Association of kidney fibrosis with urinary peptides: a path towards non-invasive liquid biopsies?

Abstract

Chronic kidney disease (CKD) is a prevalent cause of morbidity and mortality worldwide. A hallmark of CKD progression is renal fibrosis characterized by excessive accumulation of extracellular matrix (ECM) proteins. In this study, we aimed to investigate the correlation of the urinary proteome classifier CKD273 and individual urinary peptides with the degree of fibrosis. In total, 42 kidney biopsies and urine samples were examined. The percentage of fibrosis per total tissue area was assessed in Masson trichrome stained kidney tissues. The urinary proteome was analysed by capillary electrophoresis coupled to mass spectrometry. CKD273 displayed a significant and positive correlation with the degree of fibrosis (Rho = 0.430, P = 0.0044), while the routinely used parameters (glomerular filtration rate, urine albumin-to-creatinine ratio and urine protein-to-creatinine ratio) did not (Rho = −0.222; −0.137; −0.070 and P = 0.16; 0.39; 0.66, respectively). We identified seven fibrosis-associated peptides displaying a significant and negative correlation with the degree of fibrosis. All peptides were collagen fragments, suggesting that these may be causally related to the observed accumulation of ECM in the kidneys. CKD273 and specific peptides are significantly associated with kidney fibrosis; such an association could not be detected by other biomarkers for CKD. These non-invasive fibrosis-related biomarkers can potentially be implemented in future trials.

Recent advances in capillary electrophoresis‐mass spectrometry: Instrumentation, methodology and applications

“…CKD273 was recently used to predict mortality in individuals with type 2 diabetes and their response to albuminuria treatment . Other examples for the application of multi‐dimensional marker were published , and the application of CE‐MS in urinary peptidomics for the diagnosis of CKD was reviewed recently . Urinary peptidomics by CE‐MS was furthermore used for the identification of biomarkers for chronic obstructive pulmonary disease , diastolic left ventricular dysfunction , end‐stage renal disease , chronic graft‐versus‐host disease , non‐alcoholic fatty liver disease and systemic lupus erythematosus .…”

Kidney protective effects of baroreflex activation therapy in patients with resistant hypertension

“…There is evidence that CKD273 can directly reflect early kidney damage, as it is associated with renal fibrosis . This was also demonstrated with the correlation analysis of the baseline data, where CKD273 scores have a strong and significant correlation with eGFR (Figure ), superior to that of albuminuria (data are not shown).…”

Urinary Peptidomic Biomarkers in Kidney Diseases

“…Furthermore, urinary peptides may be used to diagnose and monitor renal fibrosis. Magalhaes et al [29] showed a significant and positive correlation between the urinary classifier CKD273 and the degree of fibrosis in 42 kidney biopsies, which could not be detected by the serum and urine biochemical parameters routinely used to estimate the severity of CKD. Seven fibrosis-associated collagen fragments displayed a negative association with the degree of fibrosis, which suggests they have a causal relation to the accumulation of extracellular matrix observed in renal tissue [29].…”

“…Magalhaes et al [29] showed a significant and positive correlation between the urinary classifier CKD273 and the degree of fibrosis in 42 kidney biopsies, which could not be detected by the serum and urine biochemical parameters routinely used to estimate the severity of CKD. Seven fibrosis-associated collagen fragments displayed a negative association with the degree of fibrosis, which suggests they have a causal relation to the accumulation of extracellular matrix observed in renal tissue [29]. Interestingly, some CKD-associated abnormalities such as reduction of collagen fragments were found to correlate with aging in adults [30], suggesting a reduced turnover of extracellular matrix promoting fibrosis as a major mechanism of kidney aging.…”