- Email: [email protected]
Effect of Low-Protein Diet Supplemented With Keto Acids on Progression of Chronic Kidney Disease
ISRNM PROCEEDINGS
Effect of Low-Protein Diet Supplemented With Keto Acids on Progression of Chronic Kidney Disease Liliana Garneata, MD, PhD, and Gabriel Mircescu, MD, PhD Hypoproteic diets are most often discussed for patients with chronic kidney disease (CKD) who do not receive dialysis. A very low-protein diet supplemented with ketoanalogues of essential amino acids (keto-diet) proved effective in ameliorating metabolic disturbances of advanced CKD and delaying the initiation of dialysis without deleterious effects on nutritional status. Several recent studies report that the keto-diet could also slow down the rate of decline in renal function, with better outcomes after the initiation of dialysis. Results of a single-center randomized controlled trial addressing the rate of CKD progression revealed a 57% slower decline in renal function with the keto-diet compared with a conventional low-protein diet (LPD). The keto-diet allowed the safe management of selected patients with stage 4-5 CKD, delaying dialysis for almost 1 year, with a major impact on patient quality of life and health expenditures. Therefore, the keto-diet could be a link in the integrated care model. Careful selection of patients, nutritional monitoring, and dietary counseling are required. Ó 2013 by the National Kidney Foundation, Inc. All rights reserved.
T
HE RECENTLY REVEALED high prevalence of chronic kidney disease (CKD) raises concerns all over the world, and evidence-based strategies to delay progression have been instituted. A dietary approach in the predialysis stages of CKD is often mentioned,1-6 but strong evidence is lacking. Different dietary protein regimens have been proposed for patients with CKD: (1) a conventional low-protein diet (LPD), with 0.6 g/kg/day; (2) a very low-protein diet (0.3 g/kg/day) supplemented with essential amino acids, or (3) a very low-protein diet (0.3 g/kg/day) supplemented with nitrogen-free ketoanalogues of essential amino acids (keto acid–supplemented very low-protein diet [SVLPD]; keto-diet).1 Ketoanalogues of essential amino acids provide 2 important benefits in reducing the amount of urea eliminated by the kidneys: (1) keto acids neutralize the excessive nitrogen residues through transamination and limit the production of urea, thus breaking the vicious cycle of the disease and (2) keto acid supplementation allows the preservation of nutritional status despite the very low protein intake in patients with CKD.1
even to postpone the initiation of renal replacement therapy (RRT)7; however, nutritional intervention in uremia is still under debate.8-10 The pros are related mainly to efficacy in the management of certain metabolic disturbances of CKD such as nitrogen waste products retention, metabolic acidosis, and calcium-phosphorus metabolism abnormalities. Another major point in favor of a restricted-protein diet is the possibility of postponing the initiation of RRT by amelioration of the uremic symptoms and signs and better metabolic control. On the other hand, the beneficial effect of hypoproteic diets has not yet been proved.8-10 Their nutritional safety has been frequently questioned, specifically because poor nutritional status before dialysis could increase morbidity and mortality in patients with CKD and, consequently, negatively influence the outcome after initiation of RRT. Patient compliance is generally poor, and close nutritional monitoring is therefore required. Additionally, the high costs of ketoanalogues make the keto-diet difficult to implement.
