Solidified glomerulosclerosis, identified using single glomerular proteomics, predicts end-stage renal disease in Chinese patients with type 2 diabetes

Zhao, Lijun; Liu, Fang; Li, Lin; Zhang, Junlin; Wang, Tingli; Zhang, Rui; Zhang, Wei; Yang, Xiaoyan; Zeng, Xiaoxi; Wang, Yiting; Wu, Yucheng; Yang, Hao; Wang, Shisheng; Zhong, Yi; Xu, Hong‐Xi; Wang, Shanshan; Guo, Renhua; Ren, Honghong; Yang, Lichuan; Su, Baihai; Zhang, Jie; Tong, Nanwei; Zhou, Xin; Cooper, Mark E.

doi:10.1038/s41598-021-83856-z

Cited by 12 publications

(13 citation statements)

References 58 publications

(29 reference statements)

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“…Univariate and multivariate analysis showed that diabetes duration and baseline HbA1c were not associated with progression to ESKD in patients with T2D (data not shown), which was consistent with previous studies ( 21 , 25 , 48 ). In a prospective analysis of patients with T2D, the coefficient of HbA1c variation, not the mean of serially measured fasting plasma glucose, was predictive of the development of renal complications and diabetes-related outcomes ( 49 ).…”

Section: Discussionsupporting

confidence: 91%

“…Arteriolar hyalinosis and arteriosclerosis were assessed and scored according to the RPS-DKD classification ( 24 ). In addition to the RPS-DKD classification, other pathological lesions, including global glomerulosclerosis, segmental sclerosis, extracapillary hypercellularity ( EXHC), the Kimmelstiel–Wilson (KW) lesion, mesangial proliferation, and capillary microaneurysms, were evaluated ( 25 ). The detailed definition of pathological parameters is listed in Supplementary Table 1 .…”

Section: Methodsmentioning

confidence: 99%

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Metabolic phenotypes and risk of end-stage kidney disease in patients with type 2 diabetes

Zhao

Zou

et al. 2023

Front. Endocrinol.

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BackgroundObesity often initiates or coexists with metabolic abnormalities. This study aimed to investigate the pathological characteristics and the independent or mutual relations of obesity and metabolic abnormalities with end-stage kidney disease (ESKD) in patients with type 2 diabetes (T2D) and associated diabetic kidney disease (DKD).MethodsA total of 495 Chinese patients with T2D and biopsy-confirmed DKD between 2003 and 2020 were enrolled in this retrospective study. The metabolic phenotypes were based on the body weight index (BMI)-based categories (obesity, BMI ≥ 25.0 kg/m2) and metabolic status (metabolically unhealthy status, ≥ 1 criterion National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III) excluding waist circumference and hyperglycemia) and were categorized into four types: metabolically healthy non-obesity (MHNO), metabolically healthy obesity (MHO), metabolically unhealthy non-obesity (MUNO), and metabolically unhealthy obesity (MUO). The pathological findings were defined by the Renal Pathology Society classification. Cox proportional hazards models were used to estimate hazard ratios (HRs) for ESKD.ResultsThere are 56 (11.3%) MHNO patients, 28 (5.7%) MHO patients, 176 (35.6%) MUNO patients, and 235 (47.5%) MUO patients. The high prevalence of the Kimmelstiel–Wilson nodule and severe mesangial expansion were associated with obesity, whereas severe IFTA was related to metabolically unhealthy status. In the multivariate analysis, the adjusted HR (aHR) was 2.09 [95% confidence interval (CI) 0.99–4.88] in the MHO group, 2.16 (95% CI 1.20–3.88) in the MUNO group, and 2.31 (95% CI 1.27–4.20) in the MUO group compared with the MHNO group. Furthermore, the presence of obesity was insignificantly associated with ESKD compared with non-obese patients (aHR 1.22, 95% CI 0.88–1.68), while the metabolically unhealthy status was significantly associated with ESKD compared to the metabolically healthy status in the multivariate analysis (aHR 1.69, 95% CI 1.10–2.60).ConclusionObesity itself was insignificantly associated with ESKD; however, adding a metabolically unhealthy status to obesity increased the risk for progression to ESKD in T2D and biopsy-proven DKD.

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Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Metabolic phenotypes and risk of end-stage kidney disease in patients with type 2 diabetes

Zhao

Zou

et al. 2023

Front. Endocrinol.

