- Email: [email protected]
Should protein intake be restricted in predialysis patients?
Kidney International, Vol. 55 (1999), pp. 771–777
PERSPECTIVES IN RENAL MEDICINE
Should protein intake be restricted in predialysis patients? MACKENZIE WALSER, WILLIAM E. MITCH, BRADLEY J. MARONI, and JOEL D. KOPPLE Johns Hopkins School of Medicine, Baltimore, Maryland; Emory University School of Medicine, Atlanta, Georgia; and Harbor-UCLA Medical Center and the UCLA Schools of Medicine and Public Health, Los Angeles, California, USA
It has been known for at least 100 years that protein restriction reduces symptoms in chronic renal failure (CRF) [1]. Because most of these symptoms are caused by accumulation of the products of protein metabolism, this is to be expected. The history of the use of proteinrestricted diets in renal disease has been reviewed elsewhere [2, 3]. In the last decade, two findings have cast doubt on the wisdom of administering low-protein diets to CRF patients: First, a large body of evidence has documented that hypoalbuminemia in dialysis patients is a major risk factor for mortality, whether present at the onset of dialysis or developed during dialysis [4–19]. Other indices of nutritional status, such as urea nitrogen appearance and predialysis levels of creatinine and cholesterol, are also correlated with mortality [4–19]. Second, the hypothesis that protein restriction slows the progression of CRF (another rationale for its use) has not been unequivocally confirmed (discussed later here). As a result of these findings, some workers have questioned the wisdom of restricting protein intake [20–22]. Furthermore, they have suggested that if spontaneous protein intake falls below 0.8 g/kg/day, patients are at increased risk of malnutrition, and the appropriate response is to start dialysis unless protein intake can be increased. The assumptions underlying these recommendations are that: (a) protein nutrition will improve in predialysis patients if protein intake increases; (b) dialysis improves dietary intake and nutritional status; and (c) low protein intake causes malnutrition in predialysis patients. As far as we can determine, there is no evidence supporting the first assumption in patients previously receiving a well-designed, low-protein diet. However, most predialysis patients receive little or no dietary instruction and, therefore, are not on well-designed, low-protein diets. In
such individuals, the development of malnutrition parallels the progression of uremia and anorexia, as dietary intake of calories and protein falls [23]. The appropriate response to these developments, we believe, is the institution of a well-designed, low-protein diet, rather than early dialysis. There are also no data supporting the second assumption, with the obvious exception of starting dialysis in severely uremic patients. The third assumption is also unsupported by the literature: Protein nutrition of CRF patients is usually maintained or improved by low-protein or supplemented very low protein diets. Hence, a well-planned, low-protein diet not only maintains or improves nutritional state (including serum albumin levels) in predialysis patients, but by reducing symptoms, it also delays the need for dialysis. Moreover, substantial evidence suggests that it may also slow the rate of progression of renal insufficiency. The benefits of a nutritional regimen include the following: (a) reduction in (or delayed onset of) symptoms and signs of uremia; (b) forestalling complications by lowering the accumulation of waste products at any given level of glomerular filtration rate (GFR); and (c) perhaps slowing the rate of decline of GFR. Objections that have been raised include cost, poor compliance, and perhaps the increased risk of malnutrition. In this article, we review the evidence supporting each of these benefits, as well as the evidence for each of these objections. BENEFITS Symptoms and signs It has been repeatedly demonstrated that proteinrestricted diets reduce uremic signs and symptoms [24– 43]. Almost all of the manifestations of the uremic state are ameliorated, with the exception of anemia; even peripheral neuropathy [37], insulin resistance [44, 45], red cell lipid peroxidation [46], and osteodystrophy [47, 48] can improve. Improvement in osteodystrophy may be related to the reduced phosphorus intake associated with a protein-restricted diet. Most of the same symptomatic and biochemical bene-
Key words: chronic renal failure, diet, protein metabolism, renal disease and diet, dialysis. Received for publication October 13, 1997 and in revised form June 23, 1998 Accepted for publication July 1, 1998
1999 by the International Society of Nephrology
771
772
Walser et al: Protein intake in predialysis patients
fits ensue with either low-protein diets or very low protein diets supplemented by essential amino acids or ketoacids. Although many improvements have been observed following the introduction of a very low protein diet supplemented by ketoanalogues [43–58], claims for unique biochemical effects of ketoacids have not been proven. In a small number of studies [59–63], the biochemical effects of essential amino acid supplements have been compared with the effects of ketoacid supplements to the same very low protein diet. Only minor differences in serum and urine biochemical parameters have been found between these two regimens, and no difference in nitrogen balance or protein turnover has been found [63]. Because ketoacids are not currently available in United States, this discussion focuses principally on the use of two regimens: a low-protein diet (0.6 g/kg) and an essential amino acid-supplemented, very low protein diet (0.3 g/kg). Forestalling dialysis The production of urea and other nitrogenous waste products depends on protein intake [64]. Because symptoms are correlated with (but not necessarily caused by) the level of serum urea nitrogen [27, 29, 31], symptoms at any given level of renal function are reduced by protein restriction. Unless nitrogen balance becomes negative, the decrease in urea nitrogen output must be nearly equal to the decrease in nitrogen intake, as other components of nitrogen excretion are scarcely affected by protein restriction [42, 64]. Thus, serum urea nitrogen concentration falls proportionately more than N intake. Maintenance dialysis therapy is often initiated when uremic symptoms begin. Consequently, the need to initiate dialysis may be deferred by low-protein diets, even if there is no change in the rate of loss of renal function. The number of months that dialysis is postponed will vary with the rate of progression. If GFR is declining rapidly, for example, 1 ml/min/month, protein restriction will only delay dialysis by a few months (assuming that it has no effect on progression), but if progression continues at a more common rate of 0.3 ml/min/month (3.6 ml/min/ year) [65, 66], protein restriction may postpone dialysis by a year or more. For example, in the Modification of Diet in Renal Disease (MDRD) Study, patients with lower protein intakes had significantly lower GFR and higher serum creatinine concentrations (that is, more advanced renal insufficiency) just prior to dialysis than those consuming a higher protein intake [67]. It was concluded that dietary protein restriction prolonged the interval to renal death in part by delaying the occurrence of uremic symptoms. We have found that dialysis can safely be deferred by dietary therapy for a median of one year after patients reach the GFR level (10 ml/min in nondiabetics and 15 ml/min in diabetics), which is defined by Medicare [68] as the criterion for reimburse-
ment for chronic dialysis therapy (see note added in proof). Progression The effect of protein restriction on the rate of loss of renal function remains uncertain [65]. The MDRD Study was the most extensive trial devoted to this question, but it nevertheless yielded an ambiguous result [66, 67]. This uncertainty has led some workers to conclude that protein restriction is not advisable, but as noted in the preceding section, protein restriction reduces symptoms and signs and also forestalls dialysis even if it has no effect on progression. Although the MDRD Study was a sophisticated multicenter trial, certain aspects of the design made the results difficult to interpret. These aspects have been discussed in detail [65] and are only briefly considered here. There were positive trends emerging when the MDRD Study ended after an average follow-up of only 2.2 years. This is a short trial compared with the typical course of renal failure. For example, in the Diabetes Control and Complications Trial [69], the effects of intensive blood glucose control on the development of long-term complications were examined in patients with insulin-dependent diabetes mellitus; if the patients in this trial had been followed for only 2.2 years, the study would have been negative. Also, in the MDRD Study, a high proportion of patients with polycystic kidney disease, as well as a number of patients in whom renal insufficiency was not progressing, was enrolled; their inclusion may have affected the outcome. In more advanced renal insufficiency, a control group receiving a normal protein intake could not included because this regimen was thought to be harmful. In patients with insulin-dependent diabetic nephropathy (who were excluded from the MDRD Study), protein restriction was shown to slow progression significantly in one well-controlled study [70]. Two meta-analyses of studies of the effects of protein restriction on progression [71, 72] concluded that low-protein diets slow progression of both diabetic and nondiabetic renal disease. However, the validity of meta-analyses has recently been questioned [73]. Whether ketoacid supplements exert an additional effect to slow progression beyond the effect of protein restriction remains uncertain. In a randomized cross-over study, using the ketoacid-based formulation designated “EE,” Walser et al found significantly slower progression (by 45%, P 5 0.024) in 16 patients in comparison with the same diet supplemented by essential amino acids [60]. In the Feasibility Phase of the MDRD Study, formulation “EE” plus a 0.3 g/kg protein diet was given to patients with advanced renal failure. These patients progressed significantly more slowly than patients given an essential amino acid supplement to the same diet [74]. In the full-scale MDRD Study, a different ketoacid for-
Walser et al: Protein intake in predialysis patients
