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

doi:10.1053/j.ajkd.2008.07.021

American Journal of Kidney Diseases

Volume 53, Issue 1, January 2009, Pages 16-25

https://doi.org/10.1053/j.ajkd.2008.07.021 Get rights and content

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.

Section snippets

Patients and Protocol

This study is a post hoc analysis of a randomized, double-blind, placebo-controlled, crossover trial. The protocol was described in detail elsewhere.¹³ In brief, all included patients were aged 18 to 70 years and did not have diabetes. Patients had stable proteinuria with protein greater than 2 g and less than 10 g/d and stable kidney function (ie, creatinine clearance >30 mL/min and <6 mL/min/y decrease in the year preceding the study; creatinine clearance in mL/min may be converted to mL/s by

Patient Characteristics and Dietary Adherence

Thirty-four patients (25 men, 9 women; all white; mean age, 50 years; range, 23 to 68 years) were included. Baseline characteristics are listed in Table 1. Diagnoses were membranous glomerulopathy (7 patients), focal segmental glomerular sclerosis (8 patients), membranoproliferative glomerulonephritis (2 patients), minimal change disease with secondary glomerulosclerosis (2 patients), hypertensive nephropathy (5 patients), immunoglobulin A nephropathy (5 patients), Alport syndrome (1 patient),

Discussion

In proteinuric patients without diabetes with well-preserved and stable kidney function, urinary KIM-1 and NAG excretion were markedly increased, indicating tubular damage. Antiproteinuric treatment decreased urinary KIM-1 excretion in these patients, which was quantitatively related to the efficacy of proteinuria reduction, but not to blood pressure. Because the decrease in urinary KIM-1 excretion also occurred during the placebo/LS period, it appears to be caused by the lower proteinuria as

Acknowledgements

We thank Corrie Nieuwenhout, BSc, for skillful assistance at the outpatient clinic; Nynke Halbesma, MSc, for assistance with statistical analyses; Jacco Zwaagstra, BSc, for technical assistance; and Mieneke Rook, MD, for critically reviewing the manuscript.

Support: This study was supported by Merck Sharp & Dohme (grant MSGP NETH-15-01). The work in Dr Bonventre's laboratory was supported by National Institutes of Health grants DK39773, DK072381, and DK074099. Dr Vaidya was supported by a

References (36)

C. Zoja et al.
Protein overload stimulates RANTES production by proximal tubular cells depending on NF-kappaB activation
Kidney Int
(1998)
P. Ruggenenti et al.
Progression, remission, regression of chronic renal diseases
Lancet
(2001)
P. Ruggenenti et al.
Retarding progression of chronic renal disease: The neglected issue of residual proteinuria
Kidney Int
(2003)
G. Remuzzi et al.
The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease
Kidney Int Suppl
(2005)
W.K. Han et al.
Kidney injury molecule-1 (KIM-1): A novel biomarker for human renal proximal tubule injury
Kidney Int
(2002)
T.D. Lockwood et al.
The use of urinary N-acetyl-beta-glucosaminidase in human renal toxicologyI. Partial biochemical characterization and excretion in humans and release from the isolated perfused rat kidney
Toxicol Appl Pharmacol
(1979)
N. Nakao et al.
Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): A randomised controlled trial
Lancet
(2003)
J. Coresh et al.
Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey
Am J Kidney Dis
(2003)
C. Bazzi et al.
Characterization of proteinuria in primary glomerulonephritidesSDS-PAGE patterns: Clinical significance and prognostic value of low molecular weight (“tubular”) proteins
Am J Kidney Dis
(1997)
C. Bazzi et al.
A modern approach to selectivity of proteinuria and tubulointerstitial damage in nephrotic syndrome
Kidney Int
(2000)

V.S. Vaidya et al.

Renal injury and repair following S-1, 2 dichlorovinyl-l-cysteine administration to mice

Toxicol Appl Pharmacol

(2003)

R.A. Wiley et al.

