End Stage Renal Disease on Dialysis, Peritoneal Dialysis Complication, Residual Kidney Function, Sodium-glucose Cotransporter-2 Inhibitor
Conditions
Brief summary
Empagliflozin, a new class of diabetes medication, has demonstrated a reduction in renal function decline among patients with chronic kidney disease, regardless of their diabetes status. However, all previous studies excluded dialysis patients. Patients starting dialysis may still produce a certain amount of urine. Importantly, patients with better preserved residual kidney function tend to have better control of blood pressure and volume status, improved nutrition status, higher quality of life and reduced mortality rate. The purpose of this study is to learn about the safety of empagliflozin in patients on peritoneal dialysis, in preparation for a future large clinical trial. Participants who newly initiate peritoneal dialysis will be randomly allocated to either empagliflozin on top of standard of care, or standard of care alone. Over a follow-up period of six months, the investigators will collect information on urine volume, blood pressure and glucose control. Safety, tolerability and drug compliance of empagliflozin will also be evaluated. If empagliflozin is found to be safe and well tolerated in patients on peritoneal dialysis, further large-scale randomized controlled trial may be conducted to evaluate its impact on residual kidney function and other relevant clinical outcomes.
Detailed description
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.
Interventions
DRUGEmpagliflozin 10 MG
empagliflozin oral 10mg daily for 6 months
Sponsors
Chinese University of Hong Kong
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Incident PD patients within 90 days of Tenckhoff catheter insertion 2. Age 18-75 years old 3. Patient with or without history of Type 2 diabetes 4. Residual GFR (defined as the average of 24-hour urinary urea and creatinine clearances) \> 2ml/min/1.73m2 AND urine volume \> 400ml per day 5. Patients who are willing to provide written informed consent
Exclusion criteria
1. Patients with history of hemodialysis (≥ 3 months) or renal transplant 2. Life expectancy \<6 months 3. Prior use of any type of SGLT2 inhibitors within 1 month before screening visit 4. Poorly controlled diabetes with HBA1c \>11% 5. Type 1 diabetes 6. History of any active malignancy within 5 years (except curatively resected basal cell or squamous cell skin cancers) 7. Peritonitis within 4 weeks 8. Ketoacidosis within 5 years 9. Known hypersensitivity to empagliflozin or other SGLT2 inhibitors 10. 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 11. Participation in any clinical trial or use of any investigational medicinal product 1 month before screening visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recruitment rate | During randomization | Number of patients who are randomized each month following the run-in period |
| Retention rate | 6 months | Proportion of patients who have completed the whole study among patients that are randomized |
| Medication adherence | 6 months | Proportion of prescribed empagliflozin that are taken by the patients (pill counting will be done by investigators at each follow up) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Difference in residual urine volume | Month 0, 2, 4, 6 | Residual urine volume is measured by 24-hour urine collection |
| Difference in volume of overhydration | Month 0, 2, 4, 6 | Volume of overhydration is measured by a validated multi-frequency bioimpedance spectroscopy |
| Difference in plasma N-terminal pro-brain type natriuretic peptide | Month 0, 2, 4, 6 | Indicator for left ventricular dysfunction |
| Difference in systolic blood pressure | Month 0, 2, 4, 6 | Office blood pressure will be measured according to standardized protocol. The average of three consecutive measurements by an automated device will be recorded. |
| Incidence of urinary tract infection | 6 months | Proportion of patients who have symptoms consistent with urinary tract infection and organisms identified by urine culture |
| Incidence of genital tract infection | 6 months | Proportion of patients who are symptomatic and require antibiotic or anti-fungal treatment |
| Incidence of ketoacidosis | 6 months | Proportion of patients who have serum pH \<7.3 and elevated serum beta hydroxybutyrate ≥3.0 mmol/L |
| Incidence of lower limb amputation | 6 months | Proportion of patients who require lower limb amputation by operation that is not secondary to trauma |
| Incidence of severe hypoglycemia | 6 months | Proportion of patients who have hypoglycemia requiring third party assistance |
| Difference in volume of ultrafiltration per day | Month 0, 1, 2, 4, 6 | The volume of fluid removed from patient by peritoneal dialysis each day |
| Slope of residual GFR | 6 months | Residual GFR is calculated as the arithmetic mean of 24-hour urinary urea and creatinine clearances |
| Time to anuria | 6 months | Anuria is defined as urine volume \<100ml per day |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in peritoneal solute transfer rate | Month 0, 6 | This is measured by dialysate-to-plasma creatinine ratio in a standard peritoneal equilibration test (PET) |
| Difference in frailty status by Fried frailty phenotype | Month 0, 6 | Fried phenotype consists of five criteria which include both patient-reported domains and objective assessments. Subjects are considered to be frail if they meet three or more criteria. |
| Difference in frailty status by Clinical Frailty Scale | Month 0, 6 | Clinical Frailty Scale is 9-point scale which is used to quantify the frailty and functional status of dialysis patients. A higher score indicates greater degree of frailty. |
Countries
Hong Kong
Contacts
Primary ContactJack KC Ng, FRCP
Backup ContactPhyllis Cheng, BN
Outcome results
None listed