mulation was employed [66, 74]. Progression was again slower in those who received the supplement, but the effect was only marginally significant (P , 0.07) despite the larger number of patients studied [66]. On the other hand, in a retrospective analysis of these data in patients with advanced renal failure, the actual (as opposed to prescribed) protein intake was associated with slowed progression [67]; prescription of the ketoacid mixture used in this trial conferred no additional benefit (compliance with this prescription was not taken into account). Further studies of these questions are needed. OBJECTIONS Cost One objection to the use of low-protein regimens is their expense. High-protein foods, however, are the most costly items on most shopping lists, and limiting them leads to substantial savings. Special low-protein foods are a useful (although not essential) adjunct to such diets (especially very low protein diets) and are more expensive. However, low-protein bread, made at home by hand or in a bread-making machine, costs little more than that purchased in a grocery store. Essential amino acid tablets, at a dose of 10 g/day, cost z$4 per day (such as Aminesst, Nestle´ Homelink), which is generally less than the foods they replace. The major cost of a lowprotein regimen is the services of a skilled dietitian. The number of times individual patients must be seen after the first visit with the dietitian varies greatly; some individuals require frequent counseling, whereas one or two visits suffice for others. In the MDRD Study, the time requirement for counseling by a dietitian was considerable, owing to the research aspects of the study [75]. The issue of the reimbursement of dietitian services is beyond the scope of this review, but needs to be addressed. Thus, low-protein regimens do not cost more than ordinary food for most patients, except for the services of the dietitian, the requirement for which varies widely between patients. More important, the cost of predialysis care, including physician and dietitian fees and laboratory expenses, is substantially less than the cost of dialysis (estimated to average $61,640 per year in 1994 to 1995) [76]; hence, savings attributable to any deferral of dialysis will outweigh the increased predialysis costs. Compliance Another objection is that compliance is difficult to obtain. It is certainly true that some patients refuse the diet, and others fail to comply. However, there are many reports in which measured protein intake averages 25 to 50% above prescribed protein intake, that is, approximately 0.7 g/kg on a prescribed intake of 0.55 g/kg or 0.40 g/kg on a prescribed intake of 0.28 g/kg plus a supplement [43, 59, 60, 66, 70, 77–79]. Although this is an
773
imperfect compliance, it represents a substantial reduction in protein intake. Although these studies employed dietary counseling and monitoring, these techniques are not difficult [34, 60, 64]. This is relevant because there is evidence for retardation of progression of renal failure even when patients are not closely compliant with the protein prescription [60, 67]. In the MDRD Study [78], subjects with the greatest level of satisfaction, in every diet group, were those whose adherence to the diet prescription was the best, as would be expected. It must be emphasized that a low-protein diet represents a major change in lifestyle. A skilled dietitian can design an attractive diet that is restricted in protein content. Support of family members and the individual who prepares the food is critical. Thus, this approach is not feasible for all subjects. However, chronic dialysis is not without its problems: The burdens of dialysis treatments three times per week and dietary as well as fluid restriction are daunting. Most patients require many months to adjust to life on dialysis. Annual mortality of end-stage renal disease patients on dialysis is 24% [80]. Of course, mortality in end-stage renal disease patients who never receive dialysis is eventually 100%, but the mortality of patients whose renal failure is sufficiently severe to qualify for reimbursement by Medicare but are treated conservatively until dialysis becomes unavoidable is far lower: 2.5% per annum in one small series of 67 patients with end-stage renal failure (see note added in proof) and 2.4% per annum in 128 MDRD patients with relatively advanced renal failure [66]. Protein malnutrition Patients on dialysis often consume less than optimal diets and are frequently malnourished [81, 82]. Even well-dialyzed patients may exhibit hypoalbuminemia [83]. The consumption of less than 1 g/kg/day of protein may contribute to the nutritional problems of dialysis patients. However, in predialysis patients, the efficacy of low-protein diets (0.6 g/kg/day) or supplemented very low protein diets (0.3 g/kg/day) in maintaining nutrition is well documented [25–41, 56, 57, 59, 60, 66, 67, 77, 79, 84, 85]. On balance, the evidence supporting the safety of low-protein diets is of moderate-to-good quality clinical science, performed in a variety of clinical situations in different geographic settings. There are several reasons why low-protein diets do not induce malnutrition in patients with CRF. First, these diets provide an adequate intake of energy and other essential nutrients. Second, by providing a greater proportion of high biological value protein (in the 0.6 g/kg protein diet) or the essential amino acids as such (in the supplemented very low protein diet), these regimens contain sufficient amino acids to achieve neutral nitrogen balance. Third, predialysis patients with CRF who do not have complicating illnesses (for example, metabolic
774
Walser et al: Protein intake in predialysis patients
acidosis or glucocorticoid therapy) can activate the same adaptive responses to a low-protein diet as normal adults [79, 86, 87]. For these reasons and because proteinuria serves as an additional stimulus to protein-conserving mechanisms [86], the minimal protein requirement of predialysis patients is no greater than in normal subjects [31, 34, 40, 79, 85–87]. In contrast, predialysis patients who eat too much protein can develop uremic symptoms, including nausea, vomiting, acidosis, and edema (from excess dietary sodium). These complications will reduce the intake of all nutrients and will lead to a decline in nutritional status. Nutritional measurements during both phases of the MDRD Study have confirmed the adequacy of proteinrestricted diets [77, 78, 88]. In the Feasibility Phase [88], which employed an essential amino acid supplement as well as a ketoacid supplement, serum albumin and transferrin levels declined in a few patients but did not become subnormal. No patients became malnourished, even though mean energy intake fell below recommended values. In the full-scale MDRD trial [77], patients assigned to the low-protein or very low protein diets lost approximately 2 kg and showed a decrease in other anthropometric parameters during the first four months only, probably because of reduced energy intake. Serum albumin levels rose but transferrin levels fell (although not to subnormal values) in patients assigned to lowprotein or very low protein diets. In summary, “Biochemical and anthropometric indices of nutritional status during follow-up were generally well within normal limits in all four diet groups” [77]. A progressive decline in creatinine excretion was observed in the low-protein groups and was probably related to reduced meat intake and/or to increasing degradation of creatinine [89]. Loss of skeletal muscle mass could not have contributed in a major way to the reduction of urinary creatinine excretion because arm muscle area remained the same or decreased only slightly. Importantly, the low-protein regimens were not associated with higher rates of death, hospitalization, or any signs of malnutrition. We reported that patients treated for 6 to 72 months with supplemented very low protein diets rarely exhibit hypoalbuminemia even at the start of renal replacement therapy, in contrast to a 25 to 50% incidence of hypoalbuminemia at the start of chronic dialysis nationwide [90]. Furthermore, survival during the first two years of dialysis was not adversely affected by protein restriction. On the contrary, it was substantially better than survival rates reported nationwide, after adjusting for age, race, gender, and diagnosis [91]. However, it is important to note that these comparisons lack statistical validity because of the marked differences in prior follow-up, comorbidities, and diagnoses. The only study that we have identified in which malnutrition may have developed on a supplemented very low
protein diet is that of Lucas et al [50], who prescribed a diet containing only 0.2 g/kg/day of protein. They found that serum albumin and transferrin levels remained constant, but body weight and arm muscle circumference decreased. By contrast, we are not aware of any studies reporting that serum albumin levels can be augmented by increasing protein intake. Encouraging patients to eat more protein could increase uremic symptoms and worsen nutritional status. Only under special conditions have recommendations to increase protein intake been advocated. For example, the recently promulgated “DOQI” guidelines [92] state, “With urinary protein losses in the nephrotic range . . . a nPNA of 0.9 g/kg/day or more may be necessary to maintain nitrogen balance. Comorbid causes of anorexia such as gastroparesis, infection, acidosis, and depression should be identified and treated. However, if these measures fail to restore nPNA to 0.8 g/kg/day or higher, the Work Group recommends that dialysis be initiated.” On the contrary, we recommend that normalized protein N appearance (nPNA) be reduced, as part of a carefully designed diet plan, before dialysis is initiated. In nephrotic patients, high-protein diets were recommended until recently to compensate for urinary protein losses. This recommendation was questioned when Kaysen et al reported that restriction of dietary protein to 0.8 g/kg led to a decrease in urinary protein loss and an increase of 0.21 g/dl in serum albumin concentration [93]. These results have been repeatedly confirmed [94]. For example, when five nephrotic patients with 3 to 14 g/day of proteinuria were fed 0.8 g/kg of dietary protein (plus 1 g of dietary protein per gram of proteinuria), nitrogen balance was neutral or positive [86]. When 16 nephrotic patients were prescribed a very low protein diet (0.3 g/kg) supplemented by essential amino acids (or, in a few, ketoacids), serum albumin increased and serum cholesterol and proteinuria decreased [94]. The small number of patients makes it impossible to generalize from these observations, but the dictum that protein should not be severely restricted in nephrotic subjects needs reconsideration. In addition to reducing the accumulation of waste nitrogen, dietary protein restriction also reduces phosphorus intake and hydrogen ion generation. In fact, the only source of acid in a subject in nitrogen balance is dietary protein. The consequences, in terms of biochemical abnormalities, of omitting dietary therapy are well demonstrated by a survey of 911 patients followed for up to seven years, apparently with little or no dietary protein restriction [95]. In patients with serum creatinine of more than 5 mg/dl, acidosis was common (serum CO2 was below 15 mm in one third of these patients), serum phosphate was above 7 mg/dl in one third, and serum urea N was above 120 mg/dl in one third. By contrast, very few of the patients we have treated long-term [27, 29, 34, 41, 59, 60, 79, 85] or followed until dialysis (see note
