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Are supplemented low-protein diets nutritionally safe?
Are Supplemented Low-Protein Diets Nutritionally Safe? Michel Aparicio, MD, Philippe Chauveau, MD, and Christian Combe, MD, PhD ● In patients with chronic renal failure (CRF), the reduction of dietary protein intake may correct uremic symptoms, slow the rate of progression of renal failure, and delay the onset on dialysis. Concerns have been made on the nutritional consequences of protein-restricted diets. Over 15 years, 239 patients were treated with a very-lowprotein diet providing 0.3 g vegetable protein/kg/day supplemented (SLPD) with essential amino acids and keto analogs. Many adverse consequences of uremia were corrected by this regimen, such as metabolic acidosis, secondary hyperparathyroidism, resistance to insulin, decreased Naⴙ-Kⴙ-ATPase activity. A joint physiciandietitian monitoring contributed to the maintenance or obtention of a satisfactory nutritional status, even in patients at risk, diabetics, patients with the nephrotic syndrome and with renal allograft chronic rejection. The outcome of these patients when treated by hemodialysis or transplantation was favorable, their nutritional status being preserved. Results from the present study and results of other studies show that SLPD can be used in patients with advanced CRF without adverse effects in carefully selected and monitored patients. © 2001 by the National Kidney Foundation, Inc. INDEX WORDS: Acidosis; chronic kidney failure; diet; nutritional status; protein.
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T HAS BEEN KNOWN for more than one century that in advanced uremia a reduction in alimentary protein intake could improve many uremic symptoms, most of which result from the accumulation of nitrogen waste products. More recently, it has been reported that reduced protein intake may also slow the rate of progression of renal failure.1 Different dietary regimens have been proposed to treat patients with chronic renal failure (CRF): a conventional low-protein diet (LPD) providing 0.6 g protein/kg/day or a verylow-protein diet providing 0.3 g vegetable protein/ kg/day supplemented (SLPD) with essential amino acids (EAAs) or an isomolar mixture of essential amino acids and nitrogen-free keto analogs (KAs). However, concerns have been raised regarding the nutritional adequacy of such dietary prescriptions. The consequences of an inadequate dietary intake could be particularly important in consideration of the adverse effects of protein-calorie malnutrition in patients with CRF before and after they began dialysis treatment.2,3 In fact, the maintenance of a satisfactory nutritional status has been reported in most series. FACTORS OF ADAPTATION TO LOW-PROTEIN DIETS
allowing to achieve a neutral nitrogen balance (BN).4 However, this balance requires approximately 90 days to reach complete equilibrium.5 In Patients With Chronic Renal Failure In patients with uncomplicated CRF without superimposed catabolic factors (eg, inflammation, infection, metabolic acidosis) Kopple and Coburn6 have shown more than 25 years ago that protein requirement was similar to that of healthy subjects: 0.6 g protein/kg/d. Goodship et al7 have confirmed that on LPD, the rates of amino acid oxidation and protein degradation decreased similarly in controls and in patients with CRF. Neutral BN is also observed in non-acidotic CRF patients when they consume less protein plus a supplement of EAAs or KAs. In 8 patients with CRF (glomerular filtration rate [GFR] 19 ⫾ 3 mL/min) on an SLPD affording daily 35 kcal/kg and 0.28 g protein/kg plus an isomolar mixture of either KAs or EAAs (average intake, 0.55 to 0.64 g protein/kg/d) for 3 weeks, Masud et al8 observed neutral BN whatever the AA supplementation was. These results were sustained in 6 patients following the same diet during 16 ⫾ 2 months: ⫹0.55 ⫾ 0.19 g/N/day at the end of the study.9
Metabolic Adaptation to Low-Protein Diet
In Healthy Subjects In healthy subjects, adaptation to dietary protein restriction involves a marked reduction in amino acid oxidation, which helps to maintain amino acid availability, and a postprandial inhibition of whole body protein degradation while protein synthesis does not change significantly,
From the Service de Ne´phrologie, Hoˆpital Pellegrin, Bordeaux; and AURAD Aquitaine, Gradignan, France. Address reprint requests to Pr Michel Aparicio, Service de Ne´phrologie, Hoˆpital Pellegrin, 33076 Bordeaux, France. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3701-0215$3.00/0 doi:10.1053/ajkd.2001.20753
American Journal of Kidney Diseases, Vol 37, No 1, Suppl 2 (January), 2001: pp S71-S76
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APARICIO ET AL
Correction of Metabolic Disorders Related to Chronic Renal Failure
Accumulation of waste products of protein metabolism, abnormal hormone responses, and ion transport abnormalities, all of which contribute to uremic syndrome, may be improved by SLPD. By correcting these abnormalities, SLPD also helps to maintain satisfactory nutritional status. Because animal protein is the main source of fixed acids, SLPD (which has a poor acidic ash) improves metabolic acidosis which promotes protein catabolism, decreases albumin synthesis, overrides the normal adaptive responses to a reduced-protein diet, and plays a leading role in the loss of lean body mass.6 When metabolic acidosis is not controlled by dietary measures or bicarbonate supplementation, it can override the metabolic adaptive response to an SLPD.10 The correction of renal hyperparathyroidism is related to the low phosphorus content of SLPD and to the increase in calcium intake, through calcium salts of keto analogs and calcium carbonate supplementation.11,12 Besides its positive effect on renal osteodystrophy, this improvement is nutritionally important in consideration of the ubiquitous effects of parathyroid hormone (PTH) which may affect, amongst others, skeletal muscle protein metabolism.13 Peripheral resistance to insulin linked to uremia is corrected by SLPD, this may be beneficial for protein metabolism.14 The changes in Na⫹K⫹ATPase activity observed in chronic uremia, which result in many adverse consequences for cellular metabolism, are improved by SLPD.15 Lastly, the reduction by protein restriction of some uremic manifestations, such as peripheral neuropathy or red cell lipid peroxidation,16 may have contributed to the correction of uremic symptoms and the maintenance of a better appetite. EFFECT OF LOW-PROTEIN DIET ON NUTRITIONAL STATUS In Normal Subjects
