Академический Документы
Профессиональный Документы
Культура Документы
Original Article
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
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.
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 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.
−5 −5
MDRD GFR time slople
−5
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
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
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-
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-
essential amino acids. Kidney Int. 1994; 45: 1182–92.
sion of CKD. 11. Walser M. Does prolonged protein restriction preceding dialysis
In conclusion, KA supplementation on over LPD lead to protein malnutrition at the onset of dialysis? Kidney Int.
delayed the progression of CKD without deteriorating 1993; 44: 1139–44.
nutritional status, and patients with diabetes or those with 12. Maroni BJ, Tom K, Masud T, Chapman T, Young VR. How is lean
a better nutritional status showed a greater likelihood of body mass conserved with the very-low protein diet regimen?
benefiting from the diet. Nevertheless, this research has Miner. Electrolyte Metab. 1996; 22: 54–7.
several limitations. As a retrospective study, we were 13. Druml W, Kleinberger G, Burger U et al. Elimination of amino
unable to evaluate compliance during the treatment acids in chronic renal failure. Infusionsther. Klin. Ernahr. 1986; 13:
262–7.
period, long-term effects of the diet and anthropometric
14. Lucas PA, Meadows JH, Roberts DE, Coles GA. The risks and
factors besides serum albumin and protein levels. In addi-
benefits of a low protein-essential amino acid-keto acid diet.
tion, the lack of a non-LPD control group made verifying Kidney Int. 1986; 29: 995–1003.
the independent effect of ketoanalog supplementation 15. Walser M. Ketoacids in the treatment of uremia. Clin. Nephrol.
impossible. Large-scale prospective studies will be required 1975; 3: 180–86.
to confirm the effects of LPD + KA on the progression 16. Richards P. The metabolism and clinical relevance of the keto acid
of CKD. 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
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
REFERENCES chronic renal insufficiency on a low protein diet. Wien. Klin.
Wochenschr. 2000; 112: 876–81.
1. Walser M, Mitch WE, Abras E. Supplements containing amino 20. Walser M, Ward L. Progression of chronic renal failure is
acids and keto acids in the treatment of chronic uremia. Kidney Int. related to glucocorticoid production. Kidney Int. 1988; 34: 859–
1983; 16 (Suppl): S285–9. 66.
2. Prakash S, Pande DP, Sharma S et al. Randomized, double- 21. Mitch WE, Clark AS. Specificity of the effects of leucine and its
blind, placebo-controlled trial to evaluate efficacy of ketodiet in metabolites on protein degradation in skeletal muscle. Biochem J.
predialytic chronic renal failure. J. Ren. Nutr. 2004; 14: 89– 1984; 222: 579–86.
96. 22. Frohling PT, Kokot F, Schmicker R, Kaschube I, Lindenau K,
3. Mitch WE, Walser M, Steinman TI et al. The effect of a Vetter K Influence of keto acids on serum parathyroid hormone
keto acid-amino acid supplement to a restricted diet on the pro- levels in patients with chronic renal failure. Clin. Nephrol. 1983;
gression of chronic renal failure. N. Engl. J. Med. 1984; 311: 20: 212–15.
623–9. 23. Teplan V, Schuck O, Votruba M et al. Metabolic effects of keto
4. Walser M, Hill SB, Ward L, Magder L. A crossover comparison of acid–amino acid supplementation in patients with chronic renal
progression of chronic renal failure: Ketoacids versus amino acids. insufficiency receiving a low-protein diet and recombinant human
Kidney Int. 1993; 43: 933–9. erythropoietin – a randomized controlled trial. Wien. Klin.
5. Kasiske BL, Lakatua JD, Ma JZ, Louis TA. A meta-analysis of the Wochenschr. 2001; 113: 661–9.
effects of dietary protein restriction on the rate of decline in renal 24. Jungers P, Chauveau P, Ployard F, Lebkiri B, Ciancioni C,
function. Am. J. Kidney Dis. 1998; 31: 954–61. Man NK. Comparison of ketoacids and low protein diet on
6. National Kidney Foundation. K/DOQI clinical practice guidelines advanced chronic renal failure progression. Kidney Int. 1987; 22
for chronic kidney disease: Evaluation, classification, and stratifi- (Suppl): S67–71.
cation. Am. J. Kidney Dis. 2002; 39: S1–266. 25. Hunsicker LG, Adler S, Caggiula A et al. Predictors of the pro-
7. Levey AS, Greene T, Beck GJ et al. Dietary protein restriction and gression of renal disease in the Modification of Diet in Renal
the progression of chronic renal disease: What have all of the Disease Study. Kidney Int. 1997; 51: 1908–19.
results of the MDRD study shown? Modification of Diet in Renal 26. Barsotti G, Guiducci A, Ciardella F, Giovannetti S. Effects on
Disease Study group. J. Am. Soc. Nephrol. 1999; 10: 2426– renal function of a low-nitrogen diet supplemented with essential
39. amino acids and ketoanalogues and of hemodialysis and free
8. Zimmermann EW, Meisinger E, Weinel B, Strauch M. Essential protein supply in patients with chronic renal failure. Nephron
amino acid/ketoanalogue supplementation: An alternative to 1981; 27: 113–17.
unrestricted protein intake in uremia. Clin. Nephrol. 1979; 11: 27. Pedrini MT, Levey AS, Lau J, Chalmers TC, Wang PH. The effect
71–8. of dietary protein restriction on the progression of diabetic and
nondiabetic renal diseases: A meta-analysis. Ann. Intern. Med. 29. Raffaitin C, Lasseur C, Chauveau P et al. Nutritional status in
1996; 124: 627–32. patients with diabetes and chronic kidney disease: A prospective
28. Hansen HP, Tauber-Lassen E, Jensen BR, Parving HH. Effect of study. Am. J. Clin. Nutr. 2007; 85: 96–101.
dietary protein restriction on prognosis in patients with diabetic
nephropathy. Kidney Int. 2002; 62: 220–28.