Introduction

Chronic kidney disease (CKD) is the state of chronic functional or structural failure of kidneys which ultimately results in the decline of renal function [1]. The current treatment includes low salt diet, lifestyle modification, blood pressure control and management of underlying disease. However, there are not yet the curative methods to reverse chronic renal damage. Therefore, kidneys ultimately fail to excrete metabolic wastes and the patients undergo renal replacement therapy when uremic symptoms occur.

As renal function declines, various small uremic toxins cannot be effectively excreted through urine. The metabolic wastes from dietary protein such as indoxyl sulfate or p-cresyl sulfate are known to act as uremic toxin which accelerate CKD progression [2]. The AST-120 (Kremezin^®, Kureha Corporation, Tokyo, Japan), an oral granule-type spherical carbon adsorbent, was developed to delay CKD progression by adsorbing uremic toxins and their precursors and excreting them into feces. Previous observational studies and animal studies demonstrated that treatment with AST-120 reduces the level of indoxyl sulfate [3,4], attenuates renal function decline [5,6] and renal sclerosis [7,8].

Renamezin^® is a capsule-type oral carbon adsorbent modified from the AST-120 and was developed by Korean pharmaceutical company (Daewon Corporation, Seoul, South Korea). While Kremezin^® uses petroleum pitch as the raw material for spherical carbonaceous adsorbents, Renamezin^® is made of furan resin which results in 2 to 10 times greater compression strength [9]. Compared to the previous granule-type Kremezin^®, it is thought to increase drug compliance and therefore enhance drug absorbing effect. Previous study by Kim et al. demonstrated that daily 6g of Renamezin^® effectively reduced the level of indoxyl sulfate as early as 4 weeks after treatment (22.5±13.9% reduction from baseline) [9]. However, there has been no clinical study evaluating the effect of Renamezin^® upon attenuation of renal function decline. Therefore, this study was designed to evaluate the efficacy of Renamezin^® in attenuating CKD progression among pre-dialysis CKD patients.

Materials and methods

Study population

A total of 1,149 pre-dialysis adult CKD patients with baseline serum creatinine between 2.0 and 5.0 mg/dL were screened for study enrollment (Fig 1). Among them, a total of 79 patients were failed to be enrolled in the study due to one of the following reasons: those with previous experience of study drug, those with gastrointestinal motility disorder or severe constipation, those with uncontrolled hypertension (systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg), those with elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) over 3 times of upper normal value, chronic alcoholics, those with active infection, pregnant or lactating women, those upon other clinical trials. Another 90 patients withdrew informed consent, 161 patients were lost to follow up, and 60 patients did not reach 24-week goal or had short duration of follow up. Another 73 patients were dropped out due to investigator’s decision including the patients who were inadequate to take medicine due to poor compliance, psychiatric or economic problems. Therefore, a total of 686 CKD patients were included in the intention-to treat (ITT) analysis. A total of 1,061 patients were included in the safety analysis including those who took medication more than once (n = 375).

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Fig 1. Study population.

A total of 1,149 patients were screened for the study and 686 patients who took the study medication for 24 weeks were included in the intention-to-treat analysis. A total of 1,061 patients who took study drug more than once were included in the safety analysis.

https://doi.org/10.1371/journal.pone.0252186.g001

Results

Baseline characteristics of the ITT population

A total of 686 patients were included in the ITT analysis. Table 1 shows the baseline demographic and clinical characteristics of the ITT population. The mean age was 63.5 and male was predominant (63.6%). About half of the population had diabetes mellitus and hypertension. Most of the patients had CKD for 1~5 years. The baseline systolic and diastolic blood pressure was 130.9±17.4 and 73.9±11.7 mmHg, respectively. The baseline serum creatinine and eGFR were 2.86±0.72 mg/dL and 22.4±6.8 mL/min/1.73m², respectively. The mean number of pills per day was 19.3, which equates to 5.5g/day. Interestingly, most of the patients (527/686, 76.8%) demonstrated high compliance with the study drug (21 capsules (6g) per day).

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Table 1. Demographic and baseline clinical characteristics of ITT population.

https://doi.org/10.1371/journal.pone.0252186.t001

Changes of serum creatinine and eGFR after Renamezin^® treatment

During mean follow-up duration of 173.3±11.1 days, serum creatinine was increased from 2.86±0.72 mg/dL to 3.06±1.15 mg/dL (p<0.001, Fig 2). Therefore, Renamezin^® treatment could not prevent the patients from elevation of serum creatinine. However, eGFR did not change significantly over the study period (22.3±6.8 mL/min/1.73m² to 22.1±9.1 mL/min/1.73m², p = 0.243).

