Laetitia Koppe

p-Cresyl Sulfate Promotes Insulin Resistance Associated with CKD

The mechanisms underlying the insulin resistance that frequently accompanies CKD are poorly understood, but the retention of renally excreted compounds may play a role. One such compound is p-cresyl sulfate (PCS), a protein-bound uremic toxin that originates from tyrosine metabolism by intestinal microbes. Here, we sought to determine whether PCS contributes to CKD-associated insulin resistance. Administering PCS to mice with normal kidney function for 4 weeks triggered insulin resistance, loss of fat mass, and ectopic redistribution of lipid in muscle and liver, mimicking features associated with CKD. Mice treated with PCS exhibited altered insulin signaling in skeletal muscle through ERK1/2 activation. In addition, exposing C2C12 myotubes to concentrations of PCS observed in CKD caused insulin resistance through direct activation of ERK1/2. Subtotal nephrectomy led to insulin resistance and dyslipidemia in mice, and treatment with the prebiotic arabino-xylo-oligosaccharide, which reduced serum PCS by decreasing intestinal production of p-cresol, prevented these metabolic derangements. Taken together, these data suggest that PCS contributes to insulin resistance and that targeting PCS may be a therapeutic strategy in CKD.

Role of altered intestinal microbiota in systemic inflammation and cardiovascular disease in chronic kidney disease

The normal intestinal microbiota plays a major role in the maintenance of health and disease prevention. In fact, the alteration of the intestinal microbiota has been shown to contribute to the pathogenesis of several pathological conditions, including obesity and insulin resistance, among others. Recent studies have revealed profound alterations of the gut microbial flora in patients and animals with chronic kidney disease (CKD). Alterations in the composition of the microbiome in CKD may contribute to the systemic inflammation and accumulation of gut-derived uremic toxins, which play a central role in the pathogenesis of accelerated cardiovascular disease and numerous other CKD-associated complications. This review is intended to provide a concise description of the potential role of the CKD-associated changes in the gut microbiome and its potential role the pathogenesis of inflammation and uremic toxicity. In addition, the potential efficacy of pre- and pro-biotics in the restoration of the microbiome is briefly described.

Probiotics and chronic kidney disease

Probiotics are the focus of a thorough investigation as a natural biotreatment due to their various health-promoting effects and inherent ability to fight specific diseases including chronic kidney disease (CKD). Indeed, intestinal microbiota has recently emerged as an important player in the progression and complications of CKD. Because many of the multifactorial physiological functions of probiotics are highly strain specific, preselection of appropriate probiotic strains based on their expression of functional biomarkers is critical. The interest in developing new research initiatives on probiotics in CKD have increased over the last decade with the goal of fully exploring their therapeutic potentials. The efficacy of probiotics to decrease uremic toxin production and to improve renal function has been investigated in in vitro models and in various animal and human CKD studies. However to date, the quality of intervention trials investigating this novel CKD therapy is still lacking. This review outlines potential mechanisms of action and efficacy of probiotics as a new CKD management tool, with a particular emphasis on uremic toxin production and inflammation.

Ectopic lipid accumulation: A potential cause for metabolic disturbances and a contributor to the alteration of kidney function

Ectopic lipid accumulation is now known to be a mechanism that contributes to organ injury in the context of metabolic diseases. In muscle and liver, accumulation of lipids impairs insulin signaling. This hypothesis accounts for the mechanism of insulin resistance in obesity, type 2 diabetes, aging and lipodystrophy. Increasing data suggest that lipid accumulation in the kidneys could also contribute to the alteration of kidney function in the context of metabolic syndrome and obesity. Furthermore and more unexpectedly, animal models of kidney disease exhibit a decreased adiposity and ectopic lipid redistribution suggesting that kidney disease may be a state of lipodystrophy. However, whether this abnormal lipid partitioning during chronic kidney disease (CKD) may have any functional impact in these tissues needs to be investigated. Here, we provide a perspective by defining the problem and analyzing the possible causes and consequences. Further human studies are required to strengthen these observations, and provide novel therapeutic approaches.

Insulin resistance in chronic kidney disease: new lessons from experimental models

Insulin resistance (IR) is a common feature of chronic kidney disease (CKD), but the underlying mechanisms still remain unclear. A growing body of evidence suggests that IR and its associated metabolic disorders are important contributors for the cardiovascular burden of these patients. In recent years, the modification of the intestinal flora and activation of inflammation pathways have been implicated in the pathogenesis of IR in obese and diabetic patients. All these pathways ultimately lead to lipid accumulation in ectopic sites and impair insulin signalling. These important discoveries have led to major advances in understanding the mechanisms of uraemia-induced IR. Indeed, recent studies show impairment of the intestinal barrier function and changes in the composition of the gut microbiome during CKD that can contribute to the prevailing inflammation, and the production and absorption of toxins generated from bacterial metabolism. The specific role of individual uraemic toxins in the pathogenesis of IR has been highlighted in rodents. Moreover, correcting some uraemia-associated factors by modulating the intestinal flora improves insulin sensitivity. This review outlines potential mechanisms by which important modifications of body homeostasis induced by the decline in kidney function can affect insulin sensitivity, and the relevance of recent advances in the field to provide novel therapeutic approaches to reduce IR associated cardiovascular mortality.

Protein-bound uremic toxins…new targets to prevent insulin resistance and dysmetabolism in patients with chronic kidney disease.

