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NEPHROLOGY 2009; 14 , 750–757 Original Article doi:10.1111/j.1440-1797.2009.01115.x Influence of ketoanalogs

NEPHROLOGY 2009; 14, 750–757

Original Article

doi:10.1111/j.1440-1797.2009.01115.x

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 HAN 3,4 and SUG KYUN SHIN 5

1 Department of Internal Medicine, Gachon University of Medicine and Science, Incheon, 2 Department of Internal Medicine, Seoul National University Hospital 3 Department of Internal Medicine, College of Medicine, and 4 The Institute of Kidney Disease, Yonsei University, Seoul, and 5 Department 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 kidney disease (CKD), the prevalence of terminal renal failure, which requires kidney replacement, continues to increase. In addition, previous methods, such as blood sugar or blood pressure (BP) control, angiotensin-converting

Correspondence: Dr Sug Kyun Shin, Divison of Nephrology, Depart- ment of Internal Medicine, National Health Insurance Corporation Ilsan Hospital 1232 Baeksokdong, Ilsan-gu, Goyang-si, Gyeonggi-do, 410-360, Korea. Email: sskyun@hotmail.com *These authors contributed equally to this work. Accepted for publication 22 February 2009.

© 2009 The Authors Journal compilation © 2009 Asian Pacific Society of Nephrology

enzyme inhibitors and angiotensin receptor blockers, have proven insufficient. Thus, additional conservative treat- ments (e.g. treatment for lipid abnormality or anaemia and protein-restricted diet) are used in conjunction with other methods. Among these additional treatments, a low-protein diet (LPD) is used to maintain protein supply and energy balance in patients with CKD, while restricting dietary protein as much as possible. 1 This strategy alleviates uremic symptoms caused by phosphorus, sulphates, various organic acids and amine, which accumulate during protein catabo- lism; LPD also counters the increased urea concentrations observed in patients with CKD. However, protein-restricted diet may result in essential amino acids (EAA) deficiency, and thus deteriorate the patient’s nutritional status.

Influence of ketoanalogs in CKD with LPD

Table 1 Components of the essential amino acids/essential amino acids ketoanalogs supplement†

1 tablet of ketoanalogs contains

(mg)

Calcium-DL-3-methyl-2-oxovaleric acid

67

(a

-ketoanalog to isoleucine, calcium salt)

Calcium-4-methyl-2-oxovaleric acid

101

(a

-ketoanalog to leucine, calcium salt)

Calcium-2-oxo-3-phenylpropionic acid

68

(a

-ketoanalog to phenylalanine, calcium salt)

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)

L-lysine acetate

105

L-threonine

53

L-tryptophan

23

L-histidine

38

L-tyrosine

30

Total calcium

50

Total nitrogen

36

†Ketosteril ® , Fresenius Kabi, Bad Homburg, Germany.

Essential amino acids ketoanalogs, which are converted into EAA in the body via transamination, are used to prevent nutritional deficiencies caused by protein-restricted diets. Thus, the progression of renal failure can be retarded if patients are restricted to ketoanalogs-supplemented LPD. 2 Although several studies have reported significant positive 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 Our objective was to evaluate the effects of EAA ketoanalogs and a protein-restricted diet on slowing the decline of renal function in Korean patients. We also exam- ined the clinical characteristics of patients who responded positively to LPD with ketoanalogs supplementation (LPD + ketoanalogs of essential amino acids (KA)) and identified the predictive markers.

