## 8 Disease Management Options within the Context of a Disturbed Gastrointestinal Barrier  
### Pharmacological Intervention in CKD  
There are many options to treat such a complex disease as CKD. These mainly focus on preventing further renal decline and managing the resulting comorbidities. The application of phosphate binders and a phosphate-reduced diet are used to treat hyperphosphatemia as it correlates with increased mortality [75]. It might also prevent an incline in FGF23 [5, 18]. A combination of antihypertensive medication and a salt-reduced diet is often prescribed to combat hypertension [76, 77]. While these treatments target CKD-induced comorbidities, they can also influence the GI barrier. Frequent consumption of various medications is proposed as a putative contributor to gut dysbiosis and potential intestinal barrier disruption [78]. Intestinal hyperpermeability of iatrogenic origin in CKD is presumed to compromise the gut microbiome, which may lead to increased gut permeability [79]. Even though phosphate binders are the mainstay of therapy, CKD patients receiving iron salts may be more susceptible to LGS due to potential bacterial proliferation and overgrowth caused by iron stimulation [80]. On the other hand, phosphate binder ferric citrate restored colonic ZO-1 abundance in 5/6 nephrectomized rats [81]. This raised interest regarding the overall effect of phosphate binders on GI health and gut-derived uremic toxins. Therefore, the effect of Sevelamer, a phosphate-binding medication, was investigated in a double-blind, placebo-controlled, randomized clinical trial. However, no significant effect on pCS, IS, and IAA serum concentrations could be detected [82]. Phosphate binders themselves can significantly alter the gastrointestinal microbiome. A direct comparison between the treatment of HD patients with ferric citrate and calcium carbonate revealed reduced microbial diversity and altered stool composition in patients treated with calcium carbonate [83]. Therefore, a specific choice of phosphate binders could be an option to tailor treatment to patients. More information on phosphate metabolism and its effect on the GI microbiome in CKD can be found in a recently published review [84]. Orally applied charcoal adsorbents seemed to be another promising option as they bind intestinal urea and ammonia and, therefore, could prevent epithelial damage [85]. Administration of AST-120 in rats with adenine-induced CKD markedly improved general inflammation and partially restored claudin-1, occludin, and ZO-1 protein levels in the colon [85]. In addition, detected endotoxin levels, interleukin-6 and TNF\(\alpha\) were significantly reduced in AST-120-treated rats compared to the control group [85]. However, the EPPIC trial, based on a cohort of 2035 patients, did not reveal any difference between AST-120 and placebo-treated groups regarding the primary endpoints creatinine doubling, dialysis initiation or kidney transplant [86]. Post hoc analysis, on the other hand, suggests a slight delay regarding disease progression [87]. A 2016 study of stage 3 to 4 CKD patients revealed no effect on mortality, unplanned hospitalizations, and health-related quality of life score [88]. A meta-analysis of 15 randomized controlled studies confirmed a lack of effect regarding mortality. However, the incidence of ESRD was significantly lower in the treatment group [89]. To summarize, the effect of AST-120 remains debatable, but there is only a little evidence that the positive effects witnessed in rodents can be transferred to humans. The current treatment guidelines also propose individualized active vitamin D supplementation in patients with advanced CKD to manage the clinical symptoms of CKD MBD [90]. Even though vitamin D analogues, including 1,25(OH)2D and calcitriol, have been efficacious in the treatment of CKD, [91] they might contribute to an increase in circulating FGF23 levels [19].