In subjects with normal renal function, despite the absence of change in total energy provision and physical activity, a moderate initial weight loss is observed when they are shifted to a reduced protein diet. This decrease in body weight is accounted for by lean tissue loss, the most
important site of protein loss being muscle, while visceral proteins are relatively preserved. Nitrogen losses are slowly adjusted for resulting in a transient negative nitrogen balance which requires approximately 90 days to reach complete equilibrium.5 In normal subjects on creatine-free diet, whatever the protein intake, urinary creatinine is approximately 20% less than baseline at the end of the first month, then slowly declines, stabilizing after 3 months at values approximately 70% of baseline diet.17 Heymsfield who made similar observations in healthy controls on a creatinefree diet concluded that the decrease in urinary creatinine predominantly occurred because of the suppression in alimentary creatine intake and was nearly independent from changes in muscle mass.18 Therefore, urinary excretion of creatinine is not a reliable indicator of muscle mass in patients with a reduced protein intake. In Patients With Chronic Renal Failure
Clinical Results The maintenance of adaptive responses to dietary protein restriction in patients with CRF explains that conservation of a satisfactory nutritional status has been reported in most series. In the Modification of Diet in Renal Disease (MDRD) study B, 255 patients with GFRs between 13 and 24 mL/min were randomly assigned either to a low-protein diet (0.58 g/kg/d) or to a very-low-protein diet (0.28 g/kg/d) supplemented with a mixture of keto acids and amino acids. The mean duration of follow-up was 2.2 years (range, 0 to 44 months). Within the first 4 months, patients of both groups showed an abrupt decline of weight (1.5 to 2 kg) and urinary creatinine excretion (approximatively 15% to 20% from baseline) followed by a stabilization or more progressive decrease thereafter. Small but significant changes from baseline were observed in anthropometrics and serum transferrin levels while serum albumin levels increased significantly in both groups. Despite a low energy intake, respectively 22.5 ⫾ 4.8 kcal/kg/d and 22.7 ⫾ 4.9 kcal/kg/d, only two patients reached a stop point for malnutrition and the rate of hospitalizations and death were not different.19 In a group of 43 patients who were treated for 6 to 72 months (median, 26 months) with an SLPD,
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Walser20 observed that hypoalbuminemia was present in only two patients at the initiation of hemodialysis treatment, mean final serum albumin level was 41 ⫾ 4 g/L. In the aforementioned study by Tom et al,9 weight, serum albumin, transferrin, and cholesterol levels were preserved throughout the 16-month follow-up. All these results contrast with the 56.7% incidence of hypoalbuminemia recently reported at the start of dialysis treatment in a cohort of 76,737 patients from the United States.21 Only Lucas et al22 observed a decrease in body weight and arm muscle circumference while serum albumin and transferrin levels remained unchanged in 12 patients on a supplemented diet with more severe protein restriction (0.2 g kg/ day) for 6 to 12 months. Energy intake was not mentioned. In our study of 239 patients with advanced CRF (GFR ⬍25 mL/min per 1.73 m2) who were placed on SLPDs for a mean duration of 29.6 ⫾ 25.1 months, 20 patients spontaneously stopped their dietary treatment, 14 patients died, none for nutritional grounds.23 The mortality rate while patients were treated with SLPD was 2.4% per year at risk over a total of 588.2 patient-years, similar to the 2.5% annual mortality in study B of the MDRD study and to the 2.5% mortality rate observed by Walser and Hill24 in 76 predialysis patients followed until renal replacement. After an initial decline following the initiation of SLPD, body mass index (BMI) stabilized at the third month, increased thereafter to reach initial values at the 12th month, and then remained stable. As observed in healthy controls, urinary creatinine excretion stabilized after 3 months at values approximately 75% of baseline, and serum albumin concentration remained unchanged.23 The maintenance of a satisfactory nutritional status was confirmed by a study using dual energy X-ray absorptiometry (DEXA), which is a particularly useful tool for determining body composition when longitudinal monitoring is needed. The outcome of body composition was assessed in 10 patients on SLPD every 3 months for the first year of dietary treatment.25 During this period, whereas BMI, anthropometrics, and blood proteins remained
unchanged, DEXA showed modifications in body composition characterized by an increase in total body fat from 20.0 ⫾ 6.9 to 21.4 ⫾ 7.0 kg (P ⬍ 0.05) an increase in the percentage of total body fat from 29.2 ⫾ 8.7% to 31.2 ⫾ 8.8% (P ⬍ 0.03) and a decrease in lean tissue from 46.2 ⫾ 10.2 to 45.1 ⫾ 9.8 kg, ie, a loss of 2.3% of lean tissue (NS). These different changes occurred abruptly during the first 3 months, then stabilized and slightly improved thereafter to become nonsignificant in the seven patients who were surveyed for 2 years (data not shown). It is unlikely that the mean loss of 1.1 kg in lean tissue observed during the first year could account for the decrease of nearly one third of urinary creatinine output. Clinical Management of Patients on Supplemented Low-Protein Diet Frequent clinical follow-ups permit a close survey of patients and a monitoring of dietary adequacy and compliance, with the assistance of a skilled dietitian. Because low energy intake constitutes a major factor of malnutrition in patients with CRF, make sure that caloric intake is adequate. In patients on reduced protein intake, higher energy intakes allow the maintenance of a neutral or positive BN.26 Moreover energy expenditure in patients with CRF, which is similar to that of healthy subjects, increases when these patients receive an SLPD, in relation with an enhanced oxidation of carbohydrates and fats.27 If the energy intake is not sufficient, patients will be at risk of catabolizing their own endogenous protein stores. If present, acidosis needs to be corrected by bicarbonate supplementation to avoid excessive protein catabolism.10 When an intercurrent illness occurs, SLPD is provisionally stopped and patients are given a conventional protein intake until they recover. In Patients With Chronic Renal Failure With Increased Nutritional Risk
We have also observed the maintenance of a satisfactory nutritional status in subgroups of patients with CRF who could be considered a priori at risk for malnutrition when put on SLPD, such as diabetics, nephrotic patients, and patients with chronic allograft rejection.