METHODS

Subjects

Of all patients with CKD who visited the National Health Insurance 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 EAA (lysine, threonine, tryptophan, histidine and tyrosine) and EAA analogs (isoleucine, leucine, phenylalanine, valine ketoanalog and methionine hydroxyanalog; Table 1). The patients were observed for 6 months before initiating KA supplementation (LPD alone), and three or more serum creatinine analyses were performed at 1 month intervals. Next, the patients were prescribed with Ketosteril of 12 tablets per day on LPD for 6 months (LPD + KA), and those who underwent serum creatinine testing three or more times at 1 month intervals were used in the data analysis. However, we excluded patients who developed sudden critical symptoms of renal failure, those who showed an increased

© 2009 The Authors Journal compilation © 2009 Asian Pacific Society of Nephrology

751

16.0 14.0 GFR time Slope = −0.025 mL/min per 1.73 m 2 per day =
16.0
14.0
GFR time Slope
= −0.025 mL/min per 1.73 m 2 per day
= −9.125 mL/min per 1.73 m 2 per year
12.0
10.0
8.0
0
50
100
150
200
250
300
Day
MDRD GFR time slople (mL/min per 1.73 m 2 per year)

Fig. 1 Example of a best-fit line for the GFR time slope, as determined by regression analysis. GFR, glomerular filtration rate; MDRD, Modification of Diet in Renal Disease.

glomerular filtration rate (GFR) during the LPD alone period, those who did not receive education for LPD and those who could not take more than nine tablets per day of Ketosteril. Finally, we analysed 120 patients, who regularly participated in the follow-up examinations and for whom the appropriate clinical data were available.

Methods

Basic clinical data, including gender, age, weight, height and renal functions, were collected from medical records. All patients set their own LPD alone and LPD + KA periods based on the start date of ketoanalogs supplementation. The starting day of the LPD alone period was the date of the first serum creatinine test to calculate the slope of GFR before 6 months, and the last day was the day before starting 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 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 were divided into diabetic and non-diabetic subgroups for further analy- sis, and the clinical characteristics of responders (i.e. those who showed improved GFR after beginning LPD + KA diet) were evaluated.

Change in renal function

To compare renal function between periods, estimated GFR was obtained from serum creatinine measurements by using Modification of Diet in Renal Disease (MDRD) formula. 6 Regression analyses were performed to calculate the MDRD GFR time slope (Fig. 1) according to the number of days during the LPD alone and LPD + KA periods. The values were converted into yearly time slope.

Estimated GFR by MDRD study equation mL

(

min

per

=

186 × creati

nnine

1 154

.

×

age

0 203

.

× (

0

. 742

if female

)

1. 73

m

2

)

752

Amount of dietary protein

After training on LPD, it needed to confirm actual amount of dietary protein per day. For calculating the amount of dietary protein per day, 3 day recall method was adopted. Diet diary for 3 days had been dis- tributed to patients, and then they completed those themselves. Dieti- cians calculated the amount of dietary protein per day using with CANPRO 3.0 computer programme from The Korean Nutritional Society. There were 35 patients who were completed to calculate the amount of dietary protein per day both periods.

Clinical parameters

Averages BP and serum calcium, phosphorus, intact parathyroid hormone (iPTH), total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, haemoglobin, albumin, protein and total carbon dioxide levels were monitored throughout both phases. In addition, administration effects that may have affected renal function were also analysed.

Responders and non-responders

The patients were divided into responder and non-responder group. A responder was defined as an individual who showed a positive change in the MDRD GFR time slopes between the LPD alone and LPD + KA periods. Those who showed a negative change in MDRD GFR time slopes were defined as non-responders. Clinical and biochemical parameters were analysed in both groups, and independent predictive factors that may have contributed to improved GFR while receiving LPD + KA were identified.

Statistical analysis

The data are represented as the mean 1 standard deviation (SD). spss (version 13.0; SPSS Inc., Chicago, IL, USA) was used for all statistical analyses. Paired t -tests, independent t -tests and c 2 tests were used to compare independent factors, such as clinical parameters, haematologi- cal and biochemical tests and administration effects, among groups. Multivariate logistic regression analysis was used to evaluate indepen- dent risk factors. The level of significance was set at P < 0.05.

