1、Ketoacid therapy and CKD metabolic complications,3rd International Ketoanalogue symposium Seoul, March 30-31, 2007 M.Aparicio M.D,Introduction,CRF results in numerous metabolic disorders which account for severe complications responsible for major morbidity and mortality condition. Prevention of the
2、se complications should be the aim while managing CKD patients in order to improve a usually poor outcome.,Physiopathology of metabolic disorders in CRF, Accumulation of waste products usually excreted by the kidneys :- nitrogenous waste products, H+ ions, phosphate. Ion transport abnormalities Decr
3、eased hormone production : - EPO, calcitriol Decreased hormone clearance :- insulin, glucagon, leptin Inflammation,Why beneficial effects on metabolic disorders can be expected from SVLPD,SVLPD permits the restriction of the intake or of the production of nitrogenous waste products, phosphate, inorg
4、anic ions and hydrogen ions. SVLPD improves Na+K+ATPase activity in CRF patients Lastly, it is likely that SVLPD is effective in correcting inflammation as suggested by recent nutritional interventions using a conventional LPD or Mediterranean-style diet,Caloric supply,(kcal/kg bw/day),30-35,% from
5、carbohydrates,67,% from lipids,30,% from proteins,3,Protein content,(g/kg bw/day),0.3-0.4 (max. 0.6),Phosphorus content,(mg/kg bw/day),5-7,Supplemented with:,Calcium (g/day),0.5-1.0,Vitamin D (IU/day),1,000,Iron (mg/day),100 mg/kg bw/day,10-15,Dietary management in CKD Composition of a Keto Acid The
6、rapy,KA/AA (Ketosteril),Effects of SVLPD on carbohydrate metabolism disorders,Insulin resistance in CKD patients,Occurs early in the course of CRF and is present in more than 50% of CKD patients. Is favoured by :- accumulation of protein waste products - metabolic acidosis- inflammation- 2nd HPT,Ins
7、ulin resistance in CKD patients effects on carbohydrate metabolism,Insulin resistance :- decreased glucose storage- decreased glucose oxidation- increased endogenous glucose production- decreased metabolic clearance rate of insulin- elevated fasting glucose and insulin levels,Insulin resistance in t
8、ype II diabetes and in CRF,In vivo exploration of glucose metabolism : the tools,Oral glucose tolerance test : overall glucose metabolism Hyperinsulinemic euglycemic clamp : insulin sensitivity, MCR of exogenous insulin Concomitant use of indirect calorimetry : oxidative and nonoxidative pathway of
9、glucose Isotopically labeled glucose : endogenous glucose production,Plasma glucose and Insulin after oral glucose load before and after 3 months on SVLPD L.Baillet et col., Metabolism 2001,Evolution of the insulin level and of the amount glucose infused during the euglycemic hyperinsulin clamp in n
10、ondiabetic uremic patients before and after SVLPD Aparicio M. et al. Kidney Int, 1989,Keto Acids Therapy improves the metabolic clearance rate of insulin and reduces hyperinsulinemia which is associated with multiple risk factors for atherosclerosisGIN H. et al Am.J.Clin.Nutr.1994,Keto Acid Therapy
11、Improvement of insulin clearance rate,SVLPD and substrate oxidation rate Rigalleau Kidney Int.1997,REE and SVLPD in uremia Rigalleau Kidney Int. 1997,SVLPD and endogenous glucose production (EGP) Rigalleau Am.J.Clin.Nutr.1997,Insulin resistance : other effects,Independent CV risk factor :- endotheli
12、al dysfunction (decreased endothelial NO synthesis), improvement in IR improves endothelial function- atherosclerosis Protein metabolism :- increased skeletal muscle protein breakdown (UPP) Inflammation :- subclinical inflammation is part of IR syndrome,Copyright 2002 American Society of Nephrology,
13、Shinohara, K. et al. J Am Soc Nephrol 2002;13:1894-1900,Insulin resistance and outcome of ESRD patients,Mechanisms of improvement of insulin resistance by SVLPD,Decreased accumulation of nitrogenous compounds acting as inhibitors of glucose utilization Improvement of metabolic acidosis Improvement o
14、f 2nd HPT Direct beneficial effect of protein restriction on glucose metabolism when protein calories are made up by carbohydrate calories,Effects of SVLPD on secondary hyperparathyroidism,Factors of 2nd HPT,Hyperphosphatemia Decreased calcitriol synthesis Negative calcium balance Metabolic acidosis
15、,P,Ca,High phosphate levels,Low calcium levels,Phosphate-Calcium metabolism disorders in CKD,Consequences of 2nd HPT and hyperphosphatemia,Osteodystrophy Cardiovascular calcification Soft tissue calcification Refractory anemia Inflammation Increase in the relative risk of death,*,p 0.05,Design: No.
