Clinical Pharmacokinetic-Pharmacodynamic Relationships of Pharmacological Strategies for Attenuating p-Cresyl Sulfate in Patients with Kidney Disease.

p-Cresyl sulfate (pCS) is a highly toxic uremic compound that is produced from tyrosine and phenylalanine in the gut and primarily excreted renally. In patients with kidney dysfunction, the accumulation of pCS can lead to the worsening of kidney disease and manifestation of organ toxicities. Various pharmacological strategies have been proposed to reduce pCS in patients with chronic kidney disease (CKD), but systematic pharmacokinetic-pharmacodynamic assessments have not been conducted to our knowledge. The objectives of this scoping review were to comprehensively and critically summarize the available literature using a newly devised, pharmacokinetic-pharmacodynamic assessment method. We searched PubMed, Embase, and Scopus for primary research articles in patients with CKD and devised the following novel approach to systematically evaluate each study: (i) positive reduction or null reduction of pCS; (ii) dose dependency; (iii) time dependency; (iv) effects on free versus total pCS; and (v) relationships to diet regimens (e.g., protein intake), microbiome composition, blood biochemistry, and clinical outcomes (i.e., progression of renal disease measured by initiation of dialysis or renal transplant; cardiovascular outcomes such as incidence of myocardial infarction, heart failure, cardiovascular death; and changes in qualityof- life instruments). Fifty-nine studies were identified with a total of 2593 study participants (pre-dialysis CKD: n = 1060; CKD on dialysis: n = 1499; and post-transplant CKD: n = 34). The studies included AST-120 (n = 3), sevelamer (n = 9), sucroferric Noxyhydroxide (n = 1 [+ 1 overlapping with sevelamer]), prebiotics (n = 15), probiotics (n = 9), synbiotics (n = 13), antibiotics (n = 3), ketoanalogs (n=3), and curcumin (n = 3). Only AST-120 and synbiotics consistently demonstrated significant pCS reductions, and the percentage (%) reductions by AST-120 were 40.9-75.6% for free and 28.8-42.8% for total pCS; whereas the percentage reduction by synbiotics were 6.4-78.1% for total and 16.7% for free pCS, the latter only evident in a subgroup with antibiotic-free regimen. Although sevelamer was also associated with a pCS reduction, the percentage reduction was modest and only based on the total concentration. In contrast, the majority of sucroferric oxyhydroxide, prebiotics, probiotics, ketoanalogs, and curcumin studies did not demonstrate consistent pCS reductions. Furthermore, dose dependency was not established in the majority of studies, and although some temporal relationships were evident, the data were very limited. Only a few of the analyzed studies measured both bound and unbound forms of pCS, and inconsistencies have been reported in a few studies. In Ngeneral, it was also difficult to establish associations with outcomes in most studies because of limitations in experimental design, and in instances where potential pharmacokinetic-pharmacodynamic relationships were observed, they were generally weak and only with surrogate markers of commonly measured biochemistry, oxidative stress, lipid profiles, and inflammatory markers, with only a handful of studies capturing clinical outcomes. In conclusion, we have identified potential pharmacological interventions that may be further developed for the purpose of reducing pCS in patients with CKD.