RESULTS

Clinical parameters

The average age of the patients was 61.8 1 11.7 years, with a gender ratio of 73:47 (male : female) and mean height, 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/m 2 , respectively. Among all patients, 55.8% developed diabetes before kidney disease, 19.2% had chronic glomerulonephritis, 16.7% had hyper- tension, 1.7% had polycystic kidney disease and 6.7% suf- fered from unspecified diseases (Table 2).

Comparison between the LPD alone and LPD + KA Periods

The mean LPD alone period was 194.8 1 37.1 days, and the mean LPD + KA period was 189.1 1 23.5 days. Serum crea-

 

JH Chang et al.

Table 2 Demographic data (n = 120)

Age (years) Sex (male : female) Body weight (kg) Height (cm) Body mass index (kg/m 2 ) Underlying renal disease, n (%) Diabetes Chronic glomerulonephritis Hypertension Polycystic kidney disease Others and unknown

61.8 1 11.7

73:47

63.2 1 8.1 162.0 1 10.1 24.0 1 3.2

67 (55.8%)

23 (19.2%)

20 (16.7%)

2 (1.7%)

8 (6.7%)

tinine was measured 4.8 1 0.9 and 4.6 1 0.7 times, respec- tively. There was no difference statistically in the mean amount of dietary protein per day between two periods

(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

2.40 1 0.7 mg/dL,

P < 0.001), whereas MDRD GFR (29.4 1 10.7 vs 21.6 1 7.9 mL/min per 1.73 m 2 , P < 0.001) were lower during LPD + KA (Table 3). The MDRD GFR time slopes

( -10.7 1 10.3 vs - 3.8 1 9.4 mL/min per 1.73 m 2 per year,

P < 0.01) increased significantly during the LPD + KA period, indicating that the declining GFR improved after switching to LPD + KA (Fig. 2A). After starting LPD + KA, the patients showed a signifi- cant increase in serum calcium concentrations (8.48 1 0.59

LPD + KA

period (3.13 1 0.94

vs

vs 8.72 1 0.69 mg/dL, P < 0.05), whereas serum phosphorus and iPTH levels decreased; this difference, however, was not statistically significant. Total cholesterol (183.2 1 35.1 vs

162.8

1 32.1 mg/dL, P < 0.001) and triglyceride (197.6 1

128.2

vs 149.7 1 71.8 mg/dL, P < 0.05) levels also declined

after switching, but LDL and HDL cholesterol levels showed no significant change. Haemoglobin levels decreased signifi- cantly, but no significant change was observed in serum albumin or protein levels. Total carbon dioxide did not change in response to LPD + KA. The administration effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers did not differ during the two periods; although the administration frequency of hae- matopoietic hormone increased during this period, it was not statistically significant. No significant difference was observed in administration effects or the number of anti- hypertensive drugs (Table 3).

Comparison between patients with diabetes versus non-diabetic subjects

The MDRD GFR time slope was lower in patients with diabetes compared with the non-diabetic patients during

the LPD alone period. These results suggest that those with diabetes lose renal function more rapidly. In the diabetes group, the MDRD GFR time slope ( -12.3 1 11.3 vs

- 4.0 1 11.3 mL/min per 1.73 m 2 per year, P < 0.01)

increased significantly during LPD + KA compared with the

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

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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 11.7 194.8 1 37.1 4.8 1 0.9 0.68 1 0.07

62.7 1 11.7 189.1 1 23.5 4.6 1 0.7 0.65 1 0.06 10.6 1 1.6

 

<0.001

Duration

(days) of Cr estimation

NS

Numbers

NS

Dietary protein intake (g/kg per day) Mean daily dosage of KA (tablets/day) Estimated GFR

Initial

Cr (mg/dL)

NS

0.00

<

0.001

2.40 1 0.70 29.4 1 10.7 134.4 1 10.6 76.3 1 8.1

3.13 1 0.94 21.6 1 7.9 134.3 1 11.8 76.7 1 9.6

< 0.001

Initial MDRD GFR (mL/min per 1.73 m 2 )

< 0.001

Initial

systolic BP (mmHg) diastolic BP (mmHg)