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Diabetics With Chronic Renal Failure Seventeen diabetics (12 type I and 5 type II) received an SLPD for a mean duration of 19.7 ⫾ 12.0 months. During the follow-up, two patients died from cardiovascular causes. Anthropometrics remained stable and serum albumin levels increased from 33.9 ⫾ 4.7 g/L to 37.1 ⫾ 6.1 g/L (P ⬍ 0.01). Despite an increased quantity of carbohydrates necessary to maintain a satisfactory caloric intake (67% of total energy), we have observed a decrease in daily insulin requirements from 35.3 ⫾ 9.6 to 26.1 ⫾ 6.2 U/day (P ⬍ 0.01) in relation to an improvement in tissue insulin sensitivity, confirmed by the glucose clamp technique. Only Barsotti et al28 have proposed an SLPD to a small group of four patients with type I diabetic nephropathy, while four other diabetic patients received 0.55 g vegetable protein/kg. During the 17.4-month follow-up, the investigators observed a significant decrease in urinary protein loss and in daily insulin requirement while no deterioration of the nutritional status occurred.28 Larivie`re et al5 have confirmed that, in patients with type I diabetics without renal impairment, a maintenance-energy but protein-free diet for 10 days decreased insulin requirements, even in the absence of obvious insulin resistance. The investigators suggested that this effect was mediated in part by decreased hepatic gluconeogenesis and by a possible increased insulin sensitivity. Nephrotic Syndrome With Chronic Renal Failure Measurements of whole-body protein turnover have shown that conservative mechanisms could also apply to patients with nephrotic urinary protein excretion receiving a low-protein diet. Furthermore, proteinuria per se spontaneously activated nitrogen conservation by decreasing aminoacid oxidation and urea production while patients were eating the low-protein diet.29,30 These adaptative mechanisms explain the observation by Kaysen et al31 who have reported that in nephrotic patients, a moderate protein restriction (0.8 g/kg/d) led to a decrease in urinary protein loss and an increase in serum albumin level. Several other studies have confirmed the beneficial or neutral effects of a restric-
APARICIO ET AL
tive protein diet on serum albumin concentration and proteinuria. In our study, 41 patients had nephrotic syndrome. On SLPD (plus 1.25 g protein/gram U protein) for a mean duration of 26.3 months, the patients’ daily urinary protein excretion decreased from 5.7 ⫾ 2.8 to 3.0 ⫾ 2.1 g/d at the end of the survey (P ⬍ 0.001). This decrease is noteworthy, because proteinuria is an important risk factor for progressive renal disease. During the same period of time, serum albumin concentration increased significantly from 33.8 ⫾ 6.4 to 37.8 ⫾ 5.4 g/L (P ⬍ 0.002), serum cholesterol decreased from 6.5 ⫾ 2.1 to 5.8 ⫾ 2.1 mmol/L (NS). Walser et al32 prescribed a very lowprotein diet supplemented by essential amino acids (or in a few cases, keto acids) for an average of 10 months to 16 adult patients with nephrotic syndrome. In the 11 patients with the lowest GFR (ⱕ30 mL/min/1.73 m2) proteinuria, hypoalbuminemia, and hypercholesterolemia improved slightly but significantly. The 5 patients with higher GFR showed a dramatic improvement in the same parameters, whereas the GFR either remained constant or increased. Chronic Renal Transplant Rejection Because progression of chronic rejection is, at least partially, modulated by non-allo-immune factors, dietary protein restriction has been proposed to transplant recipients with progressive renal failure on stable and reduced immunosuppressive regimens. Only three short-term studies have been reported. They concerned small groups of patients receiving a daily prednisone dose not exceeding 0.2 mg/kg and put on a conventional LPD (0.55 to 0.6 g protein/kg/d). The different studies did not come to any decisive conclusion on the nutritional safety of such diets in transplant recipients.33 We have followed 28 transplant recipients with chronic rejection for 23.7 ⫾ 20.9 months (range, 4 to 90 months). All patients were on low-dose maintenance immunosuppression (mean prednisone dose, 0.16 ⫾ 0.004 mg/ kg/d, cyclosporine dose 2.3 ⫾ 0.05 mg/kg/d). During the follow-up, only one patient died from liver failure. Body weight and anthropometrics remained constant, serum albumin levels were unchanged from 37.8 ⫾ 3.4 to 37.5 ⫾ 5.0 g/L. These different data indicate that patients with advanced CRF can maintain their nutritional
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status during long-term management by SLPD, even in potential catabolic states, provided that they are regularly and attentively surveyed. The close monitoring of these highly compliant patients explains the differences with the overall predialysis population. Without frequent clinical and dietary follow-ups, CRF patients spontaneously reduce protein and energy intakes and present signs of malnutrition in 25% to 50% of cases at the initiation of dialysis treatment.2 These are actually signs of poor clinical care.
their predialysis eating habits and to increase their protein intake.3 We have prospectively followed the eating behavior in 15 hemodialysis patients previously on SLPD for 42.4 ⫾ 30.1 months with a mean GFR of 6.2 ⫾ 1.5 mL/min/1.73 m2 at the initiation of dialysis. After receiving dietary advice, when the patients started their new treatment, their alimentary protein intake increased rapidly from 0.30 ⫾ 0.06 to 1.22 ⫾ 0.29 g/kg/d (P ⬍ 0.0001) at the third month, then stabilized during the 1 year follow-up: 1.2 ⫾ 0.3 g/kg/d at the end of the survey. Energy intake which was 30.0 ⫾ 6.3 kcal/kg at the start of dialysis remained unchanged: 30.2 ⫾ 6.2 kcal/kg 1 year later.
INCIDENCE OF PREDIALYSIS SUPPLEMENTED LOW-PROTEIN DIET ON THE OUTCOME OF PATIENTS ON RENAL REPLACEMENT THERAPY Hemodialysis
Reserves have also been made on the outcome of these patients once dialysis therapy has begun.2 In a prospective study of 44 patients treated before dialysis for 6 to 72 months with an SLPD, Coresh et al34 observed that survival during the first 2 years of dialysis was much better than survival rates reported in the United States Renal Data System (USRDS) after correction for age, sex, and diagnosis.34 During this period, only two deaths occurred and the cumulative mortality rate was 7%. In our experience, 165 patients were treated by hemodialysis after 29.8 ⫾ 23.1 months on SLPD.23 At the initiation of dialysis, the GFR, which was available in 93 patients, was 5.8 ⫾ 1.5 mL/min per 1.73 m2, far below Dialysis Outcome Quality Initiative recommendations.35 The mean time of follow-up was 54 months on dialysis. On dialysis treatment, the mortality rate was 2.4%, 25%, and 50% after 1, 5, and 10 years, respectively. This mortality rate in selected patients is lower than the one reported in the overall dialysis population but may be also favorably compared with the annual death rate of 6.3 per 100 patient-years reported by Wolfe et al36 in patients on dialysis who were awaiting transplantation and who represented a priori a highly selected subgroup of patients on dialysis. Most of the deaths were due to cardiovascular or cerebrovascular causes. Only four patients died with cachexia, after 48, 49, 51, and 89 months, respectively, of dialysis treatment; all of these patients were older than 80 years. Moreover, it has been claimed that in the short-term following dialysis initiation, these patients were unable to modify
