Efficacy of an unselected protein diet (25 g) with

minor oral supply of essential amino acids and

keto analogues compared with a selective
protein diet (40 g) in chronic renal failure1
Dieter Kampf, Hans-C/i. Fischer, and Michael Kessel

ABSTRACT The efficacy of a mixed protein-poor diet (25 g) with an intake ofonhy 12 tablets
of essential amino acids or keto analogues (= 0.9 Rose units) was compared with that of a selective
protein diet (40 g). Twenty-eight patients with chronic renal insufficiency (creatinine clearance 13.2
± 5.6 mI/min per 1.73 m2) were included in the prospective study with four periods of 3 months
each. Each patient served as his own control. The mixed protein-poor diet showed a better patient

Downloaded from www.ajcn.org by guest on February 7, 2012

compliance irrespective of the type of supplement. In addition, the essential amino acid supple-
mentations showed no advantages over the standard diet. In patients with a creatinine clearance
less than 10 mI/min, the keto analogue supplementation led to an improvement of the uremic
intoxication and the nutritional state. An increase in renal function was not observed. The
phosphate decrease occurred even when there were signs of protein malnutrition. Am. J. Clin.
Nut,. 33: 1673-1677, 1980.

Previous investigations have shown (1, 2) sideration of patient compliance, uremic in-
that the daily protein requirement in uremic toxication, renal function, and nutritional
patients is close to 0.6 g/kg per day. For this state.
reason, we favored in past years a selective
Patients and methods
diet with 40 g of primarily high biological
value protein (sPD). However, in far ad- Patients

vanced renal insufficiency, its efficacy regard- The investigations were only carried out with the
ing to the uremic intoxication is rather urn- patient’s informed consent. Twenty-eight patients were
included in the study. Eight patients required dialysis
ited. In addition, the strict protein restriction
treatment because of rapid functional deterioration and
and the resulting monotony contribute to a had to be excluded from further investigation. Twenty
low patient compliance. patients completed the study. Their relevant medical
Therefore, the successful results recently characteristics are shown in Table I.
reported with a mixed protein-poor diet and
General treatment schedule andfollow-up
additional essential amino acid (EAA) or keto
The study was
conducted on an outpatient basis with
analogue (KA) supplementation were of spe-
intraindividual comparison. It was divided into four
cial interest (3, 4). The advantages ofa greater periods of 3 months each: the patients received: in period
variability and palatability were rendered A: the selective protein diet (40 g), providing primarily
questionable, however, by the recommended high biological value protein (eggs, cottage cheese); in
high tablet intake. Moreover, F#{252}rst
et al. (5) period B: the mixed protein-poor diet (25 g) with addi-
tional EAA supplementation; in period C: the mixed
have pointed out that, because of the in- protein-poor diet (25 g) with additional KA supplemen-
creased intracellular concentrations of certain tation; in period D: the selective protein diet (40 g) as
amino acids in uremia, an inappropriately described in period A. During the entire investigation
high amino acid (AA) intake could be harm- period, efforts were made to provide a calorie intake of
35 kcal/kg per day. In period B, the patients received 12
ful.
EAA tablets corresponding to 0.9 Rose units plus 0.456
The aim of the study was, therefore, to g ofhistidine and 0.360 g of tyrosine (= 6.66 g AA, EAS
compare the selective protein diet and the
mixed protein-poor diet with a relatively I From the Department of Nephrology, Free Univer-
lower EAA or KA supplementation in con- sity of Berlin, Berlin, West Germany.

The American Journal ofClinical Nutrition 33: JULY 1980, pp. 1673-1677. Printed in U.S.A. 1673
1674 KAMPF ET AL.