NS

Initial

NS

Initial laboratory test

 

Calcium (mg/dL)

8.48 1 0.59 3.82 1 0.55 77.5 1 37.2 183.2 1 35.1 47.7 1 13.5 197.6 1 128.2 122.9 1 38.9 11.5 1 1.5 3.74 1 0.53 6.51 1 0.64 23.0 1 2.5

8.72 1 0.69 3.69 1 0.78 57.3 1 21.5 162.8 1 32.1 48.3 1 14.9 149.7 1 71.8 114.3 1 35.4 10.9 1 1.4 3.73 1 0.49 6.50 1 0.67 23.0 1 2.4

 

< 0.05

Phosphorus (mg/dL)

NS

Intact PTH (pg/mL)

NS

Total cholesterol

(mg/dL)

< 0.001

HDL cholesterol

(mg/dL)

NS

Triglyceride (mg/dL) LDL cholesterol (mg/dL) Haemoglobin (g/dL) Albumin (g/dL) Protein (g/dL) Total CO 2 (mmol/L) Medications ARB and/or ACEi, n (%) Number of antihypertensives Recombinant erythropoietin, n (%) HMG CoA reductase inhibitor, n (%)

< 0.05

NS

< 0.001

NS

NS

NS

109 (90.8) 2.1 1 1.1 52 (43.4) 61 (50.8)

103 (85.8) 2.2 1 1.5 63 (52.5) 52 (43.3)

NS

NS

NS

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 0 −5 −10 −15 * −20 −25 −10.7 ± 10.3
LPD alone
LPD + KA
0
−5
−10
−15
*
−20
−25
−10.7 ± 10.3
−3.8 ± 9.4
MDRD GFR time slople
(mL/min per 1.73 m 2 per year)
LPD alone LPD + KA 0 −5 −10 −15 * −20 −25 −12.3 ± 11.3
LPD alone
LPD + KA
0
−5
−10
−15
*
−20
−25
−12.3 ± 11.3
−4.0 ± 11.3
MDRD GFR time slople
(mL/min per 1.73 m 2 per year)
LPD alone LPD + KA 0 −5 −10 * −15 −20 −25 −8.8 ± 8.7
LPD alone
LPD + KA
0
−5
−10
*
−15
−20
−25
−8.8 ± 8.7
−3.6 ± 6.4
MDRD GFR time slople
(mL/min per 1.73 m 2 per year)

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 patients, the MDRD GFR time slope ( - 8.8 1 8.7 vs

- 3.6 1 6.4 mL/min per 1.73 m 2 per year, P < 0.01) increased significantly during LPD + KA, suggesting that GFR improved after switching to LPD + KA (Fig. 2C).

© 2009 The Authors Journal compilation © 2009 Asian Pacific Society of Nephrology

Comparison between responders and non-responders

The responders, or those who showed a slower decline in renal function after starting LPD + KA, did not differ in terms of gender, age or body mass index compared with

754

JH Chang et al.

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

 
 

Responders ( n = 85)

Non-responders

 

(

n = 35)

P -value

D MDRD GFR time slope (mL/min per 1.73 m 2 per year) Age (years) Sex (% of male) Body mass index (kg/m 2 ) Prevalence of diabetes (%) Estimated GFR at the initiation of KA Cr (mg/dL)

12.0 1 11.6 63.6 1 11.1

- 5.4 1 6.2 60.4 1 12.8

< 0.001

NS

61.2

60.0

NS

24.3 1 3.1

23.4 1 3.2

NS

63.5

37.1

< 0.01

3.18 1 0.99 21.2 1 7.8

2.99 1 0.85 22.7 1 8.2

NS

MDRD

GFR

(mL/min)

NS

Initial BP in LPD + KA period

 

Systolic pressure (mmHg) Diastolic pressure (mmHg)