Dietary Intervention in CKD—Pros and Cons
Metabolic Effects Available data support the effectiveness of SVLPD in ameliorating nitrogen waste product retention, acid-base and calcium-phosphorus metabolism disturbances, and insulin-resistance, which allows the postponement of RRT initiation with no deleterious effect on nutritional status in patients with CKD.1,6,11,12 The metabolic effects were recently confirmed in a randomized controlled trial; SVLPD—0.3 g/kg/day of vegetable proteins plus Ketosteril (Frensenius Kabi, Bad Homburg, Germany) 1 tablet for each 5 kg body weight—was even more effective than a conventional LPD (0.6 g/kg/day of mixed proteins) to ameliorate
Reduced dietary protein intake has been reported for more than a century to improve uremic symptoms1-6 and Department of Nephrology, ‘‘Carol Davila’’ University of Medicine and Pharmacy, ‘‘Dr Carol Davila’’ Teaching Hospital of Nephrology, Bucharest, Romania. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Liliana Garneata, MD, PhD, ‘‘Dr Carol Davila’’ Teaching Hospital of Nephrology, 4 Calea Grivitei, sector 1, 010731, Bucharest, Romania. E-mail: [email protected] Ó 2013 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 http://dx.doi.org/10.1053/j.jrn.2013.01.030
210
Journal of Renal Nutrition, Vol 23, No 3 (May), 2013: pp 210-213
211
KETOACID WITH LOW PROTEIN DIET AND CKD PROGRESSION
nitrogen waste product retention, metabolic acidosis, and calcium-phosphorus metabolism abnormalities.13 Recent studies have revealed new beneficial metabolic effects of a keto-diet in both diabetic and nondiabetic patients with CKD. A keto acid supplemented very low protein diet was associated with significant reduction in proteinuria as well as with a slower decline in the glomerular filtration rate (GFR) in diabetic patients with CKD.14 Amelioration of glycemia and lowering of insulin levels in oral glucose tolerance test results were also reported with SVLPD, suggesting the possibility of correcting insulin resistance by this type of nutritional intervention in diabetic patients with CKD.15
Effects on the Progression of CKD Several studies report that keto acid SVLPD could also slow down the rate of decline in renal function, preserving nutritional status and providing better outcomes after the start of RRT.11,13,16 A retrospective study by Walser and Hill in 1999,7 as well as more recent prospective randomized controlled trials, showed that a keto acid SVLPD associated with close nutritional monitoring allowed safe conservative management of selected highly compliant patients with stage 4-5 CKD, delaying the initiation of RRT for almost 1 year.7,17 The possibility of postponing the initiation of RRTwith keto acid SVLPD was recently shown in elderly patients with stage 5 CKD. The initiation of dialysis in elderly nondiabetic patients with CKD could be delayed for about 1 year without increasing the risk of either death or hospitalization. Moreover, the observed 1-year survival rates were higher in the keto acid SVLPD group than in the group who started dialysis—87% versus 84%. Also, the risk of hospitalization was higher in the dialysis group.17 A single-center randomized controlled trial in 207 nondiabetic patients with CKD (stages 4-5) who did not reFigure 1. Decline in estimated glomerular filtration rate (GFR) (mean, 95% confidence interval [CI], mL/min/1.73 m2/year) seen in comparison between treatment groups. LPD, low-protein diet; SVLP-LPD, supplemented very low-protein–low-protein diet; SVLPD, (keto acid) supplemented very lowprotein diet.
ceive dialysis was performed in Romania. The study aimed to assess the effects of keto acid SVLPD compared with the effects of a conventional LPD in patients with CKD over a period of 48 weeks (Garneata L, Mircescu G, unpublished data). Compliance with hypoproteic diets was one of the major inclusion criteria, and it was carefully investigated. Only 14% of participants who were screened for eligibility proved to exhibit good compliance to the diet during the assessment period and could be included in the study during the 3-year enrollment period. Enrolled patients were randomized to receive either keto acid supplemented very low protein diet (0.3 g/kg body weight per day of vegetable proteins plus Ketosteril, 1 tablet/5 kg body weight per day) or conventional LPD (0.6 g/ kg body weight per day). Metabolic disturbances in advanced CKD (nitrogen waste products retention, metabolic acidosis, and calciumphosphorus metabolism abnormalities) were monitored. Nutritional status was also assessed. The primary end point looked at the rate of progression of CKD and was set as the need for initiation of RRT or more than 50% reduction in the initial estimated GFR. The results showed keto acid SVLPD to be superior to a conventional LPD in ameliorating the nitrogen balance, correcting metabolic acidosis, and improving calciumphosphate metabolism abnormalities. A ketoanalogue SVLPD diet was associated with a significantly lower percentage of patients requiring initiation of RRT compared with patients receiving an LPD (7% vs. 26%) and a lower proportion of patients with a primary end point event (9% vs. 32%). Similarly, the calculated annual decline in the estimated GFR showed a 57% slower rate of progression of CKD in patients receiving keto acid SVLPD compared with those receiving an LPD (22.8 vs. 25.3 mL/min/1.73 m2/year) (Fig. 1) (Garneata L, Mircescu G, unpublished data). 0 –1 –2 –3 –4
