*5.2. Clinical Observations*

Thus, it is now clear that SCFAs may have a central and promising role in the treatment of renal failure. Indeed, several clinical trials have already been initiated. In the inflammation and oxidative stress observed in CKD, uremic toxins of intestinal origin also play a central role, promoting excess morbidity and mortality. This may be due to intestinal dysbiosis and the insufficient consumption of fermentable, complex carbohydrates, which consequently lead to reduced SCFA concentrations. Thus, a pilot study was conducted at the 'A Landolfi' Hospital (Solofra, Italy) in which 20 stable patients aged between 18 and 90 years were recruited, of which the most frequent causes of renal failure were diabetes mellitus and chronic glomerulonephritis. All of the subjects suffered from vascular and cardiac complications. Biochemical analyses were performed on the sera, and elevated levels of inflammatory and pro-oxidant markers were observed. However, when SCFAs, in particular sodium propionate, were administered, significant improvements were observed: no patient discontinued the treatment, and their body weight remained stable, there was a significant decrease in pro-inflammatory and pro-oxidant parameters such as high-sensitivity C-reactive protein (hs-CRP), IL-2, IL-6, IL-10, IL-17a, TNF-α, INF (Interferon)-γ, TGF-β, and endotoxins/lipopolysaccharides compared to the significant increase in the anti-inflammatory cytokine IL-10. In addition, the levels of MDA and uremic toxins, indoxyl sulphate and p-cresyl sulphate, were reduced. This study, therefore, from its conclusion, provided new information on the benefits of SCFAs for treating systemic inflammation, oxidative stress, and metabolic disorders [158]. Considering that elevated blood pressure and cardiovascular morbidity occur very often in patients with CKD. Some studies have shown that SCFAs can improve cardiovascular outcomes in CKD patients with kidney disease [159,160]. In fact, in 2019, the first clinical study was conducted to verify that SCFAs can bind to both the Olfr78 receptors expressed in the kidney on the afferent arteriole of the juxtaglomerular apparatus involved in the production of renin and the GPR41 receptor in the renal vascular system with contrasting effects on blood pressure [161–164]. Jadoon and colleagues examined the potential link between SCFAs and cardiovascular outcomes in patients with chronic renal failure. In a subcohort of 214 patients with CKD in the Clinical Phenotyping Resource and Biobank Core (CPROBE), including 81 patients with coronary artery disease (CAD) and self-reported cardiovascular disease (CVD), they measured the plasma levels of SCFAs by liquid chromatography-mass spectrometry and high-performance liquid chromatography. The results showed improved cardiovascular function in CKD patients, which was linked to significantly higher levels of SCFAs [165]. Furthermore, SCFAs have also been shown to significantly decrease systolic blood pressure in hemodialysis patients [166]. SCFA levels improved by diet also seems to have a positive effect on CKD. In fact, diet can improve the course of CKD by reducing urea levels [167], metabolic acidosis [168], and insulin resistance [169], as well as positively modulating the intestinal microbiome and, consequently, increasing SCFA concentrations [170,171]. Type 2-resistant starch-enriched biscuits (RS2) were administered to hemodialysis patients with chronic renal failure for 4 weeks. The results showed an increase in SCFA-producing bacteria *Roseburia* and *Ruminococcus gauvreauii* and a downregulation of the pro-inflammatory parameters [172]. While, in the course of another prospective, randomised, crossover study (Medika Study), for the first time, the effect of different diets on the modulation of the intestinal microbiota and, consequently, on the modification of the serum levels of IS and pCS were evaluated in patients with chronic renal failure. Sixty patients with grade 3B-4 chronic renal failure were recruited and given a free diet (FD), a very-low protein diet (VLPD) and a Mediterranean diet (MD). The stool and serum samples were collected at the end of each dietary regimen for the evaluation of IS and pCS levels or serum D-lactate levels. The results indicated that MD and VLPD increased bacterial species with anti-inflammatory potential and butyrate producers, circulating levels of IS and pCS were reduced, and an improvement in structural integrity and intestinal permeability was observed. Furthermore, VLPD reduced serum D-lactate and improved systolic blood pressure [173]. Wu and colleagues, on the other hand, evaluated changes in the composition of the gut microbiota

in patients with chronic renal failure who followed a low-protein diet (LPD). In this study, 43 patients with chronic renal failure were involved, and changes in bacterial population, SCFAs production and uremic toxins were evaluated. These results also confirmed that nutritional therapy based on low protein intake improved renal function, reduced IS and pCS levels, and increased butyrate-producing bacterial populations [174].

The study sections and results are summarised in Table 3.


**Table 3.** Clinical studies report a related improvement in SCFA levels both in in vitro and animal models.

Abbreviations: hs-CRP, high-sensitivity C-reactive protein; IL, Interleukin; INF-γ, Interferon gamma; MDA, Malondialdehyde; *TGF-β*, Transforming Growth Factor beta; TNF-α, Tumor Necrosis Factor alpha; IS, Indoxyl Sulfate; pCS, pCresil Sulfate; CVD, Cardiovascular disease; HD, Hemodialysis; CKD, Chronic Kidney Disease; LPD, Low-Protein Diet; SCFA, Short-chain Fatty Acids; FD, Free Diet; MD, Mediterranean Diet; VLPD, Very-Low Protein Diet.

D-Lactate