134.5 1 10.7 76.6 1 8.0

134.3 1 10.5 78.3 1 8.0

NS

NS

Initial laboratory test in LPD + KA period Calcium (mg/dL) Phosphorus (mg/dL) Intact PTH (pg/mL)

8.52 1 0.53 3.77 1 0.60 80.8 1 68.1 176.3 1 35.2 45.9 1 10.9 181.6 1 87.3 115.0 1 34.7 11.6 1 1.6 23.1 1 2.6 3.81 1 0.53

8.51 1 0.54 3.68 1 0.93 84.5 1 48.1 186.3 1 40.1 46.8 1 16.9 189.3 1 170.5 135.8 1 53.1 11.3 1 1.1 22.7 1 2.3 3.58 1 0.50

NS

NS

NS

Total

cholesterol (mg/dL)

NS

HDL

cholesterol (mg/dL)

NS

Triglyceride (mg/dL)

NS

LDL cholesterol (mg/dL) Haemoglobin (g/dL) Total CO 2 (mmol/L)

NS

NS

NS

Albumin

(g/dL)

Medication ARB and/or ACEi (%) HMG CoA reductase inhibitor (%) Recombinant erythropoietin (%)

< 0.05

90.6

91.4

NS

55.3

40.0

NS

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 among responders (63.5%) than non-responders (37.1%, P < 0.01) before developing CKD. When starting the LPD + KA diet, serum creatinine and MDRD GFR did not differ between responders and non-responders. Systolic and diastolic BP did not differ between groups during the LPD alone period. Serum calcium, phosphorus, iPTH, total cho- lesterol, HDL cholesterol, LDL cholesterol and triglyceride levels did not differ between groups, although serum 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 either group (Table 4). When only patients with diabetes were analysed, BP and lipid levels did not differ between responders and non-responders; glycosylated haemoglobin (HbA1c) levels were slightly lower among responders, although this difference was not statistically significant. However, serum albumin levels were significantly higher among responders with diabetes compared with non- 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 difference between two groups. We used logistic regression analysis to identify indepen- dent predictive factors that contribute to the observed

Table 5 Predictive factors for responders, as determined by logistic regression analysis

 

HR

95% CI

P-value

Diabetes Albumin (LPD alone period) Diastolic blood pressure

3.50

1.42–8.62

0.006

3.13

1.30–7.54

0.011

0.97

0.92–1.03

0.971

Adjustment for age, sex. CI, confidence interval; HR, hazards ratio; KA, ketoanalogs of essential amino acids; LPD, low-protein diet.

attenuation of declining renal function during LPD + KA. After correcting for age and gender, diabetes (hazards ratio = 3.50 (1.42–8.62), P = 0.006) and serum albumin level (hazards ratio = 3.13 (1.30–7.54), P = 0.011) showed statistical significance during the LPD alone, implying that diabetes and nutritional status are predictive factors for preserving renal function during LPD + KA (Table 5).

DISCUSSION

Restriction of dietary protein as a conservative treatment for 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