Renal Transplantation
Twelve patients were transplanted without prior initiation of dialysis while they were treated by a conservative treatment with SLPD. Despite the large doses of steroids used in the early posttransplantation period and the stresses of surgery, the course of these patients was benign during the initial months. Similarly, none of the 54 patients who were transplanted while treated by hemodialysis died during the first year. Among these 66 patients, there were 4 late deaths, none of them were in relation with malnutrition. CONCLUSION
Our results, like those reported in other studies, show that, in patients with advanced CRF who are carefully selected, highly motivated, and regularly followed, the SLPD had no adverse effect on nutritional status even in potential catabolic situations. Although the date of the initiation of renal replacement therapy was substantially delayed, no deleterious effect was observed in patients, whether they were treated by hemodialysis or transplantation. REFERENCES 1. Pedrini MT, Levey AS, Lau J, Chalmers TC, Wang PH: The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: A meta-analysis. Ann Intern Med 124:627-632, 1996 2. Hakim RM, Lazarus JM: Initiation of dialysis. J Am Soc Nephrol 6:1319-1328, 1995 3. Pollock CA, Ibels LS, Zhu FY, Warnant M, Caterson RJ, Waugh DA, Mahony JF: Protein intake in renal disease. J Am Soc Nephrol 8:777-783, 1997 4. Price SR, Mitch WE: Metabolic acidosis and uremic toxicity: Protein and amino acid metabolism. Semin Nephrol 14:232-237, 1994
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5. Larivie`re F, Chiasson JL, Schiffrin A, Taveroff A, Hoffer LJ: Effects of dietary protein restriction on glucose and insulin metabolism in normal and diabetic humans. Metabolism 43:462-467, 1994 6. Kopple JD, Coburn JW: Metabolic studies of low protein diets in uremia. I. Nitrogen and potassium. Medicine (Baltimore) 52:583-595, 1973 7. Goodship TH, Mitch WE, Hoerr RA, Wagner DA, Steinman TI, Young VR: Adaptation to low-protein diets in renal failure: Leucine turnover and nitrogen balance. J Am Soc Nephrol 1:66-75, 1990 8. Masud T, Young VR, Chapman T, Maroni BJ: Adaptive responses to very low protein diets: The first comparison of ketoacids to essential amino acids. Kidney Int 45:11821192, 1994 9. Tom K, Young VR, Chapman T, Masud T, Akpele L, Maroni BJ: Long-term adaptive responses to dietary protein restriction in chronic renal failure. Am J Physiol 268:E668677, 1995 10. Williams B, Hattersley J, Layward E, Walls J: Metabolic acidosis and skeletal muscle adaptation to low protein diets in chronic uremia. Kidney Int 40:779-786, 1991 11. Combe C, Aparicio M: Phosphorus and protein restriction and parathyroid function in chronic renal failure. Kidney Int 46:1381-1386, 1994 12. Combe C, Morel D, de Pre`cigout V, Blanchetier V, Bouchet JL, Potaux L, Fournier A, Aparicio M: Long-term control of hyperparathyroidism in advanced renal failure by low-phosphorus low-protein diet supplemented with calcium (without changes in plasma calcitriol). Nephron 70:287-295, 1995 13. Garber AJ: Effects of parathyroid hormone on skeletal muscle protein and amino acid metabolism in the rat. J Clin Invest 71:1806-1821, 1983 14. Rigalleau V, Blanchetier V, Combe C, Guillot C, Deleris G, Aubertin J, Aparicio M, Gin H: A low-protein diet improves insulin sensitivity of endogenous glucose production in predialytic uremic patients. Am J Clin Nutr 65:15121516, 1997 15. Aparicio M, Vincendeau P, Combe C, Caix J, Gin H, de Pre`cigout V, Be`zian JH, Bouchet JL, Potaux L: Improvement of leucocytic Na⫹ K⫹ pump activity in uremic patients on low protein diet. Kidney Int 40:238-242, 1991 16. Peuchant E, Delmas-Beauvieux MC, Dubourg L, Thomas MJ, Perromat A, Aparicio M, Clerc M, Combe C: Antioxidant effects of a supplemented very low protein diet in chronic renal failure. Free Radic Biol Med 22:313-320, 1997 17. Crim MC, Calloway DH, Margen S: Creatine metabolism in men: Urinary creatine and creatinine excretions with creatine feeding. J Nutr 105:428-438, 1975 18. Heymsfield SB, Arteaga C, McManus C, Smith J, Moffitt S: Measurement of muscle mass in humans: validity of the 24-hour Urinary creatinine method. Am J Clin Nutr 37:478-494, 1983 19. Kopple JD, Levey AS, Greene T, Chumlea WC, Gassman JJ, Hollinger DL, Maroni BJ, Merrill D, Scherch LK, Schulman G, Wang SR, Zimmer GS: Effect of dietary protein restriction on nutritional status in the Modification of Diet in Renal Disease Study. Kidney Int 52:778-791, 1997 20. Walser M: Does prolonged protein restriction preceding dialysis lead to protein malnutrition at the onset of dialysis? Kidney Int 44:1139-1144, 1993
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21. Obrador GT, Ruthazer R, Port FK, Held PJ, Pereira BJG: Markers of quality of pre-ESRD care in the US. J Am Soc Nephrol 8:145A, 1997 (abstr) 22. Lucas PA, Meadows JH, Roberts DE, Coles GA: The risks and benefits of a low protein-essential amino acid-keto acid diet. Kidney Int 29:995-1003, 1986 23. Aparicio M, Chauveau P, de Pre`cigout V, Bouchet JL, Lasseur C, Combe C: Nutrition and outcome on renal replacement therapy of patients with chronic renal failure treated by a supplemented very low protein diet. J Am Soc Nephrol 11:708-716, 2000 24. Walser M, Hill S: Can renal replacement be deferred by a supplemented very low protein diet? J Am Soc Nephrol 10:110-116, 1999 25. Chauveau P, Barthe N, Rigalleau V, Ozenne S, Castaing F, Delclaux C, de Pre`cigout V, Combe C, Aparicio M: Outcome of nutritional status and body composition of uremic patients on a very low protein diet. Am J Kidney Dis 34:500-507, 1999 26. Kopple JD, Monteon FJ, Shaib JK: Effect of energy intake on nitrogen metabolism in nondialyzed patients with chronic renal failure. Kidney Int 29:734-742, 1986 27. Rigalleau V, Combe C, Blanchetier V, Aubertin J, Aparicio M, Gin H: Low protein diet in uremia: Effects on glucose metabolism and energy production rate. Kidney Int 51:1222-1227, 1997 28. Barsotti G, Ciardella F, Morelli E, Cupisti A, Mantovanelli A, Giovannetti S: Nutritional treatment of renal failure in type 1 diabetic nephropathy. Clin Nephrol 29:280287, 1988 29. Maroni BJ, Staffeld C, Young VR, Manatunga A, Tom K: Mechanisms permitting nephrotic patients to achieve nitrogen equilibrium with a protein-restricted diet. J Clin Invest 99:2479-2487, 1997 30. Lim VS, Wolfson M, Yarasheski KE, Flanigan MJ, Kopple JD: Leucine turnover in patients with nephrotic syndrome: Evidence suggesting body protein conservation. J Am Soc Nephrol 9:1067-1073, 1998 31. Kaysen GA, Gambertoglio J, Jimenez I, Jones H, Hutchison FN: Effect of dietary protein intake on albumin homeostasis in nephrotic patients. Kidney Int 29:572-577, 1986 32. Walser M, Hill S, Tomalis EA: Treatment of nephrotic adults with a supplemented, very low-protein diet. Am J Kidney Dis 28:354-364, 1996 33. Pruchno CJ, Hunsicker GL: Nutritional requirements of renal transplant patients, in Mitch WE, Klahr S (eds): Nutrition and the Kidney (ed 2). Boston, MA, Little, Brown, 1993, pp 326-364 34. Coresh J, Walser M, Hill S: Survival on dialysis among chronic renal failure patients treated with a supplemented low-protein diet before dialysis. J Am Soc Nephrol 6:1379-1385, 1995 35. NKF-DOQI clinical practice guidelines for hemodialysis adequacy. National Kidney Foundation. Am J Kidney Dis 30:S15-66, 1997 36. