Original investigations: pathogenesis and treatment of kidney disease and hypertension
Urinary measurement of Na+/H+ exchanger isoform 3 (NHE3) protein as new marker of tubule injury in critically ill patients with ARF

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Abstract

Background: It has been shown that apical sodium transporters of the renal tubule can be detected by immunoblotting of urine membrane fraction from rats. We raised the hypothesis that protein levels of the Na+/H+ exchanger isoform 3 (NHE3), the most abundant apical sodium transporter in renal tubule, should be increased in urine of patients presenting with acute renal failure (ARF) with severe tubular cell damage and thus might be a noninvasive marker of acute tubular necrosis (ATN). Methods: Sixty-eight patients admitted to the intensive care unit were studied prospectively (54 patients with ARF, 14 controls without renal dysfunction). Patients with ARF were divided into 3 subgroups as follows: prerenal azotemia, ATN, and intrinsic ARF other than ATN. Urinary NHE3 protein abundance was estimated from semiquantitative immunoblots of urine membrane fraction samples collected from patients. The amount of urinary NHE3 was compared with the fractional excretion of sodium (FeNa) and urinary retinol-binding protein (RBP). Results: NHE3 was not detected in urine from controls. Levels of urinary NHE3 normalized to urinary creatinine level were increased in patients with prerenal azotemia and 6 times as much in patients with ATN, without overlap (ATN, 0.78 ± 0.36; prerenal azotemia, 0.12 ± 0.08; P < 0.001). Conversely, urinary NHE3 protein was not detected in patients with intrinsic ARF other than ATN. Normalized NHE3 level correlated positively with serum creatinine level in patients with tubular injury (R2 = 0.305; P = 0.0003). Values for FeNa and normalized urinary RBP did not discriminate ATN from intrinsic ARF other than ATN and prerenal azotemia, respectively. Conclusion: In patients with ARF, urinary NHE3 abundance might be a novel noninvasive marker of renal tubule damage, helping to differentiate prerenal azotemia, ATN, and intrinsic ARF other than ATN.

Section snippets

Study population

The study was approved by the Ethics Committee of the University Hospital of Caen (France) and conducted in a 22-bed medical ICU between September 2001 and June 2002. All consecutive patients admitted to the ICU with ARF or who developed ARF during their ICU stay were enrolled in the study if they met the following criteria (described in5, 24): ARF defined as a sudden increase in serum creatinine level to 2 mg/dL (177 μmol/L) or greater to a value 50% greater than the basal concentration when

Patient characteristics

Patient characteristics are listed in Table 1, Table 2. Sixty-eight intensive care patients were enrolled in the study. Patients were divided into 2 groups depending on the presence or absence of ARF when admitted to the ICU: a group of 54 patients with ARF and a group of 14 patients without renal dysfunction (control group). There were no statistically significant differences between groups for age, sex, admission type, or McCabe score. Severity of critical diseases, assessed by means of

Discussion

The aim of the present study is to test whether urinary NHE3 might be used as a marker of renal tubule injury. Our initial hypothesis was that urinary NHE3 protein level should be increased in patients with ATN, in whom renal tubular reabsorption of sodium chloride is expected to be decreased.1 We also looked for an abundance of NHE3 protein in urine from patients with prerenal azotemia, in which tubular reabsorption of sodium chloride usually is thought to be preserved, which suggests the

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    Copyright © 2003 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.