21 research outputs found
Clinical, genetic and molecular aspects of membranous nephropathy
No full textMembranous Nephropathy (MN) is one of the leading causes of end-stage renal
disease (ESRD). MN is an autoimmune disease in which autoantibodies target
antigens at the level of the glomerular basement membrane. The nature of these
antibodies and the reason why they develop are not fully understood.
One of the strategies towards a better understanding of the disorder is genetic
analysis, of which two approaches have been attempted: linkage mapping, based
on a family suggestive for X-linked transmission of the MN trait; and whole
genome association mapping, based on three case-control cohorts. The first
cohort (335 cases and ethnically matched controls from the UK) was genotyped
using SNP markers and analysed in an exploratory study which led to the
identification of two highly significant loci of association. Two cohorts (146
biopsy proven MN cases and ethnically matched controls from the Dutch
research group in Nijmegen and 75 biopsy proven cases and ethnically matched
controls from the French research group in Paris) were used to successfully
replicate the results.
The two loci which we identified and independently confirmed are located on
chromosome 2 and on chromosome 6.
The chromosome 2 locus includes the PLA2R gene, confirming the hypothesis of
Beck et al. which identified PLA2R as a key antigen in idiopathic MN by using
an immunological approach [1].
The chromosome 6 locus lies within the extended Human Leukocyte Antigene
(HLA) system locus, with the highest significance for association reached by
alleles of HLA-DQA1.
Our results suggest that the susceptibility to membranous nephropathy is
associated to genetic variants at the level of both PLA2R1 and HLA loci. The
causative variants could be some of the polymorphisms captured by the
genotyping array which was analysed or, more likely variants (single nucleotide
or copy number variant type) situated nearby (and therefore in linkage
disequilibrium)
Chronic Kidney Disease – Where Next? : Predicting Outcomes And Planning Care Pathways
No full textPeer reviewe
Application of the International IgA Nephropathy Prediction Tool one or two years post-biopsy
No full textThe International IgA Nephropathy (IgAN) Prediction Tool is the preferred method in the 2021 KDIGO guidelines to predict, at the time of kidney biopsy, the risk of a 50% drop in estimated glomerular filtration rate or kidney failure. However, it is not known if the Prediction Tool can be accurately applied after a period of observation post-biopsy. Using an international multi-ethnic derivation cohort of 2,507 adults with IgAN, we updated the Prediction Tool for use one year after biopsy, and externally validated this in a cohort of 722 adults. The original Prediction Tool applied at one-year without modification had a coefficient of variation (R2) of 55% and 54% and four-year concordance (C statistic) of 0.82 but poor calibration with under-prediction of risk (integrated calibration index (ICI) 1.54 and 2.11, with and without race, respectively). Our updated Prediction Tool had a better model fit with higher R2 (61% and 60%), significant increase in four-year C-statistic (0.87 and 0.86) and better four-year calibration with lower ICI (0.75 and 0.35). On external validation, the updated Prediction Tool had similar R2 (60% and 58%) and four-year C-statistics (both 0.85) compared to the derivation analysis, with excellent four-year calibration (ICI 0.62 and 0.56). This updated Prediction Tool had similar prediction performance when used two years after biopsy. Thus, the original Prediction Tool should be used only at the time of biopsy whereas our updated Prediction Tool can be used for risk stratification one or two years post-biopsy
Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group
No full textSince 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
Effect of oral methylprednisolone on clinical outcomes in patients With IgA nephropathy: The TESTING randomized clinical trial
No full textGuidelines recommend corticosteroids in patients with IgA nephropathy and persistent proteinuria, but the effects remain uncertain
The Oxford IgA nephropathy clinicopathological classification is valid for children as well as adults
No full textTo study the predictive value of biopsy lesions in IgA nephropathy in a range of patient ages we retrospectively analyzed the cohort that was used to derive a new classification system for IgA nephropathy. A total of 206 adults and 59 children with proteinuria over 0.5 g/24h/1.73 m(2) and an eGFR of stage-3 or better were followed for a median of 69 months. At the time of biopsy, compared with adults children had a more frequent history of macroscopic hematuria, lower adjusted blood pressure, and higher eGFR but similar proteinuria. Although their outcome was similar to that of adults, children had received more immunosuppressants and achieved a lower follow-up proteinuria. Renal biopsies were scored for variables identified by an iterative process as reproducible and independent of other lesions. Compared with adults, children had significantly more mesangial and endocapillary hypercellularity, and less segmental glomerulosclerosis and tubulointerstitial damage, the four variables previously identified to predict outcome independent of clinical assessment. Despite these differences, our study found that the cross-sectional correlation between pathology and proteinuria was similar in adults and children. The predictive value of each specific lesion on the rate of decline of renal function or renal survival in IgA nephropathy was not different between children and adults. Kidney International (2010) 77, 921-927; doi: 10.1038/ki.2010.43; published online 3 March 201