–0.1 –2.1 LPD –3.3
–2.9 SVLPD
–4.9
–5
–5.5
–6 Group
+2.8
Estimated GFR decline (mL/min per year) Mean
95% CI
SVLPD (n = 90)
– 2.1
(–2.9,–0.1)
LPD (n = 69)
– 4.9
(–5.5,–3.3)
SVLP-LPD
+2.8
(+2.6, +3.2)
212
GARNEATA AND MIRCESCU
There were no significant differences between the study groups in the amount of proteinuria (,1 g per gram of urinary creatinine as inclusion criterion), blood pressure control, or the percentage of patients receiving angiotensinconverting enzyme inhibitors or angiotensin receptor blockers. Therefore, these data suggest a possible positive impact of a keto acid SVLPD per se in slowing down the rate of decline in renal function; the role of angiotensinconverting enzyme inhibitors or angiotensin receptor blockers, or both, could not be disregarded. Both types of nutritional intervention proved to be nutritionally safe, as reflected by stable anthropometric and biochemical markers and also by stable nutritional status, as assessed by the Subjective Global Assessment tool, as long as the total energy intake was preserved. In a meta-analysis of 5 randomized controlled trials with 1,413 diabetic and nondiabetic patients enrolled, an LPD was associated with a reduction in the risk of renal failure or death of 33%.2 A more recent meta-analysis by Fouque et al.18 that included 10 studies revealed similar results: a reduction in the occurrence of renal death of 32% with hypoproteic diets compared with diets with higher or unrestricted protein intake.
Economic Impact The possible delay of RRT initiation through nutrition could have a major impact on patient quality of life. On the other hand, postponing RRT could also have a serious economic impact, which is particularly important in countries where the dialysis facilities still do not meet the needs of patients. Table 1. Cost Comparison: RRT Alone Versus RRT and SVLPD in Selected Patients for 100 Patients With Stage 4-5 CKD Treatment Modality All RRT* Hemodialysis† Peritoneal dialysis‡ Total RRT RRT (86%) and SVLPD (14%) Hemodialysis Peritoneal dialysis SVLPD§ Total RRT and SVLPD Difference (RRT 1 SVLPD) All RRT
Number
Cost (Euro)
90 10 100
1.530.000 120.000 1.650.000
77 9 14 100
1.315.800 103.200 67.200 1.486.200 2163.800
CKD, chronic kidney disease; RRT, renal replacement therapy; SVLPD, supplemented very low-protein diet. Bold font represents the cost savings with SVLPD in selected patients. *Current allocation ratio for RRT methods in Romania: HD/ PD 5 9:1. †Total cost of hemodialysis (euro per year per patient): 17.000. ‡Total cost of peritoneal dialysis (euro per year per patient): 12.000. §Total cost of SVLPD (euro per year per patient): 4.800, 3.600 for ketoanalogues, and 1.200 for dietary counseling and monitoring.
Considering the actual costs of hemodialysis and peritoneal dialysis and preserving the current allocation ratio for RRT methods in Romania, comparing the cost of RRT alone versus the cost of keto acid SVLPD in well-selected highly motivated patients (around 14% of all patients with CKD [Garneata L, Mircescu G, unpublished data]) and the cost of RRT for the rest of the patients, modeled for 100 patients with stage 4-5 CKD, revealed an annual cost savings of V163.800 with keto acid SVLPD (Table 1).19 An economic evaluation conducted in Italy to compare benefits and costs of keto acid SVLPD versus dialysis in 57 elderly patients with CKD stage 5 found a significant net benefit in favor of the keto-diet.20 In conclusion, a severe LPD supplemented with ketoanalogues of essential amino acids seems to be effective in selected patients with CKD for ameliorating metabolic disturbances, postponing the initiation of RRT, and reducing the rate of decline in renal function without any negative influence on nutritional status. Therefore, nutritional intervention, particularly keto acid SVLPD, could be a new link in the RRT integrated care model. However, a careful selection of motivated patients who could benefit from such a diet and close nutritional monitoring and dietary counseling are highly required.