The effect of nephrotoxic furans on urinary N-acetylglucosaminidase levels in mice

Toxicol Lett

(1982)

L. Tylicki et al.

Addition of aldosterone receptor blocker to dual renin-angiotensin-aldosterone blockade leads to limitation of tubulointerstitial injury of kidney

Kidney Int

(2007)

V. Bailly et al.

Shedding of kidney injury molecule-1, a putative adhesion protein involved in renal regeneration

J Biol Chem

(2002)

Y. Wang et al.

Induction of monocyte chemoattractant protein-1 by albumin is mediated by nuclear factor kappaB in proximal tubule cells

J Am Soc Nephrol

(1999)

M. Morigi et al.

Protein overload-induced NF-kappaB activation in proximal tubular cells requires H(2)O(2) through a PKC-dependent pathway

J Am Soc Nephrol

(2002)

S. Tang et al.

Albumin stimulates interleukin-8 expression in proximal tubular epithelial cells in vitro and in vivo

J Clin Invest

(2003)

A.A. Eddy

Interstitial nephritis induced by protein-overload proteinuria

Am J Pathol

(1989)

Cited by (104)

Urinary biomarkers in kidney disease
2024, Clinica Chimica Acta
Chronic kidney disease (CKD) affects many people worldwide and early diagnosis is essential for successful treatment and improved outcome. Unfortunately, current methods are insufficient especially for early disease detection. However, advances in the analytical methods for urinary biomarkers may provide a unique opportunity for diagnosis and management of CKD. This review explores evolving technology and highlights the importance of early marker detection in these patients.
A search strategy was set up using the terms CKD, biomarkers, and urine. The search included 53 studies comprising 37 biomarkers. The value of these biomarkers for CKD are based on their ability to diagnose CKD, monitor progression, assess mortality and nephrotoxicity.
KIM-1 was the best marker for diagnosis as it increased with the development of incident CKD. DKK3 increased in patients with declining eGFR, whereas UMOD decreased in those with declining kidney function. Unfortunately, none fulfilled all criteria to adequately assess mortality and nephrotoxicity.
New developments in the field of urinalysis using smart toilets may open several possibilities for urinary biomarkers. This review explored which biomarkers could be used for CKD disease detection and management.
Long-Term Renal Outcomes in Children With Acute Kidney Injury Post Cardiac Surgery
2021, Kidney International Reports
The long-term renal outcomes of survivors of pediatric acute kidney injury (AKI) are varied within the current literature, and we aim to establish long-term renal outcomes for pediatric patients after cardiac surgery. We studied long-term renal outcomes and markers of kidney injury in pediatric patients after congenital cardiac surgery.
In a prospective case-control observational study (the Renal Outcomes in Children with acute Kidney injury post cardiac Surgery [ROCKS] trial) we reviewed all children who underwent cardiac surgery on cardiopulmonary bypass (December 2010–2017).
During the study period, 2035 patients underwent cardiac surgery, of whom 9.8% developed AKI postoperatively. Forty-four patients who had postoperative AKI had a long-term follow-up, met our inclusion criteria, and were compared with 49 control subjects. We conducted a univariate analysis of reported parameters. At a median follow-up of 41 months, the cases had significantly higher urine levels of neutrophil gelatinase–associated lipocalin (NGAL), interleukin-18 (IL-18), and kidney injury molecule-1 (KIM-1). The biomarkers remained higher after adjusting for the urine creatinine, and the ratio of urine KIM-1/urine creatinine was significantly higher among cases. None of the patients had proteinuria or hypertension on follow-up. The presence of AKI, AKI stage, and younger age were not associated with the occurrence of low glomerular filtration rate (GFR) at follow-up.
Urinary biomarker abnormalities persist years after a congenital cardiac surgery in children, who may have a low GFR on follow-up. The presence of AKI, AKI stage, and younger age at surgery are not associated with the occurrence of low GFR at follow-up. Children with a higher surgical complexity score have lower GFR on follow-up.
The Use of Renin-Angiotensin System Inhibitors in Patients With Chronic Kidney Disease
2019, Canadian Journal of Cardiology
