Uremic Toxins And Protein-Bound Therapeutics in AKI And CKD: Up-to-Date Evidence Ⅲ

6. The Arising Concept of PBUTs Removal after AKI

6.1. PBUTs 

Adsorbent Of extrarenal origin, dysfunction of target organs, including heart, lung, liver, skeletal muscle, or gastrointestinal tract leads to a metabolic imbalance by increased generation, change of metabolism, decreased excretion, or enhanced intestinal absorption of uremic toxins into organ compartments. Therefore, it is reasonable to assume that uremic toxins accumulation in AKI is similar to those in the CKD spectrum but might occur at an accelerated rate. However, the impact of uremic toxins on renal progression after AKI insult remained unknown and deserved further research. Recently, the treatment of uremic toxin adsorbent AST-120 (Kremezin) in CKD patients has been approved in Japan, Korea, and the Philippines [72]. AST-120 is a spherical adsorptive carbon particle with numerous pores able to remove certain acidic and basic organic compounds, especially for protein-bound uremic toxins: IS and PCS. The precursor of IS, indole is absorbed in the intestines by AST- 120, which decreases the formation of IS from liver metabolism. To date, studies support the effects of AST-120 on renal outcomes and delay the initiation of dialysis in patients with advanced-stage CKD. Despite the positive result to retard CKD progression in several small clinical trials, there are still no reports that unequivocally demonstrate the improvement of hard renal endpoints [73]. Currently, the concept of uremic toxins' early elimination has been proposed in several studies. Chen et al. found that oral intake of AST-120 can alleviate IS accumulation-induced renal fibrosis and ER stress in a two-stage IRI model [32]. Shen et al. demonstrated that the AST-120 administration in a mouse IRI model improved cardiac dysfunction through IS-mediated NF-κB/ICAM-1 proinflammatory signaling and apoptosis (Table 1) [74]. 

ORGANIC HERBS FOR KIDNEY HEALTH

6.2. Probiotic Supplements 

The health benefits of probiotics supplements have caught worldwide attention [75], especially for the CKD population. Many clinical trials show promising outcomes in the prevention of renal function decline and PBUT accumulation in CKD cohorts [76–78]. However, there is only one ongoing phase 3 clinical study to investigate the effect of probiotic supplements in sepsis-induced AKI patients (NCT03877081) and one research article that applied probiotic supplements in an AKI rat model. Lee et al. demonstrated that supplementation with the probiotic Lactobacillus salivarius: BP121 can protect against cisplatin-induced AKI through ameliorating renal function parameters BUN and sCr and reducing serum IS and PCS formation in circulation (Table 1) [79].

Moreover, the BP121 supplement also inhibited cisplatin-induced inflammation, oxidative stress, apoptosis, and modulation of the gut environment. 

6.3. Albumin Binding Displacer

The feature of protein binding of uremic toxins makes it difficult for them to pass through hemodialysis membranes [80]. To solve this problem, Madero et al. demonstrated a novel strategy to enhance PBUTs' removal efficacy during hemodialysis through pre-treatment with ibuprofen-an albumin-binding competitor (Table 1) [81]. The idea comes from studies that indicate that the albumin-binding site of IS and PCS can be replaced by ibuprofen in vitro and ex vivo [82,83]. It has to be noticed that this is not necessarily a safe option as NSAIDs should be avoided in ESRD patients on dialysis. However, it is an interesting proposition that should be further explored by safer albumin-binding competitors. Recently, Li et al. applied salvianolic acids, an albumin-binding competitor extracted from Salvia miltiorrhiza (Danshen) [84], liberating the free form of IS and PCS from albumin binding, which provided superior PBUTs clearance efficacy than conventional hemodialysis [85]. Moreover, salvianolic acids are well known for their anti-oxidative activity. Therefore, it would be a suitable and safe PBUT binding displacer for further study. Despite the therapeutic benefit of PBUTs binding displacers in CKD still to be determined, a growing number of PBUTs binding displacer studies prove promising therapeutic strategies for PBUT removal. 

6.4. SULT Inhibitors 

Sulfotransferase (SULT) is a hepatic enzyme responsible for the xenobiotic detoxification process, known as the phase II conjugating procedure that transfers a sulfonate group to the substrate to generate hydrophilic products for urinary excretion [86]. The hepatic phase II biotransformation also plays a critical role in IS and PCS formation in the liver [87]. Therefore, Saito et al. identified the SULT inhibitors-Quercetin, Meclofenamate, and Resveratrol, which were phytochemical polyphenols extracted from Chinese medicine to prevent kidney injury IS, PCS formation in an AKI rat model (Table 1) [88–90].

7. Conclusions 

AKI can demonstrate a continuum, while initial renal injury can lead to kidney damage, and eventually result in CKD and future ESRD development [4]. Since AKI is a risk factor for CKD development and once it progresses to the CKD stage, it is hardly reversible. Therefore, eliminating the risk factors for kidney disease development is ongoing in many studies. Moreover, the concept of the deteriorating effect of PBUTs has not been limited to the CKD scenario. Studies in both animal models and AKI patients have been identified with increased serum IS and PCS levels. Furthermore, several potential therapeutic strategies have been identified that target the removal of PBUT precursors or prevent their synthesis in the early stage of AKI (Figure 2). However, there is still a need for more evidence to support the benefit of early removal of PBUTs to accelerate relevant clinical trial progression in this cohort.

Figure 2. Summary of underlying mechanisms of PBUT accumulation, adverse outcomes, and potential therapeutic interventions. After suffering from AKI, acute tubular necrosis occurs in RTECs leading to loss of PBUTs transporters OAT1/3 expression and impairment of secretory function. PBUT precursor-producing bacteria were also found to be increased after AKI and caused indole and p-cresol synthesis. Sustaining PPBUTaccumulation in the circulation accelerates the risk of CKD, heart failure, lung injury, and vascular disease progression. To prevent PBUT accumulation-induced adverse outcomes, developments, and interventions such as the oral charcoal adsorbent, probiotic supplements, and SULT inhibitor administration have been investigated in vivo studies

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