References 1. Mitch WE. Dietary protein restriction in chronic renal failure: nutritional efficacy, compliance, and progression of renal insufficiency. J Am Soc Nephrol. 1991;2:823-831. 2. Pedrini MT, Levey AS, Lau J, et al. The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: a meta-analysis. Ann Intern Med. 1996;124:627-632. 3. Levey AS, Adler S, Caggiula AW, et al. Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease Study. Am J Kidney Dis. 1996;27: 652-663. 4. Fouque D, Wang P, Laville M, et al. Low protein diets delay end-stage renal disease in non-diabetic adults with chronic renal failure. Nephrol Dial Transplant. 2000;15:1986-1992. 5. Kasiske BL, Lakatua JD, Ma JZ, et al. A meta-analysis of the effects of dietary protein restriction on the rate of decline in renal function. Am J Kidney Dis. 1998;31:954-961. 6. Mandayam S, Mitch WE. Dietary protein restriction benefits patients with chronic kidney disease. Nephrology. 2006;11:53-57. 7. Walser M, Hill S. Can renal replacement be deferred by a supplemented very low protein diet? J Am Soc Nephrol. 1999;10:110-116. 8. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med. 1994;330:877-884. 9. Johnson DW. Dietary protein restriction as a treatment for slowing chronic kidney disease progression: the case against. Nephrology. 2006;11:58-62. 10. Garneata L, Mircescu G. Nutritional intervention in uremia—myth or reality? J Ren Nutr. 2009;20:S31-S34. 11. Aparicio M, Chauveau P, De Precigout V, et al. Nutrition and outcome on renal replacement therapy of patients with chronic renal failure treated by a supplemented very low protein diet. J Am Soc Nephrol. 2000;11:708-716. 12. Aparicio M, Cano NJM, Cupisti A, et al. Consensus statement. J Ren Nutr. 2009;19:S33-S35.
KETOACID WITH LOW PROTEIN DIET AND CKD PROGRESSION 13. Mircescu G, Garneata L, Stancu SH, Capus¸a C. Effects of a supplemented hypoproteic diet in chronic kidney disease. J Ren Nutr. 2007; 17:179-188. 14. Teplan V, Schuck O, Mareckova O, et al. Antiproteinuric and metabolic effect of long-term administration ACE inhibitors and angiotensin II AT1 receptor in patients in chronic renal insufficiency. Klin Biochem Metab. 2003;11:70-73. 15. de Precigout V, Chauveau P, Delclaux C, et al. No change of hyperleptinemia despite a decrease in insulin concentration in patients with chronic renal failure on a supplemented very low protein diet. Am J Kidney Dis. 2000;36:1201-1206. 16. Martinez-Maldonado M, Sattin RW. Rate of progression of renal disease and low-protein diet. Am J Kidney Dis. 1998;31:1048-1049.
213
17. Brunori G, Viola BF, Parrinello G, et al. Efficacy and safety of a very-low-protein diet when postponing dialysis in the elderly: a prospective randomized multicenter controlled study. Am J Kidney Dis. 2007;49: 569-580. 18. Fouque D, Laville M. Low protein diets for chronic kidney disease in non diabetic adults. Cochrane Database Syst Rev. 2009;8: CD001892. 19. Garneata L, Mircescu G. Therapies addressed to CKD: efficacy and costs. In: De Santo N, ed. Survival Is Not Enough. Naples, Italy: Italian Institute for Philosophical Studies; 2010:121-129. 20. Scalone L, Borghetti F, Brunori G, et al. Cost-benefit analysis of supplemented very low-protein diet versus dialysis in elderly CKD5 patients. Nephrol Dial Transpl. 2010;25:907-913.
