Novel Urinary Protein Biomarkers Predicting the Development of Microalbuminuria and Renal Function Decline in Type 1 Diabetes

Schlatzer, Daniela; Maahs, David M.; Chance, Mark R.; Dazard, Jean-Eudes; Li, Xin; Hazlett, Fred E.; Rewers, Marian; Snell‐Bergeon, Janet K.

doi:10.2337/dc11-1491

Cited by 52 publications

(39 citation statements)

References 40 publications

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“…Seven proteins were measured simultaneously by selected reaction monitoring (SRM) in the baseline sample. The proteins were chosen because they increased in the discovery proteomic analysis (haptoglobin, angiotensinogen, agrin and mannan-binding lectin serine protease 2), decreased in the proteomic analysis (LAMP-2) or were shown to increase in diabetic nephropathy in the literature (NGAL [26–28] and uromodulin [29]). Haptoglobin was able to discriminate between groups in this verification study but agrin was not (Figure 2).…”

Section: Resultsmentioning

confidence: 99%

Urine haptoglobin levels predict early renal functional decline in patients with type 2 diabetes

Bhensdadia

Hunt

Lopes‐Virella

et al. 2013

Kidney International

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Diabetic nephropathy is the leading cause of end stage renal disease. The urinary albumin to creatinine ratio is used as a predictor for the development of nephropathy but it is neither sensitive nor specific. Here we used liquid chromatography/mass spectrometry on urine of eight normoalbuminuric patients with type 2 diabetes from the VA Diabetes Trial to identify candidate markers for loss of renal function. Initial verification of 7 markers (agrin, haptoglobin, mannan-binding lectin serine protease 2, LAMP-2, angiotensinogen, NGAL and uromodulin) in the urine of an additional 30 patients showed that haptoglobin was the best predictor of early renal functional decline. We then measured this in the urine of 204 patients with type 2 diabetes who did not yet have significant kidney disease (eGFR stage 2 or better and an albumin to creatinine ratio less than 300 mg/g). In comparing the highest to lowest tertile, the odds ratio for having early renal function decline was 2.70 (CI 1.15, 6.32) using the haptoglobin to creatinine ratio compared to 2.50 (CI 1.14, 5.48) using the albumin to creatinine ratio after adjusting for treatment group and use of ACE inhibitors. Addition of the haptoglobin to creatinine ratio to a model using the albumin to creatinine ratio to predict early renal function decline resulted in improved predictive performance. Thus, the haptoglobin to creatinine ratio may be useful to predict patients with type 2 diabetes at risk of nephropathy prior to the development of macroalbuminuria or reduced GFR.

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Section: Resultsmentioning

confidence: 99%

Urine haptoglobin levels predict early renal functional decline in patients with type 2 diabetes

Bhensdadia

Hunt

Lopes‐Virella

et al. 2013

Kidney International

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“…Last, we used a commercially available ELISA, which has been evaluated in prior studies of clinical outcomes, to assay uromodulin in our study. 14,33-35 …”

Section: Discussionmentioning

confidence: 99%

Urinary Uromodulin and Risk of Urinary Tract Infections: The Cardiovascular Health Study

Garimella

Bartz

et al. 2017

American Journal of Kidney Diseases

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Background Laboratory studies suggest that urinary uromodulin, the most common protein in the urine of healthy adults, may protect against urinary tract infection (UTI). Epidemiological studies evaluating this relationship in humans are lacking. Study Design Prospective longitudinal cohort study. Setting & Participants 953 participants enrolled in the Cardiovascular Health Study. Predictor Uromodulin assayed using ELISA in spot urine samples. Outcomes Composite of outpatient UTI events or UTI-related hospitalizations and each of them individually identified using ICD-9 codes using negative binomial regression with robust standard errors adjustment for age, race, sex, body mass index, diabetes, eGFR, urinary albumin and urinary creatinine. Results The median uromodulin level was 25.9 (IQR, 17.3-38.9) μg/ml, the mean age of participants was 78 years, 61% were women, and 15% were Black. There were 331 outpatient UTI events and 87 UTI related hospitalizations among 186 participants over a median 9.9 years of follow up. Persons in the highest quartile (>38.93 μg/ml) of uromodulin concentration had a significantly lower risk of composite outcome (incidence rate ratio [IRR], 0.47; 95% CI, 0.29-0.79) compared to those in the lowest quartile (≤17.26 μg/ml). This association remained significant for outpatient UTI events (highest versus lowest quartile even after excluding those with prior UTI: IRR, 0.42; 95% CI, 0.23-0.77). The direction of association with UTI hospitalization was similar, but not statistically significant (IRR, 0.78; 95% CI, 0.39-1.58). Limitations Use of ICD-9 codes to identify outcomes and lack of generalizability to younger populations. Conclusions High urinary uromodulin levels are associated with a lower risk of UTI in older community dwelling adults independent of traditional UTI risk factors. This finding supports prior laboratory data indicating a protective role of uromodulin against UTI. Further research is needed to understand if this may lead to new treatments to prevent or treat UTI.

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“…Our results concur with the postulated function of apoJ as a part of the quality control system for preventing the accumulation of protein aggregates (4). apoJ expression increases during various physiologic and pathologic stresses (44, 46‐48), and its binding to client proteins in blood, such as albumin, fibrinogen, or ceruloplasmin, is promoted after inducing shear stress in plasma (6). In the context of cardiovascular disease, a number of studies have reported different protective effects of apoJ (49).…”

Section: Discussionmentioning

confidence: 99%

Clusterin/apolipoprotein J binds to aggregated LDL in human plasma and plays a protective role against LDL aggregation

et al. 2014

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Clusterin/apolipoprotein J (apoJ) is an extracellular chaperone involved in the quality control system against protein aggregation. A minor part of apoJ is transported in blood bound to LDLs, but its function is unknown. Our aim was to determine the role of apoJ bound to LDLs. Total LDL from human plasma was fractionated into native LDL [LDL(+)] and electronegative LDL [LDL(-)]. The latter was separated into nonaggregated [nagLDL(-)] and aggregated LDL(-) [agLDL(-)]. The content of apoJ was 6-fold higher in LDL(-) than in LDL(+) and 7-fold higher in agLDL(-) than in nagLDL(-). The proportion of LDL particles containing apoJ (LDL/J+) was 3-fold lower in LDL(+) than in LDL(-). LDL/J+ particles shared several characteristics with agLDL(-), including increased negative charge and aggregation. apoJ-depleted particles (LDL/J-) showed increased susceptibility to aggregation, whether spontaneous or induced by proteolysis or lipolysis, as was revealed by turbidimetric analysis, gel filtration chromatography, lipoprotein precipitation, native gradient gel electrophoresis, circular dichroism, and transmission electronic microscopy. The addition of purified apoJ to total LDL also prevented its aggregation induced by proteolysis or lipolysis. These findings point to apoJ as a key modulator of LDL aggregation and reveal a putative new therapeutic strategy against atherosclerosis.

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Novel Urinary Protein Biomarkers Predicting the Development of Microalbuminuria and Renal Function Decline in Type 1 Diabetes

Cited by 52 publications

References 40 publications

Urine haptoglobin levels predict early renal functional decline in patients with type 2 diabetes

Urine haptoglobin levels predict early renal functional decline in patients with type 2 diabetes

Urinary Uromodulin and Risk of Urinary Tract Infections: The Cardiovascular Health Study

Clusterin/apolipoprotein J binds to aggregated LDL in human plasma and plays a protective role against LDL aggregation

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