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“…Our previous study using single-nephron proteomic analysis and immunohistochemical staining suggested complement factors such as C3, C8, and C9 are overactivated in solidified glomerulosclerosis in patients with DN. Solidified glomerulosclerosis was shown to be an independent pathological finding that predicts future diabetic ESRD [ 43 ]. C9 binds C8 in the C5b-8 complex and forms the MAC that causes cellular and organ damage.…”

Section: Discussionmentioning

confidence: 99%

Urinary complement proteins and risk of end-stage renal disease: quantitative urinary proteomics in patients with type 2 diabetes and biopsy-proven diabetic nephropathy

Zhao

Zhang

Liu

et al. 2021

J Endocrinol Invest

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Purpose To investigate the association between urinary complement proteins and renal outcome in biopsy-proven diabetic nephropathy (DN). Methods Untargeted proteomic and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses and targeted proteomic analysis using parallel reaction-monitoring (PRM)-mass spectrometry was performed to determine the abundance of urinary complement proteins in healthy controls, type 2 diabetes mellitus (T2DM) patients, and patients with T2DM and biopsy-proven DN. The abundance of each urinary complement protein was individually included in Cox proportional hazards models for predicting progression to end-stage renal disease (ESRD). Results Untargeted proteomic and functional analysis using the KEGG showed that differentially expressed urinary proteins were primarily associated with the complement and coagulation cascades. Subsequent urinary complement proteins quantification using PRM showed that urinary abundances of C3, C9, and complement factor H (CFAH) correlated negatively with annual estimated glomerular filtration rate (eGFR) decline, while urinary abundances of C5, decay-accelerating factor (DAF), and CD59 correlated positively with annual rate of eGFR decline. Furthermore, higher urinary abundance of CFAH and lower urinary abundance of DAF were independently associated with greater risk of progression to ESRD. Urinary abundance of CFAH and DAF had a larger area under the curve (AUC) than that of eGFR, proteinuria, or any pathological parameter. Moreover, the model that included CFAH or DAF had a larger AUC than that with only clinical or pathological parameters. Conclusion Urinary abundance of complement proteins was significantly associated with ESRD in patients with T2DM and biopsy-proven DN, indicating that therapeutically targeting the complement pathway may alleviate progression of DN.

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“…To identify relevant studies, we searched databases, such as PubMed, Excerpta Medica Database, Cochrane library, and Web of Science, on September 2023 with medical subject heading terms and text words in multiple combinations: "diabetic nephropathy", "diabetic kidney disease", "crescent", and "extracapillary hypercellularity." Accordingly, 4 retrospective cohort studies including DKD patients were used because information on HRs of the ESKD outcome and the presence of glomerular crescents were available (22,23,24,25). The pooled effect estimates and associated 95% CIs were calculated using a common effect model.…”

Section: Discussionmentioning

confidence: 99%

Glomerular crescents are associated with the risk of type 2 diabetic kidney disease progression: a retrospective cohort study

Bae,

Yun,

Lee

et al. 2023

Preprint

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Background Diabetic kidney disease (DKD) stands as the predominant cause of chronic kidney disease and end-stage kidney disease. Its diverse range of manifestations complicates the treatment approach for patients. Although kidney biopsy is considered the gold standard for diagnosis, it lacks precision in predicting the progression of kidney dysfunction. Herein, we addressed whether the presence of glomerular crescents is linked to the outcomes in patients with biopsy-confirmed type 2 DKD. Methods A comprehensive review was conducted, involving 327 patients diagnosed with biopsy-confirmed DKD in the context of type 2 diabetes, excluding cases with other glomerular diseases, from nine tertiary hospitals. Hazard ratios (HRs) were calculated using a Cox regression model to assess the risk of kidney disease progression, defined as either ≥ 50% decrease in estimated glomerular filtration rates or the development of end-stage kidney disease, based on the presence of glomerular crescents. Results Out of ten patients (3.1%), glomerular crescents were observed in their biopsied tissues. Over the follow-up period (median of 19 months, with a maximum of 18 years), the crescent group exhibited a higher risk of kidney disease progression than the no crescent group, with an adjusted HR of 2.82 (1.32–6.06) (P = 0.008). The presence of heavy proteinuria was associated with an increased risk of developing glomerular crescents. Conclusion The presence of glomerular crescents is indeed linked to the progression of type 2 DKD. Therefore, it may be necessary to include histological monitoring of glomerular crescents in the management of patients to provide more intensive treatment.

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Solidified glomerulosclerosis, identified using single glomerular proteomics, predicts end-stage renal disease in Chinese patients with type 2 diabetes

Cited by 12 publications

References 58 publications

Metabolic phenotypes and risk of end-stage kidney disease in patients with type 2 diabetes

Metabolic phenotypes and risk of end-stage kidney disease in patients with type 2 diabetes

Urinary complement proteins and risk of end-stage renal disease: quantitative urinary proteomics in patients with type 2 diabetes and biopsy-proven diabetic nephropathy

Glomerular crescents are associated with the risk of type 2 diabetic kidney disease progression: a retrospective cohort study

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