Effect of Low-Protein Diet Supplemented With Keto Acids on Progression of Chronic Kidney Disease Liliana Garneata, MD, PhD, and Gabriel Mircescu, MD, PhD Hypoproteic diets are most often discussed for patients with chronic kidney disease (CKD) who do not receive dialysis. A very low-protein diet supplemented with ketoanalogues of essential amino acids (keto-diet) proved effective in ameliorating metabolic disturbances of advanced CKD and delaying the initiation of dialysis without deleterious effects on nutritional status. Several recent studies report that the keto-diet could also slow down the rate of decline in renal function, with better outcomes after the initiation of dialysis. Results of a single-center randomized controlled trial addressing the rate of CKD progression revealed a 57% slower decline in renal function with the keto-diet compared with a conventional low-protein diet (LPD). The keto-diet allowed the safe management of selected patients with stage 4-5 CKD, delaying dialysis for almost 1 year, with a major impact on patient quality of life and health expenditures. Therefore, the keto-diet could be a link in the integrated care model. Careful selection of patients, nutritional monitoring, and dietary counseling are required. Ó 2013 by the National Kidney Foundation, Inc. All rights reserved.
T
HE RECENTLY REVEALED high prevalence of chronic kidney disease (CKD) raises concerns all over the world, and evidence-based strategies to delay progression have been instituted. A dietary approach in the predialysis stages of CKD is often mentioned,1-6 but strong evidence is lacking. Different dietary protein regimens have been proposed for patients with CKD: (1) a conventional low-protein diet (LPD), with 0.6 g/kg/day; (2) a very low-protein diet (0.3 g/kg/day) supplemented with essential amino acids, or (3) a very low-protein diet (0.3 g/kg/day) supplemented with nitrogen-free ketoanalogues of essential amino acids (keto acid–supplemented very low-protein diet [SVLPD]; keto-diet).1 Ketoanalogues of essential amino acids provide 2 important benefits in reducing the amount of urea eliminated by the kidneys: (1) keto acids neutralize the excessive nitrogen residues through transamination and limit the production of urea, thus breaking the vicious cycle of the disease and (2) keto acid supplementation allows the preservation of nutritional status despite the very low protein intake in patients with CKD.1
even to postpone the initiation of renal replacement therapy (RRT)7; however, nutritional intervention in uremia is still under debate.8-10 The pros are related mainly to efficacy in the management of certain metabolic disturbances of CKD such as nitrogen waste products retention, metabolic acidosis, and calcium-phosphorus metabolism abnormalities. Another major point in favor of a restricted-protein diet is the possibility of postponing the initiation of RRT by amelioration of the uremic symptoms and signs and better metabolic control. On the other hand, the beneficial effect of hypoproteic diets has not yet been proved.8-10 Their nutritional safety has been frequently questioned, specifically because poor nutritional status before dialysis could increase morbidity and mortality in patients with CKD and, consequently, negatively influence the outcome after initiation of RRT. Patient compliance is generally poor, and close nutritional monitoring is therefore required. Additionally, the high costs of ketoanalogues make the keto-diet difficult to implement.
