#2971 A low-protein diet improves metabolic health and reduces blood uremic toxins in non-diabetic CKD
Authors: Koppe Laetitia , Verdier Vincent , Benoit Bérengère , François Leulier , Filipe De Vadder , Karim Chikh , Vidal Hubert 
Published: May 2024

Abstract

Background and Aims
Despite the demonstrated efficacy of a low-protein diet (LPD) in slowing the progression of chronic kidney disease (CKD), the underlying mechanisms remain inadequately understood. Given the potential drawbacks, including poor compliance and a risk of malnutrition, gaining insights into the molecular mechanisms driving these benefits is crucial for safe clinical translation. In this study, our objectives were to 1) assess the impact of an LPD on the metabolic health of individuals and mice with CKD; 2) investigate the hypothesis that these effects are mediated by a reduction in uremic toxins; and 3) explore whether the combination of an LPD and supplementation with a strain of Lactiplantibacillus plantarum (strain LpWJL), selected for its ability to enhance growth in a Drosophila model of diet-induced stunting, could synergistically amplify the positive effects of the LPD while minimizing its potential adverse consequences.

Method
We recruited CKD patients with no diabetes or prediabetes, who were randomized to a LPD and cetoanalogues (0.4 g/kg/day) (n = 5) or a normal diet (ND) (0.8 g/kg/day, n = 6) for 3 months. A glucose tolerance test was measured at baseline and after 3 months. Four groups of mice were studied: a sham group with a ND (n = 4), 5/6th nephrectomized mice with a ND (n = 7), and 5/6th nephrectomized mice with LPD (5% w/w) and LPwjl (n = 7) or placebo (n = 7) for 6 weeks. Blood samples and liver tissues were analyzed with the MxP 500 Quant® (Biocrates) kit by LC-MS/MS (XEVO TQ-XS, Waters).

Results
Under LPD, beta cell function showed improvement (Matsuda index, P = 0.049, and AUC insulin, P = 0.02). Although the diet did not influence body composition, the LPD group exhibited a reduction in muscle strength (P = 0.02). LPD decreased blood concentration several uremic toxins such as indoxyl sulfate and TMAO. Insulin sensitivity and beta-cell function demonstrated negative correlations with urea, TMAO, and indoxyl sulfate. Mouse studies confirmed the positive impact of LPD on glucose homeostasis but also revealed detrimental effects on lean mass and fat mass. Supplementation with LpWJL during LPD mitigated the loss of fat mass, improved the insulin tolerance test, and enhanced the reduction of certain blood uremic toxins, including indoxyl sulfate. LpWJL supplementation exerted a substantial impact on the hepatic metabolome, resulting in increased triglyceride accumulation and decreased levels of diglycerides, acylcarnitines, and phosphocholines.

Conclusion
We have highlighted the substantial benefits of a 3-month LPD on markers of glucose homeostasis and uremic toxins in mice and humans without diabetes. LpWJL induced profound modifications in both blood and liver metabolome and was associated with a limitation of trophic alterations in LPD diet-induced CKD mice, while also enhancing glucose homeostasis. Further studies are essential to gain a better understanding of the underlying mechanisms involved.