Abstract
Use of immunosuppressive drugs is still unavoidable in kidney-transplanted patients. Since their discovery, calcineurin inhibitors (CNI) have been considered the first-line immunosuppressive agents, in spite of their known nephrotoxicity. Chronic CNI toxicity (CNIT) may lead to kidney fibrosis, a threatening scenario for graft survival. However, there is still controversy regarding CNIT diagnosis, monitoring and therapeutic management, and their specific effects at the molecular level are not fully known. Aiming to better characterize CNIT patients, in the present study, we collected urine from kidney-transplanted patients treated with CNI who (i) had a normal kidney function, (ii) suffered CNIT, or (iii) presented interstitial fibrosis and tubular atrophy (IFTA). Urinary extracellular vesicles (uEV) were enriched and the proteome was analyzed to get insight into changes happening during CNI. Members of the uroplakin and plakin families were significantly upregulated in the CNIT group, suggesting an important role in CNIT processes. Although biomarkers cannot be asserted from this single pilot study, our results evidence the potential of uEV as a source of non-invasive protein biomarkers for a better detection and monitoring of this renal alteration in kidney-transplanted patients.
Highlights
The calcineurin inhibitors (CNI) cyclosporine A [1,2] and tacrolimus have become the current first-line immunosuppressive agents in kidney transplantation [3,4,5] for more than 30 years
The diagnosis of CNI toxicity (CNIT) was further supported by the high blood levels of tacrolimus, determined according to the study by Cosio et al [21] or high blood levels of cyclosporine A based on the Symphony study [22]
The Urinary extracellular vesicles (uEV) proteome of kidney-transplanted patients diagnosed with CNIT was analyzed and compared to either kidney-transplanted patients with clinically normal kidney function or diagnosed with interstitial fibrosis and tubular atrophy (IFTA) without CNIT, all of them receiving a similar immunosuppressive regime including CNI
Summary
The calcineurin inhibitors (CNI) cyclosporine A [1,2] and tacrolimus have become the current first-line immunosuppressive agents in kidney transplantation [3,4,5] for more than 30 years. Acute CNIT (aCNIT) is histologically associated with the appearance of isometric vacuolization of the tubular epithelium [10,11,12], while chronic CNI (cCNIT) produces chronic renal lesions such as interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, and glomerulosclerosis [13,14], all contributing to the progressive and irreversible deterioration of the renal function and graft-loss [15,16] To avoid this scenario, CNI levels in patients should be maintained within a narrow therapeutic window, a big challenge due to the high inter- and intraindividual pharmacokinetic variability of these drugs [17,18]. There are currently no specific markers of CNIT, and tacrolimus or cyclosporine A trough levels not always correlate with CNIT [19]
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