Walser et al: Protein intake in predialysis patients
added in proof) have exhibited such severe abnormalities. Treatment of the predialysis patient also involves other measures, such as control of hypertension, fluid balance, calcium and phosphorus levels and bone demineralization, serum concentrations of bicarbonate, potassium and uric acid, and anemia, and optimizing energy intake. Correction of acidosis is particularly important because acidosis promotes protein catabolism [96]. We attempt to keep serum CO2 $ 22 mEq/liter and prescribe sodium bicarbonate in a large proportion of our patients with advanced renal failure. Several groups have recently reported that patient education by a multidisciplinary team can forestall dialysis, reduce the frequency of urgent initiation of dialysis, and reduce the number of hospital days in the first month of dialysis [97–99]. Thus, there are many as yet unexplored opportunities for improving the quality of predialysis care, not the least of which is a protein-restricted diet. In summary, the evidence indicates that when properly implemented, low-protein diets preserve nutritional status in patients with chronic renal failure. The benefits include the amelioration of uremic symptoms and biochemical abnormalities, delaying the time to dialysis, and possibly slowing the rate of progression of renal failure. Neither compliance nor cost need be obstacles in most subjects. These considerations do not provide clear guidance as to how to manage a patient who has not received dietary counseling and who has become progressively uremic and hypoalbuminemic. Starting dialysis will surely ameliorate the symptoms and perhaps correct the hypoalbuminemia (this has yet to be shown), but will expose the patient to the inconvenience and expense of this treatment. Furthermore, once dialysis has begun, the likelihood of returning to conservative treatment is low. Starting a low-protein regimen and correcting electrolyte and acid-base balance as well as anemia may forestall dialysis but is not likely to be successful unless some renal function remains, for example, a GFR of 5 ml/min or greater. CONCLUSIONS Protein-restricted diets have been recommended for decades in the management of CRF in order to reduce the accumulation of waste products. However, evidence that protein malnutrition in chronic dialysis patients predicts an unfavorable outcome has led some workers to advise increasing protein intake in predialysis patients, with an aim to preventing protein malnutrition at the onset of dialysis and also to recommend earlier dialysis as a means of preventing protein malnutrition. The available evidence indicates that, on the contrary, proteinrestricted diets are beneficial in symptomatic predialysis patients. Rather than causing protein malnutrition, these
775
regimens tend to prevent it, provided the diet contains sufficient calories. Dialysis, by contrast, is associated with hypoalbuminemia in 25 to 50% of patients, as well as other evidence for protein–calorie malnutrition, and entails an annual mortality of approximately 24%. Although it has yet to be firmly established that protein restriction slows progression, reduction in signs and symptoms in response to protein restriction has been repeatedly demonstrated; this effect alone will defer dialysis. We conclude that, with rare exceptions, patients with CRF should receive a trial of a protein-restricted regimen before being started on dialysis. NOTE ADDED IN PROOF Walser M, Hill S: Can renal replacement be deferred by a supplemented very low protein diet? J Am Soc Nephrol (in press) Reprint requests to Dr. Mackenzie Walser, Johns Hopkins School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA. E-mail: [email protected]
REFERENCES 1. Beale LS: Kidney Diseases, Urinary Deposits and Calculous Disorders, Their Nature and Treatment. Philadelphia, Lindsay and Blakiston, 1869 2. Bergstro¨m J: Discovery and rediscovery of low protein diet. Clin Nephrol 21:29–34, 1994 3. Giovannetti S: A historical review of low-protein diets, in Nutritional Treatment of Chronic Renal Failure, edited by Giovannetti S, Boston, Kluwer Academic, 1989, pp 1–4 4. Bergstro¨m J: Nutrition and mortality on hemodialysis. J Am Soc Nephrol 6:29–34, 1995 5. Collins AJ, Ma JZ, Umen A, Keshaviah P: Urea index and other predictors of hemodialysis patient survival. Am J Kidney Dis 23:272–282, 1993 6. Goldwasser P, Mittman M, Antigani A, Burrell D, Michel M-A, Collier J, Avram MM: Predictors of mortality on hemodialysis. J Am Soc Nephrol 3:1613–1622, 1993 7. Iseki K, Kawazoe N, Fukiyama K: Serum albumin is a strong predictor of death in chronic dialysis patients. Kidney Int 44:115– 119, 1993 8. Iseki K, Uehara H, Nishime K, Tokuyama K, Yoshihara K, Kinjo K, Shiohira Y, Fukiyama K: Impact of the initial levels of laboratory variables on survival in chronic dialysis patients. Am J Kidney Dis 28:541–548, 1996 9. Kaminski MV Jr, Lowrie EG, Rosenblatt SG, Haase T: Malnutrition is lethal, diagnosable and treatable in ESRD patients. Transplant Proc 23:1810–1815, 1991 10. Lowrie EG, Lew NL: Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 15:458–482, 1990 11. Mailloux LU, Napolitano B, Bellucci AG, Mossey RT, Vernace MA, Wilkes BM: The impact of co-morbid risk factors at the start of dialysis upon the survival of ESRD patients. ASAIO J 42:164–169, 1996 12. Spiegel DM, Breyer JA: Serum albumin: A predictor of long-term outcome in peritoneal dialysis patients. Am J Kidney Dis 23:283–285, 1994 13. Struijk DG, Krediet RT, Koomen GCM, Boeschoten EW, Arisz L: The effect of serum albumin at the start of continuous ambulatory peritoneal dialysis on patient survival. Perit Dial Int 14:121– 126, 1994 14. Khan IH, Catto GR, Edward N, MacLeod AM: Death during the first 90 days of dialysis: A case control study. Am J Kidney Dis 25:276–280, 1995
776
Walser et al: Protein intake in predialysis patients
15. Jungers P, Zingraff J, Albouze G, Chauveau P, Page B, Hannedouche T, Man NK: Late referral for maintenance dialysis: Detrimental consequences. Nephrol Dial Transplant 8:1089–1093, 1993 16. Barrett BJ, Parfrey PS, Morgan J, Barre´ P, Fine A, Goldstein MB, Handa SP, Jindal KK, Kjellstrand CM, Levin A, Mandin H, Muirhead N, Richardson RMA: Prediction of early death in end-stage renal disease patients starting dialysis. Am J Kidney Dis 29:214–222, 1997 17. Avram MM, Goldwasser P, Erroa M, Fein PA: Predictors of survival in continuous ambulatory peritoneal dialysis patients: The importance of prealbumin and other nutritional markers. Am J Kidney Dis 23:91–98, 1994 18. Kopple JD: McCollum Award Lecture, 1996: Protein-energy malnutrition in maintenance dialysis patients. Am J Clin Nutr 65:1544– 1557, 1997 19. Blake PG, Flowerdew G, Blake RM, Orepoulos DG: Serum albumin in patients on continuous ambulatory peritoneal dialysis: Predictors and correlations with outcomes. J Am Soc Nephrol 3:1501–1507, 1993 20. Hakim RM: Initiation of dialysis. Adv Nephrol 23:295–309, 1994 21. Ikizler TA, Hakim RM: Nutrition in end-stage renal disease. Kidney Int 50:343–357, 1996 22. Mehrotra R, Saran R, Moore HL, Prowant BF, Khanna R, Nolph KD: Toward targets for initiation of dialysis. Perit Dial Int 17:497–508, 1997 23. Ikizler TA, Greene J, Wingard RL, Parker RA, Hakim RM: Spontaneous dietary protein intake during progression of chronic renal failure. J Am Soc Nephrol 6:1386–1391, 1995 24. Giordano C: The use of exogenous and endogenous urea for protein synthesis in normal and uremic subjects. J Lab Clin Med 62:231–235, 1963 25. Giovannetti S, Maggiore Q: A low-nitrogen diet with protein of high biological value for severe chronic uremia. Lancet 1:1000– 1004, 1964 26. Schloerb PR: Essential L-amino acid administration in uremia. Am J Med Sci 252:650–659, 1966 27. Kopple JD, Sorenson MK, Coburn JW, Gordon S, Rubini ME: Controlled comparison of 20-g and 40-g protein diets in the treatment of chronic uremia. Am J Clin Nutr 21:553–564, 1968 28. Berlyne GM, Gaan D, Ginks WR: Dietary treatment of chronic renal failure. Am J Clin Nutr 21:547–552, 1968 29. Kopple JD, Shinabaerger JH, Coburn JW, Sorensen MK, Rubini ME: Evaluating modified protein diets for uremia. J Am Diet Assoc 54:481–485, 1969 30. Anderson CF, Nelson RA, Margie JD, Johnson WJ, Hunt JC: Nutritional therapy for adults with renal disease. JAMA 223:68–72, 1973 31. Kopple JD, Coburn JW: Metabolic studies of low protein diets in uremia. I. Nitrogen and potassium. Medicine 52:593–595, 1973 32. Walser M: Ketoacids in the treatment of uremia. Clin Nephrol 3:180–186, 1975 33. Nore´e L-O, Bergstro¨m J: Treatment of chronic uremic patients with protein-poor diet and oral supply of essential amino acids. II. Clinical results of long-term treatment. Clin Nephrol 3:195–203, 1975 34. Kopple JD: Treatment with low protein and amino acid diets in chronic renal failure, in Proceedings of the VIIth International Congress of Nephrology, Montreal, S. Karger, 1978, pp 497–507 35. Attman P-O, Bucht H, Isaksson B, Uddebom G: Nitrogen balance studies with amino acid supplemented low-protein diet in uremia. Am J Clin Nutr 32:2033–2039, 1979 36. Attman P-O, Bucht H, Larsson O, Uddebom G: Protein-reduced diet in diabetic renal failure. Clin Nephrol 19:217–220, 1983 37. Barsotti G: Effects of dietary therapy on uremic symptoms and complications, in Nutritional Therapy of Chronic Renal Failure, edited by Giovannetti S, Boston, Kluwer Academic, 1989, pp 235–240 38. Giovannetti S: The effect of nutritional therapy on blood chemical abnormalities of chronic renal failure, in Nutritional Treatment of Chronic Renal Failure, edited by Giovannetti S, Boston, Kluwer Academic, 1989, pp 231–234 39. Hirschberg RR, Kopple JD: Nutritional therapy in patients with
40. 41.
42. 43. 44.
45.
46.
47.
48.
49. 50. 51. 52.
53.
54.
55.
56.
57.
