Pediatric Nephrology

Pediatr Nephrol (1991) 5:496-500 9 IPNA 1991

Nutrition Original article

Low-protein diet in children with chronic renal failure 1-year results European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood* Anne-Margret Wingen, Claudia Fabian-Bach, and Otto Mehls Division of Paediatric Nephrology,UniversityChildren's Hospital, Im NeuenheimerFeld 150, W-6900 Heidelberg,FederalRepublic of Germany Received December20, 1990;receivedin revised form and acceptedFebruary25, 1991

Abstract. In 1988 the European Study for Nutritional Treatment of Children with Chronic Renal Failure started its multicentre randomized trial to investigate the influence of protein intake on the progression of renal failure. A total of 284 children had been registered. Of these 221 were accepted for the study. The data from 105 patients after 1 year of study are available for preliminary analysis. Fifty children were randomized for the diet group and 55 for the control group. Both groups were comparable concerning age, glomuerlar filtration rate (GFR) and height standard deviation score for chronological age at the start of the study period and the distribution of primary renal diseases and sex. Limits for protein and energy intake were set according to the safe levels and recommendations given by the World Health Organization. The compliance with dietary prescriptions as calculated from dietary diaries was good. A low-protein diet did not do any harm to the children with respect to length gain and weight gain. The progression of renal failure was minimal in the diet group (mean loss of GFR 3.6 ml/min per 1.73 m 2 per year) as well as in the control group (2.3 ml/min per 1.73 m2 per year). The differences between the diet group and the control group were statistically not significant when either all patients or only subgroups of various primary renal diseases were analysed. When only patients with a good compliance were considered (documented by dietary diaries or by urea nitrogen excretion) the same results were obtained.

* Contributing investigators (in alphabetical order of centres): I. R~itschCatalini (Ancona), K. Michelis (Athens), E Jung, T. Lennert (Berlin I), S. Gellert (Berlin H). T. Tulassay, R Sallay (Budapest), T. yon Lilien (Cologne), M.-A. von Wendt-G/3knur(Erlangen), K. E. Bonzel (Essen) R. Gusmano, E. Verrina (Genova), G. Offner (Hannover), O. Mehls, A.-M. Wingen,C. Fabian-Bach(Heidelberg,co-ordinators),A. Appiani, A. Bettinelli (Milan), J. Feber (Prague), S. Picca (Rome), H.J. Stolpe (Rostock), J. Kist-van Holthe, E. Wolff (Rotterdam co-ordinatorsof the centres Amsterdam, Antwerp, Groningen, Nijmegen, Rotterdam), U. Berg (Stockholm), M. Fischbach (Strasbourg), E. Dobos (Szeged), E. Balzar (Vienna), T. Neuhaus (Ziirich) Offprint requests to: A.-M. Wingen

In summary, reduction of protein intake was accepted by the majority of patients. There was no significant influence on growth, weight gain and progression of renal failure within the 1st year of study.

Key words: Chronic renal failure - Low-protein diet Deterioration of renal function

Introduction In animal experiments glomerular hyperfiltration caused by high-protein intake has been identified as one contributing factor for the progressive deterioration of renal function in chronic renal failure (CRF) [1, 2]. It has been anticipated that similar mechanisms may exist in humans. But, the role of dietary intervention in the progression of CRF in humans has not yet been identified clearly. Various studies in adult patients give some evidence that low-protein diets might be able to slow down progressive deterioration of renal function [3-6]. But few of these studies have been performed as controlled randomized studies in a sufficient number of patients over an adequate period of time [7]. The influence of the primary renal disease has not clearly been established. In children there are only limited studies with low-protein diets in very small groups of patients [8]. Furthermore, the degree of protein reduction sufficient for normal growth and development is not well defined. Therefore, in 1988 a European multicentre controlled trail in children was started. The aims of the study are to assess: (1) the spontaneous protein and calorie intake in children with CRF, (2) the influence of protein-restricted diets on the rate of progression of renal failure, (3) the influence of such diets on growth and development, and (4) the practicability and acceptance of a low-protein diet over a long period of time.