The retention of p-cresyl sulfate (PCS), the prototype of protein-bound uremic toxins that is produced by the gut microbiota and normally excreted by the kidney, may contribute to the development of insulin resistance in patients with chronic kidney disease. In a recent study, we demonstrated in mice, as in cultured muscle cells, that PCS interferes with intracellular insulin signaling pathways and triggers insulin resistance. The treatment of CKD mice with a prebiotic that reduces the intestinal production and decreases blood levels of PCS prevented insulin resistance and lipid abnormalities, suggesting new opportunities to prevent metabolic disturbances in patients with CKD. This study highlights the uremic toxins as new actors in metabolic alterations associated with CKD and allows for the consideration of new therapeutic approaches (e.g., prebiotics, probiotics, adsorbents) to better prevent them.

Human Uremic Plasma and not Urea Induces Exuberant Secretion of Leptin in 3T3-L1 Adipocytes

Chronic kidney disease (CKD) is frequently associated with malnutrition, anorexia, and hyperleptinemia. This study was designed to test the hypothesis that a component of the uremic milieu may trigger leptin release by adipocytes. To this end, mouse 3T3-L1 adipocytes were incubated for 16 hours in culture medium containing urea (80 mM) or plasma from either healthy volunteers or patients with CKD (20%, v/v). Uremic plasma and not urea induced a large release of leptin (+557%, P < .01). These results suggest that the hyperleptinemia reported in patients with CKD, could be, at least in part, because of an overproduction of leptin by the adipose tissue.

CMPF: A Biomarker for Type 2 Diabetes Mellitus Progression?

The factors that precipitate the transition from insulin resistance to type 2 diabetes mellitus (T2DM) remain elusive. A recent study showed that circulating levels of the furan fatty acid (FA) metabolite 3-Carboxy-4-Methyl-5-Propyl-2-Furanopropanoic Acid (CMPF) increase in individuals who progress from prediabetes to T2DM. CMPF increases oxidative stress and impairs insulin granule maturation and secretion.

The relationship between renal function and plasma concentration of the cachectic factor zinc-alpha2-glycoprotein (ZAG) in adult patients with chronic kidney disease.

Zinc-α2-glycoprotein (ZAG), a potent cachectic factor, is increased in patients undergoing maintenance dialysis. However, there is no data for patients before initiation of renal replacement therapy. The purpose of the present study was to assess the relationship between plasma ZAG concentration and renal function in patients with a large range of glomerular filtration rate (GFR). Plasma ZAG concentration and its relationship to GFR were investigated in 71 patients with a chronic kidney disease (CKD) stage 1 to 5, 17 chronic hemodialysis (HD), 8 peritoneal dialysis (PD) and 18 non-CKD patients. Plasma ZAG concentration was 2.3-fold higher in CKD stage 5 patients and 3-fold higher in HD and PD patients compared to non-CKD controls (P<0.01). The hemodialysis session further increased plasma ZAG concentration (+39%, P<0.01). An inverse relationship was found between ZAG levels and plasma protein (rs = −0.284; P<0.01), albumin (rs = −0.282, P<0.05), hemoglobin (rs = −0.267, P<0.05) and HDL-cholesterol (rs = −0.264, P<0.05) and a positive correlation were seen with plasma urea (rs = 0.283; P<0.01). In multiple regression analyses, plasma urea and HDL-cholesterol were the only variables associated with plasma ZAG (r2 = 0.406, P<0.001). In CKD-5 patients, plasma accumulation of ZAG was not correlated with protein energy wasting. Further prospective studies are however needed to better elucidate the potential role of ZAG in end-stage renal disease.

p-Cresyl glucuronide is a major metabolite of p-cresol in mouse: in contrast to p-cresyl sulphate, p-cresyl glucuronide fails to promote insulin resistance

Background The role of uraemic toxins in insulin resistance associated with chronic kidney disease (CKD) is gaining interest. p-Cresol has been defined as the intestinally generated precursor of the prototype protein-bound uraemic toxins p-cresyl sulphate (p-CS) as the main metabolite and, at a markedly lower concentration in humans, p-cresyl glucuronide (p-CG). The objective of the present study was to evaluate the metabolism of p-cresol in mice and to decipher the potential role of both conjugates of p-cresol on glucose metabolism. Methods p-CS and p-CG were measured by high performance liquid chromatography-fluorescence in serum from control, 5/6 nephrectomized mice and mice injected intraperitoneously with either p-cresol or p-CG. The insulin sensitivity in vivo was estimated by insulin tolerance test. The insulin pathway in the presence of p-cresol, p-CG and/or p-CS was further evaluated in vitro on C2C12 muscle cells by measuring insulin-stimulated glucose uptake and the insulin signalling pathway (protein kinase B, PKB/Akt) by western blot. Results In contrast to in humans, where p-CS is the main metabolite of p-cresol, in CKD mice both conjugates accumulated, and after chronic p-cresol administration with equivalent concentrations but a substantial difference in protein binding (96% for p-CS and <6% for p-CG). p-CG exhibited no effect on insulin sensitivity in vivo or in vitro and no synergistic inhibiting effect in combination with p-CS. Conclusions The relative proportion of the two p-cresol conjugates, i.e. p-CS and p-CG, is similar in mouse, in contrast to humans, pinpointing major inter-species differences in endogenous metabolism. Biologically, the sulpho- (i.e. p-CS) but not the glucuro- (i.e. p-CG) conjugate promotes insulin resistance in CKD.