The effect of Renin-Angiotensin-Aldosterone system blockage on peritoneal membrane function and economic outcomes in peritoneal dialysis patients

Abstract

Peritoneal dialysis (PD) was an important form of renal replacement therapy. This technique is more adaptable than hemodialysis. According to recent research, the treatment effects of PD are better than hemodialysis in the first 2-3 years of treatment. However, the technique survival in long-term PD is a great concern. the literature illustrated that only 50-70% of patients have survived more than five years. It also motivates researchers to investigate strategies to minimize premature dialysis failure by preserving peritoneal and renal function. Experiments studies have demonstrated that the renin-angiotensin-aldosterone system (RAAS) blockade that suppress Angiotensin II activity can delay the development of peritoneal fibrosis. It has long been established that these medications have a beneficial effect on maintaining renal function in patients with chronic kidney disease. It seems reasonable to extrapolate this result to patients undergoing dialysis. However, only a few studies have published on the efficacy of RAAS blockade therapy on RRF in PD patients. While potential membrane-protective properties of RAAS blockade have not been established in patients treated with PD, the objective of this study was to determine the peritoneal membrane and reno-protective effect of RAAS blockade as well as the economic impact of these drugs in Thailand. This research consisted of three phases. Phase 1 systematic review and network meta-analysis (NMA) was performed to summarize the current data on the efficacy of RAAS blockade therapy in patients with peritoneal dialysis. The key finding from the literature reviews and network meta-analysis is that long-term use more than 1 year of ACEI and ARB may have beneficial effects on maintaining rGFR mean difference 0.62 ml/min/1.73 m2 (95%CI 0.10 - 1.14) and avoiding anuria HR 0.62 (95%CI 0.41 - 0.95) in patients with PD in addition to their primary indications for hypertension and heart failure treatment, without raising adverse effects as compared to other antihypertensive medications. However, data on PD patients treated with RAAS blockade are limited. Observational data indicate a high degree of inconsistency among ACEI/ARB treatment comparison in patient with PD due to a total lack of evidence regarding their effectiveness, especially on peritoneal membrane function. Phase 2 studies examined the impact of RAAS inhibition on peritoneal function in patients treated long-term PD. The first one is a multi-center retrospective cohort study with 1,073 PD patients included. During a mean follow-up of three years (range 1-9 years), 424 patients received ACEI/ARB prescriptions. the remaining 649 patients were not received any ACEI/ARB prescription during the study period. The primary outcomes were ultrafiltration failure and technique failure. When inverse probability weighting propensity score was used, the ACEI/ARB treated group demonstrated lower ultrafiltration failure HR 0.53 (95%CI 0.40 – 0.69) and provide better technique survival HR 0.59 (95%CI 0.42 – 0.83) when compared to the control group. The second study was a pilot RCT designed to assess the effect of adding spironolactone (an aldosterone receptor antagonist) to losartan (an ARB) on peritoneal membrane function as measured by PET. all patients involved in this study received PD for a minimum of three months. Twenty-seven patients were randomly allocated to receive losartan in combination with spironolactone, and 23 patients received losartan alone. When the peritoneal membrane transport parameters D/P Cr, D/D0 glucose, and CA-125 were compared, no major difference between the two groups was observed. As compared to losartan alone, the spironolactone plus losartan group has a higher rate of side effect including hyperkalemia (14%), hypotension (3.6%), and mastitis (7%). The results of phase 2 indicated that the use of ACEI/ARB could prevent ultrafiltration failure and increase technique survival in patients with peritoneal dialysis. In comparison to ACEI or ARB alone, adding aldosterone receptor antagonist did not result in increased advantage and trend toward increased adverse events. However, RCTs with a longer follow-up period and greater samples are essential to establish the effect of add-on therapy on membrane protection. Phase 3 The aim of this study was to ascertain the cost-utility of treatment with ACEI/ARB in Thailand's PD patient population. This research compared two treatment strategies for patients with peritoneal dialysis. the first treatment strategy was patients treated with an ACEI/ARB and second strategy was those treated with other antihypertensive drugs (non-ACEI/ARB). A Markov model with a lifetime horizon was developed using previously published data from Thailand to simulate the progression of disease in peritoneal dialysis patients. A healthcare provider perspective was carried out. In the base-case analysis, PD patients treated with ACEI and ARB results was not only higher in quality adjusted life year gain (0.11 QALYs and 0.09 QALYs for ACEI and ARB, respectively), but also higher costs (7,692 Baht and 4,689 Baht for ACEI and ARB, respectively). The ICER was lower than Thailand's appropriate willingness to pay threshold of 160,000 Thai baht/QALY, as determined by the analysis ICER for ACEI prescription which was 72,773 Baht/QALY, ICER for ARB was 53,690 Baht/QALY and ICER for ACEI compared to ARB was 163,561 Baht/QALY. In conclusion, ACEI and ARB therapy for non-anuric patients on peritoneal dialysis was cost-effective in Thai peritoneal dialysis patients and thus should be considered as a first-line antihypertensive treatment in patient treated with peritoneal dialysis.