Urine Complement Proteins and the Risk of Kidney Disease Progression and Mortality in Type 2 Diabetes

Vaisar, Tomáš; Durbin‐Johnson, Blythe; Whitlock, Kathryn B.; Babenko, Ilona; Mehrotra, Rajnish; Rocke, David M.; Afkarian, Maryam

doi:10.2337/dc18-0699

Cited by 25 publications

(20 citation statements)

References 35 publications

(34 reference statements)

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“…91 In addition, the analysis of urine samples of patients with diabetes has shown the excessive secretion of complement activation factors such as factor H-related protein 2, C3a, C5a, and C5b-9 that were positively correlated to the disease progression and increased mortality rate. 93,94 Overall, these studies confirm the involvement of the complement system in DKD.…”

Section: Activation Of the Complement Systemsupporting

confidence: 72%

Advances in understanding the innate immune‐associated diabetic kidney disease

Wan

Jiao

et al. 2021

FASEB j.

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Section: Activation Of the Complement Systemsupporting

confidence: 72%

Advances in understanding the innate immune‐associated diabetic kidney disease

Wan

Jiao

et al. 2021

FASEB j.

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“…Immunohistochemical staining confirmed increased staining of C7 in early DN kidneys compared with nondiabetic controls 35 . Furthermore, urinary concentrations of C3, C7, and C5b-9 correlate significantly with urinary protein excretion and eGFR in patients with diabetes 36 , 37 . However, it is less likely that nonspecific trapping of complement components in solidified glomeruli associated with DN occurs, because solidified glomeruli in FSGS do not show significant complement deposition, as in the present study.…”

Section: Discussionmentioning

confidence: 87%

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

Zhao

Liu

et al. 2021

Sci Rep

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Few histological prognostic indicators for end-stage renal disease (ESRD) have been validated in diabetic patients. This biopsy-based study aimed to identify nephropathological risk factors for ESRD in Chinese patients with type 2 diabetes. Histological features of 322 Chinese type 2 diabetic patients with biopsy-confirmed diabetic nephropathy (DN) were retrospectively analysed. Cox proportional hazards analysis was used to estimate the hazard ratio (HR) for ESRD. Single glomerular proteomics and immunohistochemistry were used to identify differentially expressed proteins and enriched pathways in glomeruli. During the median follow-up period of 24 months, 144 (45%) patients progressed to ESRD. In multivariable models, the Renal Pathology Society classification failed to predict ESRD, although the solidified glomerulosclerosis (score 1: HR 1.65, 95% confidence interval [CI] 1.04–2.60; score 2: HR 2.48, 95% CI 1.40–4.37) and extracapillary hypercellularity (HR 2.68, 95% CI 1.55–4.62) were identified as independent risk factors. Additionally, single glomerular proteomics, combined with immunohistochemistry, revealed that complement C9 and apolipoprotein E were highly expressed in solidified glomerulosclerosis. Therefore, solidified glomerulosclerosis and extracapillary hypercellularity predict diabetic ESRD in Chinese patients. Single glomerular proteomics identified solidified glomerulosclerosis as a unique pathological change that may be associated with complement overactivation and abnormal lipid metabolism.

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“…CD59 is a transmembrane protein that inhibits formation of the membrane attack complex (MAC), thereby protecting cells from complement-mediated injury. Vaisar et al reported that lower urinary CD59 was an independent predictor of higher risk of future ESRD and allcause mortality in a Mexican-American cohort with T2DM and CKD [32]. Transgenic mice expressing human DAF and CD59 had reduced C3 and C9 deposition in the kidney and inhibition of terminal complement pathway [42], suggesting that targeting DAF and CD59 may prevent renal injury.…”

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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Urine Complement Proteins and the Risk of Kidney Disease Progression and Mortality in Type 2 Diabetes

Abstract: In a largely Mexican American cohort with type 2 diabetes and proteinuric DKD, urine abundance of several complement and complement regulatory proteins was strongly associated with progression to ESRD and death.

Cited by 25 publications

References 35 publications

Advances in understanding the innate immune‐associated diabetic kidney disease

Advances in understanding the innate immune‐associated diabetic kidney disease

Solidified glomerulosclerosis, identified using single glomerular proteomics, predicts end-stage renal disease in Chinese 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

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