Dietary Intake and Nutritional Status in Diabetic and Nondiabetic Patients With Chronic Kidney Disease Stage 4-5 (NutriDiab Study).

OBJECTIVES: The aim of the present study was to assess the dietary intake and nutritional status of patients with chronic kidney disease (CKD) stage 4-5 according to the presence of diabetes. METHODS: This observational and cross-sectional study included adult patients with CKD stage 4-5 referred to a nephrology unit, between October 2018 and March 2019. Daily dietary intake was evaluated by 24-hour dietary inquiry and urine excretion. Nutritional status was assessed by measuring body composition using bioimpedance analysis and muscle function using handgrip strength. Undernutrition was considered using the protein energy wasting score. RESULTS: A total of 75 CKD patients were included, 36 (48%) of whom had diabetes; median age (interquartile range) was 71 (60-80) years. The median weight-adjusted dietary energy intake (DEI) was 22.6 (19.1-28.2) kcal/kg/day and the mean weight-adjusted dietary protein intake (DPI) was 0.86 ± 0.19 g/kg/day. There was no significant difference in DEI and DPI between patients with diabetes and those without, except for weight-adjusted DPI which was significantly lower in diabetic patients (P = .022). In univariate analysis, diabetes was associated with weight-adjusted DPI (coefficient [95% confidence interval] -0.237 [-0.446; -0.004] kcal/kg/day; P = .040), but this association did not remain significant in multivariate analysis. Nutritional status did not differ significantly between diabetic and nondiabetic patients except for lean tissue mass, which was lower in diabetic patients (P = .046). The proportion of patients with protein energy wasting was not significantly different between diabetic and nondiabetic patients (13.9% vs. 10.2%, respectively). CONCLUSIONS: In the present cohort, DPI and DEI were not significantly different between diabetic and nondiabetic CKD patients. Diabetes was not found to be associated with dietary intakes in CKD stage 4-5 patients.

Indoxyl sulfate inhibits muscle cell differentiation via Myf6/MRF4 and MYH2 downregulation.

BACKGROUND: Chronic kidney disease (CKD) is associated with a significant decrease in muscle strength and mass, possibly related to muscle cell damage by uremic toxins. Here, we studied in vitro and in vivo the effect of indoxyl sulfate (IS), an indolic uremic toxin, on myoblast proliferation, differentiation and expression of myogenic regulatory factors (MRF)-myoblast determination protein 1 (MyoD1), myogenin (Myog), Myogenic Factor 5 (Myf5) and myogenic regulatory factor 4 (Myf6/MRF4)-and expression of myosin heavy chain, Myh2. METHODS: C2C12 myoblasts were cultured in vitro and differentiated in myotubes for 7 days in the presence of IS at a uremic concentration of 200 µM. Myocytes morphology and differentiation was analyzed after hematoxylin-eosin staining. MRF genes' expression was studied using reverse transcription polymerase chain reaction in myocytes and 5/6th nephrectomized mice muscle. Myf6/MRF4 protein expression was studied using enzyme-linked immunosorbent assay; MYH2 protein expression was studied using western blotting. The role of Aryl Hydrocarbon Receptor (AHR)-the cell receptor of IS-was studied by adding an AHR inhibitor into the cell culture milieu. RESULTS: In the presence of IS, the myotubes obtained were narrower and had fewer nuclei than control myotubes. The presence of IS during differentiation did not modify the gene expression of the MRFs Myf5, MyoD1 and Myog, but induced a decrease in expression of Myf6/MRF4 and MYH2 at the mRNA and the protein level. AHR inhibition by CH223191 did not reverse the decrease in Myf6/MRF4 mRNA expression induced by IS, which rules out the implication of the ARH genomic pathway. In 5/6th nephrectomized mice, the Myf6/MRF4 gene was down-regulated in striated muscles. CONCLUSION: In conclusion, IS inhibits Myf6/MRF4 and MYH2 expression during differentiation of muscle cells, which could lead to a defect in myotube structure. Through these new mechanisms, IS could participate in muscle atrophy observed in CKD.

The impact of dietary nutrient intake on gut microbiota in the progression and complications of chronic kidney disease.

