title: Improved clinical trial enrollment criterion to identify patients with diabetes at risk of end-stage renal disease.
abstract: Design of Phase III trials for diabetic nephropathy currently requires patients at a high risk of progression defined as within three years of a hard end point (end-stage renal disease, 40% loss of estimated glomerular filtration rate, or death). To improve the design of these trials, we used natural history data from the Joslin Kidney Studies of chronic kidney disease in patients with diabetes to develop an improved criterion to identify such patients. This included a training cohort of 279 patients with type 1 diabetes and 134 end points within three years, and a validation cohort of 221 patients with type 2 diabetes and 88 end points. Previous trials selected patients using clinical criteria for baseline urinary albumin-to-creatinine ratio and estimated glomerular filtration rate. Application of these criteria to our cohort data yielded sensitivities (detection of patients at risk) of 70-80% and prognostic values of only 52-63%. We applied classification and regression trees analysis to select from among all clinical characteristics and markers the optimal prognostic criterion that divided patients with type 1 diabetes according to risk. The optimal criterion was a serum tumor necrosis factor receptor 1 level over 4.3 ng/ml alone or 2.9-4.3 ng/ml with an albumin-to-creatinine ratio over 1900 mg/g. Remarkably, this criterion produced similar results in both type 1 and type 2 diabetic patients. Overall, sensitivity and prognostic value were high (72% and 81%, respectively). Thus, application of this criterion to enrollment in future clinical trials could reduce the sample size required to achieve adequate statistical power for detection of treatment benefits.
authors.affiliation: Section on Genetics and Epidemiology, Research Divisions, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamanouchi
authors.affiliation: Section on Genetics and Epidemiology, Research Divisions, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Department of Metabolic Disease, Jagellonian University Medical College, Krakow, Poland. Electronic address: Jan.Skupien@uj.edu.pl.
authors.forename: Jan
authors.initials: J
authors.lastname: Skupien
authors.affiliation: Section on Genetics and Epidemiology, Research Divisions, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Monika A
authors.initials: MA
authors.lastname: Niewczas
authors.affiliation: Section on Genetics and Epidemiology, Research Divisions, Joslin Diabetes Center, Boston, Massachusetts, USA.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Smiles
authors.affiliation: Section on Genetics and Epidemiology, Research Divisions, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Doria
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Renal Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Stanton
authors.affiliation: Institute of Gerontology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
authors.forename: Andrzej T
authors.initials: AT
authors.lastname: Galecki
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Company Inc. Corporate Center, Indianapolis, Indiana, USA.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Duffin
authors.affiliation: Pfizer Inc., 610 Main Street, Cambridge, Massachusetts, 02139, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Pullen
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Company Inc. Corporate Center, Indianapolis, Indiana, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Breyer
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Renal Division, Brigham & Women Hospital, Boston, Massachusetts, USA.
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.affiliation: Section on Genetics and Epidemiology, Research Divisions, Joslin Diabetes Center, Boston, Massachusetts, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Warram
authors.affiliation: Section on Genetics and Epidemiology, Research Divisions, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: Andrzej.krolewski@joslin.harvard.edu.
authors.forename: Andrzej S
authors.initials: AS
authors.lastname: Krolewski
mesh_terms: D000328:Adult; D000419:Albuminuria / Q000209:etiology / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood / Q000652:urine; D017326:Clinical Trials, Phase III as Topic / Q000379:methods*; D003404:Creatinine / Q000652:urine; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000175:diagnosis; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000175:diagnosis; D003928:Diabetic Nephropathies / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology / Q000628:therapy; D018450:Disease Progression; D023381:Endpoint Determination; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007668:Kidney / Q000503:physiopathology*; D007676:Kidney Failure, Chronic / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D011237:Predictive Value of Tests; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors
chemical_list: D015415:Biomarkers; D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human; D003404:Creatinine
keywords: acute kidney injury; chronic kidney disease; diabetes