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.

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.

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.

Effects of severe protein restriction with ketoanalogues in advanced renal failure.

OBJECTIVE: To compare a severe protein restriction diet supplemented with ketoanalogues to a moderate protein restriction diet in order to limit glomerular filtration rate (GFR) decrease in an advanced renal insufficiency stage. DESIGN: Prospective randomised study conducted to compare a severe protein restriction diet (0.30 g/kg/day) supplemented with a preparation of ketoanalogues, hydroxyanalogues of aminoacids and aminoacids (Group A) to a moderate protein restriction diet (0.65 g/kg/day) (Group B). PATIENTS: 50 uremic patients included (25 in each group) with GFR is <20 mL/min/1.73m2. RESULTS: There were no statistically significant differences between the two dietary regimens for the renal survival. But uremia decreased significantly in Group A (22.7+/-5.2 to 18.5+/-6.7 mmol/L) and increased in Group B (26.8+/-9.0 to 34.9+/-9.9 mmol/L). Calcemia increased in Group A from 2.28+/-0.18 to 2.42+/-0.17 mmol/L, p<0.01 with a stable phosphoremia while calcemia decreased in Group B (2.33+/-0.18 to 2.25+/-0.17 mmol/L, p<0.05). At the end of the study, Group A was different from Group B for calcemia (2.42+/-0.17 vs. 2.25+/-0.17 mmol/L, p<0.01), phosphoremia (1.39+/-0.30 vs. 1.80+/-0.65 mmol/L, p<0.02), alkaline phosphatase (61.42+/-22.93 vs. 78.8+/-27.0, p<0.05) and parathormone plasma levels (2.71+/-1.55 vs. 5.91+/-1.41 ng/mL, p<0.001). COMMENTS: Compared to a moderate protein restriction (0.65 g/kg/day), a severe protein restriction (0.3 g/kg/day) supplemented by ketoanologues does not limit GFR decrease when GFR is below 20 mL/min/1.73m2, but improves phosphocalcic plasma parameters.

Efectos de la dieta muy baja en proteínas (DMBP) suplementada con cetoanalogos en insuficiencia renal crónica moderada / Effects of the very low protein diet (VLPD) supplemented with alfaketoanalogues (KA) in moderated chronic renal failure

Se valoraron los efectos de una dieta muy baja en proteína (DMBP) suplementada con alfa cetoanálogos (ca) (Cetosteril Marca Reg.) sobre la función renal y el estado de la nutrición de pacientes con insuficiencia renal crónica (IRC) moderada. En cinco pacientes con IRC moderada, causada por glomerulonefritis se valoró el estado nutricional en tres períodos diferentes, de seis meses cada uno: I. Con dieta baja en proteínas (DBP) de 0.6 g/kg/día. II. Con DMBP (0.4 g/kg/día) más ca (una tableta por cada 5 kg/peso) y finalmente, III. Con DBP sin ca. Se valoraron los siguientes índices en los tres períodos: presión arterial, peso corporal índice de masa corporal, circunferencia del tercio medio del brazo, grosor de la piel en el tríceps, urea, creatinina, colesterol, calcio y fósforo séricos; proteinuria y depuración de creatinina de 24 horas. Los análisis estadísticos se valoraron con análisis de varianza y prueba de T de Student, siendo significativos con valores de p < 0.05.Los índices antropométricos mejoraron, durante DMBP más ca, observándose también en este período una reducción de las concentraciones séricas de urea, fósforo y colesterol, más una reducción de la proteinuria con mejoría de la seroalbúmina. Estas mejorías desaparecieron durante el período sin ca. Por tanto, los ca son útiles en el control de las concentraciones sanguíneas de urea y para mejorar el estado de la nutrición en la IRC moderada.

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.

Nutrition of uremic patients in the course of CAPD treatment.

Our aim was an evaluation of daily protein and energy intake, plasma protein, albumin, and cholesterol concentrations as well as total iron binding capacity in the course of continuous ambulatory peritoneal dialysis (CAPD) for up to 36 months. Our results indicate that CAPD patients, despite adequate clinical laboratory scores for up to 36 months of treatment, usually do not show optimal protein intake. When protein calorie malnutrition is prolonged, plasma proteins decrease. On the other hand, the greater the peritoneal permeability the lower the plasma protein intake.

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.

Improvement of leucocytic Na+ K+ pump activity in uremic patients on low protein diet.