Chronic kidney diseasehas been associated with changes in the function and composition of the gut microbiota. The ecosystem of the human gut consists of trillions of microorganisms forming an authentic metabolically active organ that is fueled by nutrients to produce bioactive compounds. These microbiota-derived metabolites may be protective for kidney function (e.g., short-chain fatty acids from fermentation of dietary fibers) or deleterious (e.g., gut-derived uremic toxins such as trimethylamine N-oxide, p-cresyl sulfate, and indoxyl sulfate from fermentation of amino acids). Although diet is the cornerstone of the management of the patient with chronic kidney disease, it remains a relatively underused component of the clinician's armamentarium. In this review, we describe the latest advances in understanding the diet-microbiota crosstalk in the uremic context and how this communication might contribute to chronic kidney disease progression and complications. We then discuss how this knowledge could be harnessed for personalized nutrition strategies to prevent patients with chronic kidney disease progressing tokidney failureand its detrimental consequences.

A prospective observational study for justification, safety, and efficacy of a third dose of mRNA vaccine in patients receiving maintenance hemodialysis.

The level of protection achieved by the standard two doses of COVID-19 mRNA vaccines in patients receiving maintenance hemodialysis (MHD) remains unclear. To study this we used the French Renal Epidemiology and Information Network (REIN) Registry to compare the incidence and severity of 1474 cases of COVID-19 diagnosed in patients receiving MHD after none, one or two doses of vaccine. Vaccination significantly reduce COVID-19 incidence and severity, but 11% of patients infected after two doses still died. Lack of vaccinal protection in patients naïve for SARS-CoV-2 could be due to defective Tfh response [38% of patients with negative spike-specific CD4+ T-cell interferon gamma release assay] and failure to generate viral neutralizing titers of anti-spike receptor binding domain (RBD) IgGs (63% of patients with titer at or under 997 BAU/ml, defining low/no responders) after two doses of vaccine. To improve protection, a third dose of vaccine was administered to 75 patients [57 low/no responders, 18 high responders after two doses] from the ROMANOV cohort that prospectively enrolled patients receiving MHD vaccinated with BNT162b2 (Pfizer). Tolerance to the third dose was excellent. High responders to two doses did not generate more anti-RBD IgGs after three doses but had more side effects. Importantly, 31 (54%) of low/no responders to two doses reached neutralizing titers of anti-RBD IgGs after three doses. A positive interferon gamma release assay and/or suboptimal titer of anti-RBD IgGs after two doses were the only predictive variables for response to three doses in multivariate analysis. Thus, the standard scheme of vaccination insufficiently protects patients receiving MHD. Anti-RBD IgG and specific CD4+ T-cell response after two doses can guide personalized administration of the third dose, which improves the humoral response of SARS-CoV-2-naïve patients receiving MHD.

3-methylhistidine and clinical outcomes in maintenance haemodialysis patients.

BACKGROUND: Chronic kidney disease is an important contributor to morbidity and mortality. 3-methylhistidine (3-MH) is the by-product of actin and myosin degradation reflecting skeletal muscle turnover. Markedly elevated 3-MH levels have been documented in uraemic patients, but the interpretation of high 3-MH concentration in maintenance haemodialysis (MHD) patients remains unclear. Indeed, it is not known whether elevated serum 3-MH levels are a marker of excessive muscle catabolism or a better lean tissue mass. Here, we evaluated the association between serum 3-MH levels and clinical outcomes in these patients. METHODS: Serum 3-MH concentration was measured by reverse-phase liquid chromatography/tandem mass spectrometry in a cohort of MHD patients. We analysed the relationships between various clinical/laboratory indices, lean tissue mass measured by bioimpedance spectroscopy, mortality and cardiovascular (CV) events. RESULTS: Serum 3-MH concentration was positively correlated with serum albumin, normalized protein catabolic rate (nPCR), simplified creatinine index (SCI) and lean tissue mass. Of 291 MHD patients, during a mean follow-up of 847 days, 91 patients died and 101 patients experienced a CV event. Survival was significantly better in patients with high 3-MH concentrations (P = .002). A higher level of 3-MH was also associated with a lower CV mortality and lower incidence of CV events (P = .015 and P < .001, respectively). Low serum 3-MH levels remained significantly associated with CV events but not with mortality after adjustment for demographic, metabolic and CV risk factors. CONCLUSION: Elevated serum 3-MH concentration appears to be a marker of better lean tissue mass and nutritional status. Low serum 3-MH is a robust and independent predictor of CV events in the MHD population.

Natriuretic Peptides as Predictors of Protein-Energy Wasting in Hemodialysis Population.

