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NEPHROLOGY 2009; 14, 750–757 doi:10.1111/j.1440-1797.2009.01115.

Original Article

Influence of ketoanalogs supplementation on the progression


in chronic kidney disease patients who had training on
low-protein diet
JAE HYUN CHANG,1* DONG KI KIM,2* JUNG TAK PARK,3,4 EA WHA KANG,5
TAE HYUN YOO,3,4 BEOM SEOK KIM,3,4 KYU HUN CHOI,3,4 HO YUNG LEE,3,4 DAE-SUK HAN3,4
and SUG KYUN SHIN5

1
Department of Internal Medicine, Gachon University of Medicine and Science, Incheon, 2Department of
Internal Medicine, Seoul National University Hospital 3Department of Internal Medicine, College of Medicine,
and 4The Institute of Kidney Disease, Yonsei University, Seoul, and 5Department of Internal Medicine,
NHIC Ilsan Hospital, Goyang, Gyeonggi-do, Korea

SUMMARY: nep_1115 750..757

Aim: A low-protein diet (LPD) is a conservative treatment in patients with chronic kidney disease (CKD) to
improve uremic symptoms and slow the progression of renal dysfunction. However, the deleterious effects of
protein restriction on nutritional status have raised concern. We investigated whether ketoanalogs supplemen-
tation in CKD patients who had training on LPD retards the progression of CKD and maintains nutritional
status.
Methods: Data were collected retrospectively from 120 consecutive patients in the CKD stages III and IV. Firstly
all patients were restricted to LPD alone for 6 months (LPD alone), and then ketoanalogs of essential amino acids
(KA) were supplemented for 6 months.
Results: The adequate LPD had not achieved in both periods. The declining slopes of glomerular filtration rate
(GFR) during the LPD + KA period were significantly lower than those during the LPD alone period. This
improvement in GFR was apparent in both subjects with diabetics and non-diabetic patients. Mean serum total
cholesterol levels decreased in LPD + KA compared with LPD alone period. However, serum albumin levels did
not change. Responders showed a higher prevalence of diabetes and higher serum albumin levels during the
LPD alone period. Multivariate analysis revealed that responsiveness to LPD + KA was independently related to
diabetes (p = 0.006) and high serum albumin levels (p = 0.011) in the LPD alone period.
Conclusion: KA supplementation on over LPD delayed the progression of CKD without deteriorating nutritional
status, and initial serum albumin levels could be an independent factor.

KEY WORDS: chronic kidney disease, ketoanalogs, low-protein diet.

Despite various efforts to slow the progression of chronic enzyme inhibitors and angiotensin receptor blockers, have
kidney disease (CKD), the prevalence of terminal renal proven insufficient. Thus, additional conservative treat-
failure, which requires kidney replacement, continues to ments (e.g. treatment for lipid abnormality or anaemia and
increase. In addition, previous methods, such as blood sugar protein-restricted diet) are used in conjunction with other
or blood pressure (BP) control, angiotensin-converting methods. Among these additional treatments, a low-protein
diet (LPD) is used to maintain protein supply and energy
Correspondence: Dr Sug Kyun Shin, Divison of Nephrology, Depart- balance in patients with CKD, while restricting dietary
ment of Internal Medicine, National Health Insurance Corporation protein as much as possible.1 This strategy alleviates uremic
Ilsan Hospital 1232 Baeksokdong, Ilsan-gu, Goyang-si, Gyeonggi-do, symptoms caused by phosphorus, sulphates, various organic
410-360, Korea. Email: sskyun@hotmail.com acids and amine, which accumulate during protein catabo-
*These authors contributed equally to this work. lism; LPD also counters the increased urea concentrations
Accepted for publication 22 February 2009.
observed in patients with CKD. However, protein-restricted
© 2009 The Authors diet may result in essential amino acids (EAA) deficiency,
Journal compilation © 2009 Asian Pacific Society of Nephrology and thus deteriorate the patient’s nutritional status.
Influence of ketoanalogs in CKD with LPD 751

Table 1 Components of the essential amino acids/essential

MDRD GFR time slople (mL/min per 1.73 m2 per year)


amino acids ketoanalogs supplement† 16.0

1 tablet of ketoanalogs contains (mg)