Leucocytic Na+ K+ pump activity was assessed in 20 patients with advanced renal failure. Na+ K(+)-ATPase activity was reduced when compared with the values obtained from normal subjects (101.8 +/- 48.6 versus 165.13 +/- 8.9 microM of Pi hr-1.g-1; P less than 0.001) and the mean 86Rb uptake by U 937 cells was depressed by 38% after the addition of patients' sera. Subsequently, patients were put on a diet providing 0.3 g protein/kg body weight daily and supplemented with ketoacids. After three months of dietary treatment Na+ K(+)-ATPase activity increased to 142 +/- 48.3 (P less than 0.01) and reached normal values at the sixth month (162.8 +/- 54.70 microM of Pi hr-1.g-1; P less than 0.001) whereas 86Rb uptake increased by 23 percent when compared to initial values. These data suggest that among the different mechanisms which have been advanced to explain the defects in the Na+ pump observed in uremic patients, circulating inhibitors deriving from alimentary protein intake may affect cation transport.

Effect of low-protein diet on renal function: are there definite conclusions from adult studies?

Low-protein diets have been used for roughly a century in order to alleviate uraemic symptoms and to delay progression of chronic renal failure (CRF). Currently a number of different low-protein diets are used, supplying either 0.6 g protein/kg body weight or 0.3-0.4 g supplemented with amino-acids or keto-acids. Single centre trials have attempted to demonstrate the efficacy of these diets in slowing down the progression of CRF. The results from these trials are, however, sometimes inconclusive, showing either a high efficiency of the low-protein diet or no efficiency at all. Conclusive data from multicentre trials, however, are not yet available. A crucial point in analysing the efficacy of low-protein diets is the degree of compliance with the protein restriction. Today, the data available indicate that sometimes only a poor degree of compliance is achieved both in single and in multicentre trials.

The beneficial effect of ketoacids on serum phosphate and parathyroid hormone in patients with chronic uremia.

Hyperphosphatemia and secondary hyperparathyroidism are regular complications in patients suffering from advanced renal failure. As aluminum-containing drugs carry the well-known risk of aluminum intoxication, we were interested in testing in a prospective study a mixture of ketoanalogues and amino acids which have been shown to lower the serum phosphate and parathyroid hormone in uremic patients. For 3 months, in addition to their diet, 17 uremic patients and 12 hemodialysis patients received a daily supplement of this mixture. Although no additional phosphate binders were administered, serum phosphate decreased significantly in the former group and was slightly lower in the latter. The serum parathyroid hormone level was consistently lowered when the initial concentration was not higher than 20 times normal.

Effect of a low-protein diet on chemiluminescence production by leukocytes from uremic patients.

Chemiluminescence (CL) emission from leukocytes was studied in 20 uremic patients after ingestion of opsonized zymosan. CL production was impaired when compared with control groups. Six months after a low-protein, low-phosphorus diet supplemented with essential amino acids and ketoanalogues (SD) was started, a significant improvement in CL production was observed. SD may be expected to decrease the susceptibility of uremic patients to bacterial infections.

Protein-restricted diets and progression of renal failure.

Interest in dietary therapy of chronic uremia has reawakened because such therapy may slow or halt progression of renal insufficiency. The efficacies of three regimens: 0.6 g protein/kg/day; 0.3 g protein/kg/day plus essential amino acids, and 0.3 g protein/kg/day plus keto acid regimens, have been tested. Each can maintain nitrogen balance if properly administered but if dietary protein and/or the supplement are inadequate, muscle wasting will occur. Data showing that each can slow the rise in serum creatinine are presented. The problems with using serum creatinine, potential mechanisms for the effect on progression and methods for monitoring compliance are discussed.

Amino acids and keto acids in the treatment of chronic renal failure.

Clinical trials using very low protein supply supplemented with amino acid or keto acid preparations have shown the possibility of slowing the rate of decline of renal function in patients with advanced chronic renal failure together with preservation of nutritional status. The possible mechanisms by which this effect is obtained are reviewed. The potential advantages of keto acids upon amino acids, the optimal composition of the preparations used, and the best time to start treatment in chronic uremics are discussed. Projection of recent data indicate that a prolongation of renal autonomy of about 4 years instead of a spontaneous duration of 15 months until dialysis can be expected using keto acid treatment if started when plasma creatinine reaches 500 mumol/l.