497 Table 1. Protein and energy intakes of 105 patients during the adaptation and study periods Adaptation period

Study period diet

No of patients Disease group 1 Disease group 2 Disease group 3 Disease group 4 Males Females

105 18 63 23 1 72 33

50 9 30 11 0 34 16

55 9 33 12 1 38 17

Age at start (years)

10.1 --+4.5

GFR at start (ml/min per 1.73 m2)

38.3-+13.2

37.1-+15.1

36.2-+14.0

Protein intake (g/kg per day)

1.74-+0.62

0.99-+0.18

1.78 _ 0.60

104-+19

182-+56

Protein inake t80-+56 (% of WHO safe levels)

10.6-+4.8

control

10.5-+4.5

Energy intake (kcal/day)

63 -+21

56 -+ 17

63 -+21

Energy intake (% of WHO recommendations)

95 -+23

87 _+21

95 _+23

osteopathy. The evaluation of glomerular filtration rate (GFR) by inulin or 51 chromium ethylenediaminetetra-acetic acid clearance was recommended (optional) at yearly intervals. As most of the patients suffered from uropathies, reliable collection of 24-h urine samples was a problem in many children. Therefore, GFR was calculated with the formula given by Schwartz et al. [11]. The factor used in this formula was calculated for each centre with the endogenous creatinine clearance, the centrally re-evaluated serum creatinine values and the inulin or 51 Cr EDTA clearances. Standard deviation scores (SDS) for height and growth velocity were calculated from the data of Prader et al. [12] with a special computer programme [13]. Ideal body weight per height was calculated from the data of Prader et al. [12].

Statistical analyses. All biochemical methods have accepted ranges of error. When calculating GFR using the formula of Schwartz et al. [11] this error is increased by the error in measuring body height. Additionally, serum creatinine values may be affected by intercurrent infections, hydration or other factors. Hence, the calculated GFR may fluctuate without reflecting changes in renal function. Therefore, we tested three different methods for smoothing data. The running mean was calculated from the raw data of three overlapping observations; smoothing was performed once for each patient. Kernel estimation was carried out as published previously [14]. Linear regression was also calculated for disease progression of each patient. The Wilcoxon test was used to assess the statistical significance between mean values. Slopes were compared with the analysis of variance of regression. For all the statistical procedures SAS programmes were applied [15].

GFR, Glomerular filtration rate

Results Methods Study design. Patients aged 2-18 years with a creatinine clearance of less then 60 and more than 15 ml/min per 1.73 m2 and with good conservative treatment were accepted for the study. Children with uncontrolled arterial hypertension, uraemic symptoms, systemic diseases like lupus erythematosus, amyloidosis or oxalosis, severe cardiac diseases or treatment with immunosnppressive drugs during the previous 6 months were excluded from the study. For adaptation, an obligatory 6-month period was required. Only patients willing and able to visit the outpatient clinic regularly and to write dietary diaries were considered for the trial. Children accepted for the trial were grouped according to the primary renal disease: (1) glomerular diseases, e.g. focal segmental sclerosing glomerulonephritis and status post-haemolytic-uraemic syndrome, (2) uropathy, renal hypoplasia and dysplasia and oligomeganephronia (3) congenital and hereditary nephropathies, e.g. Alport's syndrome, polycystic kidney disease, and (4) nephropathic cystinosis. Randomization for diet or control group was carried our for each disease group with a blocking factor of 4. Patients of the diet group were advised to reduce protein intake to the safe levels of the World Health Organiszation (WHO), i.e. 1.1-0.8 g/kg per day [9], with an energy intake of at least 70% of WHO recommendations [ 10]. Patients in the control group were instructed to ingest the same amount of calories with an unrestricted protein intake. During the adaptation period and the 2-year study period patients had to visit the outpatient clinic every 2 months. The regular check-ups included: a physical examination, anthropometric measurements (height, weight and skinfolds), routine laboratory tests including collection of 24-h urine samples and storage of an additional serum sample for central laboratory investigations (e. g. parathyroid hormone and central re-evahiation of creatinlne). At least every 4 months the patients had to keep a dietary diary for a period of 4 days, to include 1 weekend (weighing method). Every 6 months serum lipids were measured in the fasting state and a plasma sample was stored for the central evaluation of plasma amino acids. Every year an X-ray of the left hand was carried out and a copy sent to the co-ordinating centre for estimation of bone age and renal