OBJECTIVE: Imbalance between anabolism and catabolism is linked to cachexia and protein-energy wasting (PEW), especially in frail populations such as patients with chronic kidney disease. PEW is responsible of poor outcomes with increased morbidity and mortality. Several causes are involved in PEW such as insulin resistance, acidosis, or hyperparathyroidism. Natriuretic peptides (NPs) have recently been described as activators of resting energy expenditure through the induction of browning of white adipose tissue in rodents with chronic kidney disease. The present study was therefore implemented to investigate whether NPs could be associated with PEW criteria and predict clinical outcomes. METHODS: We quantified serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) in a prospective cohort of 231 patients undergoing maintenance hemodialysis and atrial natriuretic peptide in a subgroup of 35 patients. Body composition parameters were measured with bioimpedance spectroscopy. RESULTS: NT-proBNP was inversely associated with serum albumin, prealbumin, and body mass index and, conversely, positively associated with age and C-reactive protein. NT-proBNP as well as atrial natriuretic peptide were significantly higher in patients with PEW criteria. NT-proBNP was negatively associated with body fat mass. In multiple linear regression, NT-proBNP remained associated with body mass index. Kaplan-Meier analysis revealed a significant correlation between serum NT-proBNP concentrations and all-cause mortality and cardiovascular events. This association remained significant after multivariable Cox regression models adjusted for demographic factors and cardiovascular risk factors. CONCLUSION: Accumulation of NPs seems to be associated with poor nutritional status and reduced survival among hemodialysis patients. Further studies are needed to confirm this association using resting energy expenditure measurement and adipose tissue biopsy.

The ROMANOV study found impaired humoral and cellular immune responses to SARS-CoV-2 mRNA vaccine in virus-unexposed patients receiving maintenance hemodialysis.

Patients on maintenance hemodialysis (MHD), which are at high risk of infection by SARS-CoV-2 virus and death due to COVID-19, have been prioritized for vaccination. However, because they were excluded from pivotal studies and have weakened immune responses, it is not known whether these patients are protected after the "standard" two doses of mRNA vaccines. To answer this, anti-spike receptor binding domain (RBD) IgG and interferon gamma-producing CD4+ and CD8+ specific-T cells were measured in the circulation 10-14 days after the second injection of BNT162b2 vaccine in 106 patients receiving MHD (14 with history of COVID-19) and compared to 30 healthy volunteers (four with history of COVID-19). After vaccination, most (72/80, 90%) patients receiving MHD naïve for the virus generated at least one type of immune effector, but their response was weaker and less complete than that of healthy volunteers. In multivariate analysis, hemodialysis and immunosuppressive therapy were significantly associated with absence of both anti-RBD IgGs and anti-spike CD8+ T cells. In contrast, previous history of COVID-19 in patients receiving MHD correlated with the generation of both types of immune effectors anti-RBD IgG and anti-spike CD8+ T cells at levels similar to healthy volunteers. Patients receiving MHD naïve for SARS-Cov-2 generate mitigated immune responses after two doses of mRNA vaccine. Thus, the good response to vaccine of patients receiving MHD with a history of COVID-19 suggest that these patients may benefit from a third vaccine injection.

Myostatin and muscle atrophy during chronic kidney disease.

Chronic kidney disease (CKD) patients often exhibit a low muscle mass and strength, leading to physical impairment and an increased mortality. Two major signalling pathways control protein synthesis, the insulin-like growth factor-1/Akt (IGF-1/Akt) pathway, acting as a positive regulator, and the myostatin (Mstn) pathway, acting as a negative regulator. Mstn, also known as the growth development factor-8 (GDF-8), is a member of the transforming growth factor-ß superfamily, which is secreted by mature muscle cells. Mstn inhibits satellite muscle cell proliferation and differentiation and induces a proteolytic phenotype of muscle cells by activating the ubiquitin-proteasome system. Recent advances have been made in the comprehension of the Mstn pathway disturbance and its role in muscle wasting during CKD. Most studies report higher Mstn concentrations in CKD and dialysis patients than in healthy subjects. Several factors increase Mstn production in uraemic conditions: low physical activity, chronic or acute inflammation and oxidative stress, uraemic toxins, angiotensin II, metabolic acidosis and glucocorticoids. Mstn seems to be only scarcely removed during haemodialysis or peritoneal dialysis, maybe because of its large molecule size in plasma where it is linked to its prodomain. In dialysis patients, Mstn has been proposed as a biomarker of muscle mass, muscle strength or physical performances, but more studies are needed in this field. This review outlines the interconnection between Mstn activation, muscle dysfunction and CKD. We discuss mechanisms of action and efficacy of pharmacological Mstn pathway inhibition that represents a promising treatment approach of striated muscle dysfunction. Many approaches and molecules are in development but until now, no study has proved a benefit in CKD.