16、of patients: n=17 (GFR 20 ml/min)Duration: 12 monthsDiet: 0.3 g protein/kg bw/d+ 1 tabl. Ketosteril/5 kg bw/d + 1 g CaCO3 + 1,000 IU vitamin D2,LAFAGE et al. (1992): Kidney Int, 42, 1217 - 1225,Keto Acid Therapy Phosphate-Calcium metabolism disorders,p 0.01,*,Parameters,(mean + SD),Normal range,Befo
17、re the diet,After 12 months,of diet,Calcium (mmol/l),2.1 - 2.65,2.29 0.15,2.32 0.16,Phosphate (mmol/l),0.8 - 1.45,1.54 0.42,1.30 0.28 (a),Bicarbonate (mmol/l),24 - 30,23.1 4.6,27.6 3 (c),Intact PTH (g/ml),10 - 60,168 101,83 68 (b),Alk. Phophatase (IU/l),30 - 120,88 45,86 38,Osteocalcin (g/ml),3.7 -
18、6.9,40 29,31 25,1-25 OH Vitamin D (pg/ml),12.- 32,15.3 6.8,17.5 6.9,LAFAGE et al. (1992): Kidney Int, 42, 1217 - 1225,Results are expressed as mean + SD: (a) p 0.05; (b) p 0.01; (c) p 0.001,Keto Acid Therapy Phosphate-Calcium metabolism disorders,Design: No. of patients: n = 21Creatinine serum: 6.5
19、mg/dlDiet: VLPD (0.3 g/kg bw/d) + AA/KA + 2-4 g CaCO3Duration: 4 2 months, PTH level can be reduced by 49 % due to the dietary therapy.,BARSOTTI et al. (1998): sHPT in severe CRF is corrected by very-low dietary phosphate intake and calcium carbonate supplementation. Nephron, 79, 137-141,*,p 0.001,*
20、,p 0.001,Keto Acid Therapy Phosphate-Calcium metabolism disorders,Keto Acid Therapy Phosphate-Calcium metabolism disorders,Improvement in osteofibrotic and osteomalacic changes after 12 months of treatment with a Keto Acid Therapy.M.H Lafage et al. Kidney Int.1992,Keto Acid Therapy Phosphate-Calcium
21、 metabolism disorders,Evolution of histological data after 12 months on SVLPD M.H.Lafage et al. Kidney Int.1992,Mixed osteopathy (n=4) :- mineralization rate (u/d) : 0.32+/-0.15 to 0.67+/-0.02- osteoid thickness (u) : 13+/-2.5 to 8+/-2- BFR (u3/u2/d) : 0.005 +/-0.006 to 0.044+/-0.02 Osteitis fibrosa
22、 (n=9) :- osteoblastic surface (%) : 8.4+/-2.6 to 6+/-3.1- osteoclastic surface (%) : 7.7+/-2.8 to 3.1+/-2.2- BFR (u3/u2/d) : 0.087+/-0.43 to 0.044+/-0.03,Mechanisms of improvement of 2nd HPT by SVLPD,Reduced phosphate intake (1g protein = 13 mg P) Improvement of metabolic acidosis Ca salts of ketoa
23、cids :- increased Ca intake- act as phosphate binders,Effects of SVLPD on metabolic acidosis,Fixed acid production,Approximately 1mmol acid/kg body weight is generating every day by adults eating a regular diet Fish, meat, grain products and cheeses have a high potential renal acid load. In contrast
24、, fruits and vegetables supply alkali-ash,Metabolic acidosis in CRF pathogenesis,Decreased ability to excrete nonvolatil acidsReduced renal synthesis of bicarbonate,Metabolic acidosis in CRF consequences -I-,Nutritional status :- increased protein catabolism- decreased muscle protein and albumin syn
