Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies
Open accessAbstract
Background: There is strong biologic plausibility to support change in albuminuria as a surrogate endpoint for progression of chronic kidney disease (CKD), but empirical evidence to supports its validity in epidemiologic studies is lacking. Methods: We analyzed 28 cohorts including 693,816 individuals (80% with diabetes) and 7,461 end-stage kidney disease (ESKD) events, defined as initiation of kidney replacement therapy. Percent change in albuminuria was quantified during a baseline period of 1, 2 and 3 years using linear regression. Associations with subsequent ESKD were quantified using Cox regression in each cohort, followed by random-effects meta-analysis. Further adjustment for regression dilution was used to take into account the high variability of albuminuria. Findings: Change in urine albumin-to-creatinine ratio (ACR) was consistently related to subsequent risk of ESKD. The adjusted hazard ratio of ESKD following a 30% decrease in ACR during a 2-year baseline period was 0.83 (95% CI 0.74–0.94); after further adjustment for regression dilution it was 0.78 (95% CI 0.66–0.92). Adjusted hazard ratios were relatively consistent across cohorts and subgroups but were somewhat stronger at higher ACR (p-interaction<0.05). In a group of persons with baseline ACR >30 mg/g, an average reduction in ACR of 30% over 2-years was estimated to confer >1% absolute reduction in 10-year ESKD risk, even at earlier stages of CKD. Results were generally similar when using change in urine protein-to-creatinine ratio (PCR), or when study populations from clinical trials were evaluated. Limitations include potential residual confounding, modeling assumptions, and heterogeneity. Interpretation: Change in albuminuria was consistently associated with subsequent risk of ESKD across a wide range of cohorts, lending support to using average change in albuminuria as a surrogate endpoint in clinical trials of CKD progression in the setting of elevated albuminuria. Funding: US National Kidney Foundation, National Institute of Diabetes and Digestive and Kidney Diseases.
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In clinical trials of ACE inhibitor or ARB therapy in people with type 2 diabetes, reducing albuminuria to levels <300 mg/g creatinine or by >30% from baseline has been associated with improved kidney and cardiovascular outcomes.
“In addition, in clinical trials of ACE inhibitor or ARB therapy in people with type 2 diabetes, reducing albuminuria to levels <300 mg/g creatinine or by >30% from baseline has been associated with improved kidney and cardiovascular outcomes, leading to the recommendation that medications should be titrated to maximize reduction in UACR (8).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [8]
The Discussion (page unavailable) reports that a 30% reduction in albuminuria was associated with lower end-stage kidney disease risk. But this is primarily an observational analysis, not evidence specifically from ACE-inhibitor or ARB trials in people with type 2 diabetes. The Results (page unavailable) report no statistically significant association between a 30% ACR decrease and lower cardiovascular mortality; the paper also does not establish a target below 300 mg/g or recommend titrating medication to maximize UACR reduction. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRemission of albuminuria may occur spontaneously, and cohort studies evaluating associations of change in albuminuria with clinical outcomes have overall reported cardiovascular and kidney outcome benefits.
“Remission of albuminuria may occur spontaneously, and cohort studies evaluating associations of change in albuminuria with clinical outcomes have overall reported cardiovascular and kidney outcome benefits (9,45,46).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [9]
The Discussion (page not provided) reports that reduced albuminuria was associated with lower subsequent ESKD risk, and cites earlier observational analyses linking albuminuria change to cardiovascular mortality. It describes variation in albuminuria without intervention, but does not establish that albuminuria can remit spontaneously; that part of the claim is unsupported. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn clinical trials of ACE inhibitor or ARB therapy in people with type 2 diabetes, reducing albuminuria to levels <300 mg/g creatinine or by >30% from baseline has been associated with improved kidney and cardiovascular outcomes.
“In addition, in clinical trials of ACE inhibitor or ARB therapy in people with type 2 diabetes, reducing albuminuria to levels <300 mg/g creatinine or by >30% from baseline has been associated with improved kidney and cardiovascular outcomes, leading to the recommendation that medications should be titrated to maximize reduction in UACR as residual risk persists with elevated UACR (9).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [9]
The Discussion (page unavailable) reports that a 30% decrease in albuminuria was associated with lower subsequent end-stage kidney disease risk. But this is an observational analysis, not specifically a finding from ACE inhibitor or ARB trials in people with type 2 diabetes. The Results (page unavailable) give a cardiovascular-mortality estimate for a 30% decrease whose confidence interval includes no effect; the cited passages do not establish a <300 mg/g treatment target or recommend titrating medication to maximize UACR reduction. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPost hoc analyses of randomized trials and observational cohorts have demonstrated that an initial larger albuminuria reduction is associated with better long-term outcomes.
