Abstract
Background and Aims
During the last years, with the increase in secondary diseases following obesity the focus on the context of abnormally high body weight and chronic kidney disease (CKD) has changed. While in individual care, CKD along with obesity and improving renal function along with weight loss can be seen frequently and trials on obesity reduction yielded promising renal results, systematic insight into the pathogenesis and epidemiology of nephropathy related to obesity without diabetes (Obesity-related nephropathy, ORN) is rather limited. This work reaches out to investigate impact of BMI on urine peptides and to characterize yet non-specified peptide patterns in urine that may be indicative of ORN and may indicate possible molecular mechanisms of ORN pathophysiology. We used urine samples from earlier projects which could be characterized for presence of diabetes, BMI, eGFR, and age. By defining such urinary peptide patterns, pathophysiology-enlightening hypotheses should be stimulated and pathways suggested to enable specific future characterization of ORN.
Method
In this study we investigated the association of urinary peptides with body mass index (BMI), and renal function in proteome datasets from 4015 individuals. For this study urinary proteome data stored in the Human Urine Proteome Database obtained by capillary electrophoresis coupled to mass spectrometry (CE-MS) were assessed.
Results
365 urinary peptides significantly associated with BMI could be identified. The majority of these peptides were collagen fragments. In addition, most of the peptides also demonstrated a significant concordant association with eGFR in the investigated cohort with diabetes exhibiting no significant association. A classifier based on 150 urine peptides enabled distinguishing non-obese subjects with preserved kidney function from obese, non-diabetic subjects with eGFR>45 mL/min/1.73m in an independent cohort with an area under curve (AUC) of 0.93 (Fig.). The vast majority of significantly associated peptides are specific collagen fragments, most of them from collagen type I, and most of them (in fact all of the 10 most significant ones) are reduced with increasing BMI.
Conclusion
These analyses in a huge cohort of urine samples from patients with known eGFR, BMI and diabetes status showed a complex multi-level association between peptide fragments with renal risk in obesity. Of particular note, these relationships could be retrieved although the overall cohort inherited an almost negative eGFR – BMI gross correlation, presumably due to the origin of the dataset from a non-obesity-directed approach. Most peptides associated with GFR and BMI belonged to the collagen superfamily and were inversely associated with BMI but directly with eGFR.
This concordant observation indicates a reduction of collagen degradation with increasing BMI and/or reduced kidney function. It is tempting to speculate that collagen homeostasis along with body mass on one hand, and kidney function on the other, are substantially interconnected. The very strict association of BMI with collagen fragments was surprising, but also indicates specificity.
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