Serum uromodulin-a marker of kidney function and renal parenchymal integrity

Jürgen E Scherberich, Rudolf Gruber, Wolfgang Andreas Nockher, Erik Ilsø Christensen, Hans Schmitt, Victor Herbst, Matthias Block, Jürgen Kaden, Wolfgang Schlumberger, Jürgen E Scherberich, Rudolf Gruber, Wolfgang Andreas Nockher, Erik Ilsø Christensen, Hans Schmitt, Victor Herbst, Matthias Block, Jürgen Kaden, Wolfgang Schlumberger

Abstract

Background: An ELISA to analyse uromodulin in human serum (sUmod) was developed, validated and tested for clinical applications.

Methods: We assessed sUmod, a very stable antigen, in controls, patients with chronic kidney disease (CKD) stages 1-5, persons with autoimmune kidney diseases and recipients of a renal allograft by ELISA.

Results: Median sUmod in 190 blood donors was 207 ng/mL (women: men, median 230 versus 188 ng/mL, P = 0.006). sUmod levels in 443 children were 193 ng/mL (median). sUmod was correlated with cystatin C (rs = -0.862), creatinine (rs = -0.802), blood urea nitrogen (BUN) (rs = -0.645) and estimated glomerular filtration rate (eGFR)-cystatin C (rs = 0.862). sUmod was lower in systemic lupus erythematosus-nephritis (median 101 ng/mL), phospholipase-A2 receptor- positive glomerulonephritis (median 83 ng/mL) and anti-glomerular basement membrane positive pulmorenal syndromes (median 37 ng/mL). Declining sUmod concentrations paralleled the loss of kidney function in 165 patients with CKD stages 1-5 with prominent changes in sUmod within the 'creatinine blind range' (71-106 µmol/L). Receiver-operating characteristic analysis between non-CKD and CKD-1 was superior for sUmod (AUC 0.90) compared with eGFR (AUC 0.39), cystatin C (AUC 0.39) and creatinine (AUC 0.27). sUmod rapidly recovered from 0 to 62 ng/mL (median) after renal transplantation in cases with immediate graft function and remained low in delayed graft function (21 ng/mL, median; day 5-9: relative risk 1.5-2.9, odds ratio 1.5-6.4). Immunogold labelling disclosed that Umod is transferred within cytoplasmic vesicles to both the apical and basolateral plasma membrane. Umod revealed a disturbed intracellular location in kidney injury.

Conclusions: We conclude that sUmod is a novel sensitive kidney-specific biomarker linked to the structural integrity of the distal nephron and to renal function.

Keywords: kidney failure; renal biomarker; serum assay; thick ascending limb; uromodulin.

© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.

Figures

FIGURE 1
FIGURE 1
Relationship between serum uromodulin and creatinine (A), blood urea nitrogen (B), cystatin C (C) and eGFRcystC (D). rs: Spearman’s rank correlation coefficient.
FIGURE 2
FIGURE 2
Serum uromodulin concentration of patients without kidney diseases (non-CKD) and patients with CKD (stage 1 to stage 5) based on eGFRcysC assignment.
FIGURE 3
FIGURE 3
ROC analysing the ability of different parameters to differentiate patients without kidney disease (non-CKD) and CKD stage 1; BUN =  blood urea nitrogen, eGFR = estimated glomerular filtration rate, AUC =  area under the curve.
FIGURE 4
FIGURE 4
Post-kidney transplant comparison of serum uromodulin and creatinine in patients with immediate and delayed graft function.
FIGURE 5
FIGURE 5
Immunohistochemical distribution of Umod in the normal human kidney (a–c); semithin cryosections. (a) Apical, basolateral and cytoplasmatic staining, (b) transition of the thin ascending limb (negative) to the TAL (positive, arrows), (c) macula densa reveals a faint staining pattern only (arrowheads).
FIGURE 6
FIGURE 6
Immunogold labelling of Umod revealing the transport of the antigen within cytoplasmatic vesicles (small arrowheads) to the apical (a) as well as to the basolateral cell pole (b). Shuttle of uromodulin (c) from the endoplasmatic reticulum (RER) to the Golgi apparatus (G) (inset to C), through cytoplasmic vesicles (arrowheads). Basolateral membrane (BM) labelling (arrow). M, mitochondria.
FIGURE 7
FIGURE 7
Cartoon demonstrating the proposed bidirectional physiological transfer of Umod to the urinary space and to the tubulointerstitial space. As shown in Figure 6b, Umod is physiologically released from basolateral plasma membranes and membrane infoldings into the interstitium and enters the blood compartment (a). Umod serum levels are correlated with eGFR. sUmod concentrations may depend on the cellular integrity of the TAL segment. Therefore, sUmod might be released into serum at a decreased rate in renal injury (b).

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