TABLE I
Patient details

Patient Age Sex Diagnosis BUN Creatinine C.,. Proteinuna

yr kg mg/dl mi/mini!. 73 m giday

A.E. 30 F 75 Polycystic kidneys 68 5. 1 16.3 0.9

A.P. 72 F 63 Chronic pyelonephritis 43 2.8 18.0 0.6
BE. 48 F 62 Chronic pyelonephritis 31 2.6 26.5 1.4
F.M. 62 M 79 Chronic pyehonephritis 7 1 6.0 10. 1 0
F.C. 64 F 78 Chronic pyehonephritis 69 7. 1 8.5 0.6
GB. 43 F 7 1 Chronic glomerulonephritis 62 7. 1 10.8 2.3
G.R. 33 F 60 Chronic glomerulonephritis 90 7.0 12.5 3.7
G.E. 62 F 62 Chronic pyelonephritis 64 6.3 7.6 2.0
H.H. 45 M 86 Polycystic kidneys 86 12.3 5.1 0.3
K.E. 56 F 100 Chronic pyelonephritis 48 3.8 1 8.3 1.1
KG. 53 M 75 Nephrosclerosis 79 6.9 7.6 1.8
K.E. 65 F 56 Chronic pyelonephritis 94 7.6 12.0 1.0
L.R. 55 F 53 Chronic pyelonephritis 47 3.3 22.0 0.2
N.E. 56 F 78 Chronic pyehonephritis 55 4.3 17.6 0.4
P.D. 45 F 65 Chronic glomeruhonephritis 35 3.8 15.4 4.2

Downloaded from www.ajcn.org by guest on February 7, 2012

R.P. 68 F 63 Chronic glomerulonephritis 52 3. 1 22.4 0.8
Sch.P. 24 M 55 Chronic ghomerulonephritis 90 6.8 13.6 2.6
Th.K. 69 F 70 Chronic pyelonephritis 55 3.7 19.5 0.4
Th.H. 58 M 93 Chronic glomerulonephritis 40 4.3 20.8 3.4
Th.G. 51 M 64 Chronic glomeruhonephritis 35 5.5 13. 1 4.2
Range 24-72 53-100 31-96 2.6-12.3 5.1-26.5 0-4.2
Mean 53.0 70.4 61.0 5.5 14.9 1.6
SD 13.3 12.7 20.3 2.3 5.8 1.4

oral Fresenius). In period C, a-keto analogues (as Ca TABLE 2

salts) of 5 EAA (isoleucine, leucine, phenylalanine, va- Composition of EAA and KA preparations
line, methionine) in equimolar concentrations to period administered per 24 hr
B plus the remaining EAA, histidine and tyrosine were
EAA KA
administered (Ketosteril, Fresenius) (Table 2). The total
N intake (diet + tablets) amounted to about 6.4 g in giday

period A, 4.85 g in period B, 4.43 g in period C, and 6.4 Isoleucine 0.708 0.804
g in period D. Leucine 1.068 1.212
Clinical and laboratory routine examinations were Methionine 0.624 0.708
performed at 2 to 3 week intervals. At each visit the Phenyhahanine 0.732 0.816
patients were
asked about a complete tablet intake (pe- Valine 0.900 I .032
riods Then, they were given the exact number
B+C). of Lysine #{216}9fJfJa

tablets for the next interval. At every 2nd visit, the Threonine 0.636’
dietary record kept by the patient in the previous week Tryptophan 0.276#{176}
was discussed with a nutritionist and another oonsulta- Tyrosine 0.360#{176}
tion was held. Histidine 0.456#{176}
Total N 0.852 0.432
Laboratory data a EAA in both preparations.
Sodium, potassium, calcium, phosphate, bicarbonate,
creatinine, urea-N, uric acid, and glucose were deter-
mined by standard auto-analyzer techniques. Hemoglo- the selective protein diet. The additional in-
bin, total protein, and albumin were measured by routine take of 12 tablets was well tolerated by 3/4 of
methods, iminunoglobuhins (G, A, M), transferrin, and all patients. A preference for one or the other
C3 complement by radial immunodiffusion. Quantitative supplementation was not noted. In particular,
amino acid analysis was carried out on deproteinised
plasma specimens using a single-columm amino acid
there were no reports of bad taste, nausea, or
analyzer (Beckmann, Multichrom M). Statistical assess- vomiting in connection with the tablet intake.
ment was done according to the Student’s t test for paired At the routine consultation at the end of each
samples. period, 10 patients reported a clear improve-
ment in their state of health after the EAA or
Results
KA period without being able to differentiate
Ofthe 20 patients that completed the study, between these two periods.
10 preferred the mixed protein diet and three The biochemical follow-up showed a con-
 DIET AND CHRONIC RENAL FAILURE 1675