“Post hoc analyses of randomized trials and observational cohorts have demonstrated that an initial larger albuminuria reduction is associated with better long-term outcomes.”
From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [55]
Semiquantitative or qualitative dipstick screening will need to be confirmed by UACR values in an accredited laboratory.
“Thus, semiquantitative or qualitative (dipstick) screening will need to be confirmed by UACR values in an accredited laboratory (9,10).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [9]
The Methods (Procedures; page unavailable) describe measuring albuminuria by ACR, and the Discussion (page unavailable) notes the value of repeat albuminuria testing. Neither passage addresses confirming qualitative or semiquantitative dipstick screening with UACR in an accredited laboratory; searches for dipstick screening and confirmation found no such recommendation. (LLM, conf=0.77)
Experimental — accuracy not yet measured
Therapies that reduce albuminuria by 25-30% are likely to confer significant benefits in reducing the risk of long-term clinical kidney outcomes.
“These effects are clinically relevant because therapies that reduce albuminuria by 25–30% are likely to confer significant benefits in reducing the risk of long-term clinical kidney outcomes (27,28).”
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References 39 · Cited by 338
- Authors
- Coresh, J., Heerspink, H. J. L., Sang, Y., Matsushita, K., Arnlov, J., Astor, B. C., Black, C., Brunskill, N. J., Carrero, J.-J., Feldman, H. I., Fox, C. S., Inker, L. A., Ishani, A., Ito, S., Jassal, S., Konta, T., Polkinghorne, K., Romundstad, S., Solbu, M. D., Stempniewicz, N., Stengel, B., Tonelli, M., Umesawa, M., Waikar, S. S., Wen, C.-P., Wetzels, J. F. M., Woodward, M., Grams, M. E., Kovesdy, C. P., Levey, A. S., Gansevoort, R. T., Appel, L. J., Greene, T., Chen, T. K., Chalmers, J., Arima, H., Perkovic, V., Levin, A., Djurdjev, O., Tang, M., Nally, J., Navaneethan, S. D., Schold, J. D., Weldegiorgis, M., Herrington, W. G., Smith, M., Hsu, C. Y., Hwang, S.-J., Chang, A. R., Kirchner, H. L., Green, J. A., Ho, K., Marks, A., Prescott, G., Clark, L. E., Fluck, N., Shalev, V., Chodick, G., Blankestijn, P. J., Van Zuilen, A., Van den Brand, J. A., Sarnak, M. J., Bottinger, E., Nadkarni, G. N., Ellis, S. G., Nadukuru, R., Metzger, M., Flamant, M., Houillier, P., Haymann, J.-P., Froissart, M., Kenealy, T., Elley, R. C., Collins, J. F., Drury, P. L., Cuddeback, J. K., Ciemins, E. L., Stempniewicz, R., Nelson, R. G., Knowler, W. C., Bakker, S. J., Major, R. W., Medcalf, J. F., Shepherd, D., Barrett-Connor, E., Bergstrom, J., Ix, J. H., Molnar, M. Z., Sumida, K., de Zeeuw, D., Brenner, B., Qureshi, A. R., Elinder, C.-G., Runesson, B., Evans, M., Segelmark, M., Stendahl, M., Schön, S., Naimark, D. M., Tangri, N., Sud, M., Hirayama, A., Ichikawa, K., Bilo, H. J., Landman, G. W., Van Hateren, K. J., Kleefstra, N., Hallan, S. I., Ballew, S. H., Chen, J., Kwak, L., Surapaneni, A., Parving, H.-H., Rodby, R. A., Rohde, R. D., Lewis, J. B., Lewis, E., Perrone, R. D., Abebe, K. Z., Hou, F. F., Xie, D., Hunsicker, L. G., Imai, E., Kobayashi, F., Makino, H., Ito, S., Remuzzi, G., Ruggenenti, P., Eckardt, K.-U., Gudmundsdottir, H., Maciulaitis, R., Manley, T., Smith, K., Stockbridge, N., Thompson, A., Vetter, T., Willis, K., & Zhang, L.