Accumulation of natriuretic peptides is associated with protein energy wasting and activation of browning in white adipose tissue in chronic kidney disease.

Protein energy wasting is a common feature of patients with chronic kidney disease (CKD) and is associated with poor outcomes. Protein energy wasting and cachexia, a severe form of protein energy wasting, are characterized by increased resting energy expenditure but the underlying mechanisms are unclear. Browning corresponds to the activation of inducible brown adipocytes in white adipose tissue and occurs in states of cachexia associated with hypermetabolic disease such as cancer. Here we tested the hypothesis that CKD-associated protein energy wasting could result from browning activation as a direct effect of the uremic environment on adipocytes. In a murine model of CKD (5/6 nephrectomy), there was increased resting energy expenditure, expression of uncoupling protein 1 (a thermogenic protein uncoupling oxidative phosphorylation in mitochondria) and citrate synthase activity (a proxy of mitochondrial density in white adipose tissue). Mice with CKD also exhibited increased levels of atrial natriuretic peptide, a well known activator of browning. The incubation of primary adipose cells with plasma from patients receiving dialysis treatment and having signs of protein energy wasting led to an increased synthesis of uncoupling protein 1. Similarly, primary adipose cells exposed to atrial natriuretic peptide at concentrations relevant of CKD led to a significant increase of uncoupling protein 1 content. Thus, accumulation of cardiac natriuretic peptides during CKD could contribute to the browning of white adipose tissue and protein energy wasting.

Emerging role of myostatin and its inhibition in the setting of chronic kidney disease.

The past two decades have witnessed tremendous progress in our understanding of the mechanisms underlying wasting and cachexia in chronic kidney disease (CKD) and in other chronic illnesses, such as cancer and heart failure. In all these conditions wasting is an effect of the activation of protein degradation in muscle, a response that increases the risk of morbidity and mortality. Major recent advances in our knowledge on how CKD and inflammation affect cellular signaling include the identification of the myostatin (MSTN)/activin system, and its related transcriptional program that promotes protein degradation. In addition, the identification of the role of MSTN/activin in the vascular wall shows premise that its inhibition can better control or prevent some effects of CKD on vessels, such as accelerated atherosclerosis and vascular calcifications. In this review, we summarize the expanding role of MSTN activation in promoting muscle atrophy and the recent clinical studies that investigated the efficacy of MSTN/activin pathway antagonism in sarcopenic patients. Moreover, we also review the utility of MSTN inhibition in the experimental models of CKD and its potential advantages in CKD patients. Lessons learned from clinical studies on MSTN antagonism in sarcopenic patients tell us that the anabolic intervention is likely better if we use a block of the two ActRII receptors. At the same time, however, it is becoming clear that MSTN-targeted therapies should not be seen as a substitute for physical activity and nutritional supplementation which are mandatory to successfully manage patients with wasting.

The Role for Protein Restriction in Addition to Renin-Angiotensin-Aldosterone System Inhibitors in the Management of CKD.

In experimental studies a low-protein diet (LPD) and renin-angiotensin-aldosterone system (RAAS) inhibitors are both reported to slow the progression of chronic kidney disease (CKD) and reduce proteinuria. RAAS activity contributes to increased blood pressure, fluid retention, and positive sodium balance, but also to kidney damage by enhancing glomerular capillary filtration pressure and synthesis of profibrotic molecules such as transforming growth factor ß. It has been well established that an LPD decreases glomerular hyperfiltration and the generation of uremic toxins, as well as the burden of acid load, phosphorus, and sodium. In different animal CKD models, a significant reduction in proteinuria and glomerulosclerosis has been achieved when an RAAS inhibitor and LPD were combined. To date, high-quality intervention trials investigating this combined strategy are lacking. We summarize the experimental and clinical studies that have examined a potential additive action of these therapies on CKD progression. We outline potential mechanisms of action and additive efficacy of an LPD and RAAS inhibitors in CKD, with a particular emphasis on phosphate levels, uremic toxin production, acid load, and salt intake. Finally, although the evidence is inadequate to recommend combining RAAS inhibitors and an LPD to slow the progression of CKD, we provide a perspective to support a large-scale randomized clinical trial to study this combination.

