Despite improvements in the past 20 years in glycemic and blood pressure control, and the introduction of 'renoprotective'drugs such as renin-angiotensin system blockers (RASB), the incidence of end-stage renal disease (ESRD) in type 1 diabetes (T1D) is not declining. Novel therapies to complement these interventions are urgently needed. Mounting evidence from prospective studies indicates that moderately elevated serum uric acid is a strong, independent predictor of an increased risk of chronic kidney disease and increased rates of loss of kidney function among T1D persons. To study whether uric acid lowering can reduce glomerular filtration rate (GFR) loss in T1D, we have established a consortium that includes investigators from the Joslin Diabetes Center, the Universities of Minnesota, Colorado, Toronto, and Michigan, and the Steno Diabetes Center. Currently, we are envisioning a four-year, multi-center, double- blind, placebo-controlled, randomized clinical trial evaluating the efficacy of the urate-lowering drug allopurinol, as compared to placebo, in reducing kidney function loss among subjects with T1D. The trial will specifically target T1D patients with microalbuminuria or moderate macroalbuminuria and serum uric acid levels e 5 mg/dl, since these are the patients who are at very high risk of having rapid rates of GFR decline and might most benefit from reductions in uric acid levels. Study subjects will be required to have a GFR e 60 ml/min, consistent with the goal of intervening relatively early in the natural history of kidney disease, when kidney function can still be preserved, rather than at later stages when structural changes are far advanced and most of kidney function is already lost. The primary endpoint of the study will be the GFR (as measured by the iohexol plasma disappearance) at the end of the 4-year intervention. Preliminary calculations suggest that ~200 subjects in each treatment arm would provide us with reasonable power to detect a clinically meaningful and achievable reduction in GFR decline in the allopurinol as compared to the placebo group. With the R03 support, we intend to bring this study concept closer to implementation by accomplishing the following Specific Aims: 1.To finalize the Study Protocol;2.To identify the best site specific mechanisms to query the respective patient databases for the quickest identification of eligible subjects;3.To prepare a Manual of Operation;4.To file IRB applications at all study sites. By accomplishing these aims, we will be optimally positioned to successfully apply for an R34 grant, during which we will establish the clinical trial infrastructue and test it in a vanguard phase of the trial. If we can then demonstrate in the full trial that allopurinol can halt or slow GFR decline in T1D subjects, we will have a simple, safe, and inexpensive intervention to prevent or delay kidney failure in T1D that can be applied at the earliest clinically detectable stages of renal injury. It is difficult to overstate how significantthis discovery would be, both from the perspective of public health and that of individual diabetic patients.
The trial that we propose, if successful, will introduce a new pharmacological intervention to prevent or delay kidney failure in T1D. The reduction in morbidity and mortality resulting from this would have a major impact on the lives of T1D patients as well as on society at large, significantly reducing the human and financial costs associated with this condition.
| Sirota, Jeffrey C; McFann, Kim; Targher, Giovanni et al. (2013) Elevated serum uric acid levels are associated with non-alcoholic fatty liver disease independently of metabolic syndrome features in the United States: Liver ultrasound data from the National Health and Nutrition Examination Survey. Metabolism 62:392-9 |
| Maahs, David M; Caramori, Luiza; Cherney, David Z I et al. (2013) Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study. Curr Diab Rep 13:550-9 |
| Doria, Alessandro; Niewczas, Monika A; Fiorina, Paolo (2012) Can existing drugs approved for other indications retard renal function decline in patients with type 1 diabetes and nephropathy? Semin Nephrol 32:437-44 |
| Sirota, Jeffrey C; McFann, Kim; Targher, Giovanni et al. (2012) Association between nonalcoholic liver disease and chronic kidney disease: an ultrasound analysis from NHANES 1988-1994. Am J Nephrol 36:466-71 |