decreasing the accumulation of uremic substances produced during nitrogen metabolism, 7 but the resultant lack of EAA and calories, along with decreased protein catabolism raise additional concerns. 8 Furthermore, poor nutritional status and protein deficiency are often observed in patients with CKD following a normal diet. 9 These results indicate that patients with CKD are prone to malnutrition, which may then lead to low albumin levels and subsequent increases in mortality in those with terminal kidney disease. However, several studies have reported that a LPD with EAA or EAA ketoanalogs supplementation is sufficient to maintain anthropometric nutritional indices, as well as nitrogen balance and serum protein levels. 1012 EAA or EAA ketoanalogs are considered important because protein defi- ciency often occurs in the process of gluconeogenesis among patients with CKD, when EAA become critical because of tissue hypoxia caused by renal anaemia. 13 Nevertheless, MDRD analysis demonstrates that the degree of protein restriction, rather than ketoanalogs supplementation, is an independent factor for attenuating the decline of GFR. 7 Moreover, Lucas et al. argued that LPD + KA may reduce muscle mass. 14 In Korea, supplementation with EAA and EAA ketoanalogs was first introduced in 2006, and this is the first study regarding the effects of LPD with supplemen- tation on the progression of kidney disease or nutritional status in Korea. With the exception of lysine and threonine, EAA ketoanalogs are converted into EAA in the liver, intestines and muscles via transamination, thus minimizing any AA deficiency that may result from a LPD. In addition, ketoana- logs have been reported to contain less nitrogen than EAA, thus reducing nitrogen load on the kidney, alleviating uremic symptoms, 15 slowing the decline of renal function, 16 delaying the need for kidney replacement 17 and decreasing the mortality rate after kidney replacement. 18 MDRD analy- sis demonstrates that a very low-protein diet (VLPD) with a combination of EAA and EAA ketoanalogs is more effec- tive in slowing the decline of GFR than the same diet supplemented with nitrogen-containing EAA alone. 19 In addition to preserving renal function through reduced nitro- gen load, ketoanalogs supplementation retards the produc- tion of glucocorticoids, thus reducing protein catabolism 11 and slowing the progression of chronic renal failure. 20 Furthermore, previous studies showed that a ketoanalog- supplemented diet increased renal tubular resorption of AA in patients with renal failure, thus reducing albuminuria. 19 Furthermore, a -ketoisocaproate, a ketoanalog of the EAA leucine, decreases protein catabolism in skeletal muscle; 21 because this ketoanalog exists as a phosphorus-free calcium salt, it also reduces phosphorus concentrations and the inci- dence of hyperparathyroidism. 22 In addition, Teplan et al. 23 reported that patients with CKD receiving erythropoietin and LPD showed significantly lower cholesterol, LDL cho- lesterol and triglyceride levels, and higher HDL cholesterol levels, when receiving ketoanalog supplementation, indi- cating that ketoanalog-supplemented LPD is more effective in improving lipid metabolism than LPD alone. Previous clinical studies have examined ketoanalog- supplemented VLPD that limited protein to 2 0.4 g/kg per

© 2009 The Authors Journal compilation © 2009 Asian Pacific Society of Nephrology

755

day; however, responsiveness to this treatment was very poor. For this reason, we focused on a ketoanalog- supplemented LPD that limits protein to 20.6 g/kg per day; as a result, the decline in the GFR was significantly attenu- ated among both patients with diabetes and non-diabetic subjects, indicating that LPD + KA slows the progression of renal failure. No change was observed in serum albumin or protein concentrations, indicating that LPD + KA does not result in severe malnutrition. Prakash et al. followed pre-dialytic patients with chronic renal failure for 9 months and reported that a LPD significantly reduced the decline in the GFR. 2 Further- more, a ketoanalog-supplemented VLPD did not change the GFR 9 months after starting the diet, demonstrating that ketoanalog supplementation helps to preserve renal function. Similarly, Jungers et al. reported that a ketoanalog-supplemented VLPD ( 2 0.4 g/kg per day) was more effective than a LPD in retarding the decline of renal function without causing malnutrition. 24 However, these studies compared differences in the decline in the GFR based on diet, whereas we compared the decline in renal function in the same patients, before and after beginning the diet. We chose this strategy because the conditions related to GFR decline may vary according to the individual and the disease; 25 in fact, the rate of decline may vary even within the same kidney disease. Therefore, without a suf- ficiently large sample size, comparison between diets may result in error even if no distribution difference exists in the diseases that the patients had before developing kidney disease. Barsotti et al. 26 compared GFR before and after ketoanalog supplementation and reported a significant improvement, but the number of subjects was considered insufficient. In addition, this study analysed the preclinical param- eters of responders who showed significant enhancement in the GFR after switching to LPD + KA. Diabetes and high serum albumin were significantly more prevalent among responders. According to our multivariate analysis, patients with diabetes and high serum albumin levels had a greater possibility of benefiting from LPD + KA, in terms of slowing the decline of renal function. Although patients with dia- betes can preserve renal function and reduce mortality through LPD + KA, 27,28 no previous study has compared these effects with non-diabetic patients. In addition, the mechanism underlying improved renal function in patients with diabetes during LPD + KA remains unclear, but increased insulin sensitivity or improved BP control and reduced nitrogen load may be involved. Further research is required to clarify this point. We observed that HbA1c levels were slightly lower among responders when other factors, such as the use of insulin and hypoglycaemic agents, were not corrected; however, this difference was not statistically significant. In addition, we observed no change in BP or lipid abnormality. However, among patients with diabetes, individuals with higher serum albumin levels before LPD + KA responded more positively to the diet, implying that nutritional status before treatment is important. Patients with better nutri-