58.
renal failure, in Care of the Renal Patient, edited by Levine DZ, New York, Saunders, 1991, pp 169–180 Mitch WE, Walser M: Nutritional therapy of the uremic patient, in The Kidney (5th ed), edited by Brenner BM, New York, WB Saunders, 1996, pp 2382–2423 Kopple JD: Nutritional management of nondialyzed patients with chronic renal failure, in Nutritional Management of Renal Disease, edited by Kopple JD, Massry SG, Baltimore, Williams and Wilkins, 1997, pp 479–531 Kopple JD, Gao X-L, Qing DP: Dietary protein, urea nitrogen appearance and total nitrogen appearance in chronic renal failure and CAPD patients. Kidney Int 52:486–494, 1997 Mitch WE, Abras EA, Walser M: Long-term effects of a new ketoacid amino acid supplement in patients with chronic renal failure. Kidney Int 22:48–53, 1982 Gin H, Aparicio M, Potaux L, Merville P, Combe CH, de Precigout V, Bouchet J-L, Aubertin J: Low-protein, low-phosphorus diet and tissue insulin sensitivity in insulin-dependent diabetic patients with chronic renal failure. Nephron 57:411–415, 1991 Gin H, Combe C, Rigalleau V, Delafaye C, Aparicio M, Aubertin J: Effects of a low-protein, low-phosphorus diet on metabolic insulin clearance in patients with chronic renal failure. Am J Clin Nutr 59:663–666, 1994 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 Barsotti G, Morelli E, Guiducci A, Ciardella A, Gianonni A, Lupetti S, Giovannetti S: Reversal of hyperparathyroidism in severe uremics following a very low-protein and low-phosphorus diet. Nephron 30:310–313, 1982 Fro¨hling PT, Kokot F, Schmickler R, Kaschube I, Lindenau K, Vetter K: Influence of keto acids on serum parathyroid hormone levels in patients with chronic renal failure. Clin Nephrol 20:212– 215, 1983 Fro¨hling PT, Schmicker R, Lindenau K, Vetter K, Kokot F: Role of keto acids in the prophylaxis and treatment of renal osteopathy. Contrib Nephrol 65:123–129, 1988 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 Schaefer K, von Herrath D, Asmus G, Umlauf E: The beneficial effect of ketoacids on serum phosphate and parathyroid hormone in patients with chronic uremia. Clin Nephrol 30:93–96, 1988 Lucas PA, Brown RC, Woodhead JS, Coles GA: 1,25-Dihydroxycholecalciferol and parathyroid hormone in advanced chronic renal failure: Effects of simultaneous protein and phosphorus restriction. Clin Nephrol 25:7–10, 1986 Mak RH, Turner C, Thompson T, Haycock G, Chantler C: The effect of a low protein diet with amino acid/keto acid supplements on glucose metabolism in children with uremia. J Clin Endocrinol Metab 63:985–989, 1986 Ciardella F, Cupisti A, Catapano G, Guidi A, Pasquinucci A, Morelli E, Barsotti G: Effects of a low-phosphorus, low-nitrogen diet supplemented with essential amino acids and ketoanalogues on serum beta-endorphin in chronic renal failure. Nephron 53:129– 132, 1989 Ciardella F, Morelli ZE, Niosi F, Caprioli R, Baldi R, Petronio G, Carbone C, Barsotti G: Effect of a low phosphorus, low nitrogen diet supplemented with essential amino acids and ketoanalogues on serum triglycerides of chronic uremic patients. Nephron 42:196–199, 1989 Combe C, Deforges-Lassuer C, Caix J, Pommereau A, Marot D, Aparicio M: Compliance and effects of nutritional treatment on progression and metabolic disorders of chronic renal failure. Nephrol Dial Transplant 8:412–418, 1993 Mariani G, Barsotti G, Ciardella F, Molea N, Morelli E, Mazzuca N, Niosi F, Bonaguidi F, Fusani L, Panicucci F, Giovannetti S, Bianchi R: Albumin metabolism and nutritional status of uremic patients on a long-term very-low-protein diet supplemented with essential amino acids and keto analogues. J Nucl Med Allied Sci 28:237–244, 1984 Bernard S, Fouque D, Laville M, Zech P: Effects of low-protein
Walser et al: Protein intake in predialysis patients
59. 60. 61.
62. 63. 64. 65. 66.
67.
68.
69.
70.
71. 72.
73. 74. 75.
76. 77.
diet supplemented with ketoacids on plasma lipids in adult chronic renal failure. Miner Electrolyte Metab 22:143–146, 1996 Walser M, Hill S, Ward L: Progression of chronic renal failure on substituting a ketoacid supplement for an amino acid supplement. J Am Soc Nephrol 2:1178–1185, 1992 Walser M, Hill S, Ward L, Magder L: A crossover comparison of progression of chronic renal failure: Ketoacids vs. amino acids. Kidney Int 43:933–939, 1993 Schmicker R, Vetter K, Lindenau K, Fro¨hling PT, Kokot F: Conservative long-term treatment of chronic renal failure with keto acid and amino acid supplements. Infusionstherapie 14(Suppl 5):34–38, 1987 Teplan V, Schuck O, Mengerova O, Ruzickova J: Individualized supplemented low-protein diet in patients with chronic kidney failure. Vnitr Lek 40:623–627, 1994 Maroni BJ, Tom K, Masud T, Chapman T, Young VR: How is lean body mass conserved with the very-low protein diet? Miner Electrolyte Metab 22:54–57, 1996 Maroni BJ, Steinman TI, Mitch WE: A method for estimating nitrogen intake of patients with chronic renal failure. Kidney Int 27:58–65, 1985 Maroni BJ, Mitch WE: Role of nutrition in prevention of the progression of renal disease. Annu Rev Nutr 17:435–455, 1997 Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker LG, Kusek JW, Striker G: The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. N Engl J Med 330:877–884, 1994 Levey AS, Adler S, Caggiula AW, England BK, Greene T, Hunsicker LG, Kusek JW, Rogers NL, Teschan PE, for the Modification of Diet in Renal Disease Study Group: Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease Study. Am J Kidney Dis 27:652–663, 1996 Anonymous: End Stage Renal Disease Medical Evidence Report Medicare Entitlement and/or Patient Registration Form (HCFA 2728), Health Care Financing Administration, Washington, D.C., April 1, 1997 The Diabetes Control and Complications Trial Research Group: The effects of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. N Engl J Med 329:977–986, 1993 Zeller K, Whittaker E, Sullivan L, Raskin P, Jacobson HR: Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus. N Engl J Med 324:78–84, 1991 Fouque D, Laville M, Boissel JP, Chifflet R, Labeeuw M, Zech PY: Controlled low protein diets in chronic renal insufficiency: Meta-analysis. BMJ 304:216–220, 1992 Pedrini MT, Levey AJ, Lau J, Chalmers TC, Wang PH: The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal disease: A meta-analysis. Ann Intern Med 124:627–632, 1996 Lelorier J, Gre´goire G, Benhaddad A, Lapierre J, Derderian F: Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med 337:536–542, 1997 Walser M: Do ketoacid-supplemented diets slow progression of chronic renal failure? A review of published studies. Int Yearbook Nephrol 1996:119–126, 1996 Dolecek TA, Olson MB, Caggiula AW, Dwyer JT, Milas NC, Gillis BP, Hartman JA, Dichiro JT: Registered dietitian time requirements in the Modification of Diet in Renal Disease Study. J Am Diet Assoc 95:1307–1312, 1995 Bruns FJ, Seddon P, Saul M, Zeidel ML: The costs of caring for end-stage kidney patients: An analysis based on hospital financial records. J Am Soc Nephrol 9:884–890, 1998 Modification of Diet in Renal Disease Study Group, Kopple JD, Levey AS, Greene T, Chumlea WC, Gassman JJ, Hollimger DL, Maroni BJ, Merrill D, Scherch LK, Schulman G, Wang S-R, Zimmer GS: Effect of dietary protein restriction on nutritional
78. 79. 80. 81. 82.
83.
84. 85. 86.
87.
88. 89. 90. 91. 92.
93. 94. 95. 96. 97.
98. 99.
777
status in the Modification of Diet in Renal Disease Study. Kidney Int 52:778–791, 1997 Anonymous: Reduction of dietary protein and phosphorus in the Modification of Diet in Renal Disease Study. J Am Diet Assoc 94:986–990, 1994 Tom K, Young VR, Chapman T, Masud T, Akpele L, Maroni BJ: Long-term responses to dietary protein restriction in chronic renal failure. Am J Physiol 268:E668–E677, 1995 United States Renal Data System USRDS: Annual Data Report. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, April 1997 Bergstro¨m J: Why are dialysis patients malnourished? Am J Kidney Dis 26:229–241, 1995 Ahmed KR, Kopple JD: Nutrition in maintenance hemodialysis patients, in Nutritional Management of Renal Disease, edited by Kopple JD, Massry SG, Baltimore, Williams and Wilkins, 1997, pp 563–600 Maroni BJ, Burkhart J, Burrowes J, Cockram D, Drabik M, Dwyer J, Kusek J, Makoff R, Paranandi L, Powers S, Rocco M: Baseline nutritional characteristics of the HEMO study participants: Interim report. (abstract) J Am Soc Nephrol 7:1456, 1996 Walser M: Does prolonged protein restriction preceding dialysis lead to protein malnutrition at the onset of dialysis? Kidney Int 48:1139–1144, 1993 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 45:1182–1192, 1994 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 Goodship THJ, 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 MDRD Study Group: The Modification of Diet in Renal Disease Study: Design, methods and results from the Feasibility Study. Am J Kidney Dis 20:18–33, 1992 Mitch WE, Collier VU, Walser M: Creatinine metabolism in chronic renal failure. Clin Sci 58:327–335, 1980 Deleted in proof. Coresh J, Walser M, Hill S: Survival on dialysis among renal failure patients treated with a supplemented low-protein diet before dialysis. J Am Soc Nephrol 6:1379–1385, 1995 National Kidney Foundation-Dialysis Outcomes Quality Initiative (NKF-DOQI) Clinical Practice Guidelines for Peritoneal Dialysis Adequacy. I. Initiation of Dialysis, Guideline 2. Am J Kidney Dis 30(Suppl 2):S72–S73, 1997 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 Walser M, Hill S, Tomalis EA: Treatment of nephrotic adults with a supplemented, very low-protein diet. Am J Kidney Dis 11:354– 364, 1996 Hakim RM, Lazarus JM: Biochemical parameters in chronic renal failure. Am J Kidney Dis 9:238–247, 1988 Price SR, Mitch WE: Metabolic acidosis and uremic toxicity: Protein and amino acid metabolism. Semin Nephrol 14:232–237, 1994 Binik YM, Devins GM, Barre PE, Guttman RD, Hollomby DJ, Mandin H, Paul LC, Hons RB, Burgess ED: Live and learn: Patient education delays the need to initiate renal replacement therapy in end-stage renal disease. J Nerv Ment Dis 181:371–376, 1993 Hayslip DM, Suttle CD: Pre-ESRD patient education: A review of the literature. Adv Ren Replace Ther 2:217–226, 1995 Levin A, Lewis M, Mortiboy P, Faber S, Hare I, Porter EC, Mendelssohn DC: Multidisciplinary predialysis programs: Quantification and limitations of their impact on patient outcomes in two Canadian settings. Am J Kidney Dis 29:533–540, 1997
PERSPECTIVES IN RENAL MEDICINE