tinous rise of the creatinine with a relative Calcium and phosphate were only slightly
increase of 1.45 mg/dl over the entire study influenced by the EAA administration. Un-
period. In contrast, urea-N showed a decrease der the KA intake, an increase in serum
under KA intake which, in connection with calcium and a decrease in serum phosphate
the corresponding creatinine increase, led to were observed with simultaneous reduction
a significantly lower blood urea nitrogen ofthe Al(OH)3 administration (Table 3). The
(BUN)/creatinine ratio (Table 3). Analyzing decrease in serum phosphate was detectable
the results with respect to three different de- in all three groups.
grees of renal insufficiency, Group I (creati-
nine clearance > 15 mb/mm) showed a con- Discussion
tinuous improvement of the urea-N and of
the BUN/creatinine ratio over the entire The considerable impairment of patient
study period. In contrast to this, group II compliance by a high drug intake as well as
(creatinine clearance of 10 to 15 ml/min) and the increased intracellular concentrations of
group III (creatinine clearance of < 10 ml! alanine, glycine, leucine, and phenylalanine
min) only evidenced these changes with KA in uremia (5) were the reasons for the reduc-
supplementation (Fig. 1). tion of the EAA and KA supplementation to

Downloaded from www.ajcn.org by guest on February 7, 2012

The parameters of the nutritional state 1/3 of the originally recommended dose (3).
(such as body weight, hemoglobin, total pro- Correspondingly, the dietary protein intake
tein, transferrin) were not influenced by the was not reduced to 16 to 20 g/day (3) but
EAA administration. Only the C3 comple- only to 25 g/day. These modifications im-
ment and IgG increased significantly (Table proved the patient compliance significantly,
3). Under the KA intake, a decrease of almost compared to the selective protein diet alone.
all parameters was observed (Table 3), which With the exception of the improved patient
could largely be attributed to changes in compliance, the mixed protein-poor diet with
group I. In group III, these parameters either 6.66 g EAA supplementation did not show
remained constant or increased (Figs. 2 and any advantages over the standard diet. Nei-
3). The plasma amino acid concentrations did ther the degree of intoxication nor the protein
not show any significant changes under the metabolism were significantly influenced.
EAA or KA supplementation. The five EAA The quantitative extent ofthe C3 complement
that were substituted as keto analogues in and the IgG increase was too small to be of
period C did not show any changes either, any significance with regard to the immune
with the exception of valine (Fig. 4). defense system.

TABLE 3
Comparison of body weight, biochemical, and hematological data under different dietary regimens (mean ± SD, n
= 20)

