Despite improvements in the past 20 years in glycemia and blood pressure (BP) control, and the introduction of ?renoprotective? drugs such as renin-angiotensin system blockers (RASB), the overall incidence of end- stage renal disease (ESRD) in type 1 diabetes (T1D) is not declining. Novel therapies to complement these interventions are urgently needed. Convincing evidence from multiple cohort studies indicates that higher serum uric acid levels (SUA) predict a substantial increase in the risk of chronic kidney disease (CKD) and accelerated glomerular filtration rate (GFR) loss among persons with T1D. To study whether SUA lowering can reduce GFR loss in T1D, we established a unique consortium of investigators from 16 academic centers in the US, Canada, and Denmark. Led by co-PIs, Drs. Doria from the Joslin Kidney Study, and Mauer, formerly PI of the Renin Angiotensin System Study (RASS) clinical trial, the Consortium has been named PERL (Preventing Early Renal Function Loss in Diabetes) to emphasize its focus on intervening relatively early in the course of CKD in T1D, when renal damage is more likely to be arrestable or reversible and interventions are thus more likely to be effective. With the support of NIH grants R03 DK094484, R34 DK097808, UC4 DK101108, and a JDRF grant, the PERL Consortium is currently conducting a multi-center, double-blind, clinical trial in which 530 patients with T1D of ?8 years of duration, mild to moderate decrease in GFR, moderately increased SUA (?4.5 mg/dl), and a history of either elevated urinary excretion of albumin or accelerated GFR decline were randomized to receive the urate-lowering drug allopurinol (200 to 400 mg per day depending on renal function) or placebo for three years. The primary outcome is the GFR (as measured by iohexol plasma disappearance) at the end of a 2-month wash-out period after the 3-year intervention. PERL successfully completed randomization of the 530 participants (10% more than the initial recruitment goal) in May 2016, with the last participant visit planned for June 2019. PERL participant retention and adherence have been excellent. The purpose of this application is to renew NIH grant UC4 DK101108, which currently supports all aspects of the trial and is projected to cover costs until October 2017. Funding after that date will allow completion of the 3-year treatment period for all PERL subjects, this being necessary for adequate power to answer the trial's questions as delineated in the protocol approved by NIDDK and the DSMB. This grant renewal will also provide support for data analysis and manuscript writing upon trial completion. If PERL demonstrates that allopurinol can halt or slow the rate of GFR decline in persons with T1D, it would provide a simple, safe, and inexpensive intervention to prevent or delay ESRD in T1D that can be applied at the earliest clinically detectable stages of renal functional decline. It is difficult to overstate how significant this would be, both from the perspective of public health and that of persons with diabetes, adding an estimated 8-10 years free of hemodialysis or kidney transplant to their lives.
If this trial is successful, the reduction in morbidity and mortality resulting from the prevention or delay of ESRD due to the use of allopurinol 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 diabetic nephropathy. Because of the emphasis on relatively early intervention and its focus on preventing early GFR decline, the proposed trial, if successful, will establish a new paradigm in treatments to slow or prevent progression towards end stage kidney disease in T1D far beyond anything achieved to date.
| Kumar, Navasuja; Pop-Busui, Rodica; Musch, David C et al. (2018) Central Corneal Thickness Increase Due to Stromal Thickening With Diabetic Peripheral Neuropathy Severity. Cornea 37:1138-1142 |
| Mauer, Michael; Doria, Alessandro (2018) Uric Acid and Diabetic Nephropathy Risk. Contrib Nephrol 192:103-109 |
| Tuttle, Katherine R (2017) Back to the Future: Glomerular Hyperfiltration and the Diabetic Kidney. Diabetes 66:14-16 |
| de Boer, Ian H; Afkarian, Maryam; Tuttle, Katherine R (2016) The Surging Tide of Diabetes: Implications for Nephrology. Am J Kidney Dis 67:364-6 |
