Drug-Induced Reduction in Albuminuria Is Associated with Subsequent Renoprotection: A Meta-Analysis
Open accessAbstract
Albuminuria has been proposed as a surrogate end point in randomized clinical trials of renal disease progression. Most evidence comes from observational analyses showing that treatment-induced short-term changes in albuminuria correlate with risk change for ESRD. However, such studies are prone to selection bias and residual confounding. To minimize this bias, we performed a meta-analysis of clinical trials to correlate the placebo-corrected drug effect on albuminuria and ESRD to more reliably delineate the association between changes in albuminuria and ESRD. MEDLINE and EMBASE were searched for clinical trials reported between 1950 and April 2014. Included trials had a mean follow-up of ≥1000 patient-years, reported ESRD outcomes, and measured albuminuria at baseline and during follow-up. Twenty-one clinical trials involving 78,342 patients and 4183 ESRD events were included. Median time to first albuminuria measurement was 6 months. Fourteen trials tested the effect of renin-angiotensin-aldosterone-system inhibitors and seven trials tested other interventions. We observed variability across trials in the treatment effect on albuminuria (range, −1.3% to −32.1%) and ESRD (range, −55% to +35% risk change). Meta-regression analysis revealed that the placebo-adjusted treatment effect on albuminuria significantly correlated with the treatment effect on ESRD: for each 30% reduction in albuminuria, the risk of ESRD decreased by 23.7% (95% confidence interval, 11.4% to 34.2%; P =0.001). The association was consistent regardless of drug class ( P =0.73) or other patient or trial characteristics. These findings suggest albuminuria may be a valid substitute for ESRD in many circumstances, even taking into account possible other drug-specific effects that may alter renal outcomes.
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Secondary trial analyses indicate that cardiovascular and kidney benefits are unlikely mediated by glucose lowering.
“Secondary analyses from clinical trials have shown that the benefits on cardiovascular and kidney function are unlikely mediated by the glucose-lowering properties of these agents (Inzucchi et al., 2018; Heerspink et al., 2015).”
From A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors (2021) · cites this paper as Heerspink et al., 2015
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Cites
Ahmed, A., Jorna, T., & Bhandari, S. (2016) · The Nephron journals/Nephron journals · doi:10.1159/000447068 · Cited by 11,782 · see citing works
Brenner, B. M., Cooper, M. E., de Zeeuw, D., Keane, W. F., Mitch, W. E., Parving, H.-H., Remuzzi, G., Snapinn, S. M., Zhang, Z., & Shahinfar, S. (2001) · New England Journal of Medicine · doi:10.1056/nejmoa011161 · Cited by 7,493 · see citing works
Lewis, E. J., Hunsicker, L. G., Clarke, W. R., Berl, T., Pohl, M. A., Lewis, J. B., Ritz, E., Atkins, R. C., Rohde, R., & Raz, I. (2001) · New England Journal of Medicine · doi:10.1056/nejmoa011303 · Cited by 5,987 · see citing works
The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy
Lewis, E. J., Hunsicker, L. G., Bain, R. P., & Rohde, R. D. (1993) · New England Journal of Medicine · doi:10.1056/nejm199311113292004 · Cited by 5,394 · see citing works
Differential Diagnosis of Glomerular Disease: A Systematic and Inclusive Approach
Hebert, L. A., Parikh, S. M., Prosek, J. M., Nádasdy, T., & Rovin, B. H. (2013) · American Journal of Nephrology · doi:10.1159/000354390 · Cited by 4,391 · see citing works
Baigent, C., Landray, M. J., Reith, C., Emberson, J., Wheeler, D. C., Tomson, C., Wanner, C., Krane, V., Cass, A., Craig, J., et al. (2011) · The Lancet · doi:10.1016/s0140-6736(11)60739-3 · Cited by 2,479 · see citing works