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, Held PJ, Port FK: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 341:1725-1730, 1999
I
T HAS BEEN KNOWN for more than one century that in advanced uremia a reduction in alimentary protein intake could improve many uremic symptoms, most of which result from the accumulation of nitrogen waste products. More recently, it has been reported that reduced protein intake may also slow the rate of progression of renal failure.1 Different dietary regimens have been proposed to treat patients with chronic renal failure (CRF): a conventional low-protein diet (LPD) providing 0.6 g protein/kg/day or a verylow-protein diet providing 0.3 g vegetable protein/ kg/day supplemented (SLPD) with essential amino acids (EAAs) or an isomolar mixture of essential amino acids and nitrogen-free keto analogs (KAs). However, concerns have been raised regarding the nutritional adequacy of such dietary prescriptions. The consequences of an inadequate dietary intake could be particularly important in consideration of the adverse effects of protein-calorie malnutrition in patients with CRF before and after they began dialysis treatment.2,3 In fact, the maintenance of a satisfactory nutritional status has been reported in most series. FACTORS OF ADAPTATION TO LOW-PROTEIN DIETS
allowing to achieve a neutral nitrogen balance (BN).4 However, this balance requires approximately 90 days to reach complete equilibrium.5 In Patients With Chronic Renal Failure In patients with uncomplicated CRF without superimposed catabolic factors (eg, inflammation, infection, metabolic acidosis) Kopple and Coburn6 have shown more than 25 years ago that protein requirement was similar to that of healthy subjects: 0.6 g protein/kg/d. Goodship et al7 have confirmed that on LPD, the rates of amino acid oxidation and protein degradation decreased similarly in controls and in patients with CRF. Neutral BN is also observed in non-acidotic CRF patients when they consume less protein plus a supplement of EAAs or KAs. In 8 patients with CRF (glomerular filtration rate [GFR] 19 ⫾ 3 mL/min) on an SLPD affording daily 35 kcal/kg and 0.28 g protein/kg plus an isomolar mixture of either KAs or EAAs (average intake, 0.55 to 0.64 g protein/kg/d) for 3 weeks, Masud et al8 observed neutral BN whatever the AA supplementation was. These results were sustained in 6 patients following the same diet during 16 ⫾ 2 months: ⫹0.55 ⫾ 0.19 g/N/day at the end of the study.9
Metabolic Adaptation to Low-Protein Diet
In Healthy Subjects In healthy subjects, adaptation to dietary protein restriction involves a marked reduction in amino acid oxidation, which helps to maintain amino acid availability, and a postprandial inhibition of whole body protein degradation while protein synthesis does not change significantly,
From the Service de Ne´phrologie, Hoˆpital Pellegrin, Bordeaux; and AURAD Aquitaine, Gradignan, France. Address reprint requests to Pr Michel Aparicio, Service de Ne´phrologie, Hoˆpital Pellegrin, 33076 Bordeaux, France. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3701-0215$3.00/0 doi:10.1053/ajkd.2001.20753
American Journal of Kidney Diseases, Vol 37, No 1, Suppl 2 (January), 2001: pp S71-S76
S71
S72
APARICIO ET AL
Correction of Metabolic Disorders Related to Chronic Renal Failure
Accumulation of waste products of protein metabolism, abnormal hormone responses, and ion transport abnormalities, all of which contribute to uremic syndrome, may be improved by SLPD. By correcting these abnormalities, SLPD also helps to maintain satisfactory nutritional status. Because animal protein is the main source of fixed acids, SLPD (which has a poor acidic ash) improves metabolic acidosis which promotes protein catabolism, decreases albumin synthesis, overrides the normal adaptive responses to a reduced-protein diet, and plays a leading role in the loss of lean body mass.6 When metabolic acidosis is not controlled by dietary measures or bicarbonate supplementation, it can override the metabolic adaptive response to an SLPD.10 The correction of renal hyperparathyroidism is related to the low phosphorus content of SLPD and to the increase in calcium intake, through calcium salts of keto analogs and calcium carbonate supplementation.11,12 Besides its positive effect on renal osteodystrophy, this improvement is nutritionally important in consideration of the ubiquitous effects of parathyroid hormone (PTH) which may affect, amongst others, skeletal muscle protein metabolism.13 Peripheral resistance to insulin linked to uremia is corrected by SLPD, this may be beneficial for protein metabolism.14 The changes in Na⫹K⫹ATPase activity observed in chronic uremia, which result in many adverse consequences for cellular metabolism, are improved by SLPD.15 Lastly, the reduction by protein restriction of some uremic manifestations, such as peripheral neuropathy or red cell lipid peroxidation,16 may have contributed to the correction of uremic symptoms and the maintenance of a better appetite. EFFECT OF LOW-PROTEIN DIET ON NUTRITIONAL STATUS In Normal Subjects
In subjects with normal renal function, despite the absence of change in total energy provision and physical activity, a moderate initial weight loss is observed when they are shifted to a reduced protein diet. This decrease in body weight is accounted for by lean tissue loss, the most
important site of protein loss being muscle, while visceral proteins are relatively preserved. Nitrogen losses are slowly adjusted for resulting in a transient negative nitrogen balance which requires approximately 90 days to reach complete equilibrium.5 In normal subjects on creatine-free diet, whatever the protein intake, urinary creatinine is approximately 20% less than baseline at the end of the first month, then slowly declines, stabilizing after 3 months at values approximately 70% of baseline diet.17 Heymsfield who made similar observations in healthy controls on a creatinefree diet concluded that the decrease in urinary creatinine predominantly occurred because of the suppression in alimentary creatine intake and was nearly independent from changes in muscle mass.18 Therefore, urinary excretion of creatinine is not a reliable indicator of muscle mass in patients with a reduced protein intake. In Patients With Chronic Renal Failure