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Fig 2. Change in serum creatinine and eGFR after 24 weeks of treatment.

(A) Serum creatinine was significantly increased after treatment with Renamezin^® (2.86±0.72 and 3.06±1.15 mg/dL, p<0.001). (B) The eGFR did not significantly change after treatment (22.3±6.8 and 22.1±9.1 mL/min.1.73², p = 0.243).

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Factors associated with preservation of renal function

To evaluate clinical factors associated with preservation of renal function, we performed binary logistic regression analysis. The patients were grouped according to change of eGFR (ΔeGFR) during study period. The patients with preserved renal function (ΔeGFR ≥0) were compared with those with decreased renal function (ΔeGFR <0) over study period (Table 2). The group with preserved renal function (n = 328) showed older age (65.1±13.0 vs. 62.0±13.7 years old, p = 0.002) and lower proportion of diabetic patients (40.2% vs. 48.3%, p = 0.033). This group also showed lower systolic blood pressure (126.9±16.7 vs. 134.2±17.3 mmHg, p<0.001) and diastolic blood pressure (72.3±11.7 vs. 75.1±11.6 mmHg, p = 0.001) and more narrow pulse pressure (54.7±13.9 vs. 59.1±15.6 mmHg, p<0.001). However, either baseline eGFR (22.7±6.8 vs. 22.0±6.8, p = 0.189) or drug compliance (19.3±3.3 vs. 19.3±3.5 pills/day, p = 0.992) did not differ between groups.

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Table 2. Factors associated with preservation of renal function.

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Patients who can benefit from Renamezin^® treatment

To evaluate subgroup who are likely to get benefit from Renamezin^® treatment, we performed multivariate logistic regression analysis (Table 3). Elderly patients with age over 65 years old and those with well-controlled systolic blood pressure <130 mmHg were most likely to get benefit from Renamezin^® treatment. Since most of the enrolled patients showed good compliance with study drug, there were no statistically significant difference in ΔeGFR according to study pills. Diabetic patients were less likely to get benefit from the study drug. Although statistically not significant, study drug was more likely to be effective in the early stage of CKD (Fig 3).

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Fig 3. Subgroups who are likely to get benefit from Renamezin^® therapy.

Elderly patients with age over 65 years old and those with adequate systolic blood pressure control under 130 mmHg were likely to get benefit from Renamezin^® therapy. Patient compliance with study drug did not affect renal function preservation in this study. Diabetic patients did not show benefit upon Renamezin^® therapy.

https://doi.org/10.1371/journal.pone.0252186.g003

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Table 3. Multivariate logistic regression analysis for renal function preservation (ΔeGFR≥0).

https://doi.org/10.1371/journal.pone.0252186.t003

Adverse events

Adverse events (AEs) in the safety population are summarized in Table 4. During 24 weeks of study period, a total of 98 patients (9.2%) out of 1,061 safety population experienced 134 adverse events. Among them, 38 treatment-related adverse events (3.6%) occurred. The most commonly reported treatment-related adverse events involved gastrointestinal tract including heartburn (5, 0.5%), diarrhea (5, 0.5%), constipation (3, 0.3%), dyspepsia (3, 0.3%), vomiting (2, 0.2%), abdominal discomfort (1, 0.1%), abdominal bloating (1, 0.1%), and nausea (1, 0.1%). One mortality case occurred during the study period, but the exact causal relationship could not be classified.

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Table 4. Adverse events during the study period.

https://doi.org/10.1371/journal.pone.0252186.t004

Discussion

This is the first study to evaluate the effect of novel drug Renamezin^® for attenuation of renal function decline in moderately advanced CKD patients. Although Renamezin^® did not show significant effect upon delaying renal failure, Renamezin^® was beneficial for elderly patients and those with adequate blood pressure control. However, it was not beneficial for those with diabetes mellitus. The treatment-related adverse events were not different from those reported with Kremezin^®.

Uremic syndrome in advanced CKD involves the accumulation of uremic solutes and toxins in blood which leads to dysfunction of multiple organs and dysbiosis of the gut microbiota [10]. The representative uremic toxin is indoxyl sulfate which is produced from degradation of tryptophan in gut and metabolism by enzymes in liver. The other prototype protein-bound uremic toxin is p-cresyl sulfate which is produced from degradation of tyrosine and phenylalanine in gut [2]. Unlike small water-soluble toxins such as urea or creatinine, protein-bound uremic toxins such as indoxyl sulfate and p-cresyl sulfate are not fully removed by dialysis [11]. Therefore, preventing production of protein-bound uremic toxin from low protein diet and removing them from gut are important to reduce uremic symptoms in advanced CKD.