Self-citationKlahr, S., Levey, A. S., Beck, G. J., Caggiula, A. W., Hunsicker, L., Kusek, J. W., & Striker, G. (1994) · New England Journal of Medicine · doi:10.1056/nejm199403313301301 · Cited by 2,328 · see citing works
Wright, J. T. (2002) · JAMA · doi:10.1001/jama.288.19.2421 · Cited by 2,033 · see citing works
The GISEN Group, & MANNO, C. (1997) · The Lancet · doi:10.1016/s0140-6736(96)11445-8 · Cited by 1,863 · see citing works
Levey, A. S., & Coresh, J. (2012) · The Lancet · doi:10.1016/s0140-6736(11)60178-5 · Cited by 1,841 · see citing works
Maschio, G., Alberti, D., Janin, G., Locatelli, F., Mann, J. F. E., Motolese, M., Ponticelli, C. E., Ritz, E., & Zucchelli, P. C. (1996) · New England Journal of Medicine · doi:10.1056/nejm199604113341502 · Cited by 1,743 · see citing works
Mann, J. F. E., Schmieder, R. E., McQueen, M., Dyal, L., Schumacher, H., Pogue, J. M., Wang, X., Maggioni, A. P., Budaj, A., Chaithiraphan, S., et al. (2008) · The Lancet · doi:10.1016/s0140-6736(08)61236-2 · Cited by 1,581 · see citing works
The J-Curve Phenomenon in Hypertension
Kang, Y., & Wang, J. (2016) · Pulse · doi:10.1159/000446922 · Cited by 1,548 · see citing works
Cardiorenal end points in a trial of aliskiren for type 2 diabetes
Parving, H.-H., Brenner, B. M., McMurray, J. J. V., de Zeeuw, D., Haffner, S. M., Solomon, S. D., Chaturvedi, N., Persson, F., Desai, A. S., Nicolaides, M., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1208799 · Cited by 1,319 · see citing works
Combined angiotensin inhibition for the treatment of diabetic nephropathy
Fried, L. F., Emanuele, N., Zhang, J. H., Brophy, M., Conner, T. A., Duckworth, W., Leehey, D. J., McCullough, P. A., O'Connor, T., Palevsky, P. M., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1303154 · Cited by 1,169 · see citing works
de Zeeuw, D., Remuzzi, G., Parving, H., Keane, W. F., Zhang, Z., Shahinfar, S., Snapinn, S., Cooper, M. E., Mitch, W. E., & Brenner, B. M. (2004) · Kidney International · doi:10.1111/j.1523-1755.2004.00653.x · Cited by 963 · see citing works
Strict Blood-Pressure Control and Progression of Renal Failure in Children
The ESCAPE Trial Group (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0902066 · Cited by 951 · see citing works
Ruggenenti, P., Perna, A., Gherardi, G., Garini, G., Zoccali, C., Salvadori, M., Scolari, F., Schena, F. P., & Remuzzi, G. (1999) · The Lancet · doi:10.1016/s0140-6736(98)10363-x · Cited by 910 · see citing works
Epidemiology: Study Design and Data Analysis
(2006) · Technometrics · doi:10.1198/tech.2006.s407 · Cited by 789 · see citing works
How Does Proteinuria Cause Progressive Renal Damage?
Abbate, M., Zoja, C., & Remuzzi, G. (2006) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006040377 · Cited by 777 · see citing works
Efficacy and Safety of Benazepril for Advanced Chronic Renal Insufficiency
Hou, F. F., Zhang, X., Zhang, G. H., Xie, D., Chen, P. Y., Zhang, W. R., Jiang, J. P., Liang, M., Wang, G. B., Liu, Z. R., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa053107 · Cited by 710 · see citing works
Ruggenenti, P. L., Perna, A., Loriga, G., Ganeva, M. G., Ene‐Iordache, B., Turturro, M., Lesti, M., Perticucci, E., Chakarski, I. N., Leonardis, D., et al. (2005) · The Lancet · doi:10.1016/s0140-6736(05)71082-5 · Cited by 636 · see citing works
Statistical Principles for Clinical Trials
Kay, R. (1998) · Journal of International Medical Research · doi:10.1177/030006059802600201 · Cited by 573 · see citing works
Progression, remission, regression of chronic renal diseases
Ruggenenti, P. L., Schieppati, A., & Remuzzi, G. (2001) · The Lancet · doi:10.1016/s0140-6736(00)04728-0 · Cited by 545 · see citing works
Zoja, C., Donadelli, R., Colleoni, S., Figliuzzi, M., Bonazzola, S., Morigi, M., & Remuzzi, G. (1998) · Kidney International · doi:10.1046/j.1523-1755.1998.00905.x · Cited by 415 · see citing works
Is glomerulosclerosis a consequence of altered glomerular permeability to macromolecules?
