When Chronic Kidney Disease Therapies Meet the Allograft: Lessons From Dapagliflozin

Chronic allograft dysfunction (CAD) remains a leading cause of late graft failure and a major unmet need for transplantation. Recognition that mechanisms of progressive graft loss overlap with those driving chronic kidney disease (CKD) in native kidneys has prompted efforts to translate effective CKD therapies into the transplant setting. Yet prior randomized trials have largely been disappointing. In kidney transplant recipients, renin-angiotensin system (RAS) blockade has shown modest and inconsistent benefits,1 whereas mineralocorticoid receptor antagonists have not clearly improved kidney outcomes and increased hyperkalemia risk. Similarly, alkali treatment for metabolic acidosis has not demonstrated benefit on renal function or other clinical endpoints.2 In native CKD, sodium-glucose cotransporter-2 inhibitors (SGLT2i) have transformed practice by slowing kidney function decline and improving cardiovascular outcomes across diabetic and nondiabetic populations.3 Therefore, it is reasonable to hypothesize that these benefits might extend to the transplanted kidney, and first retrospective studies from large registries suggest potential significant benefits for renal allograft recipients. In this issue, David-Neto et al4 report the first randomized, double-blind, placebo-controlled trial of dapagliflozin in 208 kidney transplant recipients with CAD. Baseline estimated glomerular filtration rate (eGFR) averaged 40 mL/min/1.73 m2, the mean time from transplantation was 31 months, fewer than 20% had proteinuria, and approximately 20% were diabetic. For 12 mo, dapagliflozin did not improve eGFR compared with placebo and eGFR values were even numerically lower in the treatment arm at later time points. Importantly, dapagliflozin was safe and produced several expected biological effects, including reductions in proteinuria, blood pressure, body weight, and glycated hemoglobin in diabetic recipients, without an excess of serious adverse events. The physiological effects of SGLT2i were therefore preserved, but they did not translate into measurable graft function benefits over the 12-mo period. Many therapies effective in native CKD, including RAS blockers and SGLT2i, act by lowering intraglomerular pressure. In kidney transplant recipients; however, calcineurin inhibitor (CNI)-induced afferent vasoconstriction may already reduce glomerular pressure, potentially limiting these effects. SGLT2i induce afferent vasoconstriction through tubuloglomerular feedback primarily in the setting of hyperfiltration, suggesting that their hemodynamic impact may be attenuated in the allograft.5 Consistently, SGLT2i appear safe in transplant recipients, but CNIs may blunt both the characteristic early eGFR dip and the downstream renoprotective effect. The denervated state of the allograft further distinguishes it from native kidneys and may contribute to these differences. In native CKD, the early eGFR decline is generally interpreted as the hemodynamic correlate of long-term benefit. In the present study, all patients were receiving tacrolimus, and the initial eGFR dip was modest, even in per-protocol analyses and particularly among those on RAS blockade. In patients receiving CNI-free regimens, in whom afferent vasoconstriction is less pronounced and intraglomerular pressure may be relatively higher, SGLT2i could exert a more robust hemodynamic and potentially renoprotective effect. Based on data in CKD,6 patients with prior glomerular disease might be the ones who could benefit the most from these treatments. This hypothesis warrants direct testing and may help identify patient populations in whom these agents are more likely to be effective. By excluding patients with antibody-mediated rejection, transplant glomerulopathy, BK nephropathy, and other defined causes of graft dysfunction, the investigators created a rather homogeneous study population and also a narrower one that may not fully reflect clinical practice. Therefore, future studies are needed to fully address the safety/efficacy profile of SGLT2i in the full disease spectrum of CAD. The behavior of the placebo arm further complicates interpretation. Patients assigned to a placebo did not experience the degree of decline expected in a population selected for impaired or worsening graft function. This may reflect reductions in tacrolimus exposure, which appeared relatively high at enrollment; unfortunately, these data are not reported, precluding assessment of this hypothesis. Importantly, this well-executed trial4 should not be viewed as negative but rather as clarifying. It provides robust evidence supporting the safety of SGLT2i in kidney transplant recipients and confirms their expected metabolic and hemodynamic effects. However, the dissociation between these improvements and graft function underscores the need to better define meaningful intermediate endpoints in transplantation. Modest reductions in proteinuria alone may not be sufficient as surrogates for long-term graft preservation, particularly in heterogeneous populations without detailed structural characterization. These results temper enthusiasm derived from retrospective studies, where residual confounding may overestimate treatment effects. Future trials will require larger sample sizes and longer follow-up, such as the ongoing Renal Lifecycle trial, in which >500 renal allograft recipients will be randomized and followed for 4 y.7 In the study by David-Neto et al,4 the short follow-up period may have limited the detection of eGFR benefits, which in CKD typically emerge only after approximately 2 y of treatment.3 Another implication for transplant trials is the need for more informative endpoints that capture disease trajectory, such as eGFR slope or combined endpoints such as iBox. Integration of mechanistic biomarkers and, where feasible, protocol biopsies will be critical to better understand treatment effects and identify responsive subgroups. Notably, the consistent improvements in metabolic and hemodynamic parameters are biologically meaningful and suggest that SGLT2i benefits may be more evident in selected subgroups, particularly proteinuric patients.8 Because these effects suggest an overall improvement of posttransplant metabolic disease, which is associated with poor long-term outcomes,9 this result raises the possibility that the effects of SGLT2i extend beyond short-term eGFR preservation and may influence longer-term outcomes such as death with functioning graft, which is often driven by cardiovascular and metabolic factors rather than isolated graft failure. The benefits of dapagliflozin might be even higher and extend to parameters that have not been reported by the authors of the present article4 but have been previously reported by others,10 including control of hyperkalemia, hyperuricemia, and hypomagnesemia, and amelioration of the lipid profile and increased hematocrit. Transplantation has benefited greatly from advances in nephrology, but therapeutic paradigms do not translate directly. The study by David-Neto et al4 highlights that allograft biology is distinct and underscores the need for robust evidence on the benefits and risks of this promising drug class in kidney transplant recipients, with interventions tailored accordingly. At the same time, translation should not be viewed as unidirectional: as the biology of allograft injury is more precisely defined, insights from transplantation may inform therapeutic strategies in native CKD.