Empagliflozin on Residual Kidney Function in Incident Peritoneal Dialysis Patients

Diabetes is the leading cause of end stage kidney disease in developed countries. Peritoneal dialysis (PD) is a home-based and cost-effective modality of kidney placement therapy. Maintenance of residual kidney function (RKF) is one of the most crucial objectives to improve outcomes of PD patients. Observational studies showed that residual urine volume or residual glomerular filtration rate (GFR), but not peritoneal creatinine clearance, independently predicted patient survival. This benefit is likely attributed to better volume control, improved nutritional status, preserved endocrine function and enhanced clearance of uremic toxins in the presence of RKF. However, current therapeutic strategies to preserve RKF were most limited to the use of renin-angiotensin-aldosterone system (RAAS) inhibitors and biocompatible PD solutions.

Hong Kong adopted the 'PD-first' policy since 1985, and has the highest proportion of PD patients in the world. Inadequate dialysis, which is directly related to the loss of RKF, is the second most common reason for a permanent transfer to hemodialysis among PD patients. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been shown to reduce albuminuria and delay progression of chronic kidney disease even in patients with advanced stages of kidney disease. It is postulated that the renoprotective effect of SGLT-2 inhibitors may be extended to dialysis population since a considerable proportion of patients still have urine output. SGLT2 inhibitors may potentially attenuate GFR decline in PD patients because heavy proteinuria independently predicted decline in residual GFR and onset of anuria. Moreover, preclinical studies suggested that empagliflozin reduced inflammation and oxidative stress by decreasing proinflammatory cytokines, inducing expression of anti-inflammatory M2 phenotype of macrophages, and antagonizing the effect of advanced glycation products. This beneficial effect may be particularly relevant to PD patients, where subclinical inflammation is common and inversely correlated with RKF.

Despite the potential promising effect of SGLT2-inhibitors in RKF in PD patients, dialysis patients were excluded in previous randomized controlled trials. In the present study, the investigators hypothesize that oral empagliflozin in addition to RAAS inhibitor, compared to RAAS inhibitor alone, better preserves RKF in patients newly started on PD. After a run-in period of 6 to 8 weeks where the dose of RAAS inhibitors are uptitrated to maximally tolerated dose, 48 incident PD patients will be randomized to empagliflozin or control (no empagliflozin) for a total of 6 months. This study aims to explore the feasibility of conducting a full-scale, adequately powered randomized controlled trial that investigates the effect of empagliflozin on RKF in incident PD patients.

Inclusion criteria

• Incident PD patients within 90 days of Tenckhoff catheter insertion
• Age 18-75 years old
• Patient with or without history of Type 2 diabetes
• Residual GFR (defined as the average of 24-hour urinary urea and creatinine clearances) > 2ml/min/1.73m2 AND urine volume > 400ml per day
• Patients who are willing to provide written informed consent

Exclusion criteria

• Patients with history of hemodialysis (≥ 3 months) or renal transplant
• Life expectancy <6 months
• Prior use of any type of SGLT2 inhibitors within 1 month before screening visit
• Poorly controlled diabetes with HBA1c >11%
• Type 1 diabetes
• History of any active malignancy within 5 years (except curatively resected basal cell or squamous cell skin cancers)
• Peritonitis within 4 weeks
• Ketoacidosis within 5 years
• Known hypersensitivity to empagliflozin or other SGLT2 inhibitors
• Any active acute or chronic physical or mental conditions that, in the opinion of the investigator, might interfere with the compliance of participants to or the performance of this study
• Participation in any clinical trial or use of any investigational medicinal product 1 month before screening visit