Chronic kidney disease (CKD) is a growing public health issue worldwide. It is acknowledged that CKD is associated with increased risk of cardiovascular disease, which is the leading cause of morbidity and mortality in this population. The role of the renin-angiotensin-aldosterone system in the pathophysiology of hypertension, and cardiovascular and kidney diseases is well known and the renin-angiotensin-aldosterone system is a major regulator of blood pressure through its effect on body fluids and electrolyte homeostasis. For 2 decades, renin-angiotensin system inhibitors have been the mainstay of treatment for CKD. Clinical trials have shown that prescription of monotherapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers reduces albuminuria and slows the progression of nephropathy in patients with diabetes. In clinical practice guidelines, renin-angiotensin system inhibitors are recommended as the antihypertensive drug of choice in patients with CKD with or without diabetes. Moreover, renin-angiotensin system inhibitors have been shown to offer cardiovascular protection beyond those resulting after blood pressure control. However, the benefits of renin-angiotensin system inhibitor prescriptions for patients with advanced CKD remain controversial. Patients with advanced CKD or who undergo dialysis are under-represented in clinical trials, and studies in this population are urgently needed.
L’insuffisance rénale chronique (IRC) est un problème de santé publique croissant dans le monde entier. L’IRC est notoirement associée à un risque accru de maladie cardiovasculaire, principale cause de morbidité et de mortalité au sein de la population touchée. Le rôle du système rénine-angiotensine-aldostérone dans la physiopathologie de l’hypertension et des maladies cardiovasculaires et rénales est bien connu, et ce système constitue un régulateur majeur de la pression artérielle par ses effets sur l’homéostasie hydroélectrolytique. Depuis deux décennies, le traitement de l’IRC repose principalement sur l’administration d’inhibiteurs du système rénine-angiotensine. Les essais cliniques ont montré que les inhibiteurs de l’enzyme de conversion de l’angiotensine et les antagonistes des récepteurs de l’angiotensine prescrits en monothérapie réduisent l’albuminurie et ralentissent la progression de la néphropathie chez les patients diabétiques. Dans les lignes directrices de pratique clinique, les inhibiteurs du système rénine-angiotensine sont recommandés en tant qu’antihypertenseurs de première intention chez les patients atteints d’IRC, qu’ils soient diabétiques ou non. En outre, les inhibiteurs du système rénine-angiotensine offrent une protection cardiovasculaire avérée au-delà de celle que procure la maîtrise de la pression artérielle. Cependant, les avantages de la prescription d’inhibiteurs du système rénine-angiotensine chez les patients atteints d’IRC avancée demeurent controversés. Les patients atteints d’IRC avancée ou sous dialyse sont sous-représentés dans les essais cliniques, et des études au sein de cette population s’imposent de toute urgence.
Urinary Tubular Injury Biomarkers Are Associated With ESRD and Death in the REGARDS Study
2018, Kidney International Reports
Urinary neutrophil gelatinase−associated lipocalin (uNGAL) and urinary kidney injury molecule−1 (uKIM-1) are established markers of subclinical acute kidney injury. In persons with reduced estimated glomerular filtration rate (eGFR) and albuminuria who are at high risk for end-stage renal disease (ESRD) and death, the associations of these urinary markers with incident ESRD or death is an area of active investigation.
Among 1472 black and white participants from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study with eGFR ≤60 ml/min per 1.73 m² (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] cystatin, 2012) and albumin-to-creatinine ratio (ACR) ≥30 mg/g, we evaluated the associations of baseline uNGAL and uKIM-1 with progression to ESRD and all-cause death. Cox models were sequentially adjusted for urinary creatinine, traditional risk factors, C-reactive protein, ACR, and eGFR.
There were 257 ESRD events and 819 deaths over a median follow-up of 5.7 and 6.5 years, respectively. In demographic adjusted models, higher levels of uNGAL were associated with increased risk of ESRD and death, but these associations were attenuated in fully adjusted models including baseline eGFR for both ESRD (hazard ratio [HR] = 1.06 per doubling, 95% confidence interval [CI] 0.98–1.14) and death (HR = 1.04, 95% CI = 1.00–1.08). Higher levels of uKIM-1 were associated with increased risk of ESRD and death in demographic-adjusted models, and although attenuated in fully adjusted models, remained statistically significant for both ESRD (HR = 1.24 per doubling, 95% CI = 1.08–1.42) and death (HR = 1.10, 95% CI =1.03–1.19).