Clinical Results The maintenance of adaptive responses to dietary protein restriction in patients with CRF explains that conservation of a satisfactory nutritional status has been reported in most series. In the Modification of Diet in Renal Disease (MDRD) study B, 255 patients with GFRs between 13 and 24 mL/min were randomly assigned either to a low-protein diet (0.58 g/kg/d) or to a very-low-protein diet (0.28 g/kg/d) supplemented with a mixture of keto acids and amino acids. The mean duration of follow-up was 2.2 years (range, 0 to 44 months). Within the first 4 months, patients of both groups showed an abrupt decline of weight (1.5 to 2 kg) and urinary creatinine excretion (approximatively 15% to 20% from baseline) followed by a stabilization or more progressive decrease thereafter. Small but significant changes from baseline were observed in anthropometrics and serum transferrin levels while serum albumin levels increased significantly in both groups. Despite a low energy intake, respectively 22.5 ⫾ 4.8 kcal/kg/d and 22.7 ⫾ 4.9 kcal/kg/d, only two patients reached a stop point for malnutrition and the rate of hospitalizations and death were not different.19 In a group of 43 patients who were treated for 6 to 72 months (median, 26 months) with an SLPD,
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Walser20 observed that hypoalbuminemia was present in only two patients at the initiation of hemodialysis treatment, mean final serum albumin level was 41 ⫾ 4 g/L. In the aforementioned study by Tom et al,9 weight, serum albumin, transferrin, and cholesterol levels were preserved throughout the 16-month follow-up. All these results contrast with the 56.7% incidence of hypoalbuminemia recently reported at the start of dialysis treatment in a cohort of 76,737 patients from the United States.21 Only Lucas et al22 observed a decrease in body weight and arm muscle circumference while serum albumin and transferrin levels remained unchanged in 12 patients on a supplemented diet with more severe protein restriction (0.2 g kg/ day) for 6 to 12 months. Energy intake was not mentioned. In our study of 239 patients with advanced CRF (GFR ⬍25 mL/min per 1.73 m2) who were placed on SLPDs for a mean duration of 29.6 ⫾ 25.1 months, 20 patients spontaneously stopped their dietary treatment, 14 patients died, none for nutritional grounds.23 The mortality rate while patients were treated with SLPD was 2.4% per year at risk over a total of 588.2 patient-years, similar to the 2.5% annual mortality in study B of the MDRD study and to the 2.5% mortality rate observed by Walser and Hill24 in 76 predialysis patients followed until renal replacement. After an initial decline following the initiation of SLPD, body mass index (BMI) stabilized at the third month, increased thereafter to reach initial values at the 12th month, and then remained stable. As observed in healthy controls, urinary creatinine excretion stabilized after 3 months at values approximately 75% of baseline, and serum albumin concentration remained unchanged.23 The maintenance of a satisfactory nutritional status was confirmed by a study using dual energy X-ray absorptiometry (DEXA), which is a particularly useful tool for determining body composition when longitudinal monitoring is needed. The outcome of body composition was assessed in 10 patients on SLPD every 3 months for the first year of dietary treatment.25 During this period, whereas BMI, anthropometrics, and blood proteins remained
unchanged, DEXA showed modifications in body composition characterized by an increase in total body fat from 20.0 ⫾ 6.9 to 21.4 ⫾ 7.0 kg (P ⬍ 0.05) an increase in the percentage of total body fat from 29.2 ⫾ 8.7% to 31.2 ⫾ 8.8% (P ⬍ 0.03) and a decrease in lean tissue from 46.2 ⫾ 10.2 to 45.1 ⫾ 9.8 kg, ie, a loss of 2.3% of lean tissue (NS). These different changes occurred abruptly during the first 3 months, then stabilized and slightly improved thereafter to become nonsignificant in the seven patients who were surveyed for 2 years (data not shown). It is unlikely that the mean loss of 1.1 kg in lean tissue observed during the first year could account for the decrease of nearly one third of urinary creatinine output. Clinical Management of Patients on Supplemented Low-Protein Diet Frequent clinical follow-ups permit a close survey of patients and a monitoring of dietary adequacy and compliance, with the assistance of a skilled dietitian. Because low energy intake constitutes a major factor of malnutrition in patients with CRF, make sure that caloric intake is adequate. In patients on reduced protein intake, higher energy intakes allow the maintenance of a neutral or positive BN.26 Moreover energy expenditure in patients with CRF, which is similar to that of healthy subjects, increases when these patients receive an SLPD, in relation with an enhanced oxidation of carbohydrates and fats.27 If the energy intake is not sufficient, patients will be at risk of catabolizing their own endogenous protein stores. If present, acidosis needs to be corrected by bicarbonate supplementation to avoid excessive protein catabolism.10 When an intercurrent illness occurs, SLPD is provisionally stopped and patients are given a conventional protein intake until they recover. In Patients With Chronic Renal Failure With Increased Nutritional Risk
We have also observed the maintenance of a satisfactory nutritional status in subgroups of patients with CRF who could be considered a priori at risk for malnutrition when put on SLPD, such as diabetics, nephrotic patients, and patients with chronic allograft rejection.
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Diabetics With Chronic Renal Failure Seventeen diabetics (12 type I and 5 type II) received an SLPD for a mean duration of 19.7 ⫾ 12.0 months. During the follow-up, two patients died from cardiovascular causes. Anthropometrics remained stable and serum albumin levels increased from 33.9 ⫾ 4.7 g/L to 37.1 ⫾ 6.1 g/L (P ⬍ 0.01). Despite an increased quantity of carbohydrates necessary to maintain a satisfactory caloric intake (67% of total energy), we have observed a decrease in daily insulin requirements from 35.3 ⫾ 9.6 to 26.1 ⫾ 6.2 U/day (P ⬍ 0.01) in relation to an improvement in tissue insulin sensitivity, confirmed by the glucose clamp technique. Only Barsotti et al28 have proposed an SLPD to a small group of four patients with type I diabetic nephropathy, while four other diabetic patients received 0.55 g vegetable protein/kg. During the 17.4-month follow-up, the investigators observed a significant decrease in urinary protein loss and in daily insulin requirement while no deterioration of the nutritional status