Calcium-DL-3-methyl-2-oxovaleric acid 67
(a-ketoanalog to isoleucine, calcium salt) 14.0 GFR time Slope
Calcium-4-methyl-2-oxovaleric acid 101 = −0.025 mL/min per 1.73 m2 per day
(a-ketoanalog to leucine, calcium salt) = −9.125 mL/min per 1.73 m2 per year
Calcium-2-oxo-3-phenylpropionic acid 68
(a-ketoanalog to phenylalanine, calcium salt) 12.0
Calcium-3-methyl-2-oxobutyyric acid 86
(a-ketoanalog to valine, calcium salt)
Calcium-DL-2-hydroxy-4-(methylthio)-butyric acid 59
(a-hydroxyanalog to methionine, calcium salt) 10.0
L-lysine acetate 105
L-threonine 53
L-tryptophan 23
L-histidine 38 8.0
L-tyrosine 30 0 50 100 150 200 250 300
Total calcium 50 Day
Total nitrogen 36
Fig. 1 Example of a best-fit line for the GFR time slope, as
†Ketosteril®, Fresenius Kabi, Bad Homburg, Germany. determined by regression analysis. GFR, glomerular filtration
rate; MDRD, Modification of Diet in Renal Disease.

Essential amino acids ketoanalogs, which are converted


into EAA in the body via transamination, are used to
glomerular filtration rate (GFR) during the LPD alone period, those
prevent nutritional deficiencies caused by protein-restricted
who did not receive education for LPD and those who could not take
diets. Thus, the progression of renal failure can be retarded more than nine tablets per day of Ketosteril. Finally, we analysed 120
if patients are restricted to ketoanalogs-supplemented LPD.2 patients, who regularly participated in the follow-up examinations and
Although several studies have reported significant positive for whom the appropriate clinical data were available.
effects of ketoanalog-supplemented diets on renal failure,3,4
others have concluded that ketoanalogs supplementation
has an insignificant effect on preserving renal function.5 Methods
Our objective was to evaluate the effects of EAA
ketoanalogs and a protein-restricted diet on slowing the Basic clinical data, including gender, age, weight, height and renal
decline of renal function in Korean patients. We also exam- functions, were collected from medical records. All patients set their
ined the clinical characteristics of patients who responded own LPD alone and LPD + KA periods based on the start date of
positively to LPD with ketoanalogs supplementation ketoanalogs supplementation. The starting day of the LPD alone period
was the date of the first serum creatinine test to calculate the slope of
(LPD + ketoanalogs of essential amino acids (KA)) and
GFR before 6 months, and the last day was the day before starting
identified the predictive markers.
LPD + KA. The beginning day of the LPD + KA period was same with
the last day of LPD alone, and the last day was the date on which
METHODS underwent the final serum creatinine test after 6 months. During both
periods, renal function, BP and various haematological, biochemical
and administration effects were monitored. In addition, the patients
Subjects
were divided into diabetic and non-diabetic subgroups for further analy-
sis, and the clinical characteristics of responders (i.e. those who showed
Of all patients with CKD who visited the National Health Insurance
improved GFR after beginning LPD + KA diet) were evaluated.
Corporation Ilsan Hospital, Korea between January 2000 and July 2007,
250 patients were prescribed a LPD (20.6 g/kg per day) with keto-
analogs supplementation (Ketosteril®, Fresenius Kabi, Bad Homburg,
Germany). The supplement used in this study was a combination of Change in renal function
EAA (lysine, threonine, tryptophan, histidine and tyrosine) and EAA
analogs (isoleucine, leucine, phenylalanine, valine ketoanalog and To compare renal function between periods, estimated GFR was
methionine hydroxyanalog; Table 1). The patients were observed for obtained from serum creatinine measurements by using Modification of
6 months before initiating KA supplementation (LPD alone), and three Diet in Renal Disease (MDRD) formula.6 Regression analyses were
or more serum creatinine analyses were performed at 1 month intervals. performed to calculate the MDRD GFR time slope (Fig. 1) according to
Next, the patients were prescribed with Ketosteril of 12 tablets per day the number of days during the LPD alone and LPD + KA periods. The
on LPD for 6 months (LPD + KA), and those who underwent serum values were converted into yearly time slope.
creatinine testing three or more times at 1 month intervals were used in
the data analysis. However, we excluded patients who developed sudden Estimated GFR by MDRD study equation ( mL min per 1.73 m 2 )
critical symptoms of renal failure, those who showed an increased = 186 × creatinine −1.154 × age −0.203 × ( 0.742 if female )

© 2009 The Authors


Journal compilation © 2009 Asian Pacific Society of Nephrology
752 JH Chang et al.

