SOLIDIFIED GLOMERULOSCLEROSIS, A UNIQUE PATHOLOGICAL CHANGE IDENTIFIED USING SINGLE GLOMERULAR PROTEOMICS, PREDICTS END-STAGE RENAL DISEASE IN CHINESE PATIENTS WITH TYPE 2 DIABETES

L ZHAO1, F LIU1, J ZHOU2, M E COOPER3

1West China Hospital of Sichuan University, Chengdu, China, 2Baylor University Medical Center at Dallas, Houston, USA, 3Monash University, Melbourne, Australia

Background and aims: There are few histological prognostic indicators for diabetic end-stage renal disease (ESRD) that have been validated in Chinese patients. This biopsy-based study aimed to determine nephropathologic risk factors for ESRD in Chinese patients with type 2 diabetes.

Methods: The histological characteristics of 322 Chinese type 2 diabetic patients with diabetic nephropathy (DN) confirmed by biopsy between 2003 and 2018 were retrospectively analyzed. A competing risk model, with death as the competing risk, was used to estimate the sub-distribution hazard ratio (SHR) for ESRD. Single glomerular proteomics combined with immunohistochemistry staining were used to identify differentially expressed proteins and enriched pathways in formalin-fixed paraffin-embedded glomeruli.

Results: During a median follow-up period of 24 months, 144 (45%) patients progressed to ESRD. In multivariable models, the Renal Pathology Society (RPS) classification failed to predict ESRD, but solidified glomerulosclerosis (score 1: SHR 1.76, 95% confidence interval [CI] 1.11–2.81; score 2: SHR 2.39, 95% CI 1.32–4.31) and extra-capillary hypercellularity (SHR 2.74, 95% CI 1.77–4.26) were identified as independent risk factors for ESRD. Additionally, single glomerular proteomics revealed that the principal identified proteins were components of the extracellular matrix (collagen alpha-1/-2/-3 chain), involved in cytoskeleton organization (vimentin , actin, filamin-A, and talin-1), and regulators of glycolytic process in solidified glomerulosclerosis, which was similar with Kimmelstiel–Wilson (KW) lesions. The single glomerular proteomics combined with immunohistochemistry staining revealed that complement C9 and apolipoprotein E were highly expressed in solidified glomerulosclerosis.

Conclusions: Solidified glomerulosclerosis and extra-capillary hypercellularity predict diabetic ESRD in Chinese patients. Single glomerular proteomics identified solidified glomerulosclerosis as a unique pathologic change, which may be associated with complement overactivation and a lipid metabolism abnormality. Prospective studies of larger cohorts should be performed to validate the prognostic utility of these pathological findings.


Biography:

Lecture of Nephrology, West China Hospital.

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