Prostaglandins supplementation enhances the efficacy of standard care on renal outcomes in patients with diabetic kidney disease

To the Editor: Diabetic kidney disease (DKD) is at high risk for chronic kidney disease (CKD), accounting for at least a third of all end-stage renal disease (ESRD) cases requiring either dialysis or kidney transplantation worldwide.[1] Standards of care in diabetes with CKD recommend intensive glucose and blood pressure control, as well as the blockade of the renin-angiotensin system (RAS), and more recently, sodium-glucose cotransporter 2 (SGLT2) inhibitors. Nonetheless, despite recommended treatment, a residual risk of DKD progression remains, and newer therapies are needed. Evidence supports that prostaglandins may prevent the deterioration of renal function in diabetic subjects.[2,3] Therefore, we undertook a randomized, controlled trial to evaluate the efficacy and safety of alprostadil in type 2 diabetes mellitus (T2DM) patients with DKD. This single-center, double-blind, randomized, controlled clinical trial is registered at ChiCTR (ChiCTR2000040170, www.chictr.org.cn). This trial was performed in accordance with the principles of the Declaration of Helsinki, and all the patients provided written informed consent. Ethical approval was obtained from the institutional ethics committee of China-Japan Friendship Hospital on human research (No. 2018-45-K34). Participants with DKD who met the eligible criteria [Supplementary Table 1, https://links.lww.com/CM9/C546] were randomly assigned in a 1:1 ratio to receive an intravenous infusion of alprostadil in addition to standard-of-care treatment or to receive only standard-of-care treatment. The packaging and labeling were designed identically in appearance to maintain the blinding of the investigators and the subjects. Based on previous study,[3] the sample size was selected to demonstrate a 35% incidence of primary outcomes in the control group and a 50% decrease in the alprostadil group. A total sample size of 206 patients (103 in each group) would provide 80% power at the 5% significance level. It was planned to randomize 277 participants (alprostadil:control = 138:139), taking into account a 20% dropout rate. The therapy consisted of a once-daily regimen of intravenous infusion of 10 μg alprostadil injection (Beijing Tide Pharmaceutical Co., Ltd., Beijing, China) dissolved in 100 mL of 0.9% saline. Infusion was performed continuously for 7 days, and the treatment was performed twice a year. The standard-of-care treatment mainly included lifestyle interventions, strict pharmacological control of hyperglycemia, systemic hypertension, and hyperlipidemia. Patients treated with RAS inhibitors had been adjusted before randomization to the maximum dose on the manufacturer's label that did not cause unacceptable side effects. The patient selection process of this trial is shown in Supplementary Figure 1, https://links.lww.com/CM9/C546. Baseline information collected within a week before the initiation of the intervention is shown in Supplementary Table 2, https://links.lww.com/CM9/C546. Continuous variables in baseline characteristics were summarized as means with standard deviations (SDs) or medians with interquartile ranges (IQRs), depending on their distribution. P <0.05 was significant in the statistical analysis. All analyses were done with R (version 4.3.0, R Core Team, Vienna, Austria). The baseline characteristics and concomitant medications of the included patients were balanced between the two groups. All participants included in this study were Han Chinese. The mean age of the patients was 63.6 years, and 31.7% were women. The median HbA1c concentration was 7.3% (IQR: 6.6–8.8%), and the median estimated glomerular filtration rate (eGFR) was 44.58 mL·min–1·m–2 (IQR: 32.05–57.52 mL·min–1·m–2). Among the patients, 133 (61.0%) had a history of cardiovascular diseases. In the two groups, 61.3% and 68.8% of the patients were treated with RAS inhibitors, respectively. Thirty-two patients (23.2%) in the alprostadil group and 27 patients (19.4%) in the control group had discontinued the trial regimen. Baseline characteristics and concomitant medications of these discontinued patients are shown in Supplementary Table 3, https://links.lww.com/CM9/C546. The primary outcome, assessed in a time-to-event analysis, was a composite of a sustained decline of at least 40% in the eGFR from baseline, ESRD, or death due to renal causes. ESRD was defined as the requirement for maintenance dialysis or renal replacement therapy. The secondary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Time-to-event studies were performed using Kaplan–Meier (K–M) analysis and Cox proportional-hazards models. During the follow-up period, a primary composite outcome event occurred in 46 of 218 patients (21.1%), and 51 (23.4%) participants developed cardiovascular events. The incidence of the primary composite outcome was significantly lower in the alprostadil group than in the control group, occurring in 11 patients out of 106 patients (10.4%) and 35 patients out of 112 patients (31.2%), respectively (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.22 to 0.73; P = 0.004) [Supplementary Figure 2, https://links.lww.com/CM9/C546]. The effects of alprostadil on the primary outcome were generally consistent across prespecified subgroups [Supplementary Figure 2, https://links.lww.com/CM9/C546]. And none of the 11 subgroups showed a nominally significant interaction between treatment and subgroup. A Kaplan–Meier survival analysis, using a sustained decline of at least 40% in the eGFR from baseline, ESRD, or death from renal causes as the end points, revealed a strong correlation between kidney function and the