PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in kidney transplant recipients (KTRs) and death from CVD is the leading cause of graft loss. KTRs demonstrate abnormal endothelium-dependent dilation (EDD) and large artery stiffness, key pathophysiological antecedents to the development of CVD. Acid retention is a common feature of patients who have received a kidney transplant. KTRs have a single kidney and a decreased number of nephrons leading to an inability to excrete the daily dietary acid load. Additionally, KTRs receive several medications that can result in acid retention including calcineurin inhibitors. Acid retention results in increased ammoniagenesis leading to activation of the alternative complement pathway. Activation of the alternative complement pathway increases inflammatory factors, collagen deposition and endothelial inflammation contributing to tubulointerstitial damage and vascular dysfunction. We show that complement activation fragments are increased in KTRs compared to healthy controls and are inversely correlated with eGFR and EDD. Lower serum bicarbonate levels, even within the normal laboratory range, in KTRs are associated with an increased risk of graft loss, cardiovascular events and mortality. Small interventional trials have shown that treatment with alkali therapy slows progression of kidney disease, even in patients with normal serum bicarbonate levels. In our preliminary data, alkali therapy improved vascular endothelial function in 20 patients with chronic kidney disease stage 3-4. Because acid retention is common in KTRs, it is plausible that alkali therapy in KTRs may also result in improved vascular and graft function. In our preliminary data, we show in a randomized, double-blind, placebo-controlled crossover safety and feasibility study that sodium bicarbonate therapy is safe and feasible in KTRs and there is a trend towards improved EDD. We are proposing a randomized, double-blinded, placebo-controlled, 12 month study in 120 KTRs to examine the effect of sodium bicarbonate therapy on surrogate markers of CVD and graft function. Our overall hypothesis is that treatment with bicarbonate will improve indicators of vascular and graft function in KTRs by decreasing complement activation. In Aim 1, we will compare changes over time in brachial artery flow- mediated dilation and arterial stiffness, measured by aortic pulse wave velocity, before and after 12 months of sodium bicarbonate therapy or placebo. In Aim 2, we will compare changes over time in tubular atrophy and interstitial fibrosis in kidney biopsies before and after 12 months of sodium bicarbonate therapy or placebo. In Aim 3, we will examine changes in plasma and urine complement activation fragments (Ba and sC5b-9) and complement deposition in kidney tissue before and after 12 months of sodium bicarbonate therapy or placebo. The results of this novel study have the potential to inform clinical practice by provi...