Nutritional Efficacy, Compliance, and Progression of Renal. Insufficiency1. William E. Mitch2. WE. Mitch,. Renal. Division. Emory. University. School of. Medicine,.
Dietary Protein Restriction in Chronic Renal Failure: Nutritional Efficacy, Compliance, and Progression of Renal Insufficiency1 William
E. Mitch2 change
WE. Mitch, Renal Medicine, Atlanta, (J. Am.
Soc.
Division. GA
Nephrot.
Emory
1991;
University
2:823-83
School
of
1)
ABSTRACT Two findings prompted Investigators to examine the effects of dietary manipulation on progression of chronic renal failure: dietary protein restriction is an effective method of ameliorating uremic symptoms and the course of renal insufficiency in an individual patient Is predictable. Results from studies of patients and animals with chronic renal failure suggested that a low-protein, phosphorus-restricted diet could slow the rate of loss of renal function. In evaluating these studies, three questions should be considered. First, is the diet nutritionally adequate? Second, has dietary compliance been monitored and achieved? Third, Is there evidence that restricting the diet will change the rate of loss of renal function? The scientific basis for each of these questions is addressed in thIs review. Key
Words:
progression
Uremia,
nitrogen
of renal
failure
balance,
dietary
compliance.
he economic impact of end-stage renal failure (ESRD) on the federal budget has been well descrIbed (1). ESRD also has a major impact on the social activities and lifestyle of the patients. For both reasons, a safe regimen that can interrupt the pattern of progressive chronic renal failure (CRF) could have a major impact on the treatment of CRF patients. Although not yet proven, reports suggest that implementation of a protein-restricted diet can Received
May
Clifton
Rood.
9, 1991.
Accepted
to Dr. W.E. NE. Atlanta,
June Mitch.
25.
Renal
1991. Division,
Emory
GA 30322.
I 046-6673/0204-0823503.00/0 Journal of the Amedcan Society of Nephrology CopyrIght 0 1991 by the AmerIcan Society of N.phrology
Journal
of the American
Society
of Nephrology
UniversIty,
definitive
evidence.
In this review, three questions to consider when evaluating reports of the effects of low-protein diets (LPD) on progression of CRF will be emphasized. First, is the new diet nutritionally adequate? Second, has compliance been monitored? Third, what published evidence supports the efficacy of restricting the diet in changing the course of renal insufficiency? NUTRITIONAL
T
2Correspondence
the prognosis of patients with progressive failure. These reports underscore the difficulties in clinical Investigation: patients must participate with monthly visits for 1 or more years; a consistent change in the diet must be maintained; and the rate and pattern of changes in renal function must be analyzed. Some of these reports have been criticized for study design (including the lack of randomization), the use of data obtained retrospectively, inadequate attention to compliance, and/or the use of serum creatinine or creatinine clearance to estimate changes in residual renal function. For these reasons, conclusions regarding the efficacy of dietary protein and/or phosphorus restriction on progression In humans must be considered tentative. Results from ongoing, multicenter trials should provide more renal
1364
ADEQUACY
OF LPD
Three types of low-protein dietary regimens have been used in attempts to slow the progression of CRF: (1) a conventional LPD containing 0.6 g of protein! kg ideal body wt/day of primarily high-quality protein; (2) 0.3 g of protein/kg/day of predominantly vegetable proteins supplemented with a mixture of essential amino acids (EAA); or (3) the predominantly vegetable protein diet supplemented with a mixture of EAA and the nitrogen-free analogs of amino acids, called ketoacids. LPD were initially used in CRF patients to relieve uremic symptoms associated with excessive accumulation of nitrogenous waste products. To suppress formation of waste products, the diets supplied less than the minimum daily protein requirement for normal adults and resulted in a period of negative nitrogen balance (BN) lasting many weeks. It was reported
823
Dietary
Protein
Restriction
in CRF
that, ultimately, the patients achieved neutral BN (2,3), and It was proposed that CRF patients were capable of developing or activating a metabolic pathway that used the nitrogen in urea to synthesize amino acids. This would accomplish two goals: It would limit nitrogen waste product formation, and it would increase the supply of amino acids for protein synthesis. Subsequent reports showed that urea is not important in meeting the nitrogen requirements of CRF patients (4-6). In fact, the minimum daily protein requirement of normal subjects, about 0.6 g of protein/kg ideal body wt/day (7), is also required by CRF patients (8). In fact, the neutral BN Is possible only if the following conditions are met: (1) a high proportion of the protein (>60%) must be of high biological value, i.e., proteins containing a high proportion of EAA; (2) caloric intake must be adequate (9); and (3) a daily supplement of B and C vitamins must be taken (10,11). Obviously, active participation of a skilled dietitian is critical to ensure that the regimen is nutritionally sufficient and that the food preferences of a patient are included when recipes are planned. Evidence indicates that compliance can be achieved, i.e., nitrogen intake can be reduced substantially during long-term therapy (12-14).
