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.

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.

Mediterranean diet as the diet of choice for patients with chronic kidney disease.

Traditional dietary management of chronic kidney disease (CKD) focuses on the quantity within the diet of energy and protein, and the restriction of single micronutrients, with little mention of dietary quality. Dietary patterns that are more plant-based, lower in meat (including processed meat), sodium and refined sugar, and have a higher content of grains and fibres are now included in multiple clinical guidelines for chronic disease prevention. The Mediterranean diet (MD) has been associated with reduced cardiovascular disease incidence in both observational and interventional studies. A wealth of evidence links MD with other beneficial effects on chronic diseases such as diabetes, obesity or cognitive health. This review examines each constituent of the classical MD and evaluates their suitability for the management of patients with CKD. We also evaluate the potential hyperkalaemia risk of increasing fruit and vegetable intake. Overall, a decrease in net endogenous acid production and increase in fibre may lead to a better control of metabolic acidosis. This, together with other putative favourable effects of MD on endothelial function, inflammation, lipid profile and blood pressure, provide mechanistic pathways to explain the observed reduced renal function decline and improved survival in CKD patients adhering to an MD.

Do ketoanalogues still have a role in delaying dialysis initiation in CKD predialysis patients?

Early versus later start of dialysis is still a matter of debate. Low-protein diets have been used for many decades to delay dialysis initiation. Protein-restricted diets (0.3-0.6 g protein/kg/day) supplemented with essential amino acids and ketoanalogues (sVLPD) can be offered, in association with pharmacological treatment, to motivated stage 4-5 chronic kidney disease (CKD) patients not having severe comorbid conditions; they probably represent 30-40% of the concerned population. A satisfactory adherence to such dietary prescription is observed in approximately 50% of the patients. While the results of the studies on the effects of this diet on the rate of progression of renal failure remain inconclusive, they are highly significant when initiation of dialysis is the primary outcome. The correction of uremic symptoms allows for initiation of dialysis treatment at a level of residual renal function lower than that usually recommended. Most of the CKD-associated complications of cardiovascular and metabolic origin, which hamper both lifespan and quality of life, are positively influenced by the diet. Lastly, with regular monitoring jointly assumed by physicians and dietitians, nutritional status is well preserved as confirmed by a very low mortality rate and by the absence of detrimental effect on the long-term outcome of patients once renal replacement therapy is initiated. On account of its feasibility, efficacy and safety, sVLPD deserves a place in the management of selected patients to safely delay the time needed for dialysis.

Vegetarianism: advantages and drawbacks in patients with chronic kidney diseases.

Vegetarian diet is a very old practice that is liable to confer some health benefits. Recent studies have demonstrated that modification of the dietary pattern with a reduction of animal protein intake and increased consumption of plant-based foods could influence cardiovascular risk profile and mortality rate. Moreover, phosphate bioavailability from plant proteins is reduced. These statements could lead to some benefits for chronic kidney disease (CKD) patients. This review summarizes the characteristics and benefits of vegetarian diets in the general population and the potential beneficial effects of such a diet on phosphate balance, insulin sensitivity, and the control of metabolic acidosis in CKD patients. Potential drawbacks exist when a vegetarian diet is associated with protein intake that is too restrictive and/or insufficient energy intake, justifying an early and regular nutritional follow-up jointly assumed by a nephrologist and a renal dietitian.

Protein-restricted diets plus keto/amino acids--a valid therapeutic approach for chronic kidney disease patients.