Dietary Intervention in CKD—Pros and Cons
Metabolic Effects Available data support the effectiveness of SVLPD in ameliorating nitrogen waste product retention, acid-base and calcium-phosphorus metabolism disturbances, and insulin-resistance, which allows the postponement of RRT initiation with no deleterious effect on nutritional status in patients with CKD.1,6,11,12 The metabolic effects were recently confirmed in a randomized controlled trial; SVLPD—0.3 g/kg/day of vegetable proteins plus Ketosteril (Frensenius Kabi, Bad Homburg, Germany) 1 tablet for each 5 kg body weight—was even more effective than a conventional LPD (0.6 g/kg/day of mixed proteins) to ameliorate
Reduced dietary protein intake has been reported for more than a century to improve uremic symptoms1-6 and Department of Nephrology, ‘‘Carol Davila’’ University of Medicine and Pharmacy, ‘‘Dr Carol Davila’’ Teaching Hospital of Nephrology, Bucharest, Romania. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Liliana Garneata, MD, PhD, ‘‘Dr Carol Davila’’ Teaching Hospital of Nephrology, 4 Calea Grivitei, sector 1, 010731, Bucharest, Romania. E-mail: [email protected] Ó 2013 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 http://dx.doi.org/10.1053/j.jrn.2013.01.030
210
Journal of Renal Nutrition, Vol 23, No 3 (May), 2013: pp 210-213
211
KETOACID WITH LOW PROTEIN DIET AND CKD PROGRESSION
nitrogen waste product retention, metabolic acidosis, and calcium-phosphorus metabolism abnormalities.13 Recent studies have revealed new beneficial metabolic effects of a keto-diet in both diabetic and nondiabetic patients with CKD. A keto acid supplemented very low protein diet was associated with significant reduction in proteinuria as well as with a slower decline in the glomerular filtration rate (GFR) in diabetic patients with CKD.14 Amelioration of glycemia and lowering of insulin levels in oral glucose tolerance test results were also reported with SVLPD, suggesting the possibility of correcting insulin resistance by this type of nutritional intervention in diabetic patients with CKD.15
Effects on the Progression of CKD Several studies report that keto acid SVLPD could also slow down the rate of decline in renal function, preserving nutritional status and providing better outcomes after the start of RRT.11,13,16 A retrospective study by Walser and Hill in 1999,7 as well as more recent prospective randomized controlled trials, showed that a keto acid SVLPD associated with close nutritional monitoring allowed safe conservative management of selected highly compliant patients with stage 4-5 CKD, delaying the initiation of RRT for almost 1 year.7,17 The possibility of postponing the initiation of RRTwith keto acid SVLPD was recently shown in elderly patients with stage 5 CKD. The initiation of dialysis in elderly nondiabetic patients with CKD could be delayed for about 1 year without increasing the risk of either death or hospitalization. Moreover, the observed 1-year survival rates were higher in the keto acid SVLPD group than in the group who started dialysis—87% versus 84%. Also, the risk of hospitalization was higher in the dialysis group.17 A single-center randomized controlled trial in 207 nondiabetic patients with CKD (stages 4-5) who did not reFigure 1. Decline in estimated glomerular filtration rate (GFR) (mean, 95% confidence interval [CI], mL/min/1.73 m2/year) seen in comparison between treatment groups. LPD, low-protein diet; SVLP-LPD, supplemented very low-protein–low-protein diet; SVLPD, (keto acid) supplemented very lowprotein diet.
ceive dialysis was performed in Romania. The study aimed to assess the effects of keto acid SVLPD compared with the effects of a conventional LPD in patients with CKD over a period of 48 weeks (Garneata L, Mircescu G, unpublished data). Compliance with hypoproteic diets was one of the major inclusion criteria, and it was carefully investigated. Only 14% of participants who were screened for eligibility proved to exhibit good compliance to the diet during the assessment period and could be included in the study during the 3-year enrollment period. Enrolled patients were randomized to receive either keto acid supplemented very low protein diet (0.3 g/kg body weight per day of vegetable proteins plus Ketosteril, 1 tablet/5 kg body weight per day) or conventional LPD (0.6 g/ kg body weight per day). Metabolic disturbances in advanced CKD (nitrogen waste products retention, metabolic acidosis, and calciumphosphorus metabolism abnormalities) were monitored. Nutritional status was also assessed. The primary end point looked at the rate of progression of CKD and was set as the need for initiation of RRT or more than 50% reduction in the initial estimated GFR. The results showed keto acid SVLPD to be superior to a conventional LPD in ameliorating the nitrogen balance, correcting metabolic acidosis, and improving calciumphosphate metabolism abnormalities. A ketoanalogue SVLPD diet was associated with a significantly lower percentage of patients requiring initiation of RRT compared with patients receiving an LPD (7% vs. 26%) and a lower proportion of patients with a primary end point event (9% vs. 32%). Similarly, the calculated annual decline in the estimated GFR showed a 57% slower rate of progression of CKD in patients receiving keto acid SVLPD compared with those receiving an LPD (22.8 vs. 25.3 mL/min/1.73 m2/year) (Fig. 1) (Garneata L, Mircescu G, unpublished data). 0 –1 –2 –3 –4
