Two Toxic Lipid Aldehydes, 4-hydroxy-2-hexenal (4-HHE) and 4-hydroxy-2-nonenal (4-HNE), Accumulate in Patients with Chronic Kidney Disease.

Lipid aldehydes originating from the peroxidation of n-3 and n-6 polyunsaturated fatty acids are increased in hemodialysis (HD) patients, a process already known to promote oxidative stress. However, data are lacking for patients with chronic kidney disease (CKD) before the initiation of HD. We prospectively evaluated the changes of plasma concentrations of two major lipid aldehydes, 4-HHE and 4-HNE, according to the decrease of glomerular filtration rate (GFR) in 40 CKD and 13 non-CKD participants. GFR was measured by inulin or iohexol clearance. Thus, 4-hydroxy-2-nonenal (4-HNE) and 4-hydroxy-2-hexenal (4-HHE) were quantitated in plasma by gas chromatography coupled with mass spectrometry and their covalent adducts on proteins were quantified by immunoblotting. On the one hand, 4-HHE plasma concentration increased from CKD stage I-II to CKD stage IV-V compared to non-CKD patients (4.5-fold higher in CKD IV-V, p < 0.005). On the other hand, 4-HNE concentration only increased in CKD stage IV-V patients (6.2-fold, p < 0.005). The amount of covalent adducts of 4-HHE on plasma protein was 9.5-fold higher in CKD patients than in controls (p < 0.005), while no difference was observed for 4-HNE protein adducts. Plasma concentrations of 4-HNE and 4-HHE are increased in CKD IV-V patients before the initiation of hemodialysis.

Elevation of Trimethylamine-N-Oxide in Chronic Kidney Disease: Contribution of Decreased Glomerular Filtration Rate.

Gut microbiota-dependent Trimethylamine-N-oxide (TMAO) has been reported to be strongly linked to renal function and to increased cardiovascular events in the general population and in Chronic Kidney Disease (CKD) patients. Considering the lack of data assessing renal handling of TMAO, we conducted this study to explore renal excretion and mechanisms of accumulation of TMAO during CKD. We prospectively measured glomerular filtration rate (mGFR) with gold standard methods and plasma concentrations of trimethylamine (TMA), TMAO, choline, betaine, and carnitine by LC-MS/MS in 124 controls, CKD, and hemodialysis (HD) patients. Renal clearance of each metabolite was assessed in a sub-group of 32 patients. Plasma TMAO was inversely correlated with mGFR (r2 = 0.388, p < 0.001), confirming elevation of TMAO plasma levels in CKD. TMAO clearances were not significantly different from mGFR, with a mean ± SD TMAO fractional excretion of 105% ± 32%. This suggests a complete renal excretion of TMAO by glomerular filtration with a negligible participation of tubular secretion or reabsorption, during all stages of CKD. Moreover, TMAO was effectively removed within 4 h of hemodiafiltration, showing a higher fractional reduction value than that of urea (84.9% ± 6.5% vs. 79.2% ± 5.7%, p = 0.04). This study reports a strong correlation between plasma TMAO levels and mGFR, in CKD, that can be mainly related to a decrease in TMAO glomerular filtration. Clearance data did not support a significant role for tubular secretion in TMAO renal elimination.

Estimated Glomerular Filtration Rate Bias in Participants with Severe Obesity Regardless of Deindexation.

OBJECTIVE: Morbid obesity is associated with a higher independent risk of chronic kidney disease (CKD). Estimated glomerular filtration rate (eGFR) has been evaluated in a limited number of study participants with severe obesity. METHODS: A total of 706 measured GFR (mGFR) results from 598 participants with obesity (BMI ≥ 35 kg/m2 ) were retrospectively collected. The performance of the Modification of Diet in Renal Disease (MDRD) equation, Chronic Kidney Disease-Epidemiology (CKD-EPI) equation, and deindexed eGFR were compared with mGFR from the gold standard technique (inuline or iohexol), adjusted (mGFRr) or nonadjusted (mGFR) to body surface area. Absolute bias, precision, and accuracy were calculated. RESULTS: Mean mGFRr (58 ± 31 mL/min/1.73 m2 ) was significantly different from CKD-EPI and MDRD (P < 0.001). Mean mGFR (nonindexed) (70 ± 40 mL/min) was significantly higher than mGFRr (P < 0.001). eGFR showed important biases and low accuracies for CKD-EPI and MDRD (10.7 ± 10.7 and 12.2 ± 13.7 mL/min/1.73 m2 ; 78% vs. 75% respectively). Deindexation worsened bias and accuracy 30% (percentage of GFR estimates within 30% of mGFRr or mGFR) between eGFR and mGFR. CONCLUSIONS: eGFR overestimates mGFR and is associated with important biases and inaccuracies in patients with severe obesity, and deindexing eGFR worsens the overestimation. These findings may have important implications in examining kidney function in patients with obesity.

Adenine Rich Diet Is Not a Surrogate of 5/6 Nephrectomy in Rabbits.

BACKGROUND: Animal models are important tools needed to understand the mechanisms underlying the progression of renal disease and to implement new therapeutic approaches. A non-surgical model of chronic kidney disease (CKD) developed by chemical nephrectomy using an adenine-enriched diet has been shown to be a robust model to induce kidney failure in mice and rats. The purpose of this study was to implement an adenine diet to induce CKD in rabbits. METHODS: Male New Zealand rabbits were fed for 4 weeks with a diet containing 0.75% (w/w) adenine, and renal function was assessed by measuring plasma urea and creatinine concentrations. The glomerular filtration rate (GFR) was measured using the plasmatic clearance of Iohexol. Kidney histology was performed with haematoxylin erythrosine saffron and Sirius red staining. RESULTS: In contrast to what was observed in rodents, adenine diet failed to induce kidney failure in rabbits as is evident in the plasma concentrations of creatinine and urea and the direct measurement of GFR or histopathological studies. CONCLUSION: Adenine diet is not a surrogate of subtotal nephrectomy to induce kidney failure in rabbits. Several interspecies differences in metabolism and renal physiology could account for this observation.

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.

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.

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.

White adipose tissue overproduces the lipid-mobilizing factor zinc α2-glycoprotein in chronic kidney disease.

Chronic kidney disease (CKD) is frequently associated with protein-energy wasting, a recognized strong predictive factor of mortality. Zinc α2-glycoprotein (ZAG) is a new adipokine involved in body weight control through its lipid-mobilizing activity. Here we tested whether the uremic environment in CKD could alter ZAG production by white adipose tissue and contribute to CKD-associated metabolic disturbances. Compared with normal plasma, uremic plasma induced a significant increase in ZAG synthesis (124%), was associated with a significant increase in basal lipolysis (31%), and significantly blunted lipogenesis (-53%) in 3T3-L1 adipocytes in vitro. In 5/6 nephrectomized rats and mice in vivo, there was a significant decrease in white adipose tissue accretion (-44% and -43%, respectively) and a significantly higher white adipose tissue content of ZAG protein than in sham-operated, pair-fed control animals (498% and 106%, respectively). Subcutaneous white adipose tissue biopsies from patients with end-stage renal disease exhibited a higher content of ZAG (573%) than age-matched controls. Thus, the ZAG content is increased in white adipose tissue from patients or animal models with CKD. Overproduction of ZAG in CKD could be a major contributor to metabolic disturbances associated with CKD.

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.