Risk Factors for Renal Dysfunction in Type 2 Diabetes: U.K. Prospective Diabetes Study 74 Ravi Retnakaran, Carole A Cull, Kerensa I Thorne, Amanda I Adler, Rury R Holman Diabetes. Jun Vol. 55

BACKGROUND Type 2 diabetes : leading cause of ESRD In the UKPDS, 24.9% developed microalbuminuria But only 0.8% developed ESRD Classical paradigm : annual transitional rate: 2-3% NormoalbuminuriaMicroalbuminuria MacroalbuminuriaESRD

OBJECTIVE To identify clinically evident risk factors that are associated with the subsequent development of renal dysfunction

METHODS UKPDS : 5,102 with newly diagnosed type 2 diabetes between 1977 and 1991 Exclusion criteria  myocardial infarction or stroke  severe vascular disease  uncontrolled hypertension  proliferative or preproliferative retinopathy  plasma creatinine ≥175 µmol/l (=3.15mg/dl)  treatment with systemic steroids  severe previous illness

METHODS Renal outcomes  Microalbuminuria : urinary albumin concentration mg/l  Macroalbuminuria : urinary albumin concentration ≥300 mg/l  Reduced glomerular filtration rate : : estimated creatinine clearance ≤60 ml/min  Doubling of baseline plasma creatinine AlbuminuriaRenal impairment

RESULTS

METHODS

RESULTS 1,544 of 4031 (38%)1,449 of 5,032 (29%)

RESULTS In 4,006 patients with the requisite data for both outcomes, 1,534 (38%) developed albuminuria 1,132 (28%) developed renal impairment 557 (14%) developed both conditions Of the 1,534 patients who developed albuminuria, 977 (64%) no renal impairment 372 (24%) albuminuria → renal impairment 12% renal impairment before developing albuminuria Of the 1,132 patients who developed renal impairment, 575 (51%) no albuminuria 185 (16%) albuminuria → renal impairment 33% developed albuminuria before developing renal impairment

DISCUSSION Over 15 years after type 2 DM diagnosis in UKPDS, 38% developed albuminuria 29% developed renal impairment WESDR study  In renal impairment patients, 61% : no albuminuria beforehand 39% : never developed albuminuria during the study  In albuminuria patients, : only 24% subsequently developed renal impairment Risk factors for both albuminuria and renal impairment  SBP  urinary albumin excretion  plasma creatinine  Indian-Asian ethnicity

DISCUSSION Albuminuria : a marker of nephropathic risk in type 2 diabetes However, microalbuminuria alone : may not high risk factor  stabilization of microalhuminuria without progression and regression of albuminuria  underlying renal structural lesions  Third National Heath and Nutrition Examination Survey : 30% - neither albuminuria nor retinopathy Identification of other risk factors is needed Distinction between risk factors for albuminuria and for renal impairment

DISCUSSION Most highly risk factors for albuminuria  urinary albumin  systolic blood pressure  plasma triglycerides  Indian-Asian ethnicity

DISCUSSION Plasma triglycerides  Elevated triglyceride-to-HDL ratio : independently associated with progression of microalbuminuria  Fasting TG : a strong independent determinant of both microalbuminuria and macroalbuminuria Indian-Asian ethnicity  Increased incidence of renal failure in U.K. Indian-Asian patients  In cross sectional studies, higher prevalence of microalbuminuria in Indian Asians

DISCUSSION Previous prospective studies : several other risk factors for incident albuminuria age, male sex. duration of diabetes, smoking, obesity, and the presence of retinopathy white cell count both type 2 diabetes and atherosclerotic vascular disease : states of chronic low-grade inflammation activated leukocytes : nephrotoxic cytokines

DISCUSSION The most highly associated risk factors for creatinine clearance ≤60 : plasma creatinine, systolic blood pressure, age, female, height, decreased waist circumference Sex and waist circumference : paradoxical associations  male and increased central obesity → albumiiutria  female and decreased waist circumference → renal impairment

CONCLUSION 15 years from diagnosis of type 2 diabetes, nearly 40% developed albuminuria nearly 30% developed renal impairment Risk factors for both albuminuria & renal impairment : systolic blood pressure, Indian-Asian ethnicity, urinary albumin excretion, plasma creatinine Albuminuria and renal impairment are not inexorably linked in type 2 diabetes