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tional status have previously been reported to show a slower decline in renal function. 29 Our results indicate that nutri- tional status is a predictive factor for the preservation of renal function through a LPD; thus, nutritional status should be considered when diet is used to delay the progres- sion of CKD. In conclusion, KA supplementation on over LPD delayed the progression of CKD without deteriorating nutritional status, and patients with diabetes or those with a better nutritional status showed a greater likelihood of benefiting from the diet. Nevertheless, this research has several limitations. As a retrospective study, we were unable to evaluate compliance during the treatment period, long-term effects of the diet and anthropometric factors besides serum albumin and protein levels. In addi- tion, the lack of a non-LPD control group made verifying the independent effect of ketoanalog supplementation impossible. Large-scale prospective studies will be required to confirm the effects of LPD + KA on the progression of CKD.

ACKNOWLEDGEMENTS

This study was supported by NHIC Ilsan Hospital Clinical Research Fund. We really appreciated all members of Nutritional Service Department, Ilsan Hospital for giving us great efforts.

REFERENCES

1. Walser M, Mitch WE, Abras E. Supplements containing amino acids and keto acids in the treatment of chronic uremia. Kidney Int. 1983; 16 (Suppl): S285–9.

2. Prakash S, Pande DP, Sharma S et al. Randomized, double- blind, placebo-controlled trial to evaluate efficacy of ketodiet in predialytic chronic renal failure. J. Ren. Nutr. 2004; 14 : 89–

96.

3. Mitch WE, Walser M, Steinman TI et al. The effect of a keto acid-amino acid supplement to a restricted diet on the pro- gression of chronic renal failure. N. Engl. J. Med. 1984; 311 :

623–9.

4. Walser M, Hill SB, Ward L, Magder L. A crossover comparison of progression of chronic renal failure: Ketoacids versus amino acids.

Kidney Int. 1993; 43 : 933–9.

5. Kasiske BL, Lakatua JD, Ma JZ, Louis TA. A meta-analysis of the effects of dietary protein restriction on the rate of decline in renal function. Am. J. Kidney Dis. 1998; 31 : 954–61.

6. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratifi- cation. Am. J. Kidney Dis. 2002; 39: S1–266.

7. Levey AS, Greene T, Beck GJ et al. Dietary protein restriction and the progression of chronic renal disease: What have all of the results of the MDRD study shown? Modification of Diet in Renal Disease Study group. J. Am. Soc. Nephrol. 1999; 10 : 2426–

39.

8. Zimmermann EW, Meisinger E, Weinel B, Strauch M. Essential amino acid/ketoanalogue supplementation: An alternative to unrestricted protein intake in uremia. Clin. Nephrol. 1979; 11 :

71–8.

JH Chang et al.

9. Ikizler TA, Greene JH, Wingard RL, Parker RA, Hakim RM.

Spontaneous dietary protein intake during progression of chronic renal failure. J. Am. Soc. Nephrol. 1995; 6: 1386–91.

10. 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. 1994; 45: 1182–92.

11. Walser M. Does prolonged protein restriction preceding dialysis lead to protein malnutrition at the onset of dialysis? Kidney Int. 1993; 44 : 1139–44.