occurred.28 Larivie`re et al5 have confirmed that, in patients with type I diabetics without renal impairment, a maintenance-energy but protein-free diet for 10 days decreased insulin requirements, even in the absence of obvious insulin resistance. The investigators suggested that this effect was mediated in part by decreased hepatic gluconeogenesis and by a possible increased insulin sensitivity. Nephrotic Syndrome With Chronic Renal Failure Measurements of whole-body protein turnover have shown that conservative mechanisms could also apply to patients with nephrotic urinary protein excretion receiving a low-protein diet. Furthermore, proteinuria per se spontaneously activated nitrogen conservation by decreasing aminoacid oxidation and urea production while patients were eating the low-protein diet.29,30 These adaptative mechanisms explain the observation by Kaysen et al31 who have reported that in nephrotic patients, a moderate protein restriction (0.8 g/kg/d) led to a decrease in urinary protein loss and an increase in serum albumin level. Several other studies have confirmed the beneficial or neutral effects of a restric-
APARICIO ET AL
tive protein diet on serum albumin concentration and proteinuria. In our study, 41 patients had nephrotic syndrome. On SLPD (plus 1.25 g protein/gram U protein) for a mean duration of 26.3 months, the patients’ daily urinary protein excretion decreased from 5.7 ⫾ 2.8 to 3.0 ⫾ 2.1 g/d at the end of the survey (P ⬍ 0.001). This decrease is noteworthy, because proteinuria is an important risk factor for progressive renal disease. During the same period of time, serum albumin concentration increased significantly from 33.8 ⫾ 6.4 to 37.8 ⫾ 5.4 g/L (P ⬍ 0.002), serum cholesterol decreased from 6.5 ⫾ 2.1 to 5.8 ⫾ 2.1 mmol/L (NS). Walser et al32 prescribed a very lowprotein diet supplemented by essential amino acids (or in a few cases, keto acids) for an average of 10 months to 16 adult patients with nephrotic syndrome. In the 11 patients with the lowest GFR (ⱕ30 mL/min/1.73 m2) proteinuria, hypoalbuminemia, and hypercholesterolemia improved slightly but significantly. The 5 patients with higher GFR showed a dramatic improvement in the same parameters, whereas the GFR either remained constant or increased. Chronic Renal Transplant Rejection Because progression of chronic rejection is, at least partially, modulated by non-allo-immune factors, dietary protein restriction has been proposed to transplant recipients with progressive renal failure on stable and reduced immunosuppressive regimens. Only three short-term studies have been reported. They concerned small groups of patients receiving a daily prednisone dose not exceeding 0.2 mg/kg and put on a conventional LPD (0.55 to 0.6 g protein/kg/d). The different studies did not come to any decisive conclusion on the nutritional safety of such diets in transplant recipients.33 We have followed 28 transplant recipients with chronic rejection for 23.7 ⫾ 20.9 months (range, 4 to 90 months). All patients were on low-dose maintenance immunosuppression (mean prednisone dose, 0.16 ⫾ 0.004 mg/ kg/d, cyclosporine dose 2.3 ⫾ 0.05 mg/kg/d). During the follow-up, only one patient died from liver failure. Body weight and anthropometrics remained constant, serum albumin levels were unchanged from 37.8 ⫾ 3.4 to 37.5 ⫾ 5.0 g/L. These different data indicate that patients with advanced CRF can maintain their nutritional
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status during long-term management by SLPD, even in potential catabolic states, provided that they are regularly and attentively surveyed. The close monitoring of these highly compliant patients explains the differences with the overall predialysis population. Without frequent clinical and dietary follow-ups, CRF patients spontaneously reduce protein and energy intakes and present signs of malnutrition in 25% to 50% of cases at the initiation of dialysis treatment.2 These are actually signs of poor clinical care.
their predialysis eating habits and to increase their protein intake.3 We have prospectively followed the eating behavior in 15 hemodialysis patients previously on SLPD for 42.4 ⫾ 30.1 months with a mean GFR of 6.2 ⫾ 1.5 mL/min/1.73 m2 at the initiation of dialysis. After receiving dietary advice, when the patients started their new treatment, their alimentary protein intake increased rapidly from 0.30 ⫾ 0.06 to 1.22 ⫾ 0.29 g/kg/d (P ⬍ 0.0001) at the third month, then stabilized during the 1 year follow-up: 1.2 ⫾ 0.3 g/kg/d at the end of the survey. Energy intake which was 30.0 ⫾ 6.3 kcal/kg at the start of dialysis remained unchanged: 30.2 ⫾ 6.2 kcal/kg 1 year later.
INCIDENCE OF PREDIALYSIS SUPPLEMENTED LOW-PROTEIN DIET ON THE OUTCOME OF PATIENTS ON RENAL REPLACEMENT THERAPY Hemodialysis
Reserves have also been made on the outcome of these patients once dialysis therapy has begun.2 In a prospective study of 44 patients treated before dialysis for 6 to 72 months with an SLPD, Coresh et al34 observed that survival during the first 2 years of dialysis was much better than survival rates reported in the United States Renal Data System (USRDS) after correction for age, sex, and diagnosis.34 During this period, only two deaths occurred and the cumulative mortality rate was 7%. In our experience, 165 patients were treated by hemodialysis after 29.8 ⫾ 23.1 months on SLPD.23 At the initiation of dialysis, the GFR, which was available in 93 patients, was 5.8 ⫾ 1.5 mL/min per 1.73 m2, far below Dialysis Outcome Quality Initiative recommendations.35 The mean time of follow-up was 54 months on dialysis. On dialysis treatment, the mortality rate was 2.4%, 25%, and 50% after 1, 5, and 10 years, respectively. This mortality rate in selected patients is lower than the one reported in the overall dialysis population but may be also favorably compared with the annual death rate of 6.3 per 100 patient-years reported by Wolfe et al36 in patients on dialysis who were awaiting transplantation and who represented a priori a highly selected subgroup of patients on dialysis. Most of the deaths were due to cardiovascular or cerebrovascular causes. Only four patients died with cachexia, after 48, 49, 51, and 89 months, respectively, of dialysis treatment; all of these patients were older than 80 years. Moreover, it has been claimed that in the short-term following dialysis initiation, these patients were unable to modify
Renal Transplantation
Twelve patients were transplanted without prior initiation of dialysis while they were treated by a conservative treatment with SLPD. Despite the large doses of steroids used in the early posttransplantation period and the stresses of surgery, the course of these patients was benign during the initial months. Similarly, none of the 54 patients who were transplanted while treated by hemodialysis died during the first year. Among these 66 patients, there were 4 late deaths, none of them were in relation with malnutrition. CONCLUSION