The AST-120, also known as Kremezin^®, is the firstly developed oral pharmaceutical agent which consists of spherical carbonaceous adsorbent. It is theoretically beneficial to absorb intestine-origin protein-bound uremic toxins and excrete them to the feces. In fact, Kremezin^® effectively lowered the level of indoxyl sulfate [12,13]. However, major randomized controlled trials did not show significant difference in composite of renal outcome (doubling of serum creatinine levels, increase in serum creatinine levels to ≥ 6.0 mg/dL, 50% reduction in estimated glomerular filtration rate (eGFR), initiation of dialysis or kidney transplantation) or all-cause mortality between study and control groups [12,14–16]. One possible reason for negative outcome is that patients find Kremezin^® difficult to tolerate because of its unpleasant texture and taste. It is also difficult to take the exact prescribed amount for patients because of granule retention in the oral cavity. Therefore, there has been a need for improving drug compliance.

Renamezin^® is a new capsule-type oral spherical carbon adsorbent which can substitute Kremezin^®. Recent study by Kim et al. showed that Renamezin^® can effectively reduce the level of indoxyl sulfate by 20%~30% from the baseline after 4 to 8 weeks of prescription [9]. In addition, Renamezin^® can improve patient adherence to medication. Kee et al. demonstrated in their cross-over study that the patient preferred Renamezin^® over Kremezin^® (65.5% vs. 34.5%) and patient adherence improved in greater degree after switching from Kremezin^® to Renamezin^® (83.4% to 90.0%, p = 0.057) [17]. However, Renamezin^® could not attenuate renal function decline in our 24-week observational study. The reason why the study drug could not delay renal progression is out of the scope of this study. However, there can be several explanations. Firstly, serum creatinine as a primary outcome can be affected by various factors such as muscle mass and food ingestion which can mitigate the change of true renal function. Indeed, previous randomized clinical trials with AST-120 also set primary outcome as either doubling of serum creatinine or developing end-stage renal disease [12,14,15]. However, this study neither was designed as a randomized controlled trial nor was performed for a long duration to evaluate doubling of serum creatinine. Therefore, our study could not prove the effect of study drug in reversing elevation of serum creatinine. Second, we did not compare the rate of renal function decline before and after prescribing medication. Third, there can be a confounding effect of serum albumin and proteinuria of which data were not available in this study. Since indoxyl sulfate and p-cresyl sulfate are protein-bound uremic toxins, the free toxin concentration can be different by the level of serum albumin [2]. Lastly, our study included the patients with more progressed renal function including CKD stage 5 (14.4% of all population). Since the study drug was more effective in the early CKD stage, a large proportion of advanced CKD patients could affect the study result.

Although the study drug did not attenuate renal function decline overall, it was beneficial for some subgroup of patients. The patients with age ≥ 65 years old revealed to get benefit from Renamezin^® treatment. The patients who are ≥ 65 years old demonstrated significant preservation of renal function after Renamezin^® treatment (OR 1.52, 95% confidence interval 1.102–2.097, p = 0.011). The patients with age ≥ 65 years old revealed to have lower serum creatinine at baseline (2.74±0.67 vs. 2.99±0.74 mg/dL, p<0.001) and lower body mass index (24.3±3.4 vs. 25.2±3.9, p = 0.032) compared to younger patients. Therefore, same amount of study drug may result in better outcome. In addition, the patients with adequate systolic blood pressure control < 130 mmHg were also likely to get benefit from Renamezin^® treatment. Finally, the patients in CKD stage 3 were more likely to get benefit from Renamezin^® treatment compared to those in more advanced CKD. Our results are similar to those from the previous studies with Kremezin^® [18,19]. Previous article suggested that longer prescription of Kremezin^® to the patients from the earlier stage of CKD will benefit the most from the therapy [20]. In addition, previous studies with Kremezin^® demonstrated that the effect of study drug was larger in the patients with diabetic nephropathy, higher proteinuria, and hematuria [18,19,21,22]. Since carbon absorbent therapy adsorbs uremic toxin, decreases the level of indoxyl sulfate as well as the levels of advanced glycation end products (AGEs), diabetic patients with overt proteinuria will benefit the most from the therapy. However, in our study, the diabetic patients were inferior in treatment effect compared to non-diabetic patients (OR 0.756, 95% confidence interval 0.548–1.043, p = 0.089). Since we neither investigate the status of diabetic nephropathy nor the level of proteinuria but only evaluated the co-existence of diabetes mellitus, our study cannot rule out the effect of Renamezin^® upon diabetic nephropathy subgroup. Therefore, further study is warranted to evaluate the effect of Renamezin^® upon renal and cardiovascular outcome in the patients with diabetic nephropathy in early CKD stages.