12. Maroni BJ, Tom K, Masud T, Chapman T, Young VR. How is lean body mass conserved with the very-low protein diet regimen? Miner. Electrolyte Metab. 1996; 22 : 54–7.

13. Druml W, Kleinberger G, Burger U et al. Elimination of amino acids in chronic renal failure. Infusionsther. Klin. Ernahr. 1986; 13:

262–7.

14. Lucas PA, Meadows JH, Roberts DE, Coles GA. The risks and benefits of a low protein-essential amino acid-keto acid diet. Kidney Int. 1986; 29: 995–1003.

15. Walser M. Ketoacids in the treatment of uremia. Clin. Nephrol. 1975; 3: 180–86.

16. Richards P. The metabolism and clinical relevance of the keto acid analogues of essential amino acids. Clin. Sci. Mol. Med. 1978; 54 :

589–93.

17. Mitch WE, Abras E, Walser M. Long-term effects of a new ketoacid-amino acid supplement in patients with chronic renal failure. Kidney Int. 1982; 22 : 48–53.

18. Coresh J, Walser M, Hill S. Survival on dialysis among chronic renal failure patients treated with a supplemented low-

protein diet before dialysis. J. Am. Soc. Nephrol. 1995; 6: 1379–

85.

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 chronic renal insufficiency on a low protein diet. Wien. Klin. Wochenschr. 2000; 112 : 876–81.

20. Walser M, Ward L. Progression of chronic renal failure is related to glucocorticoid production. Kidney Int. 1988; 34 : 859–

66.

21. Mitch WE, Clark AS. Specificity of the effects of leucine and its metabolites on protein degradation in skeletal muscle. Biochem J. 1984; 222 : 579–86.

22. Frohling PT, Kokot F, Schmicker R, Kaschube I, Lindenau K, Vetter K Influence of keto acids on serum parathyroid hormone levels in patients with chronic renal failure. Clin. Nephrol. 1983; 20: 212–15.

23. Teplan V, Schuck O, Votruba M et al. Metabolic effects of keto acid–amino acid supplementation in patients with chronic renal insufficiency receiving a low-protein diet and recombinant human erythropoietin – a randomized controlled trial. Wien. Klin. Wochenschr. 2001; 113 : 661–9.

24. Jungers P, Chauveau P, Ployard F, Lebkiri B, Ciancioni C, Man NK. Comparison of ketoacids and low protein diet on advanced chronic renal failure progression. Kidney Int. 1987; 22 (Suppl): S67–71.

25. Hunsicker LG, Adler S, Caggiula A et al. Predictors of the pro- gression of renal disease in the Modification of Diet in Renal Disease Study. Kidney Int. 1997; 51 : 1908–19.

26. Barsotti G, Guiducci A, Ciardella F, Giovannetti S. Effects on renal function of a low-nitrogen diet supplemented with essential amino acids and ketoanalogues and of hemodialysis and free protein supply in patients with chronic renal failure. Nephron 1981; 27 : 113–17.

27. Pedrini MT, Levey AS, Lau J, Chalmers TC, Wang PH. The effect of dietary protein restriction on the progression of diabetic and

© 2009 The Authors Journal compilation © 2009 Asian Pacific Society of Nephrology

Influence of ketoanalogs in CKD with LPD

nondiabetic renal diseases: A meta-analysis. Ann. Intern. Med. 1996; 124 : 627–32. 28. Hansen HP, Tauber-Lassen E, Jensen BR, Parving HH. Effect of dietary protein restriction on prognosis in patients with diabetic nephropathy. Kidney Int. 2002; 62: 220–28.

© 2009 The Authors Journal compilation © 2009 Asian Pacific Society of Nephrology

757

29. Raffaitin C, Lasseur C, Chauveau P et al. Nutritional status in patients with diabetes and chronic kidney disease: A prospective study. Am. J. Clin. Nutr. 2007; 85 : 96–101.