NDT Advance Access published August 1, 2014 Nephrol Dial Transplant (2014) 0: 1–10 doi: 10.1093/ndt/gfu255
Original Article A prospective study of multiple protein biomarkers to predict progression in diabetic chronic kidney disease Rajiv Agarwal1, Kevin L. Duffin2, Dennis A. Laska2, James R. Voelker2, Matthew D. Breyer2 1
Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
and 2Eli Lilly and Company, Indianapolis, IN, USA
Correspondence and offprint requests to: Rajiv Agarwal; E-mail: [email protected]
A B S T R AC T Background. Diabetic nephropathy imposes a substantial cardiovascular and renal burden contributing to both morbidity and excess mortality. Progression of chronic kidney disease (CKD) in diabetes mellitus is variable, and few biomarkers are available to predict progression accurately. Identification of novel predictive biomarkers may inform clinical care and assist in the design of clinical trials. We hypothesized that urinary and plasma protein biomarkers predict CKD progression independently of the known clinical markers such as albuminuria and estimated glomerular filtration rate (eGFR) in diabetic nephropathy. Methods. We studied 67 US veterans with CKD due to type 2 diabetes mellitus and 20 age-matched controls (no CKD, hypertension or cardiovascular disease). After clinical evaluation and the collection of blood and urine specimens for 24 biomarkers, we followed subjects prospectively for the next 2–6 years. CKD progression was defined in three ways: (i) clinically by examining eGFR versus time plots for each individual (slope progression), (ii) progression to end-stage renal disease (ESRD) and (iii) a composite outcome of ESRD or death. Results. Among 17 urinary and 7 plasma biomarkers evaluated, the relationship of the biomarkers with outcome was as follows: (i) for progression identified by eGFR plots, urinary C-terminal fibroblast growth factor (FGF)-23 emerged to have the strongest primary association (adjusted odds ratio [aOR] 2.08, P = 0.008); (ii) for ESRD, plasma vascular endothelial growth factor (VEGF) had an association (aOR: 1.44, P = 0.027) and (iii) for the composite outcome of death and ESRD, plasma C-terminal FGF-23 also had a robust direct association (aOR: 3.07, P = 0.008).
Published by Oxford University Press on behalf of ERA-EDTA 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
Conclusion. The relationship of biomarkers with future progression of CKD is complex and depends in part on how CKD progression is defined. Biomarkers in the FGF-23 and VEGFA pathways predicted patient progression independently of albuminuria levels in this patient cohort. Additional studies in other cohorts will help further validate this pilot study. Keywords: albuminuria, biomarkers, chronic kidney disease
INTRODUCTION Diabetic kidney disease in the USA has increased from an estimated 3.9 million adults during 1988–94 to 6.9 million during 2005–08 [1]. Chronic kidney disease (CKD) accounts for much of the increased mortality [2] and cardiovascular morbidity [3] associated with type 2 diabetes. Compared with CKD without diabetes, the care of CKD patients with diabetes mellitus is more costly [4]; end-stage renal disease (ESRD) care among these patients accounts for a major medical and financial burden to society [5]. No new proven therapy for established diabetic kidney disease has been developed in more than a decade, and efforts to reduce progression of ESRD have been hampered by a lack of biomarkers to reliably predict hard outcomes. Currently, the best biomarker to predict progression of diabetic CKD to ESRD remains the presence and the severity of albuminuria [6]. However, based on NHANES data estimating disease prevalence in the USA, no albuminuria was noted in an estimated 2 million of the 6.9 million prevalent patients [1]. Nonetheless, many such individuals progress to ESRD [7]. Thus, development of biomarkers other than albuminuria is needed to predict CKD progression [8, 9]. 1
Downloaded from http://ndt.oxfordjournals.org/ at Linkopings Universitet on August 22, 2014
and Peter G. Mitchell2
ORIGINAL ARTICLE
M AT E R I A L S A N D M E T H O D S This study was approved by the institutional review board, and all subjects signed written informed consent. Conceptually, the study has three parts. Part 1 of the study compares each of the biomarkers among patients with CKD and diabetes with a control group without CKD and diabetes. Part 2 explores the relationship among the biomarkers. Part 3 examines the association of each of the 24 biomarkers with CKD progression. Subject characteristics and follow-up Subjects in this study were recruited between June 2007 and September 2011 from the renal clinic at the VA Medical Center, Indianapolis, IN, USA. Cases were patients diagnosed with diabetic nephropathy based on clinical criteria, i.e. longstanding type 2 diabetes mellitus, nephromegaly, retinopathy and sometimes kidney biopsy. To qualify for inclusion, all cases had to have a seated clinic blood pressure (BP) of
