Reducing the Risk of Stroke in Patients with Impaired Renal Function: Nutritional Issues.

Patients with renal failure have extremely high cardiovascular risk; in dialysis patients the risk of stroke is increased approximately 10-fold over that in the general population. Reasons include not only a high prevalence of traditional risk factors such as diabetes, hypertension and dyslipidemia, but also the accumulation of toxic substances that are eliminated by the kidneys, so have very high levels in patients with renal failure. These include plasma total homocysteine, asymmetric dimethylarginine, thiocyanate, and toxic products of the intestinal microbiome (Gut-Derived Uremic Toxins; GDUT), which include trimethylamine N- oxide (TMAO), produced from phosphatidylcholine (largely from egg yolk) and carnitine (largely from red meat). Other GDUT are produced from amino acids, largely from meat consumption. Deficiency of vitamin B12 is very common, raises plasma tHcy, and is easily treated. However, cyanocobalamin is toxic in patients with renal failure. To reduce the risk of stroke in renal failure it is important to limit the intake of meat, avoid egg yolk, and use methylcobalamin instead of cyanocobalamin, in addition to folic acid.

Effect of caloric restriction on phosphate metabolism and uremic vascular calcification.

Caloric restriction (CR) is known to have multiple beneficial effects on health and longevity. To study the effect of CR on phosphorus metabolism and vascular calcification (VC), rats were fed normal or restricted calories (67% of normal). The phosphorus content of the diets was adjusted to provide equal phosphorus intake independent of the calories ingested. After 50 days of CR, rats had negative phosphorus balance, lower plasma phosphorus, glucose, triglycerides, and leptin, and higher adiponectin than rats fed normal calories. Uremia was induced by 5/6 nephrectomy (Nx). After Nx, rats were treated with calcitriol (80 ng/kg ip every other day) and high-phosphorus diets (1.2% and 1.8%). No differences in aortic calcium content were observed between rats that ate normal or restricted calories before Nx in either rats that received 1.2% phosphorus (11.5 ± 1.7 vs. 10.9 ± 2.1 mg/g tissue) or in rats that received 1.8% phosphorus (12.5 ± 2.3 vs. 12.0 ± 2.9 mg/g of tissue). However, mortality was significantly increased in rats subjected to CR before Nx in both the 1.2% phosphorus groups (75% vs. 25%, P = 0.019) and 1.8% phosphorus groups (100% vs. 45%, P < 0.001). After calcitriol administration was stopped and phosphorus intake was normalized, VC regressed rapidly, but no significant differences in aortic calcium were detected between rats that ate normal or restricted calories during the regression phase (5.7 ± 2.7 and 5.2 ± 1.5 mg/g tissue). In conclusion, CR did not prevent or ameliorate VC and increased mortality in uremic rats.

Vegetarian diet may ameliorate uremic pruritus in hemodialysis patients.

OBJECTIVES: Systemic inflammation has been reported to be associated with uremic pruritus (UP). Although a vegetarian diet can reduce systemic inflammation in hemodialysis patients, the effect of vegetarian diet on UP is not clear. The purpose of the study was to know the possible effects of vegetarian diet on UP. METHODS: A cross-sectional study was done to compare the severity of UP and blood levels of systemic inflammatory markers between vegetarian and non-vegetarian hemodialysis patients. Six non-vegetarian patients with uremic pruritus changed their non-vegetarian diet to vegetarian diet for 2 months. Visual Analogue Scale (VAS) and pruritus score (PS) were used to measure the UP severity. The serum high-sensitivity C-reactive protein (hs-CRP), and interleukin-2 (IL-2) were used as markers of inflammation. RESULTS: Both the median VAS scores (p = .043) and the median PS scores (p < .001) were lower in the Vegetarian than in the non-vegetarian group. The median values of hs-CRP in Vegetarian were lower than that for the non-vegetarian (p = .020). The median value of IL-2 was also lower in Vegetarian than that of the non-vegetarian (p = .016). There were 6 non-vegetarian patients shift to vegetarian for 2 months. The pruritus score improved and IL-2 level decreased after change to vegetarian diet. CONCLUSION: We concluded that vegetarian diet might be associated with the amelioration of the uremic pruritus severity in hemodialysis patients.