Amount of dietary protein Table 2 Demographic data (n = 120)


Age (years) 61.8 1 11.7
After training on LPD, it needed to confirm actual amount of dietary
protein per day. For calculating the amount of dietary protein per day,
Sex (male : female) 73:47
3 day recall method was adopted. Diet diary for 3 days had been dis- Body weight (kg) 63.2 1 8.1
tributed to patients, and then they completed those themselves. Dieti- Height (cm) 162.0 1 10.1
cians calculated the amount of dietary protein per day using with Body mass index (kg/m2) 24.0 1 3.2
CANPRO 3.0 computer programme from The Korean Nutritional Underlying renal disease, n (%)
Society. There were 35 patients who were completed to calculate the Diabetes 67 (55.8%)
amount of dietary protein per day both periods. Chronic glomerulonephritis 23 (19.2%)
Hypertension 20 (16.7%)
Polycystic kidney disease 2 (1.7%)
Clinical parameters Others and unknown 8 (6.7%)

Averages BP and serum calcium, phosphorus, intact parathyroid


hormone (iPTH), total cholesterol, high-density lipoprotein (HDL)
cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, tinine was measured 4.8 1 0.9 and 4.6 1 0.7 times, respec-
haemoglobin, albumin, protein and total carbon dioxide levels were tively. There was no difference statistically in the mean
monitored throughout both phases. In addition, administration effects amount of dietary protein per day between two periods
that may have affected renal function were also analysed.
(0.68 1 0.07, 0.65 1 0.06 g/kg per day, respectively, P = NS)
Overall, mean serum creatinine levels were higher during
Responders and non-responders LPD + KA period (3.13 1 0.94 vs 2.40 1 0.7 mg/dL,
P < 0.001), whereas MDRD GFR (29.4 1 10.7 vs 21.6 1 7.9
The patients were divided into responder and non-responder group. A mL/min per 1.73 m2, P < 0.001) were lower during
responder was defined as an individual who showed a positive change in LPD + KA (Table 3). The MDRD GFR time slopes
the MDRD GFR time slopes between the LPD alone and LPD + KA (-10.7 1 10.3 vs -3.8 1 9.4 mL/min per 1.73 m2 per year,
periods. Those who showed a negative change in MDRD GFR time P < 0.01) increased significantly during the LPD + KA
slopes were defined as non-responders. Clinical and biochemical period, indicating that the declining GFR improved after
parameters were analysed in both groups, and independent predictive switching to LPD + KA (Fig. 2A).
factors that may have contributed to improved GFR while receiving
After starting LPD + KA, the patients showed a signifi-
LPD + KA were identified.
cant increase in serum calcium concentrations (8.48 1 0.59
vs 8.72 1 0.69 mg/dL, P < 0.05), whereas serum phosphorus
Statistical analysis and iPTH levels decreased; this difference, however, was not
statistically significant. Total cholesterol (183.2 1 35.1 vs
The data are represented as the mean 1 standard deviation (SD). spss 162.8 1 32.1 mg/dL, P < 0.001) and triglyceride (197.6 1
(version 13.0; SPSS Inc., Chicago, IL, USA) was used for all statistical 128.2 vs 149.7 1 71.8 mg/dL, P < 0.05) levels also declined
analyses. Paired t-tests, independent t-tests and c2 tests were used to after switching, but LDL and HDL cholesterol levels showed
compare independent factors, such as clinical parameters, haematologi- no significant change. Haemoglobin levels decreased signifi-
cal and biochemical tests and administration effects, among groups.
cantly, but no significant change was observed in serum
Multivariate logistic regression analysis was used to evaluate indepen-
albumin or protein levels. Total carbon dioxide did not
dent risk factors. The level of significance was set at P < 0.05.
change in response to LPD + KA. The administration
effects of angiotensin-converting enzyme inhibitors and
RESULTS angiotensin receptor blockers did not differ during the two
periods; although the administration frequency of hae-
Clinical parameters matopoietic hormone increased during this period, it was
not statistically significant. No significant difference was
The average age of the patients was 61.8 1 11.7 years, with observed in administration effects or the number of anti-
a gender ratio of 73:47 (male : female) and mean height, hypertensive drugs (Table 3).
weight and body mass index values of 162.0 1 10.1 cm,
63.2 1 8.1 kg and 24.0 1 3.2 kg/m2, respectively. Among all
patients, 55.8% developed diabetes before kidney disease, Comparison between patients with diabetes versus
19.2% had chronic glomerulonephritis, 16.7% had hyper- non-diabetic subjects
tension, 1.7% had polycystic kidney disease and 6.7% suf-
The MDRD GFR time slope was lower in patients with
fered from unspecified diseases (Table 2).
diabetes compared with the non-diabetic patients during
the LPD alone period. These results suggest that those with
Comparison between the LPD alone and diabetes lose renal function more rapidly. In the diabetes
LPD + KA Periods group, the MDRD GFR time slope (-12.3 1 11.3 vs
-4.0 1 11.3 mL/min per 1.73 m2 per year, P < 0.01)
The mean LPD alone period was 194.8 1 37.1 days, and the increased significantly during LPD + KA compared with the
mean LPD + KA period was 189.1 1 23.5 days. Serum crea- LPD alone period, indicating that GFR declined more

