Effect of Renin-Angiotensin-Aldosterone System Inhibition, Dietary Sodium Restriction, and/or Diuretics on Urinary Kidney Injury Molecule 1 Excretion in Nondiabetic Proteinuric Kidney Disease: A Post Hoc Analysis of a Randomized Controlled Trial
Received 17 February 2007; accepted 7 July 2008. published online 29 September 2008.
Refers to article:
Kidney Injury Molecule 1: In Search of Biomarkers of Chronic Tubulointerstitial Damage and Disease Progression
Norberto Perico, Dario Cattaneo, Giuseppe Remuzzi
American Journal of Kidney Diseases
January 2009 (Vol. 53, Issue 1, Pages 1-4) Full Text |
Full-Text PDF (153 KB)
Background
Tubulointerstitial damage plays an important role in chronic kidney disease (CKD) with proteinuria. Urinary kidney injury molecule 1 (KIM-1) reflects tubular KIM-1 and is considered a sensitive biomarker for early tubular damage. We hypothesized that a decrease in proteinuria by using therapeutic interventions is associated with decreased urinary KIM-1 levels.
Study Design
Post hoc analysis of a randomized, double-blind, placebo-controlled, crossover trial.
Setting & Participants
34 proteinuric patients without diabetes from our outpatient renal clinic.
Intervention
Stepwise 6-week interventions of losartan, sodium restriction (low-sodium [LS] diet), their combination, losartan plus hydrochlorothiazide (HCT), and the latter plus an LS diet.
Outcomes & Measurements
Urinary excretion of KIM-1, total protein, and N-acetyl-β-d-glucosaminidase (NAG) as a positive control for tubular injury.
Results
Mean baseline urine protein level was 3.8 ± 0.4 (SE) g/d, and KIM-1 level was 1,706 ± 498 ng/d (increased compared with healthy controls; 74 ng/d). KIM-1 level was decreased by using placebo/LS (1,201 ± 388 ng/d; P = 0.04), losartan/high sodium (1,184 ± 296 ng/d; P = 0.09), losartan/LS (921 ± 176 ng/d; P = 0.008), losartan/high sodium plus HCT (862 ± 151 ng/d; P = 0.008) and losartan/LS plus HCT (743 ± 170 ng/d; P = 0.001). The decrease in urinary KIM-1 levels paralleled the decrease in proteinuria (R = 0.523; P < 0.001), but not blood pressure or creatinine clearance. 16 patients reached target proteinuria with protein less than 1 g/d, whereas KIM-1 levels normalized in only 2 patients. Urinary NAG level was increased at baseline and significantly decreased during the treatment periods of combined losartan plus HCT only. The decrease in urinary NAG levels was not closely related to proteinuria.
Limitations
Post hoc analysis.
Conclusions
Urinary KIM-1 level was increased in patients with nondiabetic CKD with proteinuria and decreased in parallel with proteinuria by using losartan, sodium restriction, their combination, losartan plus HCT, and the latter plus sodium restriction. These results are consistent with the hypothesis of amelioration of proteinuria-induced tubular damage. Long-term studies are warranted to evaluate whether targeting treatment on KIM-1 can improve outcomes in patients with CKD with proteinuria.
1Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
2Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
3Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
4Deparment of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Address correspondence to Gerjan Navis, MD, PhD, University Medical Center Groningen, Department of Nephrology, PO Box 30.001, 9700 RB Groningen, The Netherlands
ABSTRACT