Urinary measurement of Na+/H+ exchanger isoform 3 (NHE3) protein as new marker of tubule injury in critically ill patients with ARF

Am J Kidney Dis. 2003 Sep;42(3):497-506. doi: 10.1016/s0272-6386(03)00744-3.


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.

Publication types

  • Evaluation Study

MeSH terms

  • Acute Kidney Injury / etiology
  • Acute Kidney Injury / mortality
  • Acute Kidney Injury / urine*
  • Aged
  • Biomarkers / urine
  • Blotting, Western
  • Cell Membrane / chemistry
  • Creatinine / blood
  • Creatinine / urine
  • Female
  • Humans
  • Kidney Tubular Necrosis, Acute / complications
  • Kidney Tubular Necrosis, Acute / urine*
  • Kidney Tubules, Proximal / chemistry
  • Kidney Tubules, Proximal / physiopathology
  • Male
  • Middle Aged
  • Natriuresis
  • Protein Isoforms / urine
  • Retinol-Binding Proteins / urine
  • Sodium / metabolism
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers / urine*
  • Uremia / urine


  • Biomarkers
  • Protein Isoforms
  • Retinol-Binding Proteins
  • SLC9A3 protein, human
  • Slc9a3 protein, rat
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers
  • Sodium
  • Creatinine