Should protein intake be restricted in predialysis patients? MACKENZIE WALSER, WILLIAM E. MITCH, BRADLEY J. MARONI, and JOEL D. KOPPLE Johns Hopkins School of Medicine, Baltimore, Maryland; Emory University School of Medicine, Atlanta, Georgia; and Harbor-UCLA Medical Center and the UCLA Schools of Medicine and Public Health, Los Angeles, California, USA
It has been known for at least 100 years that protein restriction reduces symptoms in chronic renal failure (CRF) [1]. Because most of these symptoms are caused by accumulation of the products of protein metabolism, this is to be expected. The history of the use of proteinrestricted diets in renal disease has been reviewed elsewhere [2, 3]. In the last decade, two findings have cast doubt on the wisdom of administering low-protein diets to CRF patients: First, a large body of evidence has documented that hypoalbuminemia in dialysis patients is a major risk factor for mortality, whether present at the onset of dialysis or developed during dialysis [4–19]. Other indices of nutritional status, such as urea nitrogen appearance and predialysis levels of creatinine and cholesterol, are also correlated with mortality [4–19]. Second, the hypothesis that protein restriction slows the progression of CRF (another rationale for its use) has not been unequivocally confirmed (discussed later here). As a result of these findings, some workers have questioned the wisdom of restricting protein intake [20–22]. Furthermore, they have suggested that if spontaneous protein intake falls below 0.8 g/kg/day, patients are at increased risk of malnutrition, and the appropriate response is to start dialysis unless protein intake can be increased. The assumptions underlying these recommendations are that: (a) protein nutrition will improve in predialysis patients if protein intake increases; (b) dialysis improves dietary intake and nutritional status; and (c) low protein intake causes malnutrition in predialysis patients. As far as we can determine, there is no evidence supporting the first assumption in patients previously receiving a well-designed, low-protein diet. However, most predialysis patients receive little or no dietary instruction and, therefore, are not on well-designed, low-protein diets. In
such individuals, the development of malnutrition parallels the progression of uremia and anorexia, as dietary intake of calories and protein falls [23]. The appropriate response to these developments, we believe, is the institution of a well-designed, low-protein diet, rather than early dialysis. There are also no data supporting the second assumption, with the obvious exception of starting dialysis in severely uremic patients. The third assumption is also unsupported by the literature: Protein nutrition of CRF patients is usually maintained or improved by low-protein or supplemented very low protein diets. Hence, a well-planned, low-protein diet not only maintains or improves nutritional state (including serum albumin levels) in predialysis patients, but by reducing symptoms, it also delays the need for dialysis. Moreover, substantial evidence suggests that it may also slow the rate of progression of renal insufficiency. The benefits of a nutritional regimen include the following: (a) reduction in (or delayed onset of) symptoms and signs of uremia; (b) forestalling complications by lowering the accumulation of waste products at any given level of glomerular filtration rate (GFR); and (c) perhaps slowing the rate of decline of GFR. Objections that have been raised include cost, poor compliance, and perhaps the increased risk of malnutrition. In this article, we review the evidence supporting each of these benefits, as well as the evidence for each of these objections. BENEFITS Symptoms and signs It has been repeatedly demonstrated that proteinrestricted diets reduce uremic signs and symptoms [24– 43]. Almost all of the manifestations of the uremic state are ameliorated, with the exception of anemia; even peripheral neuropathy [37], insulin resistance [44, 45], red cell lipid peroxidation [46], and osteodystrophy [47, 48] can improve. Improvement in osteodystrophy may be related to the reduced phosphorus intake associated with a protein-restricted diet. Most of the same symptomatic and biochemical bene-
Key words: chronic renal failure, diet, protein metabolism, renal disease and diet, dialysis. Received for publication October 13, 1997 and in revised form June 23, 1998 Accepted for publication July 1, 1998
1999 by the International Society of Nephrology
771
772
Walser et al: Protein intake in predialysis patients
fits ensue with either low-protein diets or very low protein diets supplemented by essential amino acids or ketoacids. Although many improvements have been observed following the introduction of a very low protein diet supplemented by ketoanalogues [43–58], claims for unique biochemical effects of ketoacids have not been proven. In a small number of studies [59–63], the biochemical effects of essential amino acid supplements have been compared with the effects of ketoacid supplements to the same very low protein diet. Only minor differences in serum and urine biochemical parameters have been found between these two regimens, and no difference in nitrogen balance or protein turnover has been found [63]. Because ketoacids are not currently available in United States, this discussion focuses principally on the use of two regimens: a low-protein diet (0.6 g/kg) and an essential amino acid-supplemented, very low protein diet (0.3 g/kg). Forestalling dialysis The production of urea and other nitrogenous waste products depends on protein intake [64]. Because symptoms are correlated with (but not necessarily caused by) the level of serum urea nitrogen [27, 29, 31], symptoms at any given level of renal function are reduced by protein restriction. Unless nitrogen balance becomes negative, the decrease in urea nitrogen output must be nearly equal to the decrease in nitrogen intake, as other components of nitrogen excretion are scarcely affected by protein restriction [42, 64]. Thus, serum urea nitrogen concentration falls proportionately more than N intake. Maintenance dialysis therapy is often initiated when uremic symptoms begin. Consequently, the need to initiate dialysis may be deferred by low-protein diets, even if there is no change in the rate of loss of renal function. The number of months that dialysis is postponed will vary with the rate of progression. If GFR is declining rapidly, for example, 1 ml/min/month, protein restriction will only delay dialysis by a few months (assuming that it has no effect on progression), but if progression continues at a more common rate of 0.3 ml/min/month (3.6 ml/min/ year) [65, 66], protein restriction may postpone dialysis by a year or more. For example, in the Modification of Diet in Renal Disease (MDRD) Study, patients with lower protein intakes had significantly lower GFR and higher serum creatinine concentrations (that is, more advanced renal insufficiency) just prior to dialysis than those consuming a higher protein intake [67]. It was concluded that dietary protein restriction prolonged the interval to renal death in part by delaying the occurrence of uremic symptoms. We have found that dialysis can safely be deferred by dietary therapy for a median of one year after patients reach the GFR level (10 ml/min in nondiabetics and 15 ml/min in diabetics), which is defined by Medicare [68] as the criterion for reimburse-
ment for chronic dialysis therapy (see note added in proof). Progression The effect of protein restriction on the rate of loss of renal function remains uncertain [65]. The MDRD Study was the most extensive trial devoted to this question, but it nevertheless yielded an ambiguous result [66, 67]. This uncertainty has led some workers to conclude that protein restriction is not advisable, but as noted in the preceding section, protein restriction reduces symptoms and signs and also forestalls dialysis even if it has no effect on progression. Although the MDRD Study was a sophisticated multicenter trial, certain aspects of the design made the results difficult to interpret. These aspects have been discussed in detail [65] and are only briefly considered here. There were positive trends emerging when the MDRD Study ended after an average follow-up of only 2.2 years. This is a short trial compared with the typical course of renal failure. For example, in the Diabetes Control and Complications Trial [69], the effects of intensive blood glucose control on the development of long-term complications were examined in patients with insulin-dependent diabetes mellitus; if the patients in this trial had been followed for only 2.2 years, the study would have been negative. Also, in the MDRD Study, a high proportion of patients with polycystic kidney disease, as well as a number of patients in whom renal insufficiency was not progressing, was enrolled; their inclusion may have affected the outcome. In more advanced renal insufficiency, a control group receiving a normal protein intake could not included because this regimen was thought to be harmful. In patients with insulin-dependent diabetic nephropathy (who were excluded from the MDRD Study), protein restriction was shown to slow progression significantly in one well-controlled study [70]. Two meta-analyses of studies of the effects of protein restriction on progression [71, 72] concluded that low-protein diets slow progression of both diabetic and nondiabetic renal disease. However, the validity of meta-analyses has recently been questioned [73]. Whether ketoacid supplements exert an additional effect to slow progression beyond the effect of protein restriction remains uncertain. In a randomized cross-over study, using the ketoacid-based formulation designated “EE,” Walser et al found significantly slower progression (by 45%, P 5 0.024) in 16 patients in comparison with the same diet supplemented by essential amino acids [60]. In the Feasibility Phase of the MDRD Study, formulation “EE” plus a 0.3 g/kg protein diet was given to patients with advanced renal failure. These patients progressed significantly more slowly than patients given an essential amino acid supplement to the same diet [74]. In the full-scale MDRD Study, a different ketoacid for-
Walser et al: Protein intake in predialysis patients