are met and there is no catabolic stimulus, BN should become neutral within days of starting the diet. This occurs because metabolic responses are activated to return BN to zero during the initial period of negative BN. This response is termed adaptation and includes a reduction in both amino acid oxidation and protein degradation; changes in protein synthesis appear to be less Important (15). If the adaptation responses do not occur or are inadequate and BN remains negative, the process is called “accomodation” (16). Many attempts have been made to identify the factors causing protein wasting in patients with advanced CRF (17). To date, the only factor shown to impair protein metabolism in renal failure is metabolic acidosis. May and associates provided the first demonstration that metabolic acidosis is catabolic. During an investigation of the source of glutamine used by normal rats to excrete excess acid (18), it was found that metabolic acidosis stimulated protein degradation in muscle. Glucocorticoids appeared to play a critical role in this process. It was also found that branched-chain amino acid catabolism is increased sharply in muscle of rats with metabolic acidosis (19). The mechanism for increased amino acid catabolism was linked to stimulation of the activity of the ratelimiting enzyme, branched-chain amino acid dehydrogenase. Recent data confirm that metabolic addosis stimulates protein and amino acid breakdown
824
protein
Providing
and
calorie
requirements
supplements
of
NaHCO3
decreases
urea
production and improves the BN of CRF patients (24), and Bergstrom and coworkers find that the valine concentration in muscle is linearly related to the plasma bicarbonate concentration in dialysis patients (25). Note that successful adaptation to a LPD requires suppression of amino acid oxidation and protein esses
BN IN UREMIA If
in t’ivo (20) and that adrenalectomy blocks the increase in whole body catabolism (May et at. unpublished results). However, the role of glucocorticoids may be more complicated. England and Mitch (21) found that the addition of glucocorticoids to serumsupplemented media caused no additional increase in the proteolysis stimulated by intracellular acidification of cultured myocytes. How do these results pertain to uremia? In rats with CRF, even a mild degree of metabolic acidois (serum bicarbonate, 0.7 g/kg/day (Figure 3). It is also interesting that serum albumin and anthopometric measurements remained stable over the 18 months of follow-up, but weight, serum transferrin, and total lymphocyte count all decreased significantly. Because the phosphorus content of the protein-restricted diet was approximately 30 to 40% less than that of the unrestricted diet, the relative importance of dietary protein versus phosphorus restriction on progression cannot be determined. The decline in some, but not all, nutritional indices also raises concern about prescribing less than the minimum daily requirement of protein to patients with renal insufficiency. What is needed is a more complete understanding of the mechanisms of adaptation to these diets so they can be used safely. The response of patients with diabetic nephropathy is of interest for two reasons: first, a substantial proportion of patients with insulin-dependent diabetes develop renal failure, and this is a major cause of ESRD (1). Second, the metabolic abnormalities associated with diabetes could greatly complicate the design of the diet. One factor that seems to accelerate the proteinuria and, possibly, the rate of loss of GFR in patients with diabetic nephropathy Is hypertension. The reason for Interest in protelnuria Is that most investigators believe that the presence of ml-
828
in diabetic patients (48). Dietary protein restriction has also been reported to have a beneficial effect in patients with diabetic nephropathy. For example, short-term protein restriction reduces protein losses In diabetic patients with microalbuminuria (14,49). There are only a few reports of the influence of dietary manipulation on changes in GFR. A report from Guy’s Hospital in London detailed the course of 19 Insulin-dependent diabetic patients with persistent proteinurla. When their diet was changed from an unrestricted diet (average, 1.13 g of protein/kg/day) to a diet averaging 0.67 g of proteIn/kg/day, there was a significant reduction in the rate of decline in GFR (from 0.61 to 0.14 mL/min/month) (49). Slowing of progression was significant even after adjustments were made for differences In blood pressure, energy intake, and glycosylated hemoglobin level. Albumin excretion and its fractIonal clearance also fell with the LPD. In the United States, as well, diabetic patients appear to respond to a LPD. For example, the influence of a diet containing 0.6 g of protein/kg/day was compared with a regimen that did not restrict dietary protein (14). Besides the dietary manipulation, patients in the two groups were treated similarly over a period of 1.5 to 2 yr. Changes in renal function were evaluated by measuring serum creatinine as well as the renal clearances of creatinine and [‘25ljiothalamate; albuminuria was also measured. The results from this report provide several Interesting conclusions. First, the group prescribed the LPD ate an average of about 0.7 g of protein/kg/day and did not develop malnutrition over the 1.5 to 2 yr of study. Thus, the investigators achieved reasonable compliance with the protein-restricted diet in spite of the metabolic abnormalities of diabetes. Second, the average declines In GFR and creatinine clearance were significantly slowed by the protein-restricted diet (Figure 4). It should be emphasized that some of the patients eating the unrestricted diet did not exhibit progressive loss of GFR during the study. Obviously, a spontaneous cessation of progression is a major issue in documentIng whether the diet influences the progression of CRF. Third, the apparent beneficial effect of the dietary regimen could not be attributed to differences In blood pressure or glycemic control or to the frequency of examinations, making it most likely that dietary restriction was the major factor. The evidence for a positive effect of a more restricted diet supplemented with a mixture of EAA is more tenuous. Alvestrand and coworkers reported that this regimen was effective in slowing the decline in the reciprocal of serum creatinine concentration