Vegetarian diets and chronic kidney disease.

While dietary restriction of protein intake has long been proposed as a possible kidney-protective treatment, the effects of changes in the quality of ingested proteins on the prevalence and risk of progression of chronic kidney disease (CKD) have been scarcely studied; these two aspects are reviewed in the present article. The prevalence of hypertension, type 2 diabetes and metabolic syndrome, which are the main causes of CKD in Western countries, is lower in vegetarian populations. Moreover, there is a negative relationship between several components of plant-based diets and numerous factors related to CKD progression such as uraemic toxins, inflammation, oxidative stress, metabolic acidosis, phosphate load and insulin resistance. In fact, results from different studies seem to confirm a kidney-protective effect of plant-based diets in the primary prevention of CKD and the secondary prevention of CKD progression. Various studies have determined the nutritional safety of plant-based diets in CKD patients, despite the combination of a more or less severe dietary protein restriction. As observed in the healthy population, this dietary pattern is associated with a reduced risk of all-cause mortality in CKD patients. We propose that plant-based diets should be included as part of the clinical recommendations for both the prevention and management of CKD.

Serum levels of the adipokine zinc-alpha2-glycoprotein (ZAG) predict mortality in hemodialysis patients.

Wasting has been associated with increased cardiovascular and all-cause mortality in chronic kidney disease (CKD). We investigated whether serum zinc-alpha2-glycoprotein (ZAG), a potent cachectic and lipid-mobilizing factor that is increased in patients with CKD, predicts clinical outcomes in patients on chronic hemodialysis. We quantified serum ZAG at baseline in a prospective cohort of 252 patients undergoing maintenance hemodialysis. Serum ZAG concentrations were inversely associated with serum albumin, creatinine, and triglycerides and, conversely, positively associated with age. Although ZAG is strongly linked to protein energy wasting (PEW) in patients with cancer, higher ZAG concentrations were not associated with PEW in our cohort. During a mean study follow-up of 954 days, 49 patients died and 62 patients experienced a cardiovascular event. Kaplan-Meier analysis revealed a significant correlation between serum ZAG concentrations and all-cause mortality and cardiovascular events. In separate multivariable Cox regression models, serum ZAG concentrations remained significantly associated with all-cause mortality and cardiovascular events after adjustment for demographic factors (age, sex, and dialysis vintage), metabolic parameters (serum albumin, prealbumin, triglycerides, cholesterol, normalized protein catabolic rate, and body mass index), and cardiovascular risk factors (diabetes, dyslipidemia, history of cardiovascular disease, smoking, and diuretic use as a proxy of residual renal function). Thus, serum ZAG appears to be a strong and independent predictor of mortality and cardiovascular events in patients with end-stage renal disease. Further studies are necessary to confirm this association and to elucidate the underlying mechanisms.

Metabolic Abnormalities in Diabetes and Kidney Disease: Role of Uremic Toxins.

PURPOSE OF REVIEW: Chronic kidney disease (CKD) is characterized by the accumulation of uremic retention solutes (URS) and is associated with perturbations of glucose homeostasis even in absence of diabetes. The underlying mechanisms of insulin resistance, ß cell failure, and increase risk of diabetes in CKD, however, remain unclear. Metabolomic studies reported that some metabolites are similar in CKD and diabetic kidney disease (DKD) and contribute to the progression to end-stage renal disease. We attempted to discuss the mechanisms involved in the disruption of carbohydrate metabolism in CKD by focusing on the specific role of URS. RECENT FINDINGS: Recent clinical data have demonstrated a defect of insulin secretion in CKD. Several studies highlighted the direct role of some URS (urea, trimethylamine N-oxide (TMAO), p-cresyl sulfate, 3-carboxylic acid 4-methyl-5-propyl-2-furan propionic (CMPF)) in glucose homeostasis abnormalities and diabetes incidence. Gut dysbiosis has been identified as a potential contributor to diabetes and to the production of URS. The complex interplay between the gut microbiota, kidney, pancreas ß cell, and peripheral insulin target tissues has brought out new hypotheses for the pathogenesis of CKD and DKD. The characterization of intestinal microbiota and its associated metabolites are likely to fill fundamental knowledge gaps leading to innovative research, clinical trials, and new treatments for CKD and DKD.

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.