–0.1 –2.1 LPD –3.3
–2.9 SVLPD
–4.9
–5
–5.5
–6 Group
+2.8
Estimated GFR decline (mL/min per year) Mean
95% CI
SVLPD (n = 90)
– 2.1
(–2.9,–0.1)
LPD (n = 69)
– 4.9
(–5.5,–3.3)
SVLP-LPD
+2.8
(+2.6, +3.2)
212
GARNEATA AND MIRCESCU
There were no significant differences between the study groups in the amount of proteinuria (,1 g per gram of urinary creatinine as inclusion criterion), blood pressure control, or the percentage of patients receiving angiotensinconverting enzyme inhibitors or angiotensin receptor blockers. Therefore, these data suggest a possible positive impact of a keto acid SVLPD per se in slowing down the rate of decline in renal function; the role of angiotensinconverting enzyme inhibitors or angiotensin receptor blockers, or both, could not be disregarded. Both types of nutritional intervention proved to be nutritionally safe, as reflected by stable anthropometric and biochemical markers and also by stable nutritional status, as assessed by the Subjective Global Assessment tool, as long as the total energy intake was preserved. In a meta-analysis of 5 randomized controlled trials with 1,413 diabetic and nondiabetic patients enrolled, an LPD was associated with a reduction in the risk of renal failure or death of 33%.2 A more recent meta-analysis by Fouque et al.18 that included 10 studies revealed similar results: a reduction in the occurrence of renal death of 32% with hypoproteic diets compared with diets with higher or unrestricted protein intake.
Economic Impact The possible delay of RRT initiation through nutrition could have a major impact on patient quality of life. On the other hand, postponing RRT could also have a serious economic impact, which is particularly important in countries where the dialysis facilities still do not meet the needs of patients. Table 1. Cost Comparison: RRT Alone Versus RRT and SVLPD in Selected Patients for 100 Patients With Stage 4-5 CKD Treatment Modality All RRT* Hemodialysis† Peritoneal dialysis‡ Total RRT RRT (86%) and SVLPD (14%) Hemodialysis Peritoneal dialysis SVLPD§ Total RRT and SVLPD Difference (RRT 1 SVLPD) All RRT
Number
Cost (Euro)
90 10 100
1.530.000 120.000 1.650.000
77 9 14 100
1.315.800 103.200 67.200 1.486.200 2163.800
CKD, chronic kidney disease; RRT, renal replacement therapy; SVLPD, supplemented very low-protein diet. Bold font represents the cost savings with SVLPD in selected patients. *Current allocation ratio for RRT methods in Romania: HD/ PD 5 9:1. †Total cost of hemodialysis (euro per year per patient): 17.000. ‡Total cost of peritoneal dialysis (euro per year per patient): 12.000. §Total cost of SVLPD (euro per year per patient): 4.800, 3.600 for ketoanalogues, and 1.200 for dietary counseling and monitoring.
Considering the actual costs of hemodialysis and peritoneal dialysis and preserving the current allocation ratio for RRT methods in Romania, comparing the cost of RRT alone versus the cost of keto acid SVLPD in well-selected highly motivated patients (around 14% of all patients with CKD [Garneata L, Mircescu G, unpublished data]) and the cost of RRT for the rest of the patients, modeled for 100 patients with stage 4-5 CKD, revealed an annual cost savings of V163.800 with keto acid SVLPD (Table 1).19 An economic evaluation conducted in Italy to compare benefits and costs of keto acid SVLPD versus dialysis in 57 elderly patients with CKD stage 5 found a significant net benefit in favor of the keto-diet.20 In conclusion, a severe LPD supplemented with ketoanalogues of essential amino acids seems to be effective in selected patients with CKD for ameliorating metabolic disturbances, postponing the initiation of RRT, and reducing the rate of decline in renal function without any negative influence on nutritional status. Therefore, nutritional intervention, particularly keto acid SVLPD, could be a new link in the RRT integrated care model. However, a careful selection of motivated patients who could benefit from such a diet and close nutritional monitoring and dietary counseling are highly required.