Dietary magnesium supplementation prevents and reverses vascular and soft tissue calcifications in uremic rats.

Although magnesium has been shown to prevent vascular calcification in vitro, controlled in vivo studies in uremic animal models are limited. To determine whether dietary magnesium supplementation protects against the development of vascular calcification, 5/6 nephrectomized Wistar rats were fed diets with different magnesium content increasing from 0.1 to 1.1%. In one study we analyzed bone specimens from rats fed 0.1%, 0.3%, and 0.6% magnesium diets, and in another study we evaluated the effect of intraperitoneal magnesium on vascular calcification in 5/6 nephrectomized rats. The effects of magnesium on established vascular calcification were also evaluated in uremic rats fed on diets with either normal (0.1%) or moderately increased magnesium (0.6%) content. The increase in dietary magnesium resulted in a marked reduction in vascular calcification, together with improved mineral metabolism and renal function. Moderately elevated dietary magnesium (0.3%), but not high dietary magnesium (0.6%), improved bone homeostasis as compared to basal dietary magnesium (0.1%). Results of our study also suggested that the protective effect of magnesium on vascular calcification was not limited to its action as an intestinal phosphate binder since magnesium administered intraperitoneally also decreased vascular calcification. Oral magnesium supplementation also reduced blood pressure in uremic rats, and in vitro medium magnesium decreased BMP-2 and p65-NF-κB in TNF-α-treated human umbilical vein endothelial cells. Finally, in uremic rats with established vascular calcification, increasing dietary magnesium from 0.1% magnesium to 0.6% reduced the mortality rate from 52% to 28%, which was associated with reduced vascular calcification. Thus, increasing dietary magnesium reduced both vascular calcification and mortality in uremic rats.

Low-protein diet supplemented with ketoacids ameliorates proteinuria in 3/4 nephrectomised rats by directly inhibiting the intrarenal renin-angiotensin system.

Low-protein diet plus ketoacids (LPD+KA) has been reported to decrease proteinuria in patients with chronic kidney diseases (CKD). However, the mechanisms have not been clarified. As over-activation of intrarenal renin-angiotensin system (RAS) has been shown to play a key role in the progression of CKD, the current study was performed to investigate the direct effects of LPD+KA on intrarenal RAS, independently of renal haemodynamics. In this study, 3/4 subtotal renal ablated rats were fed 18 % normal-protein diet (Nx-NPD), 6 % low-protein diet (Nx-LPD) or 5 % low-protein diet plus 1 % ketoacids (Nx-LPD+KA) for 12 weeks. Sham-operated rats fed NPD served as controls. The level of proteinuria and expression of renin, angiotensin II (AngII) and its type 1 receptors (AT1R) in the renal cortex were markedly higher in Nx-NPD group than in the sham group. LPD+KA significantly decreased the proteinuria and inhibited intrarenal RAS activation. To exclude renal haemodynamic impact on intrarenal RAS, the serum samples derived from the different groups were added to the culture medium of mesangial cells. It showed that the serum from Nx-NPD directly induced higher expression of AngII, AT1R, fibronectin and transforming growth factor-ß1 in the mesangial cells than in the control group. Nx-LPD+KA serum significantly inhibited these abnormalities. Then, proteomics and biochemical detection suggested that the mechanisms underlying these beneficial effects of LPD+KA might be amelioration of the nutritional metabolic disorders and oxidative stress. In conclusion, LPD+KA could directly inhibit the intrarenal RAS activation, independently of renal haemodynamics, thus attenuating the proteinuria in CKD rats.

Dietary L-lysine prevents arterial calcification in adenine-induced uremic rats.