Chronic kidney disease (CKD) is increasingly common, and there is an increasing awareness that every strategy should be used to avoid complications of CKD. Restriction of dietary protein intake has been a relevant part of the management of CKD for more than 100 years, but even today, the principal goal of protein-restricted regimens is to decrease the accumulation of nitrogen waste products, hydrogen ions, phosphates, and inorganic ions while maintaining an adequate nutritional status to avoid secondary problems such as metabolic acidosis, bone disease, and insulin resistance, as well as proteinuria and deterioration of renal function. This supplement focuses on recent experimental and clinical findings related to an optimized dietary management of predialysis, dialysis, and transplanted patients as an important aspect of patient care. Nutritional treatment strategies are linked toward ameliorating metabolic and endocrine disturbances, improving/maintaining nutritional status, as well as delaying the renal replacement initiation and improving outcomes in CKD patients. A final consensus states that dietary manipulations should be considered as one of the main approaches in the management program of CKD patients and that a reasonable number of patients with moderate or severe CKD benefit from dietary protein/phosphorus restriction.

Benefits in nutritional interventions in patients with CKD stage 3-4.

The efficacy and safety of protein-restricted diets in chronic kidney disease (CKD) is still a matter of debate. However, several studies have clearly demonstrated the beneficial effects of such diets on the outcome of patients with stage 3-4 CKD. This point has been confirmed by 4 recent studies. In 2009, a meta-analysis showed that protein restriction significantly delayed the time to renal death with a substantial economic benefit for the health service. Although toxicity of urea has since long been considered as negligible, an experimental model in rats has shown a direct role of urea in the development of oxidative stress and insulin resistance, which are among the leading mechanisms of cardiovascular complications in CKD. These latter results confirm an interest in studying reduction in blood urea levels as observed in patients kept on a low-protein diet (LPD) or on a supplemented very-low protein diet (SVLPD). A reduction in proteinuria, which is associated to a LPD, has the following prognostic value: the more important the reduction in proteinuria, slower is the decline in renal function. This effect, which is additive to the one of an angiotensin-converting enzyme inhibitor (ACEI), is higher with SVLPD than with conventional LPD. Safety of a reduced protein intake has been confirmed by the study on the long-term outcomes (11 years) of patients already on SVLPD. The difference between these results and those from the extended follow-up of the modification of diet in renal disease (MDRD) study, in which no recommendations were made after the completion of the trial, confirms the importance of a close nutritional survey of patients with CKD who are put on a protein-restricted diet.

[Hygieno-dietetic recommendations in the prevention of accumulation of advanced glycation products]. / Place des recommandations hygiéno-diététiques dans la prévention de l'accumulation des produits de glycation avancée.

Advanced glycation products are proteins whose structural and functional properties have been modified by a process of oxidative glycation. The accumulation of advanced glycation products in most tissues and the oxidative stress and inflammatory reactions that accompany it, account for the multi-systemic impairment observed particularly in the elderly, diabetics and in chronic renal failure. The advanced glycation products endogenous production is continuous, related to oxidative stress, but the most important source of advanced glycation products is exogenous, mainly of food origin. Exogenous advanced glycation products are developed during the preparation of food and beverages. The advanced glycation products content is higher for animal foods, but it is mainly the preparation and cooking methods that play a decisive role. Dietary advice is based on the selection of foods and the choice of methods of preparation. Several randomized controlled studies have confirmed the favorable effect of these recommendations on serum advanced glycation products concentrations. In humans, as in animals, regular physical activity also results in a reduction of serum and tissue concentrations of advanced glycation products. There is a need for prospective clinical study to confirm the effects of hygienic and dietary recommendations that have only been appreciated, so far, on biological markers.

[Insulin resistance and chronic kidney disease]. / Insulinorésistance et insuffisance rénale chronique.

Insulin resistance is characterized by a lesser biological response to a standard level of insulin. Currently the most popular method used to quantify insulin resistance is the homeostasis model of assessment of insulin resistance (HOMA-IR). A state of insulin resistance is present from the early stages of chronic renal failure (CRF). Defects in glucose utilization observed during CRF concern both nonoxidative metabolism (storage in the form of glycogen) and oxidative metabolism. Resistance to the action of insulin during the CRF concerns traditionally peripheral tissues, particularly skeletal muscle. The mechanisms are multiple: retention of nitrogenous waste, metabolic acidosis, hypovitaminosis D or inflammation. The insulin resistance is associated with a disturbance of endothelial function and is involved in increased vascular risk and aggravates muscle metabolic disorders. Recent studies demonstrated a link between insulin resistance and progression of renal failure. Physical activity is known to improve insulin resistance status, the correction of metabolic abnormalities and attempts to reduce the inflammatory syndrome are potential targets of treatment. Thiazolidinedione have recently shown their interest, but in CRF the balance between risk and benefit remains to be evaluated.

