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      Development and validation of a predictive model for end-stage renal disease risk in patients with diabetic nephropathy confirmed by renal biopsy

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          Abstract

          This study was performed to develop and validate a predictive model for the risk of end-stage renal disease (ESRD) inpatients with diabetic nephropathy (DN) confirmed by renal biopsy. We conducted a retrospective study with 968 patients with T2DM who underwentrenal biopsy for the pathological confirmation of DNat the First Affiliated Hospital of Zhengzhou University from February 2012 to January 2015; the patients were followed until December 2018. The outcome was defined as a fatal or nonfatal ESRD event (peritoneal dialysis or hemodialysis for ESRD, renal transplantation, or death due to chronic renal failure or ESRD). The dataset was randomly split into development (75%) and validation (25%) cohorts. We used stepwise multivariablelogistic regression to identify baseline predictors for model development. The model’s performance in the two cohorts, including discrimination and calibration, was evaluated by the C-statistic and the P value of the Hosmer-Lemeshow test. During the 3-year follow-up period, there were 225 outcome events (47.1%) during follow-up. Outcomes occurred in 187 patients (52.2%) in the derivation cohort and 38 patients (31.7%) in the validation cohort. The variables selected in the final multivariable logistic regression after backward selection were pathological grade, Log Urinary Albumin-to-creatinine ratio (Log ACR), cystatin C, estimated glomerular filtration rate (eGFR) and B-type natriuretic peptide (BNP). 4 prediction models were created in a derivation cohort of 478 patients: a clinical model that included cystatin C, eGFR, BNP, Log ACR; a clinical-pathological model and a clinical-medication model, respectively, also contained pathological grade and renin-angiotensin system blocker (RASB) use; and a full model that also contained the pathological grade, RASB use and age. Compared with the clinical model, the clinical-pathological model and the full model had better C statistics (0.865 and 0.866, respectively, vs. 0.864) in the derivation cohort and better C statistics (0.876 and 0.875, respectively, vs. 0.870) in the validation cohort. Among the four models, the clinical-pathological model had the lowest AIC of 332.53 and the best P value of 0.909 of the Hosmer-Lemeshow test. We constructed a nomogram which was a simple calculator to predict the risk ratio of progression to ESRD for patients with DN within 3 years. The clinical-pathological model using routinely available clinical measurements was shown to be accurate and validated method for predicting disease progression in patients with DN. The risk model can be used in clinical practice to improve the quality of risk management and early intervention.

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          Pathologic classification of diabetic nephropathy.

          Although pathologic classifications exist for several renal diseases, including IgA nephropathy, focal segmental glomerulosclerosis, and lupus nephritis, a uniform classification for diabetic nephropathy is lacking. Our aim, commissioned by the Research Committee of the Renal Pathology Society, was to develop a consensus classification combining type1 and type 2 diabetic nephropathies. Such a classification should discriminate lesions by various degrees of severity that would be easy to use internationally in clinical practice. We divide diabetic nephropathy into four hierarchical glomerular lesions with a separate evaluation for degrees of interstitial and vascular involvement. Biopsies diagnosed as diabetic nephropathy are classified as follows: Class I, glomerular basement membrane thickening: isolated glomerular basement membrane thickening and only mild, nonspecific changes by light microscopy that do not meet the criteria of classes II through IV. Class II, mesangial expansion, mild (IIa) or severe (IIb): glomeruli classified as mild or severe mesangial expansion but without nodular sclerosis (Kimmelstiel-Wilson lesions) or global glomerulosclerosis in more than 50% of glomeruli. Class III, nodular sclerosis (Kimmelstiel-Wilson lesions): at least one glomerulus with nodular increase in mesangial matrix (Kimmelstiel-Wilson) without changes described in class IV. Class IV, advanced diabetic glomerulosclerosis: more than 50% global glomerulosclerosis with other clinical or pathologic evidence that sclerosis is attributable to diabetic nephropathy. A good interobserver reproducibility for the four classes of DN was shown (intraclass correlation coefficient = 0.84) in a test of this classification.
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            Evaluating a New International Risk-Prediction Tool in IgA Nephropathy

