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.

[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.

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.

[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.

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.

[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.

[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.

Plasma and urinary amino acid metabolomic profiling in patients with different levels of kidney function.

BACKGROUND AND OBJECTIVES: Patients with CKD display altered plasma amino acid profiles. This study estimated the association between the estimated GFR and urinary and plasma amino acid profiles in CKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Urine and plasma samples were taken from 52 patients with different stages of CKD, and plasma samples only were taken from 25 patients on maintenance hemodialysis. Metabolic profiling was performed by liquid chromatography coupled with tandem mass spectrometry after phenylisothiocyanate derivatization. RESULTS: Most plasma amino acid concentrations were decreased in hemodialysis patients, whereas proline, citrulline, asparagine, asymmetric dimethylarginine, and hydroxykynurenine levels were increased (P<0.05). Both plasma levels and urinary excretion of citrulline were higher in the group of patients with advanced CKD (CKD stages 2 and 3 versus CKD stages 4 and 5; in plasma: 35.9±16.3 versus 61.8±23.6 µmol/L, P<0.01; in urine: 1.0±1.2 versus 7.1±14.3 µmol/mol creatinine, P<0.001). Plasma asymmetric dimethylarginine levels were higher in advanced CKD (CKD stages 2 and 3, 0.57±0.29; CKD stages 4 and 5, 1.02±0.48, P<0.001), whereas urinary excretion was lower (2.37±0.93 versus 1.51±1.43, P<0.001). Multivariate analyses adjusting on estimated GFR, serum albumin, proteinuria, and other covariates revealed associations between diabetes and plasma citrulline (P=0.02) and between serum sodium and plasma asymmetric dimethylarginine (P=0.03). Plasma tyrosine to phenylalanine and valine to glycine ratios were lower in advanced CKD stages (P<0.01). CONCLUSION: CKD patients have altered plasma and urinary amino acid profiles that are not corrected by dialysis. Depending on solutes, elevated plasma levels were associated with increased or decreased urinary excretion, depicting situations of uremic retention (asymmetric dimethylarginine) or systemic overproduction (citrulline). These results give some insight in the CKD-associated modifications of amino acid metabolism, which may help improve their handling.

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.

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.

[Ethnicity and vitamin D]. / Ethnicité et vitamine D.

Cohort studies, mainly US, show that vitamin D deficiency is more common in African-American population. Social and environmental factors play a role but the difference in skin color is essential. Despite low 25-hydroxyvitamin D concentrations, a lower risk of fragility or fracture exists in these populations. Vitamin D deficiency is a contributing factor in many chronic diseases. There is a relationship between vitamin D deficiencies, progression of chronic kidney disease and increased relative risk of mortality. If the ethnicity of patients is now taken into account to estimate renal function, probably specific recommendations for vitamin D deficiency are needed.

[Evolution of the diet from the paleolithic to today: progress or regress?]. / Évolution de l'alimentation du paléolithique à nos jours : progression ou régression ?

The changes in eating habits and decreased physical activity have been responsible for part of the high prevalence of chronic diseases such as hypertension or diabetes, currently observed in the so-called civilized societies. These diseases are less prevalent in previous civilizations and several decades of nutrition research have enabled better understanding of the eating habits of our ancestors, and have demonstrated the value of diet called "Mediterranean or Paleolithic". This review provides an update on the latest research. What dietary changes since the Paleolithic period, and finally how can we adapt our current diet? Several animal studies or human clinical demonstrate the value of historical research and nutrition.

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.

[Is there a place for the physical activity in the prevention of the fractures of chronic kidney disease patients?]. / Y a-t-il une place pour l'exercice physique dans la prévention des fractures non traumatiques de l'insuffisant rénal chronique ?

The risk of non-traumatic fractures is greatly increased in kidney disease patients and well demonstrated in dialysis patients. If osteoporosis plays a major role in the general population, in chronic kidney disease renal osteodystrophy is associated with neurological and muscular disorders, which probably worsen the risk. The decrease in physical activity is a factor contributing to the loss of bone mass and the initiation of a rehabilitation program improves the prognosis. Despite the association between chronic renal disease and sedentary lifestyle, the relationship between physical inactivity and bones in dialysis patients and the effect of increased activity programs, are not well documented in the literature.

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.

Long-term outcome on renal replacement therapy in patients who previously received a keto acid-supplemented very-low-protein diet.

BACKGROUND: The consequences of a supplemented very-low-protein diet remain a matter of debate with regard to patient outcome before or after the onset of renal replacement therapy. OBJECTIVE: We evaluated the long-term clinical outcome during maintenance dialysis and/or transplantation in patients who previously received a supplemented very-low-protein diet. DESIGN: We assessed the outcome of 203 patients who received a supplemented very-low-protein diet for >3 mo (inclusion period: 1985-2000) and started dialysis after a mean diet duration of 33.1 mo (4-230 mo). RESULTS: The survival rate in the whole cohort was 79% and 63% at 5 and 10 y, respectively. One hundred two patients continued with chronic dialysis during the entire follow-up, and 101 patients were grafted at least once. Patient outcomes were similar to those of the French Dialysis Registry patients for the dialysis group and similar to the 865 patients who were transplanted in Bordeaux during the same period for the transplant group. There was no correlation between death rate and duration of diet. CONCLUSIONS: The lack of correlation between death rate and duration of diet and the moderate mortality rate observed during the first 10 y of renal replacement therapy confirm that a supplemented very-low-protein diet has no detrimental effect on the outcome of patients with chronic kidney disease who receive renal replacement therapy.