sPD EAA KA sPD

Body weight (kg) 70.0 ± 13.4 71.0 ± 8.9 70.5 ± 15.7 70.0 ± 13.4
Creatinine (mg/dl) 5.48 ± 2.48 6.13 ± 2.94 6.56 ± 3.08 6.93 ± 3.89
BUN (mg/dl) 57.6 ± 14.3 62.9 ± 18.6 61.1 ± 19.5 73.4 ± 29.5”
BUN/creatinine 10.5 ± 0.94 10.3 ± 0.84 9.3 ± 0.83a 10.6 ± 0.53
Potassium (mmole/liter) 4.30 ± 0.56 4.26 ± 0.56 4.26 ± 0.49 4.16 ± 0.38
Bicarbonate (mmole/liter) 20.0 ± 2.3 20.4 ± 2.1 20.4 ± 1.9 20.9 ± 2.8
NaHCO3 intake (g/day) 2.5 ± 0.4 2.7 ± 0.6 2.8 ± 0.7 2.3 ± 0.3
Calcium (mmole/liter) 2.17 ± 0.24 2.18 ± 0.28 2.23 ± 0.28 2.13 ± 0.38”
Phosphate (mmole/liter) 1.45 ± 0.34 1 .40 ± 0.29 1 .33 ± 0.28 1.5 1 ± 0.34”
Al(OH3) intake (g/day) 1.6 ± 0.7 1.5 ± 0.4 1.4 ± 0.3 1.9 ± 0.6
Hemoglobin (g/dl) I 1.2 ± 2.2 10.9 ± 2.3 1 1.0 ± 2.3 10.7 ± 2.4
Transferrin (mg/dl) 246.3 ± 40.2 243.6 ± 44.5 236.0 ± 38.7 271.9 ± 39.8c
Total protein (g/dl) 7.50 ± 0.50 7.66 ± 0.60 7.55 ± 0.55 7.66 ± 0.52
Albumin (g/dl) 3.42 ± 0.28 3.42 ± 0.31 3.44 ± 0.33 3.45 ± 0.33
Ig G (mg/dl) 1216 ± 423 1305 ± 437 1201 ± 363 1251 ± 325
Ig A (mg/dl) 208 ± 79 206 ± 77 195 ± 72 21 1 ± 76#{176}
IgM(mg/dl) 122±67 127±55 126±82 134±65
C3 complement (mg/dl) 65.6 ± 14.9 68.7 ± 15.1” 65.4 ± 14.6#{176} 67.1 ± 17.7
ap<oo5 bp<001
P<0.00l.
 1676 KAMPF ET AL.

[Dl IKA
LsPo1 KA]
LEAA I sPDJ [jA sPO I
Creatinine 11 --. lit tgG 1500
mg/ti
9

..------... -.--.-. ii
mg/dI

:
1200

5 1100
1000
3 S #{149} S

BUN 100 gA 260

mg/di ‘/,, mg/dI 240

80
‘..-- aii
70 __- -I.,

160 .. .. ..ItI

140
BUN 18

::

Downloaded from www.ajcn.org by guest on February 7, 2012

Zdt

10 -...._____..... ___::::: 110

100 ______________________________________
:i o - I
I

0
I I

Ccrt
I

3
I I I I

> 15 mI/min/1.73
I

m2
9

20.3 ±3 7.,
l2months

12 months ( .7)
-- II Ccreat 1015 mi/min/1.73 m2 )i= 12.4 ± 1 3n . 7)
- I Ccreat > 15 mI/min/1.73 m2 (I . 20.3 ± 3 7;n 7) --- -III Ccrt < 10 mI/min/1.73 m2 (5- 7 15 1 71,n 6)
-- it Ccreat 1015 mt/min/1.73 m2 IC. 12.4 ± 13,n -7)
---- lit ccr,at < 10 mi/min/1.73 m2 1 . 7 15 ± 1.71; n = 6) FIG. 3. Effect of EAA and KA supplement on im-
munoglobulins G, A, and M in 20 patients with different
FIG. 1. Effect of EAA and KA supplement on crc-
degrees of renal insufficiency.
atinine, BUN, and BUN/creatinine ratio in 20 patients
with different degrees of renal insufficiency.

The mixed protein-poor diet with KA sup-

I s’o KA
plementation proved to be superior to both
M IsPol
Hemoglobin 14 the standard diet and the EAA supplemen-
g/dl 13 #{149} a - *1 tation. This concerns primarily the uremic
12 intoxication and its improvement that oc-
___ curred mainly in the two groups with the
....-:.:-::::
11

10 a- _... -.--.. ii
greatest functional loss. In view of the con-
9
stant creatinine clearance, the steady im-
8
provement of the BUN/creatinine ratio in
group I (Fig. 1) can only be attributed to the
Tranoferrin 290 more intensive patient care and the better
mg/dt It
long-term adaptation o the dietary require-
ments. An improvement of renal function, as
I.tIi described by Walser (4), was not reproducible
210 in any of our patients.
The advantage of KA supplement is lim-
complement C3 80
mg/dt 70I”-.-j-2--..---2:_::::::::_:-.-_:--.------#{149} I ited by the observed signs of malnutrition.
This is only true, however, for group I with
#{176}:I#{149}- #{149}------#{149} .- III the smallest functional loss. Those patients
50 ___________________
, I I I I I I
with the most severe renal insufficiency
0 3 6 9 l2months (group III) showed stable or improved pa-
- I Ccreat > 1 5 mI/mm/i .73 m2 (I - 20.3 ± 3.7; n 7) rameters of the nutritional state. Varcoe et a!.
-- II Ccr,,t 10.15 mi/min/1.73 m2 ii . 12.4 ± 1.3., .7)
---- itt Ccreat< lOmt/min/1.73m2 )i7.15±1.71.,-6) (6) have shown that uremic patients with a
FIG. 2. Effect of EAA and KA supplement on he- low protein intake utilize more urea-N and
moglobin, transferrin, and C3-complement in 20 patients with greater efficiency for protein synthesis
with different degrees of renal insufficiency. than healthy subjects. The contradictory re-
 DIET AND CHRONIC RENAL FAILURE 1677