Remuzzi, G., & Bertani, T. (1990) · Kidney International · doi:10.1038/ki.1990.217 · Cited by 398 · see citing works
The Relationship Between Magnitude of Proteinuria Reduction and Risk of End-stage Renal Disease
Lea, J. P. (2005) · Archives of Internal Medicine · doi:10.1001/archinte.165.8.947 · Cited by 290 · see citing works
Retarding progression of chronic renal disease: The neglected issue of residual proteinuria
Ruggenenti, P. L., Perna, A., Remuzzi, G., & Investigators of the Gisen Group (2003) · Kidney International · doi:10.1046/j.1523-1755.2003.00033.x · Cited by 271 · see citing works
Developing a database of published reports of randomised clinical trials in pain research 1
Jadad, A. R., Carroll, D., Moore, A., & McQuay, H. (1996) · Pain · doi:10.1016/0304-3959(96)03033-3 · Cited by 271 · see citing works
Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study
Hou, F. F., Xie, D., Zhang, X., Chen, P. Y., Zhang, W. R., Liang, M., Guo, Z. J., & Jiang, J. P. (2007) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006121372 · Cited by 252 · see citing works
for the ORIENT study investigators, Imai, E., Chan, J. C. N., Ito, S., Yamasaki, T., Kobayashi, F., Haneda, M., & Makino, H. (2011) · Diabetologia · doi:10.1007/s00125-011-2325-z · Cited by 236 · see citing works
Wang, Y., Rangan, G. K., Tay, Y., Wang, Y., & Harris, D. C. H. (1999) · Journal of the American Society of Nephrology · doi:10.1681/asn.v1061204 · Cited by 207 · see citing works
Effect of Telmisartan on Renal Outcomes
Mann, J. F. E., Schmieder, R. E., Dyal, L., McQueen, M. J., Schumacher, H., Pogue, J., Wang, X., Probstfield, J. L., Avezum, Á., Cardona-Munoz, E., et al. (2009) · Annals of Internal Medicine · doi:10.7326/0003-4819-151-1-200907070-00122 · Cited by 194 · see citing works
Sulodexide Fails to Demonstrate Renoprotection in Overt Type 2 Diabetic Nephropathy
Packham, D., Wolfe, R. S., Reutens, A. T., Berl, T., Heerspink, H. J. L., Rohde, R., Ivory, S. E., Lewis, J., Raz, I., Wiegmann, T. B., et al. (2011) · Journal of the American Society of Nephrology · doi:10.1681/asn.2011040378 · Cited by 171 · see citing works
Delahoy, P. J., Magliano, D. J., Webb, K., Grobler, M. P., & Liew, D. (2009) · Clinical Therapeutics · doi:10.1016/j.clinthera.2009.02.017 · Cited by 167 · see citing works
Proteinuria should be used as a surrogate in CKD
Cravedi, P., Ruggenenti, P. L., & Remuzzi, G. (2012) · Nature Reviews Nephrology · doi:10.1038/nrneph.2012.42 · Cited by 153 · see citing works
Inker, L. A., Levey, A. S., Pandya, K. A., Stoycheff, N., Okparavero, A., & Greene, T. (2014) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2014.02.020 · Cited by 132 · see citing works
Activation of Mitogenic Pathways by Albumin in Kidney Proximal Tubule Epithelial Cells
Dixon, R. C., & Brunskill, N. J. (1999) · Journal of the American Society of Nephrology · doi:10.1681/asn.v1071487 · Cited by 113 · see citing works
Palmer, A. J., Annemans, L., Roze, S., Lamotte, M., Lapuerta, P., Chen, R. K., Gabriel, S., Carita, P., Rodby, R. A., de Zeeuw, D., et al. (2004) · Diabetes Care · doi:10.2337/diacare.27.8.1897 · Cited by 91 · see citing works
Hellemons, M. E., Persson, F., Bakker, S. J. L., Rossing, P. R., Parving, H., de Zeeuw, D., & Heerspink, H. J. L. (2011) · Diabetes Care · doi:10.2337/dc11-0324 · Cited by 66 · see citing works
Is the ONTARGET renal substudy actually off target?