intervention (P = 0.004), and the alprostadil group showed a much lower proportion of patients with a decreased renal function during the follow-up [Figure 1].Figure 1: Composite renal outcome. Outcomes were assessed in time-to-event analyses. Kaplan–Meier curves for the cumulative incidence of a sustained decline of at least 40% in the eGFR from baseline, ESRD, or death from renal causes. ESRD was defined as the initiation of long-term dialysis or kidney transplantation. CI: Confidence interval; eGFR: Estimated glomerular filtration rate; ESRD: End-stage renal disease; HR: Hazard ratio.In this study, the observed benefits of alprostadil were clinically significant and were obtained on a background of standard care. DKD is characterized by persistent albuminuria followed by a progressive decrease in GFR, leading to renal failure or cardiovascular death. It is noteworthy that the group treated with alprostadil had significantly lowered proteinuria (0.96 g/24 h; IQR, 0.18–2.40 g/24 h) compare with control group (1.66 g/24 h; IQR, 0.42–3.13 g/24 h), whereas eGFR in the alprostadil group and control group were observed to be (52.77 mL·min–1·1.73 m–2; IQR, 30.70–71.53 mL·min–1·1.73 m–2) and (33.16 mL·min–1·1.73 m–2; IQR, 17.41–48.56 mL·min–1·1.73 m–2), respectively [Supplementary Figure 3 and Supplementary Table 4, https://links.lww.com/CM9/C546]. Consistent with our results, a meta-analysis has shown that PGE1 appears to have a beneficial effect on DKD progression by reducing the proteinuria and improving renal function.[4] Vasodilatory prostaglandin E is known to help maintain renal hemodynamics in chronic renal insufficiency caused by diabetes or other kidney diseases.[3] Therefore, the decrease in intraglomerular pressure may better explain the reduction in urinary protein, as evidenced by the relationship between changes in urinary protein and changes in eGFR [Supplementary Figure 4, https://links.lww.com/CM9/C546]. Moreover, accumulating evidence has demonstrated the contribution of inflammation in the onset and progression of DKD. We detected the circulating inflammatory markers, such as IL-1β, IL-6, and TNF-α, during prostaglandin treatment. In patients with DKD, prostaglandin treatment diminishes some circulating inflammatory markers, including IL-6 and TNF-α [Supplementary Figure 5, https://links.lww.com/CM9/C546]. IL-6 and TNF-α, as inflammatory cytokines, have been implicated in the progression of DKD. The evidence for the current therapies in DKD that depend on anti-inflammatory actions has been reported. In the CANTATA-SU study (NCT00968812), canagliflozin reduced serum IL-6 levels in patients with T2DM.[5] The reduction of IL-6 and TNF-α has also been observed in T2DM patients treated with glucagon-like peptide 1 receptor agonists (GLP-1 RAs).[6] Therefore, the main kidney protection mechanisms of prostaglandins seem to be the reduction of intraglomerular pressure, a decrease in glomerular hyperfiltration, and anti-inflammatory action. In this study, no significant differences were noted in the incidence of adverse events that occurred during the treatment period between the alprostadil and control groups (P = 0.113). The adverse effects seen with alprostadil consist of respiratory depression leading to apnea, bronchial constriction, bradycardia, abdominal pain, diarrhea, hyperthermia, phlebitis in the site of puncture, allergic reactions, etc. All adverse events reported in this trial were of mild or moderate intensity, and no serious adverse events were reported. The main adverse event in this trial with a probable relation to alprostadil was phlebitis; three patients (2.8%) reported a total of four adverse events, and the phlebitis disappeared after taking off from the drugs. The laboratory values revealed no remarkable changes in serum potassium in the alprostadil and control groups. With regard to vital signs (blood pressure and pulse rate) and physical examinations, there were no major differences between the two groups. Intravenous infusion of alprostadil poses a challenge for its wide clinical application. However, the intravenous route of drug administration indeed has its advantages. The bioavailability is 100% for intravenous administration. The drug reaches the bloodstream immediately, having full access to the entire body. Hence, rapid action is produced, making this route the most efficient way for patients. In addition, drugs can be delivered at a uniform rate. So, a constant plasma level of the drug can be maintained, which keeps the uniformity of the drug for the patients. In patients with DKD, when added to standard care, alprostadil resulted in a lower risk of DKD progression without obvious serious adverse events, suggesting it as a potentially preferred option for managing DKD after the treatment with oral or subcutaneous medications failed. The present study has several limitations. First, it was performed as a short-term study. It is unknown whether the results of efficacy and safety would apply to the long-term use of alprostadil. Second, the study focused solely on the approved dose of alprostadil, although higher dosing and longer courses of treatment have been shown to be safe and effective. In addition, the sample size in the present study was limited; the power may have been too low to detect significant changes in urinary protein and changes in eGFR. Large-scale randomized, double-blind, placebo-controlled trials are required to explore long-term treatment outcomes and dosing variations of alprostadil. Funding This work was supported by grants from the National High Level Hospital Clinical Research Funding (No. 2023-NHLHCRF-YS-01) and National Natural Science Foundation of China (No. 82300815). Conflicts of interest None.