[Dietary acid load: A novel target for the nephrologist?] / La charge acide d'origine alimentaire : une nouvelle cible pour le néphrologue ?

The acid production of endogenous origin depends mainly on the metabolism of the food and varies with the nature of these. Of the order of 1mEq/kg/day for contemporary food in industrialized countries, it is reduced by more than one third among vegetarians and close to neutrality among vegans. The dietary acid load is eliminated by the normal kidneys, thus maintaining the acid-base equilibrium. In the setting of CKD, it will overflow the capacities of the nephrons, generating a retention of H+ ions, promoting subclinical acidosis. This tissue retention of H+ ions was confirmed by direct techniques in animal models and indirect techniques in humans. The systemic retention of H+ ions and the accompanying compensatory mechanisms have negative consequences on bone tissue, skeletal muscle, cardiovascular risk and renal function. In the animal, the substitution of casein (acid) by soy (alkaline) prevents metabolic acidosis and slows the progression of renal insufficiency. In man, various prospective studies have confirmed that the risk of renal insufficiency was positively correlated with the dietary acid load. Conversely, bicarbonate supplementation and/or a diet enriched with fruits and vegetables, have a favorable effect on renal insufficiency, including in subjects with normal bicarbonate. These results lead to reconsider the K/DOQI recommendations to correct acidosis when the bicarbonate level falls below 22mEq/L, since tissue retention of H+ ions and its negative consequences appear at higher or even normal levels of bicarbonates.

Restricted protein diet is associated with decrease in proteinuria: consequences on the progression of renal failure.

OBJECTIVE: Reduction of proteinuria is associated with a slower progression of renal failure. We questioned whether the change in proteinuria in response to a supplemented very low protein diet (SVLPD), which is known to reduce proteinuria, could function as a marker of the potential renoprotective effect of an SVLPD. DESIGN AND PATIENTS: In the 220 consecutive patients of our previously published cohort, the glomerular filtration rate (GFR) was assessed every 3 months using the (51)Cr-EDTA method. Seventy-eight patients (mean age 52 +/- 17 years, body mass index 23 +/- 3 kg/m(2), GFR 15 +/- 6 mL/min) exhibited a proteinuria more than 1 g per day at the start of the regimen. Mean protein intake assessed by urinary nitrogen appearance was 0.42 +/- 0.24 g/kg per day at 4 months. The median follow-up was 24 months. RESULTS: Proteinuria decreased significantly after patients were treated with an SVLPD. The maximum mean percent reduction was attained at 3 months (47% +/- 27%), was not influenced by the levels of baseline proteinuria, and was similar in patients receiving or not receiving angiotensin-converting enzyme inhibition at the start of the study. The percent reduction and the residual proteinuria at 3 months predicted the rate of the later GFR decline. GFR decline was significantly lower in patients whose reduction in proteinuria at 3 months was higher than 50% (0.42 +/- 0.37 mL/min/mo vs. 0.10 +/- 0.15 mL/min/mo and 1.0 +/- 0.6 mL/min/mo vs. 0.15 +/- 0.19 mL/min/mo, P < .001 in patients with proteinuria higher or lesser than 3 g/d at start, respectively). CONCLUSION: These results do not differ from those reported with therapies antagonizing angiotensin II formation and/or activity aiming at reducing proteinuria in chronic renal diseases.

Evaluation of nutritional status in patients with kidney disease: usefulness of dietary recall.