© 2009 The Authors


Journal compilation © 2009 Asian Pacific Society of Nephrology
Influence of ketoanalogs in CKD with LPD 753

Table 3 Comparison of variables between the LPD alone and LPD + KA periods
LPD alone period LDP + KA period P-value
Age (years) 61.8 1 11.7 62.7 1 11.7 <0.001
Duration (days) 194.8 1 37.1 189.1 1 23.5 NS
Numbers of Cr estimation 4.8 1 0.9 4.6 1 0.7 NS
Dietary protein intake (g/kg per day) 0.68 1 0.07 0.65 1 0.06 NS
Mean daily dosage of KA (tablets/day) 0.00 10.6 1 1.6 <0.001
Estimated GFR
Initial Cr (mg/dL) 2.40 1 0.70 3.13 1 0.94 <0.001
Initial MDRD GFR (mL/min per 1.73 m2) 29.4 1 10.7 21.6 1 7.9 <0.001
Initial systolic BP (mmHg) 134.4 1 10.6 134.3 1 11.8 NS
Initial diastolic BP (mmHg) 76.3 1 8.1 76.7 1 9.6 NS
Initial laboratory test
Calcium (mg/dL) 8.48 1 0.59 8.72 1 0.69 <0.05
Phosphorus (mg/dL) 3.82 1 0.55 3.69 1 0.78 NS
Intact PTH (pg/mL) 77.5 1 37.2 57.3 1 21.5 NS
Total cholesterol (mg/dL) 183.2 1 35.1 162.8 1 32.1 <0.001
HDL cholesterol (mg/dL) 47.7 1 13.5 48.3 1 14.9 NS
Triglyceride (mg/dL) 197.6 1 128.2 149.7 1 71.8 <0.05
LDL cholesterol (mg/dL) 122.9 1 38.9 114.3 1 35.4 NS
Haemoglobin (g/dL) 11.5 1 1.5 10.9 1 1.4 <0.001
Albumin (g/dL) 3.74 1 0.53 3.73 1 0.49 NS
Protein (g/dL) 6.51 1 0.64 6.50 1 0.67 NS
Total CO2 (mmol/L) 23.0 1 2.5 23.0 1 2.4 NS
Medications
ARB and/or ACEi, n (%) 109 (90.8) 103 (85.8) NS
Number of antihypertensives 2.1 1 1.1 2.2 1 1.5 NS
Recombinant erythropoietin, n (%) 52 (43.4) 63 (52.5) NS
HMG CoA reductase inhibitor, n (%) 61 (50.8) 52 (43.3) NS

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BP, blood pressure; Cr, creatinine; GFR, glomerular filtration
rate; HDL, high-density lipoprotein; HMG CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; KA, ketoanalogs of essential amino acids; LDL, low-
density lipoprotein; LPD, low-protein diet; MDRD, Modification of Diet in Renal Disease; NA, not applicable; NS, not significant; PTH, parathyroid
hormone.