mulation was employed [66, 74]. Progression was again slower in those who received the supplement, but the effect was only marginally significant (P , 0.07) despite the larger number of patients studied [66]. On the other hand, in a retrospective analysis of these data in patients with advanced renal failure, the actual (as opposed to prescribed) protein intake was associated with slowed progression [67]; prescription of the ketoacid mixture used in this trial conferred no additional benefit (compliance with this prescription was not taken into account). Further studies of these questions are needed. OBJECTIONS Cost One objection to the use of low-protein regimens is their expense. High-protein foods, however, are the most costly items on most shopping lists, and limiting them leads to substantial savings. Special low-protein foods are a useful (although not essential) adjunct to such diets (especially very low protein diets) and are more expensive. However, low-protein bread, made at home by hand or in a bread-making machine, costs little more than that purchased in a grocery store. Essential amino acid tablets, at a dose of 10 g/day, cost z$4 per day (such as Aminesst, Nestle´ Homelink), which is generally less than the foods they replace. The major cost of a lowprotein regimen is the services of a skilled dietitian. The number of times individual patients must be seen after the first visit with the dietitian varies greatly; some individuals require frequent counseling, whereas one or two visits suffice for others. In the MDRD Study, the time requirement for counseling by a dietitian was considerable, owing to the research aspects of the study [75]. The issue of the reimbursement of dietitian services is beyond the scope of this review, but needs to be addressed. Thus, low-protein regimens do not cost more than ordinary food for most patients, except for the services of the dietitian, the requirement for which varies widely between patients. More important, the cost of predialysis care, including physician and dietitian fees and laboratory expenses, is substantially less than the cost of dialysis (estimated to average $61,640 per year in 1994 to 1995) [76]; hence, savings attributable to any deferral of dialysis will outweigh the increased predialysis costs. Compliance Another objection is that compliance is difficult to obtain. It is certainly true that some patients refuse the diet, and others fail to comply. However, there are many reports in which measured protein intake averages 25 to 50% above prescribed protein intake, that is, approximately 0.7 g/kg on a prescribed intake of 0.55 g/kg or 0.40 g/kg on a prescribed intake of 0.28 g/kg plus a supplement [43, 59, 60, 66, 70, 77–79]. Although this is an
773
imperfect compliance, it represents a substantial reduction in protein intake. Although these studies employed dietary counseling and monitoring, these techniques are not difficult [34, 60, 64]. This is relevant because there is evidence for retardation of progression of renal failure even when patients are not closely compliant with the protein prescription [60, 67]. In the MDRD Study [78], subjects with the greatest level of satisfaction, in every diet group, were those whose adherence to the diet prescription was the best, as would be expected. It must be emphasized that a low-protein diet represents a major change in lifestyle. A skilled dietitian can design an attractive diet that is restricted in protein content. Support of family members and the individual who prepares the food is critical. Thus, this approach is not feasible for all subjects. However, chronic dialysis is not without its problems: The burdens of dialysis treatments three times per week and dietary as well as fluid restriction are daunting. Most patients require many months to adjust to life on dialysis. Annual mortality of end-stage renal disease patients on dialysis is 24% [80]. Of course, mortality in end-stage renal disease patients who never receive dialysis is eventually 100%, but the mortality of patients whose renal failure is sufficiently severe to qualify for reimbursement by Medicare but are treated conservatively until dialysis becomes unavoidable is far lower: 2.5% per annum in one small series of 67 patients with end-stage renal failure (see note added in proof) and 2.4% per annum in 128 MDRD patients with relatively advanced renal failure [66]. Protein malnutrition Patients on dialysis often consume less than optimal diets and are frequently malnourished [81, 82]. Even well-dialyzed patients may exhibit hypoalbuminemia [83]. The consumption of less than 1 g/kg/day of protein may contribute to the nutritional problems of dialysis patients. However, in predialysis patients, the efficacy of low-protein diets (0.6 g/kg/day) or supplemented very low protein diets (0.3 g/kg/day) in maintaining nutrition is well documented [25–41, 56, 57, 59, 60, 66, 67, 77, 79, 84, 85]. On balance, the evidence supporting the safety of low-protein diets is of moderate-to-good quality clinical science, performed in a variety of clinical situations in different geographic settings. There are several reasons why low-protein diets do not induce malnutrition in patients with CRF. First, these diets provide an adequate intake of energy and other essential nutrients. Second, by providing a greater proportion of high biological value protein (in the 0.6 g/kg protein diet) or the essential amino acids as such (in the supplemented very low protein diet), these regimens contain sufficient amino acids to achieve neutral nitrogen balance. Third, predialysis patients with CRF who do not have complicating illnesses (for example, metabolic
774
Walser et al: Protein intake in predialysis patients
acidosis or glucocorticoid therapy) can activate the same adaptive responses to a low-protein diet as normal adults [79, 86, 87]. For these reasons and because proteinuria serves as an additional stimulus to protein-conserving mechanisms [86], the minimal protein requirement of predialysis patients is no greater than in normal subjects [31, 34, 40, 79, 85–87]. In contrast, predialysis patients who eat too much protein can develop uremic symptoms, including nausea, vomiting, acidosis, and edema (from excess dietary sodium). These complications will reduce the intake of all nutrients and will lead to a decline in nutritional status. Nutritional measurements during both phases of the MDRD Study have confirmed the adequacy of proteinrestricted diets [77, 78, 88]. In the Feasibility Phase [88], which employed an essential amino acid supplement as well as a ketoacid supplement, serum albumin and transferrin levels declined in a few patients but did not become subnormal. No patients became malnourished, even though mean energy intake fell below recommended values. In the full-scale MDRD trial [77], patients assigned to the low-protein or very low protein diets lost approximately 2 kg and showed a decrease in other anthropometric parameters during the first four months only, probably because of reduced energy intake. Serum albumin levels rose but transferrin levels fell (although not to subnormal values) in patients assigned to lowprotein or very low protein diets. In summary, “Biochemical and anthropometric indices of nutritional status during follow-up were generally well within normal limits in all four diet groups” [77]. A progressive decline in creatinine excretion was observed in the low-protein groups and was probably related to reduced meat intake and/or to increasing degradation of creatinine [89]. Loss of skeletal muscle mass could not have contributed in a major way to the reduction of urinary creatinine excretion because arm muscle area remained the same or decreased only slightly. Importantly, the low-protein regimens were not associated with higher rates of death, hospitalization, or any signs of malnutrition. We reported that patients treated for 6 to 72 months with supplemented very low protein diets rarely exhibit hypoalbuminemia even at the start of renal replacement therapy, in contrast to a 25 to 50% incidence of hypoalbuminemia at the start of chronic dialysis nationwide [90]. Furthermore, survival during the first two years of dialysis was not adversely affected by protein restriction. On the contrary, it was substantially better than survival rates reported nationwide, after adjusting for age, race, gender, and diagnosis [91]. However, it is important to note that these comparisons lack statistical validity because of the marked differences in prior follow-up, comorbidities, and diagnoses. The only study that we have identified in which malnutrition may have developed on a supplemented very low
protein diet is that of Lucas et al [50], who prescribed a diet containing only 0.2 g/kg/day of protein. They found that serum albumin and transferrin levels remained constant, but body weight and arm muscle circumference decreased. By contrast, we are not aware of any studies reporting that serum albumin levels can be augmented by increasing protein intake. Encouraging patients to eat more protein could increase uremic symptoms and worsen nutritional status. Only under special conditions have recommendations to increase protein intake been advocated. For example, the recently promulgated “DOQI” guidelines [92] state, “With urinary protein losses in the nephrotic range . . . a nPNA of 0.9 g/kg/day or more may be necessary to maintain nitrogen balance. Comorbid causes of anorexia such as gastroparesis, infection, acidosis, and depression should be identified and treated. However, if these measures fail to restore nPNA to 0.8 g/kg/day or higher, the Work Group recommends that dialysis be initiated.” On the contrary, we recommend that normalized protein N appearance (nPNA) be reduced, as part of a carefully designed diet plan, before dialysis is initiated. In nephrotic patients, high-protein diets were recommended until recently to compensate for urinary protein losses. This recommendation was questioned when Kaysen et al reported that restriction of dietary protein to 0.8 g/kg led to a decrease in urinary protein loss and an increase of 0.21 g/dl in serum albumin concentration [93]. These results have been repeatedly confirmed [94]. For example, when five nephrotic patients with 3 to 14 g/day of proteinuria were fed 0.8 g/kg of dietary protein (plus 1 g of dietary protein per gram of proteinuria), nitrogen balance was neutral or positive [86]. When 16 nephrotic patients were prescribed a very low protein diet (0.3 g/kg) supplemented by essential amino acids (or, in a few, ketoacids), serum albumin increased and serum cholesterol and proteinuria decreased [94]. The small number of patients makes it impossible to generalize from these observations, but the dictum that protein should not be severely restricted in nephrotic subjects needs reconsideration. In addition to reducing the accumulation of waste nitrogen, dietary protein restriction also reduces phosphorus intake and hydrogen ion generation. In fact, the only source of acid in a subject in nitrogen balance is dietary protein. The consequences, in terms of biochemical abnormalities, of omitting dietary therapy are well demonstrated by a survey of 911 patients followed for up to seven years, apparently with little or no dietary protein restriction [95]. In patients with serum creatinine of more than 5 mg/dl, acidosis was common (serum CO2 was below 15 mm in one third of these patients), serum phosphate was above 7 mg/dl in one third, and serum urea N was above 120 mg/dl in one third. By contrast, very few of the patients we have treated long-term [27, 29, 34, 41, 59, 60, 79, 85] or followed until dialysis (see note