            This modeling study uses international, multi-ethnic derivation and validation cohorts of patients with biopsy-proven IgA nephropathy to evaluate a risk-prediction tool for 50% decline in kidney function or end-stage renal disease. How can we better predict, at the time of kidney biopsy, the risk of a 50% decline in kidney function or end-stage renal disease in patients with IgA nephropathy? Large international multiethnic cohorts including 3927 patients were enrolled to both derive and externally validate 2 prediction models, one that included patient race/ethnicity, and one that did not. Both models outperformed clinical measures for prediction of kidney disease progression and patient risk stratification. The 2 prediction models were shown to be accurate and validated methods to help clinicians improve management and treatment of IgA nephropathy in multi-ethnic cohorts and may aid international researchers in trial recruitment. Although 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. To 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. We 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. Cox 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 2 D measure, Akaike information criterion (AIC), C statistic, continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and calibration plots. The 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 2 D (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 (ΔC, 0.04; 95% CI, 0.03-0.04 and ΔC, 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 2 D (both 35.3%) were similar or better than in the validation cohort, with excellent calibration. In 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.
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              Clinical implications of pathologic diagnosis and classification for diabetic nephropathy.

              The usefulness of renal pathologic diagnosis in type II DM (diabetes mellitus) remains debate. We grouped the pathologic diagnoses as pure DN (diabetic nephropathy), NDRD (non-diabetic renal disease), and NDRD mixed with DN (Mixed). We classified pure DN as the criteria suggested by Tervaert. We compared the accuracy of clinical parameters to predict DN and usefulness of pathology to predict renal prognosis. Among 126 enrolled patients, there were 50 pure DN, 65 NDRN, and 11 Mixed. The sensitivity and specificity for predicting DN with the presence of retinopathy were 77.8-73.6% and, with a cut-off value of 7.5 years of diabetic duration, the sensitivity and specificity were 64.5-67.2%. ESRD (end stage renal disease) occurred in 44.0% of DN, 18.2% of Mixed, and 12.3% of NDRD (p<0.001). Among pure DN, Class IV showed the lowest estimated glomerular filtration rate (eGFR). We estimated the 5-year renal survival rate as 100.0% in Classes I and IIa, 75.0% in Class IIb, 66.7% in Class III, and 38.1% in Class IV (p=0.002). Nephropathy of type II DM was diverse and could not be completely predicted by clinical parameters. The renal pathologic diagnosis was a good predictor for renal prognosis in type II DM. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
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                Author and article information

                Contributors
                Journal
                PeerJ
                PeerJ
                peerj
                peerj
                PeerJ
                PeerJ Inc. (San Diego, USA )
                2167-8359
                11 February 2020
                2020
                : 8
                : e8499
                Affiliations
                [-1] Nephrology Hospital, the First Affiliated Hospital of Zhengzhou University , Zhengzhou, Henan province, China
                Article
                8499
                10.7717/peerj.8499
                7020820
                32095345
                4db48894-69e9-424b-890f-a78c7ca18aa9
                ©2020 Sun et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

                History
                : 27 September 2019
                : 31 December 2019
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81570690, 81873611 and 81700633
                Funded by: Science and Technology Innovation Team of Henan
                Award ID: 17IRTSTHN020
                Funded by: Foundation for Leading Personnel of the Central Plains of China
                Award ID: 194200510006
                Funded by: China Postdoctoral Science Foundation
                Award ID: 2018M642797
                This work was supported by the National Natural Science Foundation of China (Grant Nos. 81570690, 81873611 and 81700633), the Science and Technology Innovation Team of Henan (Grant No. 17IRTSTHN020), the Foundation for Leading Personnel of the Central Plains of China (Grant No. 194200510006) and the China Postdoctoral Science Foundation (Grant No. 2018M642797). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Bioinformatics
                Diabetes and Endocrinology
                Internal Medicine
                Nephrology
                Public Health

                diabetic nephropathy,type 2 diabetes mellitus,risk equation,risk factors,chronic kidney disease,end-stage renal disease,renal biopsy

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