Prognosis of chronic kidney disease with normal-range proteinuria: The CKD-ROUTE study

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Abstract

Background

Although lower estimated glomerular filtration rate (eGFR) and higher proteinuria are high risks for mortality and kidney outcomes, the prognosis of chronic kidney disease (CKD) in patients with normal-range proteinuria remains unclear.

Methods

In this prospective cohort study, 1138 newly visiting stage G2–G5 CKD patients were stratified into normal-range and abnormal-range proteinuria groups. Study endpoints were CKD progression (>50% eGFR loss or initiation of dialysis), cardiovascular events, and all-cause death.

Results

In total, 927 patients who were followed for >6 months were included in the analysis. The mean age was 67 years, and 70.2% were male. During a median follow-up of 35 months, CKD progression, cardiovascular events, and mortality were observed in 223, 110, and 55 patients, respectively. Patients with normal-range proteinuria had a significantly lower risk for CKD progression (hazard ratio, 0.20; 95% confidence interval, 0.10–0.38) than those with abnormal-proteinuria by multivariate Cox proportional hazard analysis. We also analyzed patients with normal-range proteinuria (n = 351). Nephrosclerosis was the most frequent cause of CKD among all patients with normal-range proteinuria (59.7%). During a median follow-up of 36 months, CKD progression, cardiovascular events, and mortality were observed in 10, 28, and 18 patients, respectively. The Kaplan–Meyer analysis demonstrated that the risks of CKD progression and cardiovascular events were not significantly different among CKD stages, whereas the risk of death was significantly higher in patients with advanced-stage CKD. Multivariate Cox proportional hazard analysis showed that the risk of three endpoints did not significantly differ among CKD stages.

Conclusion

Newly visiting CKD patients with normal-range proteinuria, who tend to be overlooked during health checkups did not exhibit a decrease in kidney function even in advanced CKD stages under specialized nephrology care.

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Most cited references 18

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Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts.

Ron T. Gansevoort, Kunihiro Matsushita, Marije van der Velde … (2011)

Both a low estimated glomerular filtration rate (eGFR) and albuminuria are known risk factors for end-stage renal disease (ESRD). To determine their joint contribution to ESRD and other kidney outcomes, we performed a meta-analysis of nine general population cohorts with 845,125 participants and an additional eight cohorts with 173,892 patients, the latter selected because of their high risk for chronic kidney disease (CKD). In the general population, the risk for ESRD was unrelated to eGFR at values between 75 and 105 ml/min per 1.73 m(2) but increased exponentially at lower levels. Hazard ratios for eGFRs averaging 60, 45, and 15 were 4, 29, and 454, respectively, compared with an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log ESRD risk without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 30, 300, and 1000 mg/g were 5, 13, and 28, respectively, compared with an albumin-to-creatinine ratio of 5. Albuminuria and eGFR were associated with ESRD, without evidence for multiplicative interaction. Similar associations were found for acute kidney injury and progressive CKD. In high-risk cohorts, the findings were generally comparable. Thus, lower eGFR and higher albuminuria are risk factors for ESRD, acute kidney injury and progressive CKD in both general and high-risk populations, independent of each other and of cardiovascular risk factors.

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Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes.

Giuseppe Remuzzi, Ariela Benigni, Andrea Remuzzi (2006)

The incidence of chronic kidney diseases is increasing worldwide, and these conditions are emerging as a major public health problem. While genetic factors contribute to susceptibility and progression of renal disease, proteinuria has been claimed as an independent predictor of outcome. Reduction of urinary protein levels by various medications and a low-protein diet limits renal function decline in individuals with nondiabetic and diabetic nephropathies to the point that remission of the disease and regression of renal lesions have been observed in experimental animals and even in humans. In animal models, regression of glomerular structural changes is associated with remodeling of the glomerular architecture. Instrumental to this discovery were 3D reconstruction studies of the glomerular capillary tuft, which allowed the quantification of sclerosis volume reduction and capillary regeneration upon treatment. Regeneration of capillary segments might result from the contribution of resident cells, but progenitor cells of renal or extrarenal origin may also have a role. This review describes recent advances in our understanding of the mechanisms and mediators underlying renal tissue repair ultimately responsible for regression of renal injury.

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Microalbuminuria and risk for cardiovascular disease: Analysis of potential mechanisms.

Coen Stehouwer, Fren Smulders (2006)

Microalbuminuria is a strong and independent indicator of increased cardiovascular risk among individuals with and without diabetes. Therefore, microalbuminuria can be used for stratification of risk for cardiovascular disease. Once microalbuminuria is present, cardiovascular risk factor reduction should be more "aggressive." The nature of the link between microalbuminuria and cardiovascular risk, however, remains poorly understood. There is no strong evidence that microalbuminuria causes atherothrombosis or that atherothrombosis causes microalbuminuria. Many studies have tested the hypothesis that a common risk factor underlies the association between microalbuminuria and cardiovascular disease but, again, have found no strong evidence in favor of this contention. At present, the most likely possibility is that a common pathophysiologic process, such as endothelial dysfunction, chronic low-grade inflammation, or increased transvascular leakage of macromolecules, underlies the association between microalbuminuria and cardiovascular disease, but more and prospective studies of these hypotheses are needed.

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Author and article information

Contributors

Soichiro Iimori: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: Writing – original draftRole: Writing – review & editing

Shotaro Naito: Role: Investigation

Yumi Noda: Role: Investigation

Hidehiko Sato: Role: Investigation

Naohiro Nomura: Role: Investigation

Eisei Sohara: Role: Investigation

Tomokazu Okado: Role: Investigation

Sei Sasaki: Role: InvestigationRole: Project administration

Shinichi Uchida: Role: Investigation

Tatemitsu Rai:

ORCID: http://orcid.org/0000-0001-7695-778X

Role: InvestigationRole: Writing – review & editing

Tatsuo Shimosawa: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 17 January 2018

Publication date Collection: 2018

Volume: 13

Issue: 1

Electronic Location Identifier: e0190493

Affiliations

[1 ] Department of Nephrology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan

[2 ] Department of Nephrology, Nitobe Memorial Nakano General Hospital, Nakano-ku, Tokyo, Japan

The University of Tokyo, JAPAN

Author notes

Competing Interests: The authors have declared that no competing interests exist.

* E-mail: trai.kid@ 123456tmd.ac.jp

Author information

Tatemitsu Rai http://orcid.org/0000-0001-7695-778X

Article

Publisher ID: PONE-D-17-36318

DOI: 10.1371/journal.pone.0190493

PMC ID: 5771558

PubMed ID: 29342207

SO-VID: 69b462f2-0632-4ddd-9a5e-c354c23723a1

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 17 October 2017

Date accepted : 17 December 2017

Page count

Figures: 4, Tables: 5, Pages: 13

Funding

The authors received no specific funding for this work.

Custom metadata

Data Availability Data are available from the Dryad repository (DOI: 10.5061/dryad.kq23s).

Prognosis of chronic kidney disease with normal-range proteinuria: The CKD-ROUTE study

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Abstract

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Conclusion

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Most cited references 18

Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts.

Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes.

Microalbuminuria and risk for cardiovascular disease: Analysis of potential mechanisms.

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