BACKGROUND: Three-day food recall and normalized protein nitrogen appearance calculation from pre- and postdialysis plasma urea are the most commonly used techniques to assess nutritional intake, but a 7-day dietary recall is probably more accurate to approach dietary intake in clinical practice. METHODS: A total of 99 hemodialyzed patients from two units were analyzed in a 7-day dietary record with a large range of age and without having any signs of malnutrition. Dietary protein intake was estimated from the recall and calculated (normalized protein catabolic rate) from urea kinetic modeling. Calorie intake and quality and repartition of nutrients were estimated from diaries. RESULTS: Repartition of nutrients was close to that of a reference population except for a lower glucidic contribution (glucide 47%, lipid 36%, protein 16%). Normalized protein catabolic rate and dietary protein intake were well correlated (R2 = 0.4), but a large variability existed from day to day, according to age (older patients are less variable) and day of dialysis (long or short interval). CONCLUSION: A large variation in alimentary intake exists from patient to patient and day to day. A 7-day evaluation of nutrient intake, dialysis adequacy, and nutritional parameters seems to be a good solution to guide dietetic counseling.

Eleven reasons to control the protein intake of patients with chronic kidney disease.

For many years patients with chronic kidney disease have been advised to control the protein content of their diet. This advice has been given on the basis of a number of reported metabolic effects of lowering protein intake, such as lowering serum urea nitrogen levels, improving phosphocalcic metabolism and insulin resistance and, more recently, ameliorating proteinuria (independent of antiproteinuric medications). The effects on the progression of kidney disease, although spectacular in experimental studies, have been less convincing in humans. It is possible that flawed design of clinical trials is responsible for this discrepancy. In this Review, we comment on experimental findings that indicate that limiting protein intake protects the kidney and ameliorates uremic symptoms, outline how the body adapts to a reduction in protein intake, and describe the metabolic benefits to the patient. We then review the evidence from randomized controlled trials and meta-analyses that pertains to the effects of low-protein diets in adults with chronic kidney disease.

[Common therapeutic approaches of sarcopenia in the elderly and uremic myopathy]. / Approches thérapeutiques communes de la sarcopénie du sujet âgé et de la myopathie urémique.

The gradual loss of weight and function of muscle in patients with chronic kidney disease as in the elderly impacts the quality of life. Early management should help slow the functional limitation. Physical activity is the first therapy to propose that ensures stability of muscle mass and improved function. Resistance training programs have proven effective but are not yet widely available in nephrology units. The nutritional management should not be forgotten because there is a resistance to anabolism and protein intake should be involved in physical activity program. Associated treatments should not be neglected: vitamin D, anti-inflammatory, androgens. Some are still under evaluation. Therapeutic option, tomorrow, could be anti-myostatin antibodies and glitazones.

Long-term evolution of body composition after renal transplantation: 5-year survey.

BACKGROUND: Thanks to advancements in immunosuppression, patients are living longer with kidney transplants, and nonimmunologic factors (particularly nutritional) have become a major source of morbidity and mortality after successful kidney transplantation (KTx). In this current study, we have prospectively assessed, in a cohort of kidney transplant recipients (KTR), the course of some nonimmunologic factors liable to hinder the long-term outcome of KTR. METHODS: Forty-four consecutive KTR with stable functioning grafts received dietary recommendations and were on the lowest effective dose of steroids. Biochemical nutritional markers, C-reactive protein, lipid profile, and body composition determined by dual-energy X-ray absorptiometry were studied over the first year, 2 years, and 5 years after KTx. RESULTS: No patients died during the follow-up. All patients but 2 were considered normotensive. Clinical diabetes developed in 3 patients. Visceral proteins stabilized at a normal range after the first year. Most of the patients normalized their inflammatory status. A significant improvement in lipid profile was observed. Female patients had a significant increase of weight (13.5%), mainly because of an increase in fat mass: 3.4 kg (19.4%) at 1 year and 5.6 kg (29.7%) at 2 years. In male patients, body composition remained stable and close to baseline values. The evolution of bone mass varied according to gender, total corticoid doses, and calcineurin inhibitors. Patients on low doses of steroids normalized their Z-score over the 5-year period. The increase in bone mass (paired t-test, P = .006) was only significant in patients treated with tacrolimus (analysis of variance for repeated measures, P < .001). CONCLUSIONS: Simple measures and dietary intervention to prevent or correct nonimmunologic disorders should permit improvement of long-term morbidity and mortality of KTR without compromising the functional outcome of their transplant.