Walser et al: Protein intake in predialysis patients
added in proof) have exhibited such severe abnormalities. Treatment of the predialysis patient also involves other measures, such as control of hypertension, fluid balance, calcium and phosphorus levels and bone demineralization, serum concentrations of bicarbonate, potassium and uric acid, and anemia, and optimizing energy intake. Correction of acidosis is particularly important because acidosis promotes protein catabolism [96]. We attempt to keep serum CO2 $ 22 mEq/liter and prescribe sodium bicarbonate in a large proportion of our patients with advanced renal failure. Several groups have recently reported that patient education by a multidisciplinary team can forestall dialysis, reduce the frequency of urgent initiation of dialysis, and reduce the number of hospital days in the first month of dialysis [97–99]. Thus, there are many as yet unexplored opportunities for improving the quality of predialysis care, not the least of which is a protein-restricted diet. In summary, the evidence indicates that when properly implemented, low-protein diets preserve nutritional status in patients with chronic renal failure. The benefits include the amelioration of uremic symptoms and biochemical abnormalities, delaying the time to dialysis, and possibly slowing the rate of progression of renal failure. Neither compliance nor cost need be obstacles in most subjects. These considerations do not provide clear guidance as to how to manage a patient who has not received dietary counseling and who has become progressively uremic and hypoalbuminemic. Starting dialysis will surely ameliorate the symptoms and perhaps correct the hypoalbuminemia (this has yet to be shown), but will expose the patient to the inconvenience and expense of this treatment. Furthermore, once dialysis has begun, the likelihood of returning to conservative treatment is low. Starting a low-protein regimen and correcting electrolyte and acid-base balance as well as anemia may forestall dialysis but is not likely to be successful unless some renal function remains, for example, a GFR of 5 ml/min or greater. CONCLUSIONS Protein-restricted diets have been recommended for decades in the management of CRF in order to reduce the accumulation of waste products. However, evidence that protein malnutrition in chronic dialysis patients predicts an unfavorable outcome has led some workers to advise increasing protein intake in predialysis patients, with an aim to preventing protein malnutrition at the onset of dialysis and also to recommend earlier dialysis as a means of preventing protein malnutrition. The available evidence indicates that, on the contrary, proteinrestricted diets are beneficial in symptomatic predialysis patients. Rather than causing protein malnutrition, these
775
regimens tend to prevent it, provided the diet contains sufficient calories. Dialysis, by contrast, is associated with hypoalbuminemia in 25 to 50% of patients, as well as other evidence for protein–calorie malnutrition, and entails an annual mortality of approximately 24%. Although it has yet to be firmly established that protein restriction slows progression, reduction in signs and symptoms in response to protein restriction has been repeatedly demonstrated; this effect alone will defer dialysis. We conclude that, with rare exceptions, patients with CRF should receive a trial of a protein-restricted regimen before being started on dialysis. NOTE ADDED IN PROOF Walser M, Hill S: Can renal replacement be deferred by a supplemented very low protein diet? J Am Soc Nephrol (in press) Reprint requests to Dr. Mackenzie Walser, Johns Hopkins School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA. E-mail: [email protected]
REFERENCES 1. Beale LS: Kidney Diseases, Urinary Deposits and Calculous Disorders, Their Nature and Treatment. Philadelphia, Lindsay and Blakiston, 1869 2. Bergstro¨m J: Discovery and rediscovery of low protein diet. Clin Nephrol 21:29–34, 1994 3. Giovannetti S: A historical review of low-protein diets, in Nutritional Treatment of Chronic Renal Failure, edited by Giovannetti S, Boston, Kluwer Academic, 1989, pp 1–4 4. Bergstro¨m J: Nutrition and mortality on hemodialysis. J Am Soc Nephrol 6:29–34, 1995 5. Collins AJ, Ma JZ, Umen A, Keshaviah P: Urea index and other predictors of hemodialysis patient survival. Am J Kidney Dis 23:272–282, 1993 6. Goldwasser P, Mittman M, Antigani A, Burrell D, Michel M-A, Collier J, Avram MM: Predictors of mortality on hemodialysis. J Am Soc Nephrol 3:1613–1622, 1993 7. Iseki K, Kawazoe N, Fukiyama K: Serum albumin is a strong predictor of death in chronic dialysis patients. Kidney Int 44:115– 119, 1993 8. Iseki K, Uehara H, Nishime K, Tokuyama K, Yoshihara K, Kinjo K, Shiohira Y, Fukiyama K: Impact of the initial levels of laboratory variables on survival in chronic dialysis patients. Am J Kidney Dis 28:541–548, 1996 9. Kaminski MV Jr, Lowrie EG, Rosenblatt SG, Haase T: Malnutrition is lethal, diagnosable and treatable in ESRD patients. Transplant Proc 23:1810–1815, 1991 10. Lowrie EG, Lew NL: Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 15:458–482, 1990 11. Mailloux LU, Napolitano B, Bellucci AG, Mossey RT, Vernace MA, Wilkes BM: The impact of co-morbid risk factors at the start of dialysis upon the survival of ESRD patients. ASAIO J 42:164–169, 1996 12. Spiegel DM, Breyer JA: Serum albumin: A predictor of long-term outcome in peritoneal dialysis patients. Am J Kidney Dis 23:283–285, 1994 13. Struijk DG, Krediet RT, Koomen GCM, Boeschoten EW, Arisz L: The effect of serum albumin at the start of continuous ambulatory peritoneal dialysis on patient survival. Perit Dial Int 14:121– 126, 1994 14. Khan IH, Catto GR, Edward N, MacLeod AM: Death during the first 90 days of dialysis: A case control study. Am J Kidney Dis 25:276–280, 1995
776
Walser et al: Protein intake in predialysis patients
15. Jungers P, Zingraff J, Albouze G, Chauveau P, Page B, Hannedouche T, Man NK: Late referral for maintenance dialysis: Detrimental consequences. Nephrol Dial Transplant 8:1089–1093, 1993 16. Barrett BJ, Parfrey PS, Morgan J, Barre´ P, Fine A, Goldstein MB, Handa SP, Jindal KK, Kjellstrand CM, Levin A, Mandin H, Muirhead N, Richardson RMA: Prediction of early death in end-stage renal disease patients starting dialysis. Am J Kidney Dis 29:214–222, 1997 17. Avram MM, Goldwasser P, Erroa M, Fein PA: Predictors of survival in continuous ambulatory peritoneal dialysis patients: The importance of prealbumin and other nutritional markers. Am J Kidney Dis 23:91–98, 1994 18. Kopple JD: McCollum Award Lecture, 1996: Protein-energy malnutrition in maintenance dialysis patients. Am J Clin Nutr 65:1544– 1557, 1997 19. Blake PG, Flowerdew G, Blake RM, Orepoulos DG: Serum albumin in patients on continuous ambulatory peritoneal dialysis: Predictors and correlations with outcomes. J Am Soc Nephrol 3:1501–1507, 1993 20. Hakim RM: Initiation of dialysis. Adv Nephrol 23:295–309, 1994 21. Ikizler TA, Hakim RM: Nutrition in end-stage renal disease. Kidney Int 50:343–357, 1996 22. Mehrotra R, Saran R, Moore HL, Prowant BF, Khanna R, Nolph KD: Toward targets for initiation of dialysis. Perit Dial Int 17:497–508, 1997 23. Ikizler TA, Greene J, Wingard RL, Parker RA, Hakim RM: Spontaneous dietary protein intake during progression of chronic renal failure. J Am Soc Nephrol 6:1386–1391, 1995 24. Giordano C: The use of exogenous and endogenous urea for protein synthesis in normal and uremic subjects. J Lab Clin Med 62:231–235, 1963 25. Giovannetti S, Maggiore Q: A low-nitrogen diet with protein of high biological value for severe chronic uremia. Lancet 1:1000– 1004, 1964 26. Schloerb PR: Essential L-amino acid administration in uremia. Am J Med Sci 252:650–659, 1966 27. Kopple JD, Sorenson MK, Coburn JW, Gordon S, Rubini ME: Controlled comparison of 20-g and 40-g protein diets in the treatment of chronic uremia. Am J Clin Nutr 21:553–564, 1968 28. Berlyne GM, Gaan D, Ginks WR: Dietary treatment of chronic renal failure. Am J Clin Nutr 21:547–552, 1968 29. Kopple JD, Shinabaerger JH, Coburn JW, Sorensen MK, Rubini ME: Evaluating modified protein diets for uremia. J Am Diet Assoc 54:481–485, 1969 30. Anderson CF, Nelson RA, Margie JD, Johnson WJ, Hunt JC: Nutritional therapy for adults with renal disease. JAMA 223:68–72, 1973 31. Kopple JD, Coburn JW: Metabolic studies of low protein diets in uremia. I. Nitrogen and potassium. Medicine 52:593–595, 1973 32. Walser M: Ketoacids in the treatment of uremia. Clin Nephrol 3:180–186, 1975 33. Nore´e L-O, Bergstro¨m J: Treatment of chronic uremic patients with protein-poor diet and oral supply of essential amino acids. II. Clinical results of long-term treatment. Clin Nephrol 3:195–203, 1975 34. Kopple JD: Treatment with low protein and amino acid diets in chronic renal failure, in Proceedings of the VIIth International Congress of Nephrology, Montreal, S. Karger, 1978, pp 497–507 35. Attman P-O, Bucht H, Isaksson B, Uddebom G: Nitrogen balance studies with amino acid supplemented low-protein diet in uremia. Am J Clin Nutr 32:2033–2039, 1979 36. Attman P-O, Bucht H, Larsson O, Uddebom G: Protein-reduced diet in diabetic renal failure. Clin Nephrol 19:217–220, 1983 37. Barsotti G: Effects of dietary therapy on uremic symptoms and complications, in Nutritional Therapy of Chronic Renal Failure, edited by Giovannetti S, Boston, Kluwer Academic, 1989, pp 235–240 38. Giovannetti S: The effect of nutritional therapy on blood chemical abnormalities of chronic renal failure, in Nutritional Treatment of Chronic Renal Failure, edited by Giovannetti S, Boston, Kluwer Academic, 1989, pp 231–234 39. Hirschberg RR, Kopple JD: Nutritional therapy in patients with
40. 41.
42. 43. 44.
45.
46.
47.
48.
49. 50. 51. 52.
53.
54.
55.
56.
57.