LPD alone LPD + KA LPD alone LPD + KA LPD alone LPD + KA


0 0 0
(mL/min per 1.73 m2 per year)

(mL/min per 1.73 m2 per year)

(mL/min per 1.73 m2 per year)

−5 −5
MDRD GFR time slople

MDRD GFR time slople

MDRD GFR time slople

−5

−10 −10 −10


*
−15 * −15 −15
*
−20 −20 −20

−25 −25 −25


−10.7 ± 10.3 −3.8 ± 9.4 −12.3 ± 11.3 −4.0 ± 11.3 −8.8 ± 8.7 −3.6 ± 6.4

Fig. 2 MDRD GFR time slopes improved after switching to a LPD with ketoanalog supplementation. (A) All patients (n = 120),
(B) diabetic patients (n = 67) and (C) non-diabetic patients (n = 53). *P < 0.01 vs LPD alone. GFR, glomerular filtration rate;
KA, ketoanalogs of essential amino acids; MDRD, Modification of Diet in Renal Disease.

slowly after starting LPD + KA (Fig. 2B). In non-diabetic Comparison between responders and non-responders
patients, the MDRD GFR time slope (-8.8 1 8.7 vs
-3.6 1 6.4 mL/min per 1.73 m2 per year, P < 0.01) increased The responders, or those who showed a slower decline in
significantly during LPD + KA, suggesting that GFR renal function after starting LPD + KA, did not differ in
improved after switching to LPD + KA (Fig. 2C). terms of gender, age or body mass index compared with

© 2009 The Authors


Journal compilation © 2009 Asian Pacific Society of Nephrology
754 JH Chang et al.

Table 4 Comparison of variables between responders and non-responders for LPD + KA


Responders Non-responders
(n = 85) (n = 35) P-value
DMDRD GFR time slope (mL/min per 1.73 m2 per year) 12.0 1 11.6 -5.4 1 6.2 <0.001
Age (years) 63.6 1 11.1 60.4 1 12.8 NS
Sex (% of male) 61.2 60.0 NS
Body mass index (kg/m2) 24.3 1 3.1 23.4 1 3.2 NS
Prevalence of diabetes (%) 63.5 37.1 <0.01
Estimated GFR at the initiation of KA
Cr (mg/dL) 3.18 1 0.99 2.99 1 0.85 NS
MDRD GFR (mL/min) 21.2 1 7.8 22.7 1 8.2 NS
Initial BP in LPD + KA period
Systolic pressure (mmHg) 134.5 1 10.7 134.3 1 10.5 NS
Diastolic pressure (mmHg) 76.6 1 8.0 78.3 1 8.0 NS
Initial laboratory test in LPD + KA period
Calcium (mg/dL) 8.52 1 0.53 8.51 1 0.54 NS
Phosphorus (mg/dL) 3.77 1 0.60 3.68 1 0.93 NS
Intact PTH (pg/mL) 80.8 1 68.1 84.5 1 48.1 NS
Total cholesterol (mg/dL) 176.3 1 35.2 186.3 1 40.1 NS
HDL cholesterol (mg/dL) 45.9 1 10.9 46.8 1 16.9 NS
Triglyceride (mg/dL) 181.6 1 87.3 189.3 1 170.5 NS
LDL cholesterol (mg/dL) 115.0 1 34.7 135.8 1 53.1 NS
Haemoglobin (g/dL) 11.6 1 1.6 11.3 1 1.1 NS
Total CO2 (mmol/L) 23.1 1 2.6 22.7 1 2.3 NS
Albumin (g/dL) 3.81 1 0.53 3.58 1 0.50 <0.05
Medication
ARB and/or ACEi (%) 90.6 91.4 NS
HMG CoA reductase inhibitor (%) 55.3 40.0 NS
Recombinant erythropoietin (%) 44.7 40.0 NS

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BP, blood pressure; Cr, creatinine; GFR, glomerular filtration
rate; HDL, high-density lipoprotein; HMG CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; KA, ketoanalogs of essential amino acids; LDL, low-
density lipoprotein; LPD, low-protein diet; MDRD, Modification of Diet in Renal Disease; NS, not significant; PTH, parathyroid hormone.