A multicenter study of the predictive value of crescents in IgA nephropathy
No full textThe Oxford Classification of IgA nephropathy does not account for glomerular crescents. However, studies that reported no independent predictive role of crescents on renal outcomes excluded individuals with severe renal insufficiency. In a large IgA nephropathy cohort pooled from four retrospective studies, we addressed crescents as a predictor of renal outcomes and determined whether the fraction of crescent-containing glomeruli associates with survival from either a ≥50% decline in eGFR or ESRD (combined event) adjusting for covariates used in the original Oxford study. The 3096 subjects studied had an initial mean±SD eGFR of 78±29 ml/min per 1.73 m(2) and median (interquartile range) proteinuria of 1.2 (0.7-2.3) g/d, and 36% of subjects had cellular or fibrocellular crescents. Overall, crescents predicted a higher risk of a combined event, although this remained significant only in patients not receiving immunosuppression. Having crescents in at least one sixth or one fourth of glomeruli associated with a hazard ratio (95% confidence interval) for a combined event of 1.63 (1.10 to 2.43) or 2.29 (1.35 to 3.91), respectively, in all individuals. Furthermore, having crescents in at least one fourth of glomeruli independently associated with a combined event in patients receiving and not receiving immunosuppression. We propose adding the following crescent scores to the Oxford Classification: C0 (no crescents); C1 (crescents in less than one fourth of glomeruli), identifying patients at increased risk of poor outcome without immunosuppression; and C2 (crescents in over one fourth of glomeruli), identifying patients at even greater risk of progression, even with immunosuppression
Increased chemotaxis of CD25+ PBMC to tubular epithelial cells through glomerulotubular interaction in patients with familial IgA nephropathy
No full textIgA nephropathy (IgAN) patients with severe tubulointerstitial damage are often associated with more rapid progression to end-stage renal failure. We had demonstrated that a glomerulotubular cross-talk network orchestrates interactions between infiltrating immuno-competent cells and the proximal tubular epithelial cells (PTEC). We had further shown that when compared with sporadic IgAN patients, polymeric IgA1 (pIgA1) from patients with familial IgAN has higher reactivity to mesangial cells [Kidney Int 2009; 75:1330]. In this study, we investigated whether the glomerulotubular interaction in patients with familial IgAN, compared to sporadic IgAN, will enhance the chemotaxis of peripheral blood mononuclear cells (PBMC) towards tubulointerstitium enhancing tubulointerstitial injury. We used an in vitro transwell co-culture system of PTEC and PBMC to investigate the chemotaxis of PBMC towards PTEC following activation by conditioned medium prepared from HMC cultured with pIgA1 from patients with familial IgAN (n=60) or sporadic IgAN (n=43), their asymptomatic relatives (n=181) and healthy subjects (n=43). Compared to sporadic IgAN, PTEC activated by conditioned medium from patients with familial IgAN had elevated mRNA expression of CCL2/MCP-1, CCL5/RANTES and CXCL8/IL-8. In response to conditioned medium from patients with familial IgAN, there was increase transmigration of (i) monocyte, and (ii) CD20+, CD4+ and CD8+ lymphocytes (including CD4/CD8 ratio) were shown by flow cytometry analysis. Interestingly, the percentages of CD25+ monocytes and CD25+ lymphocytes were also increased in experiments with conditioned medium from patients with familial IgAN. The up-regulated CD25 expression in transmigrated PBMC was further demonstrated by quantitative RT-PCR. Our results suggest that PTEC activated by conditioned medium from patients with familial IgAN have higher ability to promote activation and chemotaxis of immunocompetent cells. This enhanced chemotaxis through glomerulotubular interaction in patients with familial IgAN may implicate a relentless progression of familial IgAN.Renal Week 2009 - The 2009 Annual Meeting of the American Society of Nephrology (ASN), San Diego, CA., 27 October-1 November 2009. In Renal Week 2009 Digital Abstract Book, 2009, p. 307
Evaluating a New International Risk-Prediction Tool in IgA Nephropathy
