Serum uromodulin is associated with the severity of clinicopathological findings in ANCA-associated glomerulonephritis

Abstract

BackgroundUromodulin (UMOD), also known as Tamm-Horsfall protein, is a kidney-specific protein expressed by epithelial cells lining the thick ascending limb of the loop of Henle. In the current study, we aimed to clarify the clinical significance of UMOD in ANCA-associated glomerulonephritis (AAG).Materials and methodsSixty-one biopsy-proven AAG patients were included in this study. UMOD was measured using ELISA. The relationships between serum UMOD (sUMOD) levels and various clinicopathological findings were evaluated.ResultsAAG was classified into four categories (focal, crescentic, mixed, and sclerotic). In addition, tubulointerstitial lesions were classified as mild, moderate, and severe. The levels of sUMOD and urinary UMOD (uUMOD) were correlated with each other. A negative correlation between sUMOD levels and serum Cr levels, and positive correlation between sUMOD levels and eGFR were found. Patients in the high sUMOD group were associated with low serum Cr levels, focal classification, and mild tubulointerstitial injury compared to the low sUMOD group. Comparing the characteristics among histopathological classes, patients in the focal class had the best renal function and the highest levels of uUMOD/Cr and sUMOD. The focal class had significantly better renal survival compared with the severe histopathological classes (crescentic, mixed, and sclerotic). In univariate logistic regression analyses, prognostic factors for severe histopathological classes were low uUMOD/Cr, high serum Cr, and low sUMOD. Multivariate analyses revealed that low sUMOD predicted severe histopathological classes independent of serum Cr. The mean levels of sUMOD were significantly different between the focal class and severe histopathological classes, with a sensitivity of 70.6% and specificity of 90.0% (cut-off 143 ng/ml, AUC 0.80) by ROC curves.ConclusionLow sUMOD levels were associated with severe clinicopathological findings and might be considered as a risk factor for end stage renal disease in AAG.

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“…For example, the top 10 specific genes of kidney are UMOD, SLC22A8, SLC22A12, SLC12A1, SLC22A11, AQP2, SLC12A3, NPHS2, KCNJ1, and SLC22A2. As previous studies reported, uromodulin (UMOD) is a kidney-specific protein ( Tachibana et al, 2019 ) expressed by epithelial cells lining the thick ascending limb of the loop of Henle, the accumulation of mutated UMOD in endoplasmic reticulum can lead to renal injury ( Johnson et al, 2017 ; Trudu et al, 2017 ). In addtion, recent literature also demonstrated that mutation of aquaporin 2 (AQP2) is able to cause nephrogenic diabetes insipidus since AQP2 is responsible for the water reabsorption by kidney collecting duct cells ( Saglar Ozer et al, 2020 ).…”

Olfactomedin 4 as a novel loop of Henle‐specific acute kidney injury biomarker

“…Tamm‐Horsfall protein, or uromodulin, has been the main protein biomarker to date associated with the TALH (El‐Achkar et al, 2013 ; Wen & Parikh, 2021 ). Previous work has shown a negative correlation between serum uromodulin and AKI in conditions like ANCA‐associated vasculitis (Tachibana et al, 2019 ) and ischemia–reperfusion injury (IRI; El‐Achkar et al, 2013 ), and between urine uromodulin and AKI in diabetes (Chakraborty et al, 2004 ) and patients undergoing cardiac surgery (Zhang et al, 2022 ). Osteopontin, a bone phosphoprotein, is produced predominantly in the TALH but also in the distal convoluted tubule.…”

A Review of Specific Biomarkers of Chronic Renal Injury and Their Potential Application in Nonclinical Safety Assessment Studies

“…8 Several studies have reported direct correlations between serum/plasma UMOD levels and kidney function. 89,[346][347][348] Because serum UMOD often correlates significantly with albuminuria, which is itself a strong predictor of CKD progression, UMOD may also play an important role in the prediction of CKD progression. 349 One prospective study showed that low serum UMOD concentrations in CKD patients was associated with an increased risk of ESRD, independent of the traditional risk factors for progression of CKD.…”