The patients in our study showed high compliance with the study drug. The mean number of pills per day was 19.3, which equates to 5.5g/day. The medication compliance was 92 ± 16.4%, which is higher than that presented in the previous study with Kremezin^® (90 ± 11.8%) [12,15]. However, the drug compliance did not affect the renal outcome in our study. This is the opposite finding from the previous study with Kremezin^® showing that better drug compliance the better renal outcome. Since most of our patients (76.8%) took the maximum daily dose of Renamezin^®, the effect of drug compliance upon renal outcome may not be visualized in our study. This should be further elucidated in the future study.

There were fewer adverse events with Renamezin^® compared to the studies with Kremezin^®. A total of 38 (3.6%) patients among 1,061 safety population experienced treatment-related adverse events in our study. In the randomized study with Kremezin^® by Akizawa et al. the incidence of treatment-related adverse events was reported as high as 26.2% [14]. The following EPICC-1 and EPICC-2 randomized trial also reported the incidence of adverse events as 18.3% to 21.5% [15]. Together with high drug compliance, lower incidence of adverse events can be a merit of taking Renamezin^® as an alternative agent to Kremezin^®. Recent study by Kee et al. also demonstrated similar medication adherence and efficacy between Kremezin^® and Renamezin^® while Renamezin^® shows lower rates of serious adverse events compared to Kremezin^®. In addition, the affected tissue or organs in which adverse events occurred were similar to those reported in the previous studies with Kremezin^® [12,14,15]. The most common complications were gastrointestinal discomfort including diarrhea, constipation, flatulence, and nausea. Skin related complications were the second most frequent adverse events.

Our study has some strengths. This is the first study to evaluate the effect of novel drug Renamezin^® in attenuating renal function decline in a prospective observational cohort study. Although it was not a randomized controlled trial, most of the patients followed up the study schedule and took daily maximum dose of the study drug. On the other hands, our study has some limitations. The study duration was too short to evaluate the effect of the study drug upon renal function decline. We measured serum creatinine and eGFR at only 2 points, at baseline and at the end of the study. Therefore, acute decline of renal function may be mistakenly interpreted as chronic renal progression. In addition, we did not measure important variables such as serum albumin, HbA1c, C-reactive protein, the presence of hematuria, or the amount of proteinuria. At last, we did not measure the level of indoxyl sulfate before and after treatment.

In conclusion, Renamezin^® treatment did not slow down renal progression in moderately advanced CKD with serum creatinine 2.0–5.0 mg/dL. However, older patients ≥ 65 years old with adequate control of blood pressure may get benefit from the Renamezin^® treatment. Renamezin^® may be used safely with high patient compliance as an alternative to Kremezin^®.

Supporting information

Acknowledgments

Authors thank all investigators of each participating center for their dedication in patient recruitment and data acquisition. The contributors in each center is as follows: Lee SY in Seoul Eulji Medical Center, Eulji University, Seoul, Korea; Lee JE in Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea; Kang J in Sejong General Hospital, Bucheon, Korea; Lee JW in G Sam Hospital, Gunpo, Korea; Park JS in Hanyang University College of Medicine, Seoul, Korea; Kim YH in Inje University Busan Paik Hospital, Busan, Korea; Cho JH in CHA Gumi Medical Center, CHA University, Seongnam, Korea; Ahn KS in Daegu Catholic University Medical Center, Daegu, Korea; Jin K in Keimyung University Dongsan Hospital, Daegu, Korea; Kim HL in Chosun University College of Medicine, Gwangju, Korea; Kim SW in Chonnam National University Medical School, Gwangju, Korea; Jung YS in Kosin University College of Medicine, Busan, Korea; Kim HY in Chung-Buk University College of Medicine, Cheong-Ju, Korea; Lee KW in Chung-Nam University College of Medicine, Dae-Jeon, Korea; and Park K in Changwon Fatima Hospital, Changwon, Korea.