12 pmol/dl 24 pmol/dI

10 20

8 16

6 12

4- 8

Downloaded from www.ajcn.org by guest on February 7, 2012

4

0_8 0
sPD EAA KA sPD
sPO EAA KA oPD sPO EAA KA sPO sPD EAA KA sPO sPO EAA KA sPO
Valine
Isoleucine Leucine Phenylalanine Methionine
FIG. 4. Plasma concentrations of five EAA’s, which are supplemented as a-KA in period C. (Mean ± SD, n =

20), = normal range.

sults in groups I and III of our patients could optimal KA composition could alter the dif-
also support a different utilization of the ex- ferent effects observed in the patients’ various
ogenous N and/or KA supply depending on degrees of renal insufficiency. (1
the degree of renal insufficiency. References
The changes in serum calcium and phos-
1. FORD, J., U. E. PHILIPS, F. E. TOGE, V. A. LUCK
phate during KA supplementation were sim- AND H. E. DEWARDENER. Nitrogen balance in pa-
ilar to those already described by others (4, tients with chronic renal failure on diets containing
7). The decrease in serum phosphate was varying amounts of protein. Brit. Med. J. 1: 735,
even observed when symptoms of protein 1969.
2. KOPPLE, J. D.,
M. K. SORENSEN, J. W. COBURN, S.
malnutrition occurred simultaneously (group GORDON M. E. RuBINI.
AND Controlled comparison
I). A reduced serum phosphate has been de- of 20-g and 40-g protein diets in the treatment of
scribed even after long-term KA intake and chronic uremia. Am. J. Clin. Nuts. 21: 553, 1968.
normalization of protein metabolism (7). 3. BERGSTROM, J., P. FURST AND L.-O. NOREE. Treat-
ment of chronic uremic patients with protein-poor
Thus, it appears questionable to interpret the
diet and oral supply of essential amino acids. Chin.
decrease in serum phosphate during oral KA Nephrol. 3: 187, 1975.
intake as an indication of increased protein 4. WALSER, M. Ketoacids in the treatment of uremia.
synthesis (4). At least, there exists the possi- Cliii. Nephrol. 3: 180, 1975.
bility of a decreased phosphate intake or 5. FURST, P., M. AHLBERG, A. ALVESTRAND AND J.
BERGSTROM. Principles of essential amino acid ther-
increased fecal phosphate excretion due to apy in uremia. Am. J. Chin. Nutr. 31: 1744, 1978.
formation of calcium-phosphate complexes 6. VARCOE, R., D. HALLIDAY, E. R. CARSON, P. RICH-
in the gut as suggested by Heid!and et al. (7). ARDS AND A. S. TAVILL. Efficiency of utilisation of
Considering the changes in patient compli- urea nitrogen for albumin synthesis by chronically
uraemic and normal man. Chin. Sci. Mole. Med. 48:
ance, uremic intoxication and nutritional
379, 1975.
state, KA supplementation only seems to be 7. HEIDLAND, A., J. KULT, A. ROCKEL AND E. HElD-
justified in patients with a creatinine clear- BREDER. Evaluation of essential amino acids and
ance near or below 10 ml/min. It cannot be keto acids in uremic patients on how-protein diet.
ruled out that a higher KA intake or a more Am. J. Chin. Nutr. 31: 1784, 1978.