Up to September 1990, 284 children had been registered. Sixty-three had to be excluded because they did not attend the follow-up visits regularly or because they did not keep the required dietary diaries. O f the 221 patients accepted, 190 were r a n d o m i z e d and 109 have already passed their 1st year after randomization. Four of these 109 patients developed end-stage renal failure within 2 - 3 months of randomization. O n e of these patients was i n the diet group (subgroup 2), 3 patients b e l o n g e d to the control group (2 from subgroup 2, 1 from subgroup 3). Since it is unlikely that the d e v e l o p m e n t of disease was i n f l u e n c e d b y the prescribed diet, these 4 patients have been excluded from analysis. The 1-year results of the r e m a i n i n g 105 patients, 50 of w h o m were in the diet group and 55 in the control group, are reported here. The distribution of disease groups, sex, m e a n age and G F R at the start of the study period were similar in the diet group compared with the control group. Protein and calorie intake in the control group were about the same as in all 105 patients during the period of adaptation. The protein intake o f the diet group was m u c h lower than in the adaptation period or the control group and well within the range of the prescriptions. The energy intake was not significantly different a m o n g the groups; it was slightly lower in the diet group than in the control group, but did not fall below the r e c o m m e n d a t i o n s (Table 1). The low-protein diet did not adversely affect growth (SDS for height and SDS for height velocity for chronological age) and weight gain (% of ideal body weight per height). SDS for height and percentage of ideal body weight were calculated at the start of the study and 1 year later. The SDS for height velocity was calculated for height

498

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Fig. 1 a - d . Mean glomerular filtration rate (GFR)with time for protein-restricted patients (@) or controls (+) in three disease groups and in all patients combined. GFR data were smoothed with the running mean procedure

Table 2. Growth and weight gain of 50 children on a low-protein diet compared with 55 children in the control group SDS for height

SDS for height velocity

% Ideal body weight

diet

control

diet

diet

control

-1.07 1.71 -1.07

-1.06 1.14 -0.86

104 20 103

100 14 98

-1.05 1.65 -1.22

-1.06 1.15 -0.83

105 20 103

103 16 101

control

at start of study Mean SD

Median

after 1 year of study Mean SD Median

-0.14 1.44 -0.17

~.37 1.17 -0.16

SDS, Standard deviation score

gain during the 1st year of the study. All the differences between the diet and control groups at the start and 1 year later were not significant (Table 2). Besides use of the raw data, three different methods were used to smooth the data for GFR during the 1 st year after randomizaton, i.e. running mean, kernel estimation and linear regression (Table 3). Kernel estimation usually overestimated GFR while th other procedures did not differ significantly. The rate of progression per year was about the same with all the methods used (Table 3).

The rate of progression of renal failure was similar in the diet and control groups (Fig. 1). The mean loss of GFR per year amounted to about 3.6 ml/min per m 2 in the diet group and 2.3 ml/min per m2 in the control group. In none of the three disease groups was any significant difference seen (Fig. 1 a-c). Some of the patients in the diet group were non-compliant and some children in the control group had a protein intake within the recommendations of the diet group. Therefore, data were also analysed according to the protein intake calculated from the dietary diaries. For this the patients were divided into two groups (1) mean protein intake less than or equal to 110%, and (2) mean protein intake greater than 110% of the WHO recommendations. Following this classification the mean loss of GFR during the 1st year after randomization was similar in both groups (Fig. 2a). GFR loss following a low-protein intake was 2.94+5.21 ml/year (median 3.25 ml/year), following high-protein intake it was 2.89_+ 5.11 ml/year (median 2.44 ml/year). As dietary protocols may underestimate the true protein intake, data were also analysed according to the mean urea nitrogen (N) excretion (g/kg per day). The distinction between low or high urea N excretion was made using the age-related mean values of the diet group. Assuming that urea N excretion gives a reliable estimation of protein intake [16], only 38 of the 50 children seemed to adhere to their dietary prescription. But the mean loss of GFR during

