H lio Tedesco Silva

BACKGROUND: This study determined whether cyclosporine A (CsA)-treated renal allograft recipients with deteriorating renal function ("creeping creatinine") secondary to chronic allograft nephropathy (CAN) benefit from the addition of mycophenolate mofetil (MMF) to their immunosuppressive regimen, followed by withdrawal of CsA. METHODS: In a controlled, open, multicenter study, CsA-treated renal allograft recipients with progressively deteriorating renal function were randomized to have their CsA discontinued with the concomitant addition of MMF to their regimen (group A) or to continue treatment with CsA (group B). The primary endpoint was the response rate over the 6-month period after withdrawal of CsA in group A or the equivalent time in group B. Response was defined as a stabilization or reduction of serum creatinine (SCr), as evidenced by a flattening or positive slope of the 1/SCr plot and no graft loss. Secondary endpoints included the incidence of acute rejection, graft and patient survival, and changes in selected metabolic parameters. RESULTS: The response rate in the primary intent-to-treat population (n=122) was 58% (36/62) in group A versus 32% (19/60) in group B (P=0.0060). The corresponding percentages of responders in the per-protocol population (n=107) were 60% (36/60) and 26% (12/47), respectively (P=0.0008). There were no acute rejections in group A during the study period. Patients in this group also experienced a significant decrease in total cholesterol. CONCLUSIONS: In patients with progressively deteriorating renal function secondary to CAN, addition of MMF followed by withdrawal of CsA results in a significant improvement in transplant function without the risk of acute rejection.

BACKGROUND: Chronic allograft dysfunction (CAD) remains a leading cause of graft loss after kidney transplantation. Dapagliflozin (DAPA) has shown renal and cardiometabolic benefits in nontransplanted patients with chronic kidney disease. However, data on recipients with CAD are lacking. METHODS: Adult kidney transplant recipients (n = 208), with estimated glomerular filtration rate (eGFR) 25-45 mL/min/1.73 m 2 or 45-60 mL/min/1.73 m 2 with ≥10% annual decline, were randomized to receive DAPA 10 mg/d or placebo for 12 mo. The outcomes were differences in eGFR, in eGFR slopes, proteinuria, blood pressure, body mass index (BMI), and safety. RESULTS: There was no difference in eGFR between groups ( P = 0.611). However, at month 12, eGFR was higher in the PLACEBO group (n = 102; 39.4 ± 0.9 vs 36.5 ± 0.9 mL/min/1.73 m 2 ( P = 0.029). In the DAPA group (n = 106), the least square means (LSM) of eGFR slopes was -0.86 ± 0.65 mL/min/1.73 m 2 at the third month while remaining at -0.75 ± 0.65 mL/min/1.73 m 2 at 12 mo. The PLACEBO group presented an LSM slope of -0.34 ± 067 mL/min/1.73 m 2 at 3 mo and +0.51 ± 66 mL/min/1.73 m 2 at 12 mo. In a per-protocol analysis, patients in the DAPA group (n = 86) under angiotensin-converting enzyme inhibitor/ angiotensin receptor blockers (n = 23) did not present an eGFR dip, but those not under angiotensin-converting enzyme inhibitor/ angiotensin receptor blockers (n = 63) did. DAPA reduced proteinuria from 267 to 84 mg/g ( P < 0.001), body weight by 2 kg ( P = 0.02), BMI by 0.7 kg/m 2 ( P = 0.023), systolic blood pressure by 7 mm Hg ( P = 0.014), diastolic blood pressure from baseline to 9 mo (80.5 ± 1.2 vs 76.8 ± 1.2 mm Hg, P = 0.021), and glycated hemoglobin in patients with diabetes by 0.5% ( P = 0.04). The incidence of serious adverse events did not differ between groups. CONCLUSIONS: In kidney transplant recipients with CAD, DAPA did not improve eGFR compared with placebo, but presented reductions in proteinuria, blood pressure, BMI, and glycated hemoglobin, with acceptable safety.