In this cohort of high-risk patients with baseline eGFR ≤60 ml/min per 1.73 m² and albuminuria, renal tubular injury is associated with higher mortality and progression to ESRD. Further studies are necessary to investigate the mechanism underlying this increased risk.
Emerging Translatable Safety Biomarkers
2017, Comprehensive Medicinal Chemistry III
Drug safety is an important cause of drug candidate attrition in the biopharmaceutical industry. These emerging biomarkers denote an expanded toolkit of minimally invasive, stable, tractable safety biomarkers for translational use, bridging findings in preclinical to clinical drug testing. The value proposition of new safety biomarkers is to improve risk-benefit assessment at all stages of drug development. This article describes the scientific and regulatory underpinnings of the safety biomarker qualification process. The evaluation and current understanding of emerging new safety biomarkers for drug-related toxicities of the kidney, liver, adverse immunostimulation, and phospholipidosis is presented.
Uric Acid Lowering and Biomarkers of Kidney Damage in CKD Stage 3: A Post Hoc Analysis of a Randomized Clinical Trial
2020, Kidney Medicine
Citation Excerpt :
Urinary NGAL and KIM-1 levels are both well-established biomarkers for AKI, known to increase rapidly after AKI and to signify cellular injury within the kidney tubular structures.27 However, more recent data have indicated both NGAL and KIM-1 levels to be increased in patients with CKD compared with healthy adults,28-30 and there is evidence to suggest that tubular injury, detected by elevated urinary NGAL and KIM-1 levels, confers a higher risk for CKD progression in the absence of AKI.18 Furthermore, urinary NGAL and KIM-1 levels are both increased in association with hyperuricemia even in the absence of significant kidney disease.31
Hyperuricemia is associated with chronic kidney disease (CKD) progression. We evaluated whether lowering serum uric acid levels improves levels of biomarkers of kidney damage.
Post hoc analysis of clinical trial participants.
A double-blind randomized placebo-controlled study designed to lower serum uric acid levels. 80 patients with stage 3 CKD and asymptomatic hyperuricemia were randomly assigned to allopurinol treatment or placebo (300 mg/d) for 12 weeks.
Allopurinol treatment versus placebo.
We evaluated the change from baseline for the following urinary biomarkers of kidney damage: albumin-creatinine ratio (ACR), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), and transforming growth factor β1 (TGF-β1). Additionally, we evaluated CKD Epidemiology Collaboration (CKD-EPI)-estimated glomerular filtration rate (eGFR) and cystatin C eGFR.
Generalized linear mixed modeling was used.
After 12 weeks, allopurinol (compared to placebo) significantly lowered serum uric acid levels with an estimate of −3.3 mg/dL (95% CI, −4.1 to −2.5 mg/dL; P < 0.001). Estimates for the change for allopurinol versus placebo over time were 1.09 (95% CI, 0.77-1.54) for ACR, 0.77 (95% CI, 0.36-1.63) for NGAL, and 2.36 (95% CI, 0.97-5.70) for TGF-β1. The model did not converge for KIM-1, but Wilcoxon signed rank test showed no significant difference in change from baseline between study groups. There was no significant change observed in CKD-EPI eGFR or cystatin C eGFR.
Post hoc analysis and short duration of the study.
Uric acid–lowering with allopurinol is not associated with improvement in levels of biomarkers of kidney damage in patients with asymptomatic hyperuricemia and stage 3 CKD.
The study was funded by the National Institutes of Health through a career development award, K23DK088833, and the Clinical and Translational Science Award UL1TR002537.
NCT01228903.

View all citing articles on Scopus

: Originally published online as doi:10.1053/j.ajkd.2008.07.021 on September 29, 2008

View full text

Background

Study Design

Setting & Participants

Intervention

Outcomes & Measurements

Results

Limitations

Conclusions

Section snippets

Patients and Protocol

Patient Characteristics and Dietary Adherence

Discussion

Acknowledgements

Kidney Int

Lancet

Kidney Int

Kidney Int Suppl

Kidney Int

Toxicol Appl Pharmacol

Lancet

Am J Kidney Dis

Am J Kidney Dis

Kidney Int

Toxicol Appl Pharmacol

Toxicol Lett

Kidney Int

J Biol Chem

Induction of monocyte chemoattractant protein-1 by albumin is mediated by nuclear factor kappaB in proximal tubule cells

J Am Soc Nephrol

Protein overload-induced NF-kappaB activation in proximal tubular cells requires H(2)O(2) through a PKC-dependent pathway

J Am Soc Nephrol

Albumin stimulates interleukin-8 expression in proximal tubular epithelial cells in vitro and in vivo

J Clin Invest

Interstitial nephritis induced by protein-overload proteinuria

Am J Pathol