non-responders, although diabetes was more prevalent Table 5 Predictive factors for responders, as determined by
among responders (63.5%) than non-responders (37.1%, logistic regression analysis
P < 0.01) before developing CKD. When starting the
HR 95% CI P-value
LPD + KA diet, serum creatinine and MDRD GFR did not
differ between responders and non-responders. Systolic and Diabetes 3.50 1.42–8.62 0.006
diastolic BP did not differ between groups during the LPD Albumin (LPD alone period) 3.13 1.30–7.54 0.011
alone period. Serum calcium, phosphorus, iPTH, total cho- Diastolic blood pressure 0.97 0.92–1.03 0.971
lesterol, HDL cholesterol, LDL cholesterol and triglyceride
levels did not differ between groups, although serum Adjustment for age, sex. CI, confidence interval; HR, hazards ratio;
KA, ketoanalogs of essential amino acids; LPD, low-protein diet.
albumin levels were significantly higher among responders
during the LPD alone period (3.81 1 0.53 vs 3.58 1 0.50 g/
dL, P < 0.05). No administration effects were observed in
attenuation of declining renal function during LPD + KA.
either group (Table 4). When only patients with diabetes
After correcting for age and gender, diabetes (hazards
were analysed, BP and lipid levels did not differ between
ratio = 3.50 (1.42–8.62), P = 0.006) and serum albumin
responders and non-responders; glycosylated haemoglobin
level (hazards ratio = 3.13 (1.30–7.54), P = 0.011) showed
(HbA1c) levels were slightly lower among responders,
statistical significance during the LPD alone, implying
although this difference was not statistically significant.
that diabetes and nutritional status are predictive
However, serum albumin levels were significantly higher
factors for preserving renal function during LPD + KA
among responders with diabetes compared with non-
(Table 5).
responders (3.75 1 0.47 vs 3.35 1 0.63 g/dL, P < 0.05). Even
though we could not show concrete dietary data, poor
compliance with dietary regimen might contribute the DISCUSSION
difference between two groups.
We used logistic regression analysis to identify indepen- Restriction of dietary protein as a conservative treatment for
dent predictive factors that contribute to the observed CKD is thought to slow the decline of renal function by

© 2009 The Authors


Journal compilation © 2009 Asian Pacific Society of Nephrology
Influence of ketoanalogs in CKD with LPD 755