Original Article A prospective study of multiple protein biomarkers to predict progression in diabetic chronic kidney disease Rajiv Agarwal1, Kevin L. Duffin2, Dennis A. Laska2, James R. Voelker2, Matthew D. Breyer2 1
Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
and 2Eli Lilly and Company, Indianapolis, IN, USA
Correspondence and offprint requests to: Rajiv Agarwal; E-mail: [email protected]
A B S T R AC T Background. Diabetic nephropathy imposes a substantial cardiovascular and renal burden contributing to both morbidity and excess mortality. Progression of chronic kidney disease (CKD) in diabetes mellitus is variable, and few biomarkers are available to predict progression accurately. Identification of novel predictive biomarkers may inform clinical care and assist in the design of clinical trials. We hypothesized that urinary and plasma protein biomarkers predict CKD progression independently of the known clinical markers such as albuminuria and estimated glomerular filtration rate (eGFR) in diabetic nephropathy. Methods. We studied 67 US veterans with CKD due to type 2 diabetes mellitus and 20 age-matched controls (no CKD, hypertension or cardiovascular disease). After clinical evaluation and the collection of blood and urine specimens for 24 biomarkers, we followed subjects prospectively for the next 2–6 years. CKD progression was defined in three ways: (i) clinically by examining eGFR versus time plots for each individual (slope progression), (ii) progression to end-stage renal disease (ESRD) and (iii) a composite outcome of ESRD or death. Results. Among 17 urinary and 7 plasma biomarkers evaluated, the relationship of the biomarkers with outcome was as follows: (i) for progression identified by eGFR plots, urinary C-terminal fibroblast growth factor (FGF)-23 emerged to have the strongest primary association (adjusted odds ratio [aOR] 2.08, P = 0.008); (ii) for ESRD, plasma vascular endothelial growth factor (VEGF) had an association (aOR: 1.44, P = 0.027) and (iii) for the composite outcome of death and ESRD, plasma C-terminal FGF-23 also had a robust direct association (aOR: 3.07, P = 0.008).
Published by Oxford University Press on behalf of ERA-EDTA 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
Conclusion. The relationship of biomarkers with future progression of CKD is complex and depends in part on how CKD progression is defined. Biomarkers in the FGF-23 and VEGFA pathways predicted patient progression independently of albuminuria levels in this patient cohort. Additional studies in other cohorts will help further validate this pilot study. Keywords: albuminuria, biomarkers, chronic kidney disease
INTRODUCTION Diabetic kidney disease in the USA has increased from an estimated 3.9 million adults during 1988–94 to 6.9 million during 2005–08 [1]. Chronic kidney disease (CKD) accounts for much of the increased mortality [2] and cardiovascular morbidity [3] associated with type 2 diabetes. Compared with CKD without diabetes, the care of CKD patients with diabetes mellitus is more costly [4]; end-stage renal disease (ESRD) care among these patients accounts for a major medical and financial burden to society [5]. No new proven therapy for established diabetic kidney disease has been developed in more than a decade, and efforts to reduce progression of ESRD have been hampered by a lack of biomarkers to reliably predict hard outcomes. Currently, the best biomarker to predict progression of diabetic CKD to ESRD remains the presence and the severity of albuminuria [6]. However, based on NHANES data estimating disease prevalence in the USA, no albuminuria was noted in an estimated 2 million of the 6.9 million prevalent patients [1]. Nonetheless, many such individuals progress to ESRD [7]. Thus, development of biomarkers other than albuminuria is needed to predict CKD progression [8, 9]. 1
Downloaded from http://ndt.oxfordjournals.org/ at Linkopings Universitet on August 22, 2014
and Peter G. Mitchell2
ORIGINAL ARTICLE
M AT E R I A L S A N D M E T H O D S This study was approved by the institutional review board, and all subjects signed written informed consent. Conceptually, the study has three parts. Part 1 of the study compares each of the biomarkers among patients with CKD and diabetes with a control group without CKD and diabetes. Part 2 explores the relationship among the biomarkers. Part 3 examines the association of each of the 24 biomarkers with CKD progression. Subject characteristics and follow-up Subjects in this study were recruited between June 2007 and September 2011 from the renal clinic at the VA Medical Center, Indianapolis, IN, USA. Cases were patients diagnosed with diabetic nephropathy based on clinical criteria, i.e. longstanding type 2 diabetes mellitus, nephromegaly, retinopathy and sometimes kidney biopsy. To qualify for inclusion, all cases had to have a seated clinic blood pressure (BP) of