Ruggenenti, P. L., & Remuzzi, G. (2009) · Nature Reviews Nephrology · doi:10.1038/nrneph.2009.109 · Cited by 45 · see citing works
on behalf of the ONTARGET/TRANSCEND investigators, Schmieder, R. E., Schutte, R., Schumacher, H., Böhm, M., Mancia, G., Weber, M. A., McQueen, M., Teo, K. K., & Yusuf, S. (2014) · Diabetologia · doi:10.1007/s00125-014-3330-9 · Cited by 45 · see citing works
Diabetic Nephropathy: Future avenue
Viberti, G. C., Yip-Messent, J., & Morocutti, A. (1992) · Diabetes Care · doi:10.2337/diacare.15.9.1216 · Cited by 40 · see citing works
Imai, E., Haneda, M., Chan, J. C. N., et al. (2013) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gft249 · Cited by 27 · see citing works
Dual RAAS blockade has dual effects on outcome
Heerspink, H. J. L., & de Zeeuw, D. (2013) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.65 · Cited by 4 · see citing works
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Research works printed but not linked: 1
- [46]46. Viberti G, Walker JD, Pinto J: Diabetic Nephropathy , Chichester, UK, Wiley, 1992 [This article contains supplemental material online at http://jasn.asnjournals. org/lookup/suppl/doi:10.1681/ASN.2014070688/-/DCSupplemental.](http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2014070688/-/DCSupplemental) · DOI
Cited by
Sorted by citations
Perkovic, V., de Zeeuw, D., Mahaffey, K. W., Fulcher, G., Erondu, N., Shaw, W., Barrett, T. D., Weidner-Wells, M., Deng, H., Matthews, D. R., et al. (2018) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(18)30141-4 · Cited by 637 · see citing works
Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine
Agarwal, R., Kolkhof, P., Bakris, G., Bauersachs, J., Haller, H., Wada, T., & Zannad, F. (2021) · European Heart Journal · doi:10.1093/eurheartj/ehaa736 · Cited by 638 · see citing works
Levey, A. S., Gansevoort, R. T., Coresh, J., Inker, L. A., Heerspink, H. L., Grams, M. E., Greene, T., Tighiouart, H., Matsushita, K., Ballew, S. H., et al. (2020) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2019.06.009 · Cited by 591 · see citing works
Self-citationHeerspink, H. J. L., Greene, T., Tighiouart, H., Gansevoort, R. T., Coresh, J., Simon, A. L., Chan, T. M., Hou, F. F., Lewis, J. B., Locatelli, F., et al. (2019) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(18)30314-0 · Cited by 397 · see citing works
Self-citationRenoprotective effects of sodium-glucose cotransporter-2 inhibitors
Heerspink, H. J. L., Kosiborod, M., Inzucchi, S. E., & Cherney, D. Z. I. (2018) · Kidney International · doi:10.1016/j.kint.2017.12.027 · Cited by 393 · see citing works
Self-citationCherney, D. Z. I., Zinman, B., Inzucchi, S. E., Koitka-Weber, A., Mattheus, M., von Eynatten, M., & Wanner, C. (2017) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(17)30182-1 · Cited by 383 · see citing works
Canagliflozin slows progression of renal function decline independently of glycemic effects
Heerspink, H. J. L., Desai, M., Jardine, M., Balis, D., Meininger, G., & Perkovic, V. (2017) · Journal of the American Society of Nephrology · doi:10.1681/asn.2016030278 · Cited by 361 · see citing works
Self-citationCoresh, 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., et al. (2019) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(18)30313-9 · Cited by 338 · see citing works