25、thesis- negative nitrogen and total body protein balance Bone metabolism :- inhibition of osteoblast and stimulation of osteoclast function- release of calcium and phosphate to buffer H+ ions,Metabolic acidosis in CRF consequences -II-,Induces insulin resistanceImpairs triglycerides utilization,Plas
26、ma bicarbonate levels and death rate in HD patients Lowrie-Lew AJKD 1990,Keto Acid Therapy Correction of metabolic acidosis,Correlation between the changes in bicarbonate levels and the changes of the mineral apposition rate M.H.Lafage KidneyInt.1992,Effects of SVLPD on lipid disorders, HYPERTRIGLYC
27、ERIDAEMIA (due to the impairment of triglyceride hydrolysis) DYSLIPOPROTEINAEMIA - Decrease in HDL-cholesterol (most important antiatherogenic factor)- Increase of apolipoprotein C III - Decrease in apolipoprotein A I (integral part of HDL) NEPHROTIC SYNDROME- Increase in total and LDL-cholesterol,1
28、) BERNARD et al. (1996): Miner Electrolyte Metab, 22, 143-146; 2) CIARDELLA et al. (1988): Nephron, 42, 196-199; 3) ATTMAN and ALAUPOVIC (1991): Nephron, 51, 401-410,Lipid metabolism disorders in CKD,Dyslipidemia may have a role in the cardiovascular disease which is responsible of 50% of deaths aft
29、erinitiating maintenance dialysis therapy,Several reports have suggested that dyslipidemia might favour the progression of renal failure,Consequences of lipid disorders in CRF,Significant improvement of the serum lipid profile- Correction of hypertriglyceridaemia (211 +/- 139 vs. 154 +/- 102 mg/dl;
30、p 0.05)Ciardella et al. Nephron 1986- Increase in serum apolipoprotein A I (1.73 +/- 0.05 vs. 1.82 +/- 0.06 g/l; p 0.025)Bernard et al. Miner.Electrolyte Metab.1996- Increase in HDL-cholesterol (35.1 +/- 8.1 vs. 45.7 +/- 12.2 mg/dl; p 0.005)Attman and Alaupovic Nephron 1991- Decrease in total choles
31、terol (5.9 +/-1.4 vs 5.2 +/- 1.2 mmol/L; p 0.01)Chauveau et al.J.Ren.Nutr.2007,Keto Acid Therapy Overall improvement of lipid metabolism,Outcome of proteinuria according to baseline values,Correlation between outcome of proteinuria and of serum cholesterol,4,5,6,7,Chol0,Chol1,Chol3,Chol6,Chol9,Chol1
32、2,4,5,6,7,Chol0,Chol1,Chol3,Chol6,Chol9,Chol12,patients with proteinuria 3g/day at start,patients with reduction of proteinuria 50%,Antiproteinuric treatment and outcome of total serum cholesterolNavis Contrib Nephrol 1997,Mechanisms of improvement of lipid disorders by SVLPD,Decreased production of
33、 nitrogenous waste products that may act as inhibitors of lipase activity Correction of insulin resistance Parallel reduction in protein intake from animal source and in the associated saturated lipids Improvement of lipid profile in response to a reduction in proteinuria,Conclusion,Numerous studies have confirmed the efficacy of SVLPD on most of the metabolic disorders linked to CRF. These effects account for the improvement of the outcome of CKD patients and for the substantial delay in the initiation of RRT which have been reported in most series.,
