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.

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.

Twin pregnancy in a patient on chronic haemodialysis who already had three pregnancies.

Pregnancy in women with end-stage renal disease is rare. Multiple pregnancies carry a high risk of complications even in healthy individuals. We report the case of a 36-year-old woman who had four pregnancies while she was on dialysis, including one twin pregnancy. The last pregnancy occurred while in the 14th year of hemodialysis. At 8 weeks of gestation (WG), ultrasonography diagnosed a dichorionic diamniotic twin pregnancy. The frequency of dialysis was increased from 3 to 6 times a week and each session lasted 4 h. At 22 WG, polyhydramnios was diagnosed. At 25 WG, the patient presented respiratory distress and was transferred to intensive care where continuous hemodialysis, non-invasive ventilation, antibiotic and tocolysis were initiated. Because of tocolysis failure, a cesarean section was performed and she delivered male twins. The two newborns weighed 790 and 870 g, respectively. To our knowledge, this is the first report of four pregnancies in hemodialysis including one twin pregnancy. The incidence of pregnancy and a better outcome in patients on hemodialysis has increased in recent years but a tight coordination between nephrologists and obstetricians is essential.

Identification of novel antilipogenic agents targeting fatty acid biosynthesis through structure-based virtual screening.

An Asinex Gold Platinium chemical library subset of 12 055 compounds was screened employing docking simulations in the active site of the human FAS KS domain. Among them, 13 compounds were further evaluated for their ability to inhibit fatty acid biosynthesis. Four compounds were found to be active in particular ASN05064661 and ASN05374526 with IC50 values of 6.6 and 10.5 µm, respectively. A binding mode study was further conducted with these two compounds structurally related to benzene sulfonamide and aromatic polyamide. This study showed that they fit tightly with the active site with several interactions, notably with the key residues Cys161, His293, and His331.

[A giant cell arteritis revealing a Goodpasture's syndrome]. / Une artérite à cellules géantes révélatrice d'un syndrome de Goodpasture.

Goodpasture's syndrome is a triad of anti-glomerular basement membrane (anti-GBM) circulating antibodies, glomerulonephritis and pulmonary hemorrhage. We reported a 65-year-old woman with headaches, asthenia and weight loss. Giant cell arteritis was confirmed by temporal artery biopsy. The patient had associated renal condition with moderate acute renal failure, proteinuria and haematuria. Renal biopsy showed extracapillary glomerulonephritis and linear staining of immunoglobulins G along glomerular basement membrane. There was no clinical pulmonary involvement. Anti-MBG antibody was positive and allowed Goodpasture's syndrome diagnosis. The patient was treated with corticoids and cyclophosphamide. Patient's condition and renal function improved quickly and anti-MBG antibodies became negative. Goodpasture's syndrome may be characterized by isolated renal expression without pulmonary involvement. We described for the first time association of Goodpasture's syndrome with giant cell arteritis.

Leptin as an uremic toxin: Deleterious role of leptin in chronic kidney disease.

White adipose tissue secretes a large variety of compounds named adipokines amongst which, leptin exhibits pleiotropic metabolic actions. Leptin is an anorexigenic hormone, secreted in proportion of fat mass, with additional effects on the regulation of inflammation, cardiovascular system, immunity, hematopoiesis and bone metabolism. Chronic kidney disease (CKD) is characterized by an increase of plasma leptin concentration that may be explained by a lack of renal clearance. Hyperleptinemia plays a key role in the pathogenesis of complications associated with CKD such as cachexia, protein energy wasting, chronic inflammation, insulin resistance, cardiovascular damages and bone complications. Leptin is also involved in the progression of renal disease through its pro-fibrotic and pro-hypertensive actions. Most of the adverse effects of leptin have been documented both experimentally and clinically. Leptin may therefore be considered as an uremic toxin in CKD. The aim of this review is to summarize the pathophysiological and clinical role of leptin in in vitro studies, experimental models, as well as in patients suffering from CKD.

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.

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.