Self-citationCurrie, G., Taylor, A. H. M., Fujita, T., Ohtsu, H., Lindhardt, M., Rossing, P., Boesby, L., Edwards, N. C., Ferro, C. J., Townend, J. N., et al. (2016) · BMC Nephrology · doi:10.1186/s12882-016-0337-0 · Cited by 214 · see citing works
A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors
Sen, T., & Heerspink, H. J. L. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.02.016 · Cited by 161 · see citing works
Mann, J. F. E., Hansen, T., Idorn, T., Leiter, L. A., Marso, S. P., Rossing, P., Seufert, J., Tadayon, S., & Vilsbøll, T. (2020) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(20)30313-2 · Cited by 157 · see citing works
Albuminuria changes and cardiovascular and renal outcomes in type 1 diabetes: the DCCT/EDIC study
de Boer, I. H., Gao, X., Cleary, P. A., Bebu, I., Lachin, J. M., Molitch, M. E., Orchard, T., Paterson, A. D., Perkins, B. A., Steffes, M. W., et al. (2016) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.02870316 · Cited by 114 · see citing works
Dekkers, C. C. J., Wheeler, D. C., Sjöström, C. D., Stefansson, B. V., Cain, V., & Heerspink, H. J. L. (2018) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfx350 · Cited by 102 · see citing works
Piperidou, A., Sarafidis, P., Boutou, A., Thomopoulos, C., Loutradis, C., Alexandrou, M. E., Tsapas, A., & Karagiannis, A. (2019) · Journal of Hypertension · doi:10.1097/hjh.0000000000002050 · Cited by 72 · see citing works
Persson, F., Bain, S. C., Mosenzon, O., Heerspink, H. J. L., Mann, J. F. E., Pratley, R., Raz, I., Idorn, T., Rasmussen, S., von Scholten, B. J., et al. (2021) · Diabetes Care · doi:10.2337/dc20-1622 · Cited by 71 · see citing works
EMPA-REG OUTCOME: The Nephrologist's Point of View
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Changes in albuminuria and subsequent risk of incident kidney disease
Sumida, K., Molnar, M. Z., Potukuchi, P. K., George, K., Thomas, F., Lu, J. L., Yamagata, K., Kalantar-Zadeh, K., & Kovesdy, C. P. (2017) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.02720317 · Cited by 47 · see citing works
Renal nerves in physiology, pathophysiology and interoception
Evans, L. C., Dayton, A., & Osborn, J. W. (2025) · Nature Reviews Nephrology · doi:10.1038/s41581-024-00893-3 · Cited by 46 · see citing works
- Authors
- Lambers Heerspink, H. J., Kröpelin, T. F., Hoekman, J., & de Zeeuw, D.
- Affiliations
- University Medical Center Groningen (NL)
- ORCID
- Hoekman, Jarno
- Venue
- Journal of the American Society of Nephrology
- Published
- 2015-08
- Volume
- 26
- Issue
- 8
- Pages
- 2055-2064
- ISSN
- 1046-6673 (ISSN-L)
- PMC
- PMC4520175
- OpenAlex
- W2153037249
- Cited by
- 242
- References
- 51
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 12 · 2023: 20 · 2022: 12 · 2021: 14 · 2020: 25 · 2019: 40 · 2018: 26 · 2017: 29 · 2016: 27 · 2015: 12
- FWCI
- 3.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of the American Society of Nephrology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Keywords
- albuminuria, end-stage renal disease, renal protection, surrogate endpoints, renin-angiotensin-aldosterone system inhibitors, kidney disease progression, meta-regression
- MeSH terms
- Albuminuria, Humans, Kidney Failure, Chronic, Biomarkers
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