Vascular calcification (VC) is a life-threatening complication of CKD. Severe protein restriction causes a shortage of essential amino acids, and exacerbates VC in rats. Therefore, we investigated the effects of dietary l-lysine, the first-limiting amino acid of cereal grains, on VC. Male Sprague-Dawley rats at age 13 weeks were divided randomly into four groups: low-protein (LP) diet (group LP), LP diet+adenine (group Ade), LP diet+adenine+glycine (group Gly) as a control amino acid group, and LP diet+adenine+l-lysine·HCl (group Lys). At age 18 weeks, group LP had no VC, whereas groups Ade and Gly had comparable levels of severe VC. l-Lysine supplementation almost completely ameliorated VC. Physical parameters and serum creatinine, urea nitrogen, and phosphate did not differ among groups Ade, Gly, and Lys. Notably, serum calcium in group Lys was slightly but significantly higher than in groups Ade and Gly. Dietary l-lysine strongly suppressed plasma intact parathyroid hormone in adenine rats and supported a proper bone-vascular axis. The conserved orientation of the femoral apatite in group Lys also evidenced the bone-protective effects of l-lysine. Dietary l-lysine elevated plasma alanine, proline, arginine, and homoarginine but not lysine. Analyses in vitro demonstrated that alanine and proline inhibit apoptosis of cultured vascular smooth muscle cells, and that arginine and homoarginine attenuate mineral precipitations in a supersaturated calcium/phosphate solution. In conclusion, dietary supplementation of l-lysine ameliorated VC by modifying key pathways that exacerbate VC.

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.

Dietary Fibre Intake Is Associated with Serum Levels of Uraemic Toxins in Children with Chronic Kidney Disease.

Imbalanced colonic microbial metabolism plays a pivotal role in generating protein-bound uraemic toxins (PBUTs), which accumulate with deteriorating kidney function and contribute to the uraemic burden of children with chronic kidney disease (CKD). Dietary choices impact the gut microbiome and metabolism. The aim of this study was to investigate the relation between dietary fibre and gut-derived PBUTs in paediatric CKD. Sixty-one (44 male) CKD children (9 ± 5 years) were prospectively followed for two years. Dietary fibre intake was evaluated by either 24-h recalls (73%) or 3-day food records (27%) at the same time of blood sampling for assessment of total and free serum levels of different PBUTs using liquid chromatography. We used linear mixed models to assess associations between fibre intake and PBUT levels. We found an inverse association between increase in fibre consumption (g/day) and serum concentrations of free indoxyl sulfate (-3.1% (-5.9%; -0.3%) (p = 0.035)), free p-cresyl sulfate (-2.5% (-4.7%; -0.3%) (p = 0.034)), total indole acetic acid (IAA) (-1.6% (-3.0%; -0.3%) (p = 0.020)), free IAA (-6.6% (-9.3%; -3.7%) (p < 0.001)), total serum p-cresyl glucuronide (pCG) (-3.0% (-5.6%; -0.5%) (p = 0.021)) and free pCG levels (-3.3% (-5.8%; -0.8%) (p = 0.010)). The observed associations between dietary fibre intake and the investigated PBUTs highlight potential benefits of fibre intake for the paediatric CKD population. The present observational findings should inform and guide adaptations of dietary prescriptions in children with CKD.

To eat or not to eat: dietary fat in uremia is the question.

Although a diet low in protein is well known to reduce the risk of progression in patients with chronic kidney disease (CKD), the impact of dietary fat content and fat quality has largely been ignored. As a reduced protein intake results in an obligatory reduction in energy intake, and as CKD patients often suffer from energy malnutrition, this issue deserves greater attention. The present review aims to summarize what is currently known about dietary fat intake in CKD and suggests areas for further study. We conclude that although overweight per se is an important risk factor for the development of CKD, the role of obesity as a risk factor for complications in manifest CKD remains unclear. Current data support a balanced increase in dietary fat intake in patients with CKD to compensate for reduced energy intake in protein-restricted diets and anorexic patients. However, patients who are obese should be encouraged to lose weight while maintaining or, preferably, increasing muscle mass.

Nutritional intervention in uremia--myth or reality?

Nutritional intervention in uremia, specifically the restricted protein diet, has been under debate for decades. The results of various clinical trials have not been concordant, as some studies have reported positive effects of the low-protein diets, whereas others have shown no benefit. Recently published data show that the restricted protein diets seem to be effective and safe in ameliorating nitrogen waste products retention and the disturbances in acid-base and calcium-phosphorus metabolism, and in delaying the initiation of renal replacement therapy (RRT), without any deleterious effect on the nutritional status of patients with chronic kidney disease. The nutritional support and particularly the supplemented very low protein diet could be a new link to the RRT-integrated care model. A possible delay in RRT initiation through nutrition could have a major economic effect, particularly in developing countries, where the dialysis facilities still do not meet the requirements. However, a careful selection of motivated patients who could benefit from such a diet, closer nutritional monitoring, and dietary counseling are required.