Table 3. Comparison of different methods for smoothing data Raw data

Diet group GFR at starta GFR after 1 year Loss of GFtLlyear

Control group GFR at start GFR after 1 year

Loss of GFR/year

Kernel estimation

Running mean

Regression

mean

SD

median

mean

SD

median

mean

SD

median

mean

SD

median

36.99 33.55 3.44

15.01 17.37 6.59

35.61 33.72 2.02

36.77 33.19 3.59

15.28 16.43 5.43

35.59 34.27 3.89

42.73 38.45 4.28

17.24 20.00 6.86

42.57 36.33 4.70

37.39 33.49 3.90

t5.09 16.80 6.58

36.72 34.47 3.79

35.86 33.85 2.00

14.00 15.35 5.48

35.49 33.40 2.24

35.77 33.48 2.29

13.62 15.37 4.82

36.99 34.84 2.06

42.86 39.28 3.58

16.51 18.47 5.76

42.80 40.05 2.83

36.13 33.60 2.53

13.72 15.38 5.16

37.22 33.79 2.72

a GFR = ml/min per 1.73 m 2

499 50

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Fig. 2 a. Mean GFR with time for patients eating ~< 110% ( 0 , n = 47) or >110% (+, n = 58) of World Health Organization safe levels for protein intake as calculated from dietary diaries, b Mean GFR with time for patients with low ( 0 ) , n = 38) versus high (+, n = 67) urea nitrogen excretion. GFR data were smoothed with the running mean procedure

the 1st y e a after randomization was similar in both groups (Fig. 2b). Low urea N excretors demonstrated a loss in GFR of 3.64 +4.32 ml/year (median 3.68 ml/year), while high urea N excretors lost 2.49 + 5.53 ml/year (median 2.43 ml/year).

Discussion Protein-restricted diets are widely used in adult patients with CRF [17]. In contrast, there are no controlled longterm studies in an adequate number of children. While, without doubt protein restriction can ameliorate uraemic symptoms [18], whether reduction of protein intake can slow down the progression of renal failure is unclear in adults as well as children. Animal experiments demonstrate that protein-restricted diets in the early course of renal failure are more effective at slowing down the progression of renal disease [19], but there are no similar data in humans. In animal experiments, the slowing down of GFR decline was always followed by a reduction in growth rate. Because of growth, children have higher needs for protein and energy than adults [10, 20]. Therefore, dietary recommendations for adults with CRF cannot be adopted for children. The present investigation is the first prospective randomized study in children with CRF including more than 200 patients. The restrictions of protein intake in the diet group were mild in comparison with studies of adult patients (1.1-0.8 g/kg per day according to age), but very low compared with the nutritional habits in the western civilization (Table 1). In addition, the protein intake was more severely restricted than in the only published study of ten paediatric patients of Jureidini et al. [8] who prescribed 1-1.2 g/kg per day protein, supplemented with 0.3 g/kg per day essential amino acids and keto acids. In our study, it would have been unethical to recommend a lower protein intake than indicated by the WHO safe levels [9]. This argument had to be taken more seriously since the safe levels of WHO for protein intake refer to proteins with high biological values and a high degree of digestibility (egg