58.
renal failure, in Care of the Renal Patient, edited by Levine DZ, New York, Saunders, 1991, pp 169–180 Mitch WE, Walser M: Nutritional therapy of the uremic patient, in The Kidney (5th ed), edited by Brenner BM, New York, WB Saunders, 1996, pp 2382–2423 Kopple JD: Nutritional management of nondialyzed patients with chronic renal failure, in Nutritional Management of Renal Disease, edited by Kopple JD, Massry SG, Baltimore, Williams and Wilkins, 1997, pp 479–531 Kopple JD, Gao X-L, Qing DP: Dietary protein, urea nitrogen appearance and total nitrogen appearance in chronic renal failure and CAPD patients. Kidney Int 52:486–494, 1997 Mitch WE, Abras EA, Walser M: Long-term effects of a new ketoacid amino acid supplement in patients with chronic renal failure. Kidney Int 22:48–53, 1982 Gin H, Aparicio M, Potaux L, Merville P, Combe CH, de Precigout V, Bouchet J-L, Aubertin J: Low-protein, low-phosphorus diet and tissue insulin sensitivity in insulin-dependent diabetic patients with chronic renal failure. Nephron 57:411–415, 1991 Gin H, Combe C, Rigalleau V, Delafaye C, Aparicio M, Aubertin J: Effects of a low-protein, low-phosphorus diet on metabolic insulin clearance in patients with chronic renal failure. Am J Clin Nutr 59:663–666, 1994 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 Barsotti G, Morelli E, Guiducci A, Ciardella A, Gianonni A, Lupetti S, Giovannetti S: Reversal of hyperparathyroidism in severe uremics following a very low-protein and low-phosphorus diet. Nephron 30:310–313, 1982 Fro¨hling PT, Kokot F, Schmickler R, Kaschube I, Lindenau K, Vetter K: Influence of keto acids on serum parathyroid hormone levels in patients with chronic renal failure. Clin Nephrol 20:212– 215, 1983 Fro¨hling PT, Schmicker R, Lindenau K, Vetter K, Kokot F: Role of keto acids in the prophylaxis and treatment of renal osteopathy. Contrib Nephrol 65:123–129, 1988 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 Schaefer K, von Herrath D, Asmus G, Umlauf E: The beneficial effect of ketoacids on serum phosphate and parathyroid hormone in patients with chronic uremia. Clin Nephrol 30:93–96, 1988 Lucas PA, Brown RC, Woodhead JS, Coles GA: 1,25-Dihydroxycholecalciferol and parathyroid hormone in advanced chronic renal failure: Effects of simultaneous protein and phosphorus restriction. Clin Nephrol 25:7–10, 1986 Mak RH, Turner C, Thompson T, Haycock G, Chantler C: The effect of a low protein diet with amino acid/keto acid supplements on glucose metabolism in children with uremia. J Clin Endocrinol Metab 63:985–989, 1986 Ciardella F, Cupisti A, Catapano G, Guidi A, Pasquinucci A, Morelli E, Barsotti G: Effects of a low-phosphorus, low-nitrogen diet supplemented with essential amino acids and ketoanalogues on serum beta-endorphin in chronic renal failure. Nephron 53:129– 132, 1989 Ciardella F, Morelli ZE, Niosi F, Caprioli R, Baldi R, Petronio G, Carbone C, Barsotti G: Effect of a low phosphorus, low nitrogen diet supplemented with essential amino acids and ketoanalogues on serum triglycerides of chronic uremic patients. Nephron 42:196–199, 1989 Combe C, Deforges-Lassuer C, Caix J, Pommereau A, Marot D, Aparicio M: Compliance and effects of nutritional treatment on progression and metabolic disorders of chronic renal failure. Nephrol Dial Transplant 8:412–418, 1993 Mariani G, Barsotti G, Ciardella F, Molea N, Morelli E, Mazzuca N, Niosi F, Bonaguidi F, Fusani L, Panicucci F, Giovannetti S, Bianchi R: Albumin metabolism and nutritional status of uremic patients on a long-term very-low-protein diet supplemented with essential amino acids and keto analogues. J Nucl Med Allied Sci 28:237–244, 1984 Bernard S, Fouque D, Laville M, Zech P: Effects of low-protein
Walser et al: Protein intake in predialysis patients
59. 60. 61.
62. 63. 64. 65. 66.
67.
68.
69.
70.
71. 72.
73. 74. 75.
76. 77.
diet supplemented with ketoacids on plasma lipids in adult chronic renal failure. Miner Electrolyte Metab 22:143–146, 1996 Walser M, Hill S, Ward L: Progression of chronic renal failure on substituting a ketoacid supplement for an amino acid supplement. J Am Soc Nephrol 2:1178–1185, 1992 Walser M, Hill S, Ward L, Magder L: A crossover comparison of progression of chronic renal failure: Ketoacids vs. amino acids. Kidney Int 43:933–939, 1993 Schmicker R, Vetter K, Lindenau K, Fro¨hling PT, Kokot F: Conservative long-term treatment of chronic renal failure with keto acid and amino acid supplements. Infusionstherapie 14(Suppl 5):34–38, 1987 Teplan V, Schuck O, Mengerova O, Ruzickova J: Individualized supplemented low-protein diet in patients with chronic kidney failure. Vnitr Lek 40:623–627, 1994 Maroni BJ, Tom K, Masud T, Chapman T, Young VR: How is lean body mass conserved with the very-low protein diet? Miner Electrolyte Metab 22:54–57, 1996 Maroni BJ, Steinman TI, Mitch WE: A method for estimating nitrogen intake of patients with chronic renal failure. Kidney Int 27:58–65, 1985 Maroni BJ, Mitch WE: Role of nutrition in prevention of the progression of renal disease. Annu Rev Nutr 17:435–455, 1997 Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker LG, Kusek JW, Striker G: The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. N Engl J Med 330:877–884, 1994 Levey AS, Adler S, Caggiula AW, England BK, Greene T, Hunsicker LG, Kusek JW, Rogers NL, Teschan PE, for the Modification of Diet in Renal Disease Study Group: Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease Study. Am J Kidney Dis 27:652–663, 1996 Anonymous: End Stage Renal Disease Medical Evidence Report Medicare Entitlement and/or Patient Registration Form (HCFA 2728), Health Care Financing Administration, Washington, D.C., April 1, 1997 The Diabetes Control and Complications Trial Research Group: The effects of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. N Engl J Med 329:977–986, 1993 Zeller K, Whittaker E, Sullivan L, Raskin P, Jacobson HR: Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus. N Engl J Med 324:78–84, 1991 Fouque D, Laville M, Boissel JP, Chifflet R, Labeeuw M, Zech PY: Controlled low protein diets in chronic renal insufficiency: Meta-analysis. BMJ 304:216–220, 1992 Pedrini MT, Levey AJ, Lau J, Chalmers TC, Wang PH: The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal disease: A meta-analysis. Ann Intern Med 124:627–632, 1996 Lelorier J, Gre´goire G, Benhaddad A, Lapierre J, Derderian F: Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med 337:536–542, 1997 Walser M: Do ketoacid-supplemented diets slow progression of chronic renal failure? A review of published studies. Int Yearbook Nephrol 1996:119–126, 1996 Dolecek TA, Olson MB, Caggiula AW, Dwyer JT, Milas NC, Gillis BP, Hartman JA, Dichiro JT: Registered dietitian time requirements in the Modification of Diet in Renal Disease Study. J Am Diet Assoc 95:1307–1312, 1995 Bruns FJ, Seddon P, Saul M, Zeidel ML: The costs of caring for end-stage kidney patients: An analysis based on hospital financial records. J Am Soc Nephrol 9:884–890, 1998 Modification of Diet in Renal Disease Study Group, Kopple JD, Levey AS, Greene T, Chumlea WC, Gassman JJ, Hollimger DL, Maroni BJ, Merrill D, Scherch LK, Schulman G, Wang S-R, Zimmer GS: Effect of dietary protein restriction on nutritional
78. 79. 80. 81. 82.
83.
84. 85. 86.
87.
88. 89. 90. 91. 92.
93. 94. 95. 96. 97.
98. 99.
777
status in the Modification of Diet in Renal Disease Study. Kidney Int 52:778–791, 1997 Anonymous: Reduction of dietary protein and phosphorus in the Modification of Diet in Renal Disease Study. J Am Diet Assoc 94:986–990, 1994 Tom K, Young VR, Chapman T, Masud T, Akpele L, Maroni BJ: Long-term responses to dietary protein restriction in chronic renal failure. Am J Physiol 268:E668–E677, 1995 United States Renal Data System USRDS: Annual Data Report. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, April 1997 Bergstro¨m J: Why are dialysis patients malnourished? Am J Kidney Dis 26:229–241, 1995 Ahmed KR, Kopple JD: Nutrition in maintenance hemodialysis patients, in Nutritional Management of Renal Disease, edited by Kopple JD, Massry SG, Baltimore, Williams and Wilkins, 1997, pp 563–600 Maroni BJ, Burkhart J, Burrowes J, Cockram D, Drabik M, Dwyer J, Kusek J, Makoff R, Paranandi L, Powers S, Rocco M: Baseline nutritional characteristics of the HEMO study participants: Interim report. (abstract) J Am Soc Nephrol 7:1456, 1996 Walser M: Does prolonged protein restriction preceding dialysis lead to protein malnutrition at the onset of dialysis? Kidney Int 48:1139–1144, 1993 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 45:1182–1192, 1994 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 Goodship THJ, 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 MDRD Study Group: The Modification of Diet in Renal Disease Study: Design, methods and results from the Feasibility Study. Am J Kidney Dis 20:18–33, 1992 Mitch WE, Collier VU, Walser M: Creatinine metabolism in chronic renal failure. Clin Sci 58:327–335, 1980 Deleted in proof. Coresh J, Walser M, Hill S: Survival on dialysis among renal failure patients treated with a supplemented low-protein diet before dialysis. J Am Soc Nephrol 6:1379–1385, 1995 National Kidney Foundation-Dialysis Outcomes Quality Initiative (NKF-DOQI) Clinical Practice Guidelines for Peritoneal Dialysis Adequacy. I. Initiation of Dialysis, Guideline 2. Am J Kidney Dis 30(Suppl 2):S72–S73, 1997 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 Walser M, Hill S, Tomalis EA: Treatment of nephrotic adults with a supplemented, very low-protein diet. Am J Kidney Dis 11:354– 364, 1996 Hakim RM, Lazarus JM: Biochemical parameters in chronic renal failure. Am J Kidney Dis 9:238–247, 1988 Price SR, Mitch WE: Metabolic acidosis and uremic toxicity: Protein and amino acid metabolism. Semin Nephrol 14:232–237, 1994 Binik YM, Devins GM, Barre PE, Guttman RD, Hollomby DJ, Mandin H, Paul LC, Hons RB, Burgess ED: Live and learn: Patient education delays the need to initiate renal replacement therapy in end-stage renal disease. J Nerv Ment Dis 181:371–376, 1993 Hayslip DM, Suttle CD: Pre-ESRD patient education: A review of the literature. Adv Ren Replace Ther 2:217–226, 1995 Levin A, Lewis M, Mortiboy P, Faber S, Hare I, Porter EC, Mendelssohn DC: Multidisciplinary predialysis programs: Quantification and limitations of their impact on patient outcomes in two Canadian settings. Am J Kidney Dis 29:533–540, 1997