PROJECT ABSTRACT
Kidney transplantation is the desired treatment for kidney failure. While short term kidney transplantation
outcomes have improved significantly, long-term outcomes remain suboptimal. Death with functioning graft
from cardiovascular disease (CVD) is a major cause of graft loss. The annual rate of cardiovascular events in
kidney transplant recipients (KTRs) is 50 times higher than that of the general population. Over 30% of KTRs
have pre-existing type 2 diabetes (T2D) and around 10-40% will develop posttransplant T2D. T2D magnifies
risk for CVD, graft loss and mortality among KTRs. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are
now standard of care in patients with chronic kidney disease (CKD). Several large randomized controlled trials
(RCTs) have established that SGLT2i improve kidney and cardiovascular outcomes. Using single-cell RNA
sequencing (scRNA-seq) data from kidney biopsies we found that SGLT2i treatment benefits the diabetic
kidney by mitigating diabetes-induced metabolic perturbations via suppression of mammalian target of
rapamycin complex1 (mTORC1) in kidney tubules. Additional preliminary data from our group suggest that
SGLT2i is associated with improved kidney oxygenation by kidney MRI, which may contribute to the beneficial
kidney effects of SGLT2i. These potential mechanisms are particularly promising in KTRs, as our preliminary
studies in KTR biopsies found enrichment for renal metabolism and mTORC1 signaling post-transplantation.
mTORC1 plays a key role in the immune response and graft rejection in KTRs. SGLT2i may have benefits for
KTRs, such as improving graft function and lowering the risk of CVD. However, the potential benefit of
SGLT2is for KTRs has not been explored in RCTs. Accordingly, we propose a 12-month, randomized,
placebo-controlled, double-blind study in 80 adult KTRs with pre-existing T2D or new onset posttransplant
diabetes with eGFR 30-90 ml/min/1.73m2 and urine albumin-to-creatinine ratio (UACR) of 30-5000 mg/g to
examine the effects and underlying mechanisms of dapagliflozin on kidney and cardiovascular structure and
function. The primary outcomes are change in UACR and establishing safety. In Aim 1, we will assess the
effects and safety of 12 months of dapagliflozin vs. placebo on kidney graft structure and function via kidney
MRI as well as kidney allograft biopsies in a subset of participants (n=40). In Aim 2, we will determine the
effects of 12 months of dapagliflozin vs. placebo on arterial stiffness, cardiac structure and function assessed
by aortic pulse wave velocity and aortic and cardiac MRI. In Aim 3, we will implement state-of-the-art
interrogation of kidney tissue from baseline and 1-year biopsies by integrating scRNA-seq with detailed
morphometry as well as comprehensive clinical phenotyping to investigate the mechanisms of dapagliflozin in
KTRs, and associations of these mechanisms with kidney structure and function. The expected results will
provide critical insight into the efficacy, safety and mechanisms of dapagliflozin in promoting kidney graft
function and cardiovascular health in KTRs.
