that was stable on December 14, 2020 (when COVID-19 vaccines first became available). The primary outcome was disease relapse, on the basis of changes in kidney function, proteinuria, or both. Vaccination was modeled as a 30-day time-varying exposure in extended Cox regression models, stratified on disease type.
During 281 days of follow-up, 134 (12.1%) patients experienced a relapse. Although a first vaccine dose was not associated with relapse risk (hazard ratio HR=0.67; 95% confidence interval 95% CI, 0.33 to 1.36), exposure to a second or third dose was associated with a two-fold risk of relapse (HR=2.23; 95% CI, 1.06 to 4.71). The pattern of relative risk was similar across glomerular diseases. The absolute increase in 30-day relapse risk associated with a second or third vaccine dose varied from 1%-2% in ANCA-related glomerulonephritis, minimal change disease, membranous nephropathy, or FSGS to 3%-5% in IgA nephropathy or lupus nephritis. Among 24 patients experiencing a vaccine-associated relapse, 4 (17%) had a change in immunosuppression, and none required a biopsy.
In a population-level cohort of patients with glomerular disease, a second or third dose of COVID-19 vaccine was associated with higher relative risk but low absolute increased risk of relapse.
In this review, we summarize recent advances in the risk stratification of patients with immunoglobulin A (IgA) nephropathy. Several clinical variables have consistent and independent associations ...with worse kidney prognosis, including blood pressure, proteinuria, and baseline kidney function. Although one-time cross-sectional assessments of blood pressure and proteinuria are important, a more thorough understanding of risk can be achieved when these variables are considered over a follow-up period. IgA nephropathy is unique compared with other glomerular diseases in that a much lower threshold of proteinuria (protein excretion, 1 g/d) is associated with glomerular filtration rate (GFR) loss. Controlling proteinuria and blood pressure over time is important to reduce the risk of future loss of kidney function. The recently described Oxford classification has helped standardize the pathologic characterization of IgA nephropathy using a scoring system that is readily reproducible and associated with increased risk of GFR loss independent of clinical variables. We suggest an approach to risk stratification in IgA nephropathy when considering potential treatment with immunosuppression. Despite our current understanding of risk stratification in IgA nephropathy, the ability to accurately predict individual patient-level risk currently is limited, and further research into additional biomarkers or risk prediction tools is needed to improve the care of patients with IgA nephropathy.
In a randomized, controlled trial involving patients with membranous nephropathy, rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and ...was superior in maintaining proteinuria remission for up to 24 months.
Since the Oxford Classification of IgA nephropathy (IgAN) was published in 2009, MEST scores have been increasingly used in clinical practice. Further retrospective cohort studies have confirmed that ...in biopsy specimens with a minimum of 8 glomeruli, mesangial hypercellularity (M), segmental sclerosis (S), and interstitial fibrosis/tubular atrophy (T) lesions predict clinical outcome. In a larger, more broadly based cohort than in the original Oxford study, crescents (C) are predictive of outcome, and we now recommend that C be added to the MEST score, and biopsy reporting should provide a MEST-C score. Inconsistencies in the reporting of M and endocapillary cellularity (E) lesions have been reported, so a web-based educational tool to assist pathologists has been developed. A large study showed E lesions are predictive of outcome in children and adults, but only in those without immunosuppression. A review of S lesions suggests there may be clinical utility in the subclassification of segmental sclerosis, identifying those cases with evidence of podocyte damage. It has now been shown that combining the MEST score with clinical data at biopsy provides the same predictive power as monitoring clinical data for 2 years; this requires further evaluation to assess earlier effective treatment intervention. The IgAN Classification Working Group has established a well-characterized dataset from a large cohort of adults and children with IgAN that will provide a substrate for further studies to refine risk prediction and clinical utility, including the MEST-C score and other factors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The risk of venous thromboembolic events is thought to be highest in patients with membranous nephropathy. This association has been recently questioned, and it is not known whether this simply ...reflects the severity of proteinuria. To better understand the relationship between histologic diagnosis and the risk of venous thromboembolic events we evaluated patients in the Toronto Glomerulonephritis Registry. Of 1313 patients with idiopathic glomerulonephritis, 395 were diagnosed with membranous nephropathy, 370 with focal segmental glomerulosclerosis (FSGS), and 548 with immunoglobulin-A nephropathy (IgAN). Risk factors were evaluated by Cox proportional hazards for 53 image-confirmed venous thromboembolic events in 44 patients during a median follow-up of 63 months. The risk was highest in patients with membranous nephropathy and FSGS (hazard ratios of 22 and 7.8, respectively) referenced to patients with IgAN. Following adjustment for gender, cancer history, proteinuria, and serum albumin by multivariable analysis, the histologic subtype remained an independent risk for venous thromboembolic events. This risk was still highest in patients with membranous nephropathy followed by FSGS with adjusted hazard ratios of 10.8 and 5.9, respectively. Thus, in this large cohort, histologic diagnosis was an independent risk factor for venous thromboembolic events. Further studies are needed to discover mechanisms responsible for this high risk in patients with membranous nephropathy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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