Urinary glycated uromodulin in diabetic kidney disease

Abstract

Advanced glycation end-products (AGEs) form during oxidative stress, which is increased in diabetes mellitus (DM). Uromodulin is a protein with a renal protective effect, and may be subject to glycation. The implications of uromodulin glycation and AGEs in the urine are not understood. Here, immunoprecipitation and liquid chromatography-mass spectrometry identified glycated uromodulin (glcUMOD) in the urine of 62.5% of patients with diabetic kidney disease (DKD), 20.0% of patients with non-diabetic chronic kidney disease (CKD), and no DM patients with normal renal function or healthy control participants; a finding replicated in a larger cohort of 84 patients with CKD in a case-control study (35 with DM, 49 without). Uromodulin forms high molecular weight polymers that associate with microvesicles and exosomes. Differential centrifugation identified uromodulin in the supernatant, microvesicles, and exosomes of the urine of healthy participants, but only in the supernatant of samples from patients with DKD, suggesting that glycation influences uromodulin function. Finally, the diagnostic and prognostic utility of measuring urinary glcUMOD concentration was examined. Urinary glcUMOD concentration was substantially higher in DKD patients than non-diabetic CKD patients. Urinary glcUMOD concentration predicted DKD status, particularly in patients with CKD stages 1-3a aged <65 years and with urine glcUMOD concentration 9,000 arbitrary units (AU). Urinary uromodulin is apparently glycated in DKD and forms AGEs, and glcUMOD may serve as a biomarker for DKD.

Association of serum and urinary uromodulin and their correlates in older adults—The Cardiovascular Health Study

“…Ideally, future studies would evaluate patients with similar eGFR in a CKD population with distinct kidney pathologies. Last, it is possible that uUMOD glycation in diabetic kidney disease might influence accurate measurement of uUMOD …”

The Multifunctionality of CD36 in Diabetes Mellitus and Its Complications—Update in Pathogenesis, Treatment and Monitoring

“…The activated signaling pathway includes the activation of Src kinase, proapoptotic p38 MAPK, and caspase 3 [ 192 ], as in the cases of the studies on macrophages [ 198 ] and vascular endothelial cells [ 199 ]. Elevated levels of AGEs [ 200 , 201 ] and FAs [ 202 ] were found in the urine of patients with DN, suggesting that their accumulation in the tubular cells contributes to damage of the renal tubules. Moreover, CD36 contributes to interstitial fibrosis mainly by the activation of the pathways that result in TGF-β and ECM protein secretion.…”

The role of mass spectrometry in studies of glycation processes and diabetes management

“…Moreover, another advantage of using urine, instead of blood, is its easy and non‐invasive collection that allows repeated sampling for disease monitoring. In the last years, several studies have been performed, in urines, aiming to identify biomarkers that can detect early stages of DN and progressive kidney function decline in diabetic patients, as well as biomarkers that can allow for a non‐invasive diagnosis of kidney disease (Chang et al ., ; Chu et al ., ; Manwaring et al ., ; Merchant et al ., ; Lewandowicz et al ., ; Siwy et al ., ; Vitova et al ., ; Wheelock et al ., ).…”

“…Moreover, another advantage of using urine, instead of blood, is its easy and non-invasive collection that allows repeated sampling for disease monitoring. In the last years, several studies have been performed, in urines, aiming to identify biomarkers that can detect early stages of DN and progressive kidney function decline in diabetic patients, as well as biomarkers that can allow for a non-invasive diagnosis of kidney disease (Chang et al, 2017;Chu et al, 2013;Manwaring et al, 2013;Merchant et al, 2013;Lewandowicz et al, 2015;Siwy et al, 2017;Vitova et al, 2017;Wheelock et al, 2017). Siwy et al (2017) by using CE-MS aimed to verify if urinary proteome analysis holds information on disease etiology and allows to discriminate among seven different types of CKD that in the current clinical practice are defined by pathological assessment of renal biopsies.…”

“…Apart from the above studies performed in plasma, DN‐related studies are preferentially performed by analyzing urine samples, since urine contains fewer proteins, and because alterations in the constituents of urine may directly reflect changes in kidney functions (Chang et al ., ), while blood reflects the ongoing physiologic state of all tissues (Liotta et al ., ). Moreover, another advantage of using urine, instead of blood, is its easy and non‐invasive collection that allows repeated sampling for disease monitoring.…”