References 1. Mitch WE. Dietary protein restriction in chronic renal failure: nutritional efficacy, compliance, and progression of renal insufficiency. J Am Soc Nephrol. 1991;2:823-831. 2. Pedrini MT, Levey AS, Lau J, et al. The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: a meta-analysis. Ann Intern Med. 1996;124:627-632. 3. Levey AS, Adler S, Caggiula AW, et al. Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease Study. Am J Kidney Dis. 1996;27: 652-663. 4. Fouque D, Wang P, Laville M, et al. Low protein diets delay end-stage renal disease in non-diabetic adults with chronic renal failure. Nephrol Dial Transplant. 2000;15:1986-1992. 5. Kasiske BL, Lakatua JD, Ma JZ, et al. A meta-analysis of the effects of dietary protein restriction on the rate of decline in renal function. Am J Kidney Dis. 1998;31:954-961. 6. Mandayam S, Mitch WE. Dietary protein restriction benefits patients with chronic kidney disease. Nephrology. 2006;11:53-57. 7. Walser M, Hill S. Can renal replacement be deferred by a supplemented very low protein diet? J Am Soc Nephrol. 1999;10:110-116. 8. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med. 1994;330:877-884. 9. Johnson DW. Dietary protein restriction as a treatment for slowing chronic kidney disease progression: the case against. Nephrology. 2006;11:58-62. 10. Garneata L, Mircescu G. Nutritional intervention in uremia—myth or reality? J Ren Nutr. 2009;20:S31-S34. 11. Aparicio M, Chauveau P, De Precigout V, et al. Nutrition and outcome on renal replacement therapy of patients with chronic renal failure treated by a supplemented very low protein diet. J Am Soc Nephrol. 2000;11:708-716. 12. Aparicio M, Cano NJM, Cupisti A, et al. Consensus statement. J Ren Nutr. 2009;19:S33-S35.
KETOACID WITH LOW PROTEIN DIET AND CKD PROGRESSION 13. Mircescu G, Garneata L, Stancu SH, Capus¸a C. Effects of a supplemented hypoproteic diet in chronic kidney disease. J Ren Nutr. 2007; 17:179-188. 14. Teplan V, Schuck O, Mareckova O, et al. Antiproteinuric and metabolic effect of long-term administration ACE inhibitors and angiotensin II AT1 receptor in patients in chronic renal insufficiency. Klin Biochem Metab. 2003;11:70-73. 15. de Precigout V, Chauveau P, Delclaux C, et al. No change of hyperleptinemia despite a decrease in insulin concentration in patients with chronic renal failure on a supplemented very low protein diet. Am J Kidney Dis. 2000;36:1201-1206. 16. Martinez-Maldonado M, Sattin RW. Rate of progression of renal disease and low-protein diet. Am J Kidney Dis. 1998;31:1048-1049.
213
17. Brunori G, Viola BF, Parrinello G, et al. Efficacy and safety of a very-low-protein diet when postponing dialysis in the elderly: a prospective randomized multicenter controlled study. Am J Kidney Dis. 2007;49: 569-580. 18. Fouque D, Laville M. Low protein diets for chronic kidney disease in non diabetic adults. Cochrane Database Syst Rev. 2009;8: CD001892. 19. Garneata L, Mircescu G. Therapies addressed to CKD: efficacy and costs. In: De Santo N, ed. Survival Is Not Enough. Naples, Italy: Italian Institute for Philosophical Studies; 2010:121-129. 20. Scalone L, Borghetti F, Brunori G, et al. Cost-benefit analysis of supplemented very low-protein diet versus dialysis in elderly CKD5 patients. Nephrol Dial Transpl. 2010;25:907-913.