decreasing the accumulation of uremic substances produced day; however, responsiveness to this treatment was very
during nitrogen metabolism,7 but the resultant lack of EAA poor. For this reason, we focused on a ketoanalog-
and calories, along with decreased protein catabolism raise supplemented LPD that limits protein to 20.6 g/kg per day;
additional concerns.8 Furthermore, poor nutritional status as a result, the decline in the GFR was significantly attenu-
and protein deficiency are often observed in patients with ated among both patients with diabetes and non-diabetic
CKD following a normal diet.9 These results indicate that subjects, indicating that LPD + KA slows the progression of
patients with CKD are prone to malnutrition, which may renal failure. No change was observed in serum albumin or
then lead to low albumin levels and subsequent increases in protein concentrations, indicating that LPD + KA does not
mortality in those with terminal kidney disease. However, result in severe malnutrition.
several studies have reported that a LPD with EAA or Prakash et al. followed pre-dialytic patients with
EAA ketoanalogs supplementation is sufficient to maintain chronic renal failure for 9 months and reported that a LPD
anthropometric nutritional indices, as well as nitrogen significantly reduced the decline in the GFR.2 Further-
balance and serum protein levels.10–12 EAA or EAA more, a ketoanalog-supplemented VLPD did not change
ketoanalogs are considered important because protein defi- the GFR 9 months after starting the diet, demonstrating
ciency often occurs in the process of gluconeogenesis among that ketoanalog supplementation helps to preserve renal
patients with CKD, when EAA become critical because of function. Similarly, Jungers et al. reported that a
tissue hypoxia caused by renal anaemia.13 Nevertheless, ketoanalog-supplemented VLPD (20.4 g/kg per day) was
MDRD analysis demonstrates that the degree of protein more effective than a LPD in retarding the decline of renal
restriction, rather than ketoanalogs supplementation, is an function without causing malnutrition.24 However, these
independent factor for attenuating the decline of GFR.7 studies compared differences in the decline in the GFR
Moreover, Lucas et al. argued that LPD + KA may reduce based on diet, whereas we compared the decline in renal
muscle mass.14 In Korea, supplementation with EAA and function in the same patients, before and after beginning
EAA ketoanalogs was first introduced in 2006, and this is the diet.
the first study regarding the effects of LPD with supplemen- We chose this strategy because the conditions related
tation on the progression of kidney disease or nutritional to GFR decline may vary according to the individual and
status in Korea. the disease;25 in fact, the rate of decline may vary even
With the exception of lysine and threonine, EAA within the same kidney disease. Therefore, without a suf-
ketoanalogs are converted into EAA in the liver, intestines ficiently large sample size, comparison between diets may
and muscles via transamination, thus minimizing any AA result in error even if no distribution difference exists in
deficiency that may result from a LPD. In addition, ketoana- the diseases that the patients had before developing kidney
logs have been reported to contain less nitrogen than EAA, disease. Barsotti et al.26 compared GFR before and after
thus reducing nitrogen load on the kidney, alleviating ketoanalog supplementation and reported a significant
uremic symptoms,15 slowing the decline of renal function,16 improvement, but the number of subjects was considered
delaying the need for kidney replacement17 and decreasing insufficient.
the mortality rate after kidney replacement.18 MDRD analy- In addition, this study analysed the preclinical param-
sis demonstrates that a very low-protein diet (VLPD) with a eters of responders who showed significant enhancement in
combination of EAA and EAA ketoanalogs is more effec- the GFR after switching to LPD + KA. Diabetes and high
tive in slowing the decline of GFR than the same diet serum albumin were significantly more prevalent among
supplemented with nitrogen-containing EAA alone.19 In responders. According to our multivariate analysis, patients
addition to preserving renal function through reduced nitro- with diabetes and high serum albumin levels had a greater
gen load, ketoanalogs supplementation retards the produc- possibility of benefiting from LPD + KA, in terms of slowing
tion of glucocorticoids, thus reducing protein catabolism11 the decline of renal function. Although patients with dia-
and slowing the progression of chronic renal failure.20 betes can preserve renal function and reduce mortality
Furthermore, previous studies showed that a ketoanalog- through LPD + KA,27,28 no previous study has compared
supplemented diet increased renal tubular resorption of AA these effects with non-diabetic patients. In addition, the
in patients with renal failure, thus reducing albuminuria.19 mechanism underlying improved renal function in patients
Furthermore, a-ketoisocaproate, a ketoanalog of the EAA with diabetes during LPD + KA remains unclear, but
leucine, decreases protein catabolism in skeletal muscle;21 increased insulin sensitivity or improved BP control and
because this ketoanalog exists as a phosphorus-free calcium reduced nitrogen load may be involved. Further research is
salt, it also reduces phosphorus concentrations and the inci- required to clarify this point.
dence of hyperparathyroidism.22 In addition, Teplan et al.23 We observed that HbA1c levels were slightly lower
reported that patients with CKD receiving erythropoietin among responders when other factors, such as the use of
and LPD showed significantly lower cholesterol, LDL cho- insulin and hypoglycaemic agents, were not corrected;
lesterol and triglyceride levels, and higher HDL cholesterol however, this difference was not statistically significant. In
levels, when receiving ketoanalog supplementation, indi- addition, we observed no change in BP or lipid abnormality.
cating that ketoanalog-supplemented LPD is more effective However, among patients with diabetes, individuals with
in improving lipid metabolism than LPD alone. higher serum albumin levels before LPD + KA responded
Previous clinical studies have examined ketoanalog- more positively to the diet, implying that nutritional status
supplemented VLPD that limited protein to 20.4 g/kg per before treatment is important. Patients with better nutri-

© 2009 The Authors


Journal compilation © 2009 Asian Pacific Society of Nephrology
756 JH Chang et al.

tional status have previously been reported to show a slower 9. Ikizler TA, Greene JH, Wingard RL, Parker RA, Hakim RM.
decline in renal function.29 Our results indicate that nutri- Spontaneous dietary protein intake during progression of chronic
tional status is a predictive factor for the preservation of renal failure. J. Am. Soc. Nephrol. 1995; 6: 1386–91.
10. Masud T, Young VR, Chapman T, Maroni BJ. Adaptive responses
renal function through a LPD; thus, nutritional status
to very low protein diets: The first comparison of ketoacids to
should be considered when diet is used to delay the progres-
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ACKNOWLEDGEMENTS
failure. Kidney Int. 1982; 22: 48–53.
18. Coresh J, Walser M, Hill S. Survival on dialysis among
This study was supported by NHIC Ilsan Hospital Clinical
chronic renal failure patients treated with a supplemented low-
Research Fund. We really appreciated all members of protein diet before dialysis. J. Am. Soc. Nephrol. 1995; 6: 1379–
Nutritional Service Department, Ilsan Hospital for giving us 85.
great efforts. 19. Teplan V, Schuck O, Horackova M, Skibova J, Holecek M. Effect
of a keto acid-amino acid supplement on the metabolism and
renal elimination of branched-chain amino acids in patients with
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