Our results, like those reported in other studies, show that, in patients with advanced CRF who are carefully selected, highly motivated, and regularly followed, the SLPD had no adverse effect on nutritional status even in potential catabolic situations. Although the date of the initiation of renal replacement therapy was substantially delayed, no deleterious effect was observed in patients, whether they were treated by hemodialysis or transplantation. REFERENCES 1. Pedrini MT, Levey AS, Lau J, Chalmers TC, Wang PH: The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: A meta-analysis. Ann Intern Med 124:627-632, 1996 2. Hakim RM, Lazarus JM: Initiation of dialysis. J Am Soc Nephrol 6:1319-1328, 1995 3. Pollock CA, Ibels LS, Zhu FY, Warnant M, Caterson RJ, Waugh DA, Mahony JF: Protein intake in renal disease. J Am Soc Nephrol 8:777-783, 1997 4. Price SR, Mitch WE: Metabolic acidosis and uremic toxicity: Protein and amino acid metabolism. Semin Nephrol 14:232-237, 1994
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5. Larivie`re F, Chiasson JL, Schiffrin A, Taveroff A, Hoffer LJ: Effects of dietary protein restriction on glucose and insulin metabolism in normal and diabetic humans. Metabolism 43:462-467, 1994 6. Kopple JD, Coburn JW: Metabolic studies of low protein diets in uremia. I. Nitrogen and potassium. Medicine (Baltimore) 52:583-595, 1973 7. Goodship TH, Mitch WE, Hoerr RA, Wagner DA, Steinman TI, Young VR: Adaptation to low-protein diets in renal failure: Leucine turnover and nitrogen balance. J Am Soc Nephrol 1:66-75, 1990 8. Masud T, Young VR, Chapman T, Maroni BJ: Adaptive responses to very low protein diets: The first comparison of ketoacids to essential amino acids. Kidney Int 45:11821192, 1994 9. Tom K, Young VR, Chapman T, Masud T, Akpele L, Maroni BJ: Long-term adaptive responses to dietary protein restriction in chronic renal failure. Am J Physiol 268:E668677, 1995 10. Williams B, Hattersley J, Layward E, Walls J: Metabolic acidosis and skeletal muscle adaptation to low protein diets in chronic uremia. Kidney Int 40:779-786, 1991 11. Combe C, Aparicio M: Phosphorus and protein restriction and parathyroid function in chronic renal failure. Kidney Int 46:1381-1386, 1994 12. Combe C, Morel D, de Pre`cigout V, Blanchetier V, Bouchet JL, Potaux L, Fournier A, Aparicio M: Long-term control of hyperparathyroidism in advanced renal failure by low-phosphorus low-protein diet supplemented with calcium (without changes in plasma calcitriol). Nephron 70:287-295, 1995 13. Garber AJ: Effects of parathyroid hormone on skeletal muscle protein and amino acid metabolism in the rat. J Clin Invest 71:1806-1821, 1983 14. Rigalleau V, Blanchetier V, Combe C, Guillot C, Deleris G, Aubertin J, Aparicio M, Gin H: A low-protein diet improves insulin sensitivity of endogenous glucose production in predialytic uremic patients. Am J Clin Nutr 65:15121516, 1997 15. Aparicio M, Vincendeau P, Combe C, Caix J, Gin H, de Pre`cigout V, Be`zian JH, Bouchet JL, Potaux L: Improvement of leucocytic Na⫹ K⫹ pump activity in uremic patients on low protein diet. Kidney Int 40:238-242, 1991 16. Peuchant E, Delmas-Beauvieux MC, Dubourg L, Thomas MJ, Perromat A, Aparicio M, Clerc M, Combe C: Antioxidant effects of a supplemented very low protein diet in chronic renal failure. Free Radic Biol Med 22:313-320, 1997 17. Crim MC, Calloway DH, Margen S: Creatine metabolism in men: Urinary creatine and creatinine excretions with creatine feeding. J Nutr 105:428-438, 1975 18. Heymsfield SB, Arteaga C, McManus C, Smith J, Moffitt S: Measurement of muscle mass in humans: validity of the 24-hour Urinary creatinine method. Am J Clin Nutr 37:478-494, 1983 19. Kopple JD, Levey AS, Greene T, Chumlea WC, Gassman JJ, Hollinger DL, Maroni BJ, Merrill D, Scherch LK, Schulman G, Wang SR, Zimmer GS: Effect of dietary protein restriction on nutritional status in the Modification of Diet in Renal Disease Study. Kidney Int 52:778-791, 1997 20. Walser M: Does prolonged protein restriction preceding dialysis lead to protein malnutrition at the onset of dialysis? Kidney Int 44:1139-1144, 1993
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21. Obrador GT, Ruthazer R, Port FK, Held PJ, Pereira BJG: Markers of quality of pre-ESRD care in the US. J Am Soc Nephrol 8:145A, 1997 (abstr) 22. Lucas PA, Meadows JH, Roberts DE, Coles GA: The risks and benefits of a low protein-essential amino acid-keto acid diet. Kidney Int 29:995-1003, 1986 23. Aparicio M, Chauveau P, de Pre`cigout V, Bouchet JL, Lasseur C, Combe C: Nutrition and outcome on renal replacement therapy of patients with chronic renal failure treated by a supplemented very low protein diet. J Am Soc Nephrol 11:708-716, 2000 24. Walser M, Hill S: Can renal replacement be deferred by a supplemented very low protein diet? J Am Soc Nephrol 10:110-116, 1999 25. Chauveau P, Barthe N, Rigalleau V, Ozenne S, Castaing F, Delclaux C, de Pre`cigout V, Combe C, Aparicio M: Outcome of nutritional status and body composition of uremic patients on a very low protein diet. Am J Kidney Dis 34:500-507, 1999 26. Kopple JD, Monteon FJ, Shaib JK: Effect of energy intake on nitrogen metabolism in nondialyzed patients with chronic renal failure. Kidney Int 29:734-742, 1986 27. Rigalleau V, Combe C, Blanchetier V, Aubertin J, Aparicio M, Gin H: Low protein diet in uremia: Effects on glucose metabolism and energy production rate. Kidney Int 51:1222-1227, 1997 28. Barsotti G, Ciardella F, Morelli E, Cupisti A, Mantovanelli A, Giovannetti S: Nutritional treatment of renal failure in type 1 diabetic nephropathy. Clin Nephrol 29:280287, 1988 29. Maroni BJ, Staffeld C, Young VR, Manatunga A, Tom K: Mechanisms permitting nephrotic patients to achieve nitrogen equilibrium with a protein-restricted diet. J Clin Invest 99:2479-2487, 1997 30. Lim VS, Wolfson M, Yarasheski KE, Flanigan MJ, Kopple JD: Leucine turnover in patients with nephrotic syndrome: Evidence suggesting body protein conservation. J Am Soc Nephrol 9:1067-1073, 1998 31. Kaysen GA, Gambertoglio J, Jimenez I, Jones H, Hutchison FN: Effect of dietary protein intake on albumin homeostasis in nephrotic patients. Kidney Int 29:572-577, 1986 32. Walser M, Hill S, Tomalis EA: Treatment of nephrotic adults with a supplemented, very low-protein diet. Am J Kidney Dis 28:354-364, 1996 33. Pruchno CJ, Hunsicker GL: Nutritional requirements of renal transplant patients, in Mitch WE, Klahr S (eds): Nutrition and the Kidney (ed 2). Boston, MA, Little, Brown, 1993, pp 326-364 34. Coresh J, Walser M, Hill S: Survival on dialysis among chronic renal failure patients treated with a supplemented low-protein diet before dialysis. J Am Soc Nephrol 6:1379-1385, 1995 35. NKF-DOQI clinical practice guidelines for hemodialysis adequacy. National Kidney Foundation. Am J Kidney Dis 30:S15-66, 1997 36. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, Held PJ, Port FK: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 341:1725-1730, 1999