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Figure 4. Changes in GFR measured as the renal clearance of iothalamate in diabetic patients prescribed a proteinrestricted diet or an unrestricted diet. Figure drawn from the results of Zeller et a!. (14). in 17 patients with well-defined rates of progression in spite of a conventional LPD (50). Only three patients had no slowing of progression with the EAAbased regimen. An interim evaluation of the results from an ongoing prospective, randomized trial by the Stockholm group has cast doubt on whether the EAAsupplemented dietary regimen does slow progression of CRF. Instead, they have raised the possibility that improved blood pressure control and more frequent evaluations slowed progression (51). In their view, any slowing of progression appeared to be most closely related to a small (2 mm Hg), but significant, reduction in diastolic blood pressure. The regimen also tended to improve proteinuria, but firm conclusions cannot be made because of the preliminary nature of the report. Of the 57 patients initially enrolled, 10 (24%) did not progress during the baseline period while eating an “unrestricted” diet. Of the 23 patients with progressive loss of function during the baseline period, 11 were randomized to the proteinrestricted regimen and 12 were assigned to the unrestricted diet. Unfortunately, only five of the former and nine of the latter patients satisfied the requirements of dietary compliance, availability of GFR, and observation for more than 200 days. The average difference in protein intake was small (0.65 versus 0.86 g/kg/day) and, although significant, was not striking. Thus, a regimen based on EAA can control uremic symptoms but any benefit on progression is uncertain. Regarding a comparison with other regimens, there are little data. Walser and colleagues evaluated 12 patients with moderately severe CRF and a progressive decline in creatinine clearance, despite having received a diet containing 0.3 g of protein/kg/day plus an EAA supplement (52). After changing to a ketoacid supplement, all six patients whose serum creatinine exceeded 7.5 mg/dL contin-
Journal
of the American
Society
of Nephrology
ued to progress, but six of seven patients with serum creatinine values between 6.0 and 7.4 mg/dL at crossover had stable values of isotypically measured GFR during the 1- to 2-yr follow-up; one subject who was noncompliant progressed to dialysis. Few conclusions can be drawn from the study of such a small number of subjects. The effects of a ketoacid-based regimen on progression also has been studied. Barsotti and coworkers studied the rate of loss of creatinine clearance in 31 patients treated with a diet containing 0.5 g of protein/kg/day (53). They observed that the decline in clearance was linear in patients with different types of disease. The pattern was interrupted in 11 of 12 patients who were switched to a regiment containing about 0.2 g of protein/kg/day plus supplements of calcium salts of ketoacids. Similar results were reported in an examination of 48 patients (54). Twenty-seven of these patients were considered compliant, and, on average, their change in creatinine clearance was reversed from -0.65 to +0.15 mL/ mm/month (P < 0.005). Besides calcium salts, basic amino acid salts of ketoacids given as a supplement to a LPD appear to slow the loss of renal function. Among 17 patients with well-defined rates of progression as assessed by changes In the reciprocal of serum creatinine concentration, 10 (or 59%) had a significantly slower rise in serum creatinine during long-term therapy (average, 20 months) (12). The effect was seen exclusively in patients who had not reached a stage of advanced renal failure (serum creatinine, above 8 mg/dL). As noted earlier, Walser and colleagues tested whether ketoacids influence the rate of loss of GFR in patients receiving an EAAbased regimen (52). Four of five patients had significant slowing of progression. In another report from this group, the ketoacid regimen appeared to slow the loss of GFR more than an EAA-based regimen on a conventional LPD regimen (55). However, the number of patients studied was small and the differences were not significant statistically. As this review emphasizes. it has not been proven that dietary manipulation will slow progression in spite of many provocative observations. One or more of the prospective, randomized multicenter trials now in progress may answer this question. Hopefully, information in this brief review will be useful for readers examining reports evaluating the effects of dietary manipulation on patients with CRF.
ACKNOWLEDGMENTS This 37175
work from
was the
supported
by
grants
ROl
DK-40907
and
ROl
DK-
NIH.
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Held Data
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