Uremic Sarcopenia: Clinical Evidence and Basic Experimental Approach.

Sustained physical activity extends healthy life years while a lower activity due to sarcopenia can reduce them. Sarcopenia is defined as a decrease in skeletal muscle mass and strength due not only to aging, but also from a variety of debilitating chronic illnesses such as cancer and heart failure. Patients with chronic kidney disease (CKD), who tend to be cachexic and in frail health, may develop uremic sarcopenia or uremic myopathy due to an imbalance between muscle protein synthesis and catabolism. Here, we review clinical evidence indicating reduced physical activity as renal function deteriorates and explore evidence-supported therapeutic options focusing on nutrition and physical training. In addition, although sarcopenia is a clinical concept and difficult to recapitulate in basic research, several in vivo approaches have been attempted, such as rodent subtotal nephrectomy representing both renal dysfunction and muscle weakness. This review highlights molecular mechanisms and promising interventions for uremic sarcopenia that were revealed through basic research. Extensive study is still needed to cast light on the many aspects of locomotive organ impairments in CKD and explore the ways that diet and exercise therapies can improve both outcomes and quality of life at every level.

Microbiota issue in CKD: how promising are gut-targeted approaches?

In chronic kidney disease (CKD), the progressive decline in the renal excretory function leads to accumulation of urea and toxins in the blood. The CKD-associated dysbiosis of gut microbiota further contributes to uremia by increasing intestinal toxins production. Gut microbiota is involved in a complex network of human organs, mediated by microbial metabolites: in CKD, gut-heart and gut-brain axes may have a role in increased cardiovascular risk and neuropsychiatric disorders. While the cardiovascular toxicity of some microbial molecules is well known, their presumptive neurotoxicity needs to be confirmed by specific studies. In this review, we describe gut-heart and gut-brain axes in CKD, with an overview of the experimental and human studies characterizing CKD-associated gut microbiota, and we discuss the benefits coming from new approaches aimed at gut manipulation. Microbiota metabolism is emerging as a modifiable non-traditional risk factor in nephrology. In order to take advantage of this issue, it is necessary to consider the microbiota manipulation as part of the nutritional management of CKD. Integrating the low-protein nutritional approach with prebiotic, probiotic and synbiotic supplementation is a promising tool to control disease progression and comorbidities, though an extensive validation in large-scale clinical trials is still required.

How to manage elderly patients with chronic renal failure: conservative management versus dialysis.

Over the past decade the number of elderly patients reaching end-stage renal disease has more than doubled. A fundamental medical decision that nephrologists commonly have to make is when to start dialytic treatment in elderly patients. Evidence is needed to inform about decision-making for or against dialysis, in particular in those patients frequently affected by multiple comorbidities for which dialysis may not increase survival. In fact, this decision affects quality of life, incurs significant financial costs, and finally mandates use of precious dialysis resources. The negative consequence of initiating dialysis in this group of patients can be deleterious as elderly people are sensitive to lifestyle changes. Furthermore, among dialysis patients, the elderly suffer the highest overall hospitalization and complication rates and most truncated life expectancy on dialysis of any age group. Studies of the factors that affect outcomes in elderly patients on dialysis, or the possibility in postponing in a safe way the start of a dialytic treatment, were lacking until recent years. Recently in the literature, papers have been published that address these questions: the effects of dialysis on morbidity and mortality in elderly patients and the use of a supplemented very low protein diet (sVLPD) in postponing the start of dialysis in elderly. The first study demonstrated that, although dialysis is generally associated with longer survival in patients aged >75 years, those with multiple comorbidities, ischemic heart disease in particular, do not survive longer than those treated conservatively. The second one is a randomized controlled study that compared a sVLPD with dialysis in 112 non-diabetic patients aged >70 years. Survival was not different between the two groups and the number of hospitalizations and days spent in hospital were significantly lower in those on a sVLPD. These studies add to the limited evidence that is currently available to inform elderly patients, their carers and their physicians about the risk and the benefit of dialysis.

Back to the future: restricted protein intake for conservative management of CKD, triple goals of renoprotection, uremia mitigation, and nutritional health.