[Place of dietary protein restriction in the treatment of diabetic nephropathy]. / Néphropathie diabétique et restriction protidique.

The number of individuals with diabetes is rapidly growing worldwide, and in most countries, diabetic nephropathy has become the most important cause of ESRD. Although excessive protein intake may negatively influence the progression of renal disease, diabetics are rather reluctant to restrict their protein intake. However, in diabetic patients with renal failure, dietary protein restriction seems to have a beneficial effect on the course of the nephropathy without untoward effect on nutritional status. Moreover, the reduction in protein intake improves insulin sensitivity and has beneficial influences on different steps of carbohydrate metabolism. Dietary protein restriction should be considered as a safe therapy and deserves to be associated with the most important aspects of the medical management i.e. glycemic control and blood pressure control.

[Sarcopenia or uremic myopathy in CKD patients]. / Sarcopénie et myopathie urémique: similitudes et différences.

Often underestimated or misunderstood in chronic renal failure (CRF), muscle wasting is nevertheless common and concerns about 50% of dialysis patients. The consequences of this myopathy on quality of life and outcomes of patients are unfavorable, identical to those observed in sarcopenia in elderly subjects with sarcopenia. The similarities between the two situations also concern the symptoms, the underlying muscle damages and the pathogenic mechanisms and may be partly explained by the frequently high age of ESRD patients. Skeletal muscle involvement should be systematically investigated in the IRC patient as in the elderly with sarcopenia to propose as early as possible a treatment of which physical activity and nutritional interventions are the mainstay.

Dialyzer membrane permeability and survival in hemodialysis patients.

BACKGROUND: We previously showed that nutritional protein concentrations were predictive of outcome, whereas variables reflecting body composition and dialysis dose were not, in a 30-month prospective follow-up of 1,610 hemodialysis patients. Information on dialysis membrane and erythropoietin use had to be evaluated in an additional follow-up. METHODS: A subset of 650 patients from the initial cohort of 1,610 was analyzed for survival in a 2-year extension of follow-up. Detailed data were collected: demographics; cause of renal failure; time on dialysis therapy; type of membrane; erythropoietin treatment; body mass index (BMI); predialysis albumin, prealbumin, and bicarbonate levels; and outcome. Normalized protein catabolic rate (nPCR), dialysis adequacy, and lean body mass were computed from predialysis and postdialysis urea and creatinine values. RESULTS: Patient characteristics were age of 61 +/- 16 years, 58% men, BMI of 22.7 +/- 4.4 kg/m2 , time on dialysis therapy of 102 +/- 73 months, and 8.8% had diabetes. Dialysis parameters were duration of 247 +/- 31 minutes, Kt/V of 1.4 +/- 0.3, and nPCR of 1.2 +/- 0.3 g/kg/d. Albumin level was 3.73 +/- 0.53 g/dL (37.3 +/- 5.3 g/L), and prealbumin level was 31 +/- 8 mg/dL. The survival rate was 78.7% after 2 years. Survival was influenced by age, presence of diabetes, use of high-flux membrane, and serum albumin level, but not other variables, including Kt/V and prealbumin level. Two-year variations in values for urea, creatinine, and weight were predictive of survival in univariate, but not multivariate, analyses. CONCLUSION: In patients on dialysis therapy for a long period, better survival was observed when high-flux dialysis membranes were used.