and milk protein) which guarantee an adequate amount of essential amino acids. However, in the present study no corrections for digestibility and essential amino acid content of protein were recommended for practical reasons. Only when it has been shown that the recommendations of this study do not negatively influence growth will a more radical restriction of protein intake be justified in future studies. With skilled dietary advice, children in the diet group achieved a mean protein intake of 104% of the prescribed level without a significant reduction of energy intake (Table 1). In comparison, children in the control group ingested 182% of the protein prescribed for the diet group. Reduction of protein intake did not have a negative effect on growth and development. SDS for height for chronological age and percentage of ideal body weight per height did not change significantly during the 1st year of dietary intervention, and were similar to values of children in the control group. Similarly, SDS for height velocity during the study year was the same for children in the diet group and the control group respectively (Table 2). These results show that, in general, a low-protein diet with an age-corrected overall intake ranging from 1.1 for 2-year-old children to 0.8 kg/day for adolescents does not negatively influence growth in CRF. But a detailed analysis of individual patients has to be performed at the end of the study to exclude possible harmful effects in a small percentage of patients. Progression of renal failure was minimal in the entire diet group (3.6 ml/year) and in the entire control group (2.3 ml/year). Also, the small difference between diet and control subgroups in patients with glomerular diseases (Fig. 1 a) was not significant due to the small number of patients. There was no evidence that a low-protein intake slows down deterioration of renal function, since the regression line was steeper for the low protein group than the control group. In order to exclude that non-compliance with the dietary prescriptions influenced the results, the data were reeveluated according to the protein intake of patients as calculated from dietary diaries or from urea N excretion. Results were unchanged when dietary diaries or urea N excretion were used to estimate protein intake. In summary, it is possible to reduce protein intake to the safe levels of WHO in children without negative influences on growth and weight gain. The dietary modifications were accepted by the majority of children. As the progression of renal failure was minimal in all children, a positive influence of a low-protein intake on the progression of renal failure was not demonstrable after the 1st year of the study. But, 1 year's data are insufficient for general conclusions. It might very well be that dietary interventions start to show differences only after 2 years. Since the mean loss of GFR is within the error of variation of GFR estimation, 3 or 4 years of study may be needed to document or exclude significant differences.

Acknowledgements.The study was supported by BMFT grant 07047420, O. Mehls. We thank N. Gretz and C. Seidel for their help in statistical analyses.

500 We thank the dieticians involved in the study for their skillful care of the patients: A. Koulieris (Athens), Z. Michalek (Berlin I), J. Schrtiter (Berlin II), E. Iloval (Budapest), U. Spiering (Cologne), S. Rehm (Erlangen), C. Sprengel (Essen), F. Spada (Genova), K. Wimmer (Hannover), C. Funari (Milan), B. Tomaskova (Prague), M. AncineUi (Rome), C. Vetter (Rostock), L. Noordzy (Rotterdam), K. Arfwidson (Stockholm), M.-C- Burger (Strasbourg), G. Brazda (Vienna), M. Honegger (Zurich).

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9. Food and Agriculture Organization/World Health Organization (1985) Energy and protein requirements. Report of a joint FAO/WHO Expert Committee. WHO Technical Report Series No 724. WHO, Geneva 10. Food and Agriculture Organization/World Health Organization (1973) Energy and protein requirements. Report of a joint FAO/WHO Expert Committee. WHO Technical Report Series No 522. WHO, Geneva 11. Schwartz GJ, Brion LP, Spitzer A (1987) The use of plasma creatinine concentration to estimate glomerular filtration rate in infancy childhood and adolescence. Pediatr Clin North Am 34:571 -590 12. Prader A, Largo RH, Molinary L, Issler C (1989) Physical growth of Swiss children from birth to 20 years of age. Helv Paediatr Aeta [Suppl] 52:1 - 125 13. Schgfer F, Gretz N, Sikut M, Strauch M, Scb~er K (1989) A SAS procedure for evaluating growth in pediatric patients. Proc SEUGI 7: 554-563 14. Gasser T, Mtiller HG (1984) Estimating regression functions and their derivatives by the kernal estimation method. Scand J Stat 11: 171-185 15. SAS Institute (1985) SAS user's guide: basics, 5th ed. SAS Institute, Cary, North Carolina 16. Maroni B J, Steinman TI, Mitch WE (1985) A method for estimating nitrogen intake of patients with chronic renal failure. Kidney Int 27: 58-65 17. Giovannetti S (1986) Low protein diet in chronic uremia: a historical survey. Contrib Nephro153:1-6 18. Barsotti G (1989) Effects of dietary therapy on uremic symptoms and complications. In: Giovannetti S (ed) Nutritional treatment of chronic renal failure. Kluwer, Boston, pp 235 -239 19. Motomura K, Okuda S, Sanai T, Ando T, Onoyama K, Fujishima M (1988) Importance of early initiation of dietary protein restriction for the prevention of experimental progressive renal disease. Nephron 49: 144-149 20. Raymond NG, Dwyer JT, Nevins P, Kurtin P (1990) An approach to protein restriction in children with renal insufficiency. Pediatr Nephrol 4: 145-151