Lowering dietary protein intake (DPI) to approximately 0.6-0.8 g/kgBW/day may be renoprotective through various mechanisms, and it has been recommended in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) as a means to also control various metabolic consequences of advanced CKD, such as uremic symptoms, hyperparathyroidism, hypertension, hyperkalemia, and hyperphosphatemia. A meta-analysis in this issue of the Journal suggests that low-protein diet is effective and safe when used to retard progression of CKD and alleviate uremic complications. A potential deleterious consequence of lowering DPI in this population is the development or worsening of protein-energy wasting (PEW), which can contribute to poor clinical outcomes such as higher mortality and morbidity. There is currently insufficient high-level evidence to determine the ideal level of DPI in patients with NDD-CKD with high risk of PEW. For the time being we recommend a DPI of 0.6-0.8 g/kgBW/day, and increasing this as needed on an individual basis in patients with PEW. Further examination of this dilemma in randomized controlled clinical trials will be necessary.

The effect of a low protein diet with amino acid/keto acid supplements on glucose metabolism in children with uremia.

Six children with chronic renal failure were treated with dietary protein restriction and essential amino acid and keto acid supplements for 6 months. Dietary protein and phosphate intake decreased, dietary calcium increased, and dietary carbohydrate and energy did not change. Plasma urea and urea to creatinine ratio decreased significantly during treatment. Glucose metabolism was studied before and after 6 months of treatment using the hyperglycemic clamp technique. Fasting hyperglycemia, glucose intolerance, and insulin resistance improved during treatment, while fasting insulin and insulin levels during hyperglycemia did not change. These metabolic changes were not related to hyperparathyroidism and were probably due to reduction in nitrogen toxicity.

Bone mass and dynamic parathyroid function according to bone histology in nondialyzed uremic patients after long-term protein and phosphorus restriction.

One year of a very low protein diet (VLPD) can reverse secondary hyperparathyroidism in uremic patients. We studied bone histology, bone mineral density (BMD), and dynamic parathyroid function (calcium/PTH curves) in 16 nondialyzed patients with advanced renal failure who had been receiving a VLPD for a mean of 5 yr (mean protein intake, 0.34 +/- 0.12 mg/kg x day; mean phosphorus intake, 8.2 +/- 2.1 mg/kg x day) and daily supplementation with essential amino acids and their ketoanalogs (1000 IU vitamin D2 and 1-2 g calcium carbonate). Three patients exhibited a high bone formation rate (BFR), 7 patients had normal bone remodeling, and 6 patients had a low BFR, including 2 with osteomalacia and 4 with adynamic bone disease without aluminum overload. A longer diet duration and lower caloric intake were associated with low BFR. More than half of the patients exhibited moderate or severe osteoporosis at the appendicular skeleton. The t score of femur BMD explained 65% of the BFR variance. Patients with a low BFR had a dynamic parathyroid function similar to that of patients with a normal BFR, except they had a lower capacity to buffer a calcium load, whereas patients with a high BFR had a higher basal PTH/maximum PTH and a steeper calcium/PTH curve slope; the calcium set-point was identical in the three groups.

Endocrinology and metabolism in uremia and dialysis: a clinical review.

The salient information regarding the effects of uremia and dialysis on each of the metabolic fuels and hormones presented in the preceding sections is summarized in three tables. Tables 1 and 2 provide data on plasma levels, metabolism, dialysance, and literature references for each substance. Table 3 organizes the data according to the general mechanisms by which uremia and chronic dialysis may affect biological substances. Together these tables provide a reasonably complete summary of the information presently available. The pathophysiology of the uremic syndrome is still incompletely understood. The numerous metabolic and endocrine alterations associated with uremia and chronic dialytic therapy underscore the complexity of the problem and identify several specific areas for future research. One which deserves emphasis is the poolic and endocrine abnormalities found in uremia. A recent review by Chantler and Holliday (63) stressed in the importance of protein-calorie deficiency in the pathogensis of growth retardation and disturbed hormonal metabolism in children with chronic renal failure. The importance of this factor in adult patients with chronic uremia has been less well appreciated. However, striking similarities exist between the metabolic and endocrine abnormalities found in protein-calorie malnutrition and those found in uremia. These include, for example, altered albumin and amino acid metabolism, decreased levels of serum transferrin, peripheral insulin resistance and carbohydrate intolerance, elevated levels of glucagon, cortisol and growth hormone, and possibly diminished secretion of thyrotropin and thyroxine. Although not absolutely identical, the similarities between these two clinical syndromes suggest intriguing possible approaches to a better understanding of the pathophysiology of the uremic syndrome and its treatment.

