The Effect of Uric Acid Lowering in Type 1 Diabetes

Overview

Patients with type 1 diabetes mellitus (T1DM) are at high risk of developing kidney complications potentially leading to end stage renal disease. Uric acid (UA), the end product of purine metabolism, emerged as an important determinant of renal and vascular injury due to its ability activate the renin-angiotensin-aldosterone system (RAAS) and increase production of harmful reactive oxygen species (ROS). ROS cause progressive endothelial cell dysfunction, inflammation, tissue fibrosis and eventually cell death. These processes are enhanced in DM because of the effect of hyperglycemia. Since existing preventive drug therapies fail to completely prevent kidney damage, an examination of the effect of UA lowering against initiation and progression of renal and vascular complications is therefore of the utmost importance. The purpose of this study is to examine the effect of UA lowering with febuxostat on renal and systemic vascular function in patients with uncomplicated T1DM. It was hypothesized that UA lowering will improve kidney and systemic vascular function through effects on blood vessel function and anti-inflammatory effect. Kidney and blood vessel function will be assessed under conditions of normal and high blood sugar levels before and after 8 weeks of treatment with the UA lowering drug febuxostat in patients with diabetes and during normoglycemia only in health controls. Current treatment for renal and vascular complications in DM patients includes blockade of the RAAS. Unfortunately, angiotensin converting enzyme inhibitors (ACEi) and angiotensin II (AngII) receptor blockers (ARBs) lead to incomplete RAAS suppression, and do not completely prevent renal or vascular complications. Moreover, dual RAAS blockade increases renal and cardiovascular risk. Recent experimental work suggests that UA lowering therapies can block the RAAS, suppress inflammation and promote renal and systemic vascular protection. Therefore, our study is critical in determining the possible role of early UA lowering on renal and systemic hemodynamic dysfunction in young patients with T1DM.

Uric acid (UA) was recently suggested to exert deleterious effects on blood pressure and renal function, even when baseline UA levels are within the normal range. UA activates the renin angiotensin-aldosterone system (RAAS), increases oxidative stress and promotes inflammation. As a consequence, higher UA levels are associated with metabolic abnormalities (insulin resistance, hyperglycemia), cardiovascular disease (hypertension, endothelial dysfunction, arterial stiffness, cardiac diastolic dysfunction) and kidney function abnormalities (hyperfiltration - a marker for intraglomerular hypertension, proteinuria). Thus pharmacologic UA lowering may promote renal and cardiovascular protection. The mechanisms underlying these protective effects in humans, prior to the onset of clinical disease, remain unknown. This study is focused on the prevention of complications in young, normotensive type 1 diabetes mellitus (T1DM) patients with normal renal function and UA levels. The study will examine the effect of UA lowering with febuxostat (FBX) on renal hemodynamic function, vascular function and urinary inflammatory biomarkers. Based on substantial supportive pre-clinical and epidemiological data, we hypothesize that lowering UA levels that are within normal range at baseline will: 1) ameliorate hemodynamic abnormalities characteristic of T1DM, and reduce renal and systemic hypertensive responses to hyperglycemia; 2) ameliorate endothelial function abnormalities characteristic of T1DM; 3) reduce urinary inflammatory cytokines/chemokine excretion.