MS #DC13-0985 R.3. Early progressive renal decline precedes the onset of microalbuminuria and its progression to macroalbuminuria Short title: Early renal decline in Type 1 diabetes

249 words Text: 4411 words. 3 Tables 2 Figures Page 1 of 30 Diabetes Care Diabetes Care Publish Ahead of Print, published online August 12, 2013 ABSTRACT: OBJECTIVE: Progressive decrease in the glomerular filtration rate (GFR), or renal decline, in type 1 diabetes (T1D) is seen in patients with macroalbuminuria. However, it is unknown whether this decline begins during microalbuminuria (MA) or normoalbuminuria (NA). METHODS: The study group (2 nd Joslin Kidney Study) comprises patients with T1D and NA (n=286) or MA (n=248) who were followed for 4-12 years (median 8 years). Serial measurements (median 6, range 3 to 16) of serum creatinine and cystatin C were used jointly to estimate GFR (eGFRcr-cys) and assess its trajectories during follow-up. RESULTS: Renal decline (progressive eGFRcr-cys loss at least -3.3% per year) occurred in 10% of the NA and in 35% of the MA (p<0.001). In both groups, the strongest determinants of renal decline were baseline serum concentrations of uric acid (p<0.001) and a tumor necrosis factor receptor (TNFR1 or 2, p<0.001). Other significant risk factors included baseline HbA1c, age/diabetes duration and systolic blood pressure. Relative impacts of these determinants were similar in NA and MA. Renal decline was not associated with sex or baseline serum concentration of TNFa, IL-6, IL-8, IP-10, MCP-1, VCAM, ICAM, Fas or FasL. CONCLUSIONS: Renal decline in T1D begins during NA and it is determined OBJECTIVE: Progressive decrease in the glomerular filtration rate (GFR), or renal decline, in type 1 diabetes (T1D) is seen in patients with macroalbuminuria. However, it is unknown whether this decline begins during microalbuminuria (MA) or normoalbuminuria (NA). METHODS: The study group (2 nd Joslin Kidney Study) comprises patients with T1D and NA (n=286) or MA (n=248) who were followed for 4-12 years (median 8 years). Serial measurements (median 6, range 3 to 16) of serum creatinine and cystatin C were used jointly to estimate GFR (eGFRcr-cys) and assess its trajectories during follow-up. RESULTS: Renal decline (progressive eGFRcr-cys loss at least -3.3% per year) occurred in 10% of the NA and in 35% of the MA (p<0.001). In both groups, the strongest determinants of renal decline were baseline serum concentrations of uric acid (p<0.001) and a tumor necrosis factor receptor (TNFR1 or 2, p<0.001). Other significant risk factors included baseline HbA1c, age/diabetes duration and systolic blood pressure. Relative impacts of these determinants were similar in NA and MA. Renal decline was not associated with sex or baseline serum concentration of TNFa, IL-6, IL-8, IP-10, MCP-1, VCAM, ICAM, Fas or FasL. CONCLUSIONS: Renal decline in T1D begins during NA and it is determined by multiple factors, similar to MA. Thus, this early decline is the primary disease process leading to impaired renal function in T1D. Changes in AER, such as the onset of MA, or its progression to macroalbuminuria, are either caused by or develop in parallel to the early renal decline. Page 2 of 30 Diabetes Care