- Affiliations
- Johns Hopkins University (US)
- University Medical Center Groningen (NL)
- University of Wisconsin–Madison (US)
- National Health Service (GB)
- University of Leicester (GB)
- University of Pennsylvania (US)
- Brigham and Women's Hospital (US)
- Tufts Medical Center (US)
- University of Minnesota (US)
- University of California San Diego (US)
- Yamagata University (JP)
- Monash Medical Centre (AU)
- Norwegian University of Science and Technology (NO)
- University Hospital of North Norway (NO)
- American Medical Group Association (US)
- University of Calgary (CA)
- Dokkyo Medical University (JP)
- National Health Research Institutes (TW)
- Radboud University Nijmegen (NL)
- University of Tennessee Health Science Center (US)
- Tohoku University (JP)
- Corresponding author
- Coresh, Josef
- ORCID
- Coresh, Josef
- Heerspink, Hiddo J L
- Matsushita, Kunihiro
- Astor, Brad C
- Black, Corri
- Brunskill, Nigel J
- Feldman, Harold I
- Fox, Caroline S
- Inker, Lesley A
- Ishani, Areef
- Jassal, Simerjot
- Konta, Tsuneo
- Polkinghorne, Kevan
- Romundstad, Solfrid
- Solbu, Marit D
- Stempniewicz, Nikita
- Tonelli, Marcello
- Umesawa, Mitsumasa
- Waikar, Sushrut S
- Wetzels, Jack F M
- Woodward, Mark
- Grams, Morgan E
- Kovesdy, Csaba P
- Levey, Andrew S
- Gansevoort, Ron T
- Appel, Lawrence J
- Greene, Tom
- Chen, Teresa K
- Chalmers, John
- Arima, Hisatomi
- Perkovic, Vlado
- Levin, Adeera
- Tang, Mila
- Navaneethan, Sankar D
- Schold, Jesse D
- Weldegiorgis, Misghina
- Herrington, William G
- Smith, Margaret
- Hwang, Shih-Jen
- Chang, Alex R
- Kirchner, H. Lester
- Green, Jamie A
- Ho, Kevin
- Marks, Angharad
- Prescott, Gordon
- Shalev, Varda
- Chodick, Gabriel
- Blankestijn, Peter J
- Sarnak, Mark J
- Nadkarni, Girish N
- Ellis, Stephen G
- Metzger, Marie
- Flamant, Martin
- Houillier, Pascal
- Haymann, Jean-Philippe
- Froissart, Marc
- Kenealy, Timothy
- Drury, Paul L
- Ciemins, Elizabeth L
- Nelson, Robert G
- Knowler, William C
- Major, Rupert W
- Medcalf, James F
- Shepherd, David
- Barrett-Connor, Elizabeth
- Bergstrom, Jaclyn
- Ix, Joachim H
- Molnar, Miklos Z
- Sumida, Keiichi
- Qureshi, Abdul R
- Elinder, Carl-Gustaf
- Evans, Marie
- Schön, Staffan
- Naimark, David M
- Tangri, Navdeep
- Sud, Maneesh
- Hirayama, Atsushi
- Ichikawa, Kazunobu
- Bilo, Henk JG
- Landman, Gijs WD
- Kleefstra, Nanne
- Hallan, Stein I
- Ballew, Shoshana H
- Kwak, Lucia
- Surapaneni, Aditya
- Rodby, Roger A.
- Lewis, Julia B
- Lewis, Edmund
- Perrone, Ronald D
- Abebe, Kaleab Z
- Hou, Fan F
- Xie, Di
- Imai, Enyu
- Makino, Hirofumi
- Remuzzi, Giuseppe
- Eckardt, Kai-Uwe
- Smith, Kimberly
- Stockbridge, Norman
- Willis, Kerry
- Zhang, Luxia
- Venue
- The Lancet Diabetes & Endocrinology
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 7
- Issue
- 2
- Pages
- 115-127
- ISSN
- 2213-8587 (ISSN-L)
- PMC
- PMC6379893
- OpenAlex
- W2909182150
- Semantic Scholar
- 661c31b056e6175dbedb52be1c598ad61bbbb705
- Cited by
- 338
- References
- 39
- Citations by year
- 2026: 40 · 2025: 42 · 2024: 56 · 2023: 50 · 2022: 38 · 2021: 34 · 2020: 39 · 2019: 38
- FWCI
- 5.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The Lancet Diabetes & Endocrinology (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Figshare (submittedVersion, cc-by)
- Lund University Publications (Lund University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- National Kidney Foundation
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK100446–01)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Health Sciences › Medicine › Nephrology › Dialysis and Renal Disease Management
- Keywords
- albuminuria, end-stage renal disease, chronic kidney disease progression, albumin-creatinine ratio, urine protein-to-creatinine ratio, renal replacement therapy, surrogate endpoints, regression dilution, diabetes mellitus, serum creatinine, individual patient data, kidney disease mortality, cardiovascular mortality, mortality risk stratification, risk prediction model
- MeSH terms
- Albuminuria, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Kidney Function Tests, Prognosis, Risk Factors, Disease Progression, Observational Studies as Topic
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