No full textImportanceAlthough IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, there is no validated tool to predict disease progression. This limits patient-specific risk stratification and treatment decisions, clinical trial recruitment, and biomarker validation. ObjectiveTo derive and externally validate a prediction model for disease progression in IgAN that can be applied at the time of kidney biopsy in multiple ethnic groups worldwide. Design, Setting, and ParticipantsWe derived and externally validated a prediction model using clinical and histologic risk factors that are readily available in clinical practice. Large, multi-ethnic cohorts of adults with biopsy-proven IgAN were included from Europe, North America, China, and Japan. Main Outcomes and MeasuresCox proportional hazards models were used to analyze the risk of a 50% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease, and were evaluated using the R-D(2) measure, Akaike information criterion (AIC), C statistic, continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and calibration plots. ResultsThe study included 3927 patients; mean age, 35.4 (interquartile range, 28.0-45.4) years; and 2173 (55.3%) were men. The following prediction models were created in a derivation cohort of 2781 patients: a clinical model that included eGFR, blood pressure, and proteinuria at biopsy; and 2 full models that also contained the MEST histologic score, age, medication use, and either racial/ethnic characteristics (white, Japanese, or Chinese) or no racial/ethnic characteristics, to allow application in other ethnic groups. Compared with the clinical model, the full models with and without race/ethnicity had better R-D(2) (26.3% and 25.3%, respectively, vs 20.3%) and AIC (6338 and 6379, respectively, vs 6485), significant increases in C statistic from 0.78 to 0.82 and 0.81, respectively (Delta C, 0.04; 95% CI, 0.03-0.04 and Delta C, 0.03; 95% CI, 0.02-0.03, respectively), and significant improvement in reclassification as assessed by the NRI (0.18; 95% CI, 0.07-0.29 and 0.51; 95% CI, 0.39-0.62, respectively) and IDI (0.07; 95% CI, 0.06-0.08 and 0.06; 95% CI, 0.05-0.06, respectively). External validation was performed in a cohort of 1146 patients. For both full models, the C statistics (0.82; 95% CI, 0.81-0.83 with race/ethnicity; 0.81; 95% CI, 0.80-0.82 without race/ethnicity) and R-D(2) (both 35.3%) were similar or better than in the validation cohort, with excellent calibration. Conclusions and RelevanceIn this study, the 2 full prediction models were shown to be accurate and validated methods for predicting disease progression and patient risk stratification in IgAN in multi-ethnic cohorts, with additional applications to clinical trial design and biomarker research
Evaluating a New International Risk-Prediction Tool in IgA Nephropathy
No full textImportanceAlthough IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, there is no validated tool to predict disease progression. This limits patient-specific risk stratification and treatment decisions, clinical trial recruitment, and biomarker validation. ObjectiveTo derive and externally validate a prediction model for disease progression in IgAN that can be applied at the time of kidney biopsy in multiple ethnic groups worldwide. Design, Setting, and ParticipantsWe derived and externally validated a prediction model using clinical and histologic risk factors that are readily available in clinical practice. Large, multi-ethnic cohorts of adults with biopsy-proven IgAN were included from Europe, North America, China, and Japan. Main Outcomes and MeasuresCox proportional hazards models were used to analyze the risk of a 50% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease, and were evaluated using the R-D(2) measure, Akaike information criterion (AIC), C statistic, continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and calibration plots. ResultsThe study included 3927 patients; mean age, 35.4 (interquartile range, 28.0-45.4) years; and 2173 (55.3%) were men. The following prediction models were created in a derivation cohort of 2781 patients: a clinical model that included eGFR, blood pressure, and proteinuria at biopsy; and 2 full models that also contained the MEST histologic score, age, medication use, and either racial/ethnic characteristics (white, Japanese, or Chinese) or no racial/ethnic characteristics, to allow application in other ethnic groups. Compared with the clinical model, the full models with and without race/ethnicity had better R-D(2) (26.3% and 25.3%, respectively, vs 20.3%) and AIC (6338 and 6379, respectively, vs 6485), significant increases in C statistic from 0.78 to 0.82 and 0.81, respectively (Delta C, 0.04; 95% CI, 0.03-0.04 and Delta C, 0.03; 95% CI, 0.02-0.03, respectively), and significant improvement in reclassification as assessed by the NRI (0.18; 95% CI, 0.07-0.29 and 0.51; 95% CI, 0.39-0.62, respectively) and IDI (0.07; 95% CI, 0.06-0.08 and 0.06; 95% CI, 0.05-0.06, respectively). External validation was performed in a cohort of 1146 patients. For both full models, the C statistics (0.82; 95% CI, 0.81-0.83 with race/ethnicity; 0.81; 95% CI, 0.80-0.82 without race/ethnicity) and R-D(2) (both 35.3%) were similar or better than in the validation cohort, with excellent calibration. Conclusions and RelevanceIn this study, the 2 full prediction models were shown to be accurate and validated methods for predicting disease progression and patient risk stratification in IgAN in multi-ethnic cohorts, with additional applications to clinical trial design and biomarker research.Nephrolog