Comparison of the effects of keto acid analogues and essential amino acids on nitrogen homeostasis in uremic patients on moderately protein-restricted diets.

Comparisons of isonitrogenous supplements (1.2 g N) of essential amino acids and five keto acid analogues with four essential amino acids were made in seven patients with stable chronic renal failure (creatinine clearance, 4.6 to 16 ml/min) on moderately protein-restricted diets (4.60 to 7.8 g N per day). Full nitrogen balance data on the four patients who have already completed studies lasting 24 weeks are presented. No benefits of keto acid over amino acid supplements were observed. Two transient episodes of hypercalcemia occurred during keto acid treatment. There was no improvement of renal function with keto acids. Also, no carry-over effects were seen after keto acid treatment. It is concluded that any beneficial effects of keto acids in patients with chronic renal failure are only likely to occur in those taking a diet of less than 30 g protein daily.

Nutritional effects of feeding a ketoanalogue mixture in growing and adult uremic rats.

Insufficient protein diets supplemented with ketoanalogue/essential amino acid (KA/EAA) mixtures are proposed to maintain nutrition and to retard renal deterioration. We compared in growing and in adult uremic rats diets containing limited or usual amounts of protein (12%, 20% for growing rats, and 10% and 16% for adult rats) with diets containing 50% or 60% less casein plus a KA/EAA mixture providing KA at an equimolar amount of removed EAA or at higher amounts. The latter supplement caused stunting, the former caused no anorexia, a slight growth deficit when added to the lowest basal casein diets, and almost normal growth when added to higher casein diets. Growth was normal with EAA supplements. The plasma EAA changes were unrelated to intake and to growth. Thus, KA utilization is maximal, provided that basal protein is sufficient and KA are not in excess.

A low-protein diet improves insulin sensitivity of endogenous glucose production in predialytic uremic patients.

A low-protein, low-phosphorus diet (LPD) has been shown to improve insulin sensitivity in uremic patients; however, this improvement has not been studied at low physiologic concentrations of plasma insulin, and the metabolic pathways concerned with this improvement have not been located. We used the glucose clamp technique at a low (0.25 mU.kg-1.min-1) level of hyperinsulinemia associated with the infusion of D[6,6-2H2] glucose to assess the insulin sensitivity of endogenous glucose production (EGP). Eight nondialyzed uremic patients were studied before and after 3 mo on an LPD providing 0.3 g/kg protein, 5-7 mg P/kg, and 146 kJ/kg (67% of energy as carbohydrates and 30% as lipids) per day, supplemented with ketoanalog amino acids. Postabsorptive plasma glucose and insulin declined after 3 mo of the diet (plasma glucose: 5.0 +/- 0.1 mmol/L before compared with 4.7 +/- 0.1 mmol/L after the LPD, P < 0.05; plasma insulin: 82.4 +/- 20.7 pmol/L before compared with 48.8 +/- 6.0 pmol/L after, P < 0.05). Postabsorptive glucose turnover rates did not change with the diet (2.06 +/- 0.14 mg.kg-1.min-1 before compared with 2.11 +/- 0.17 mg.kg-1.min-1 after LPD; NS). The insulin metabolic clearance rate was enhanced after the diet, so a lower level of hyperinsulinemia was obtained during the clamp (168.8 +/- 28.1 pmol/L before compared with 115.2 +/- 14.7 pmol/L after; P < 0.05). However, EGP was more easily inhibited after the diet (0.90 +/- 0.31 mg.kg-1.min-1 before compared with 0.30 +/- 0.17 mg.kg-1.min-1 after; P < 0.05), providing evidence of an improved insulin sensitivity of this parameter. This beneficial influence takes place at a physiologic level of hyperinsulinemia, and it probably plays an important role in the better glucose tolerance that has been reported in uremic patients on an LPD. An abnormal insulin sensitivity of EGP may participate in the disturbances of glucose metabolism in chronic renal failure.