Transcript Bez nadpisu - กลุ่มงานเภสัช

Benjawan Chiewchantanakij
8 May 2008
Functions of the Kidney
• Excretion of exogenous (e.g.drugs) and endogenous (waste products of the protein
metabolism such as urea, uric acid, creatinine sulphates, ammonia) substances.
• Regulation of the amounts of water and electrolytes (sodium, chloride, hydrogen
ions, potassium, magnesium, calcium, phosphate) in the body.
• Regulation of the acid-base-homeostasis (blood pH 7.4).
• Hormone synthesis and breakdown
Synthesis: erythropoietin
vitamin D3
renin
Breakdown: e.g. parathyroid hormone, calcitonin and insulin
Stages of Chronic Kidney Disease (CKD)
STAGE
GFR
DESCRIPTION
1.
 90 ml/min/1.73 m2
2.
60-89 ml/min/1.73 m2
Kidney damage with mild decrease
in GFR
3.
30-59 ml/min/1.73 m2
Moderate decrease in GFR
4.
15-30 ml/min/1.73 m2
Severe decrease in GFR
5.
< 15 ml/min/1.73 m2
* According to NKF/KDOQI guidelines 2002
Kidney damage with normal or
increased GFR
Kidney failure
Progression of CKD
Hyperfiltration
Amino acid-induced hyperfiltration:
Amino acids
cAMP
2
1
Glucagon
1+2
Branched-chain
amino/keto acids
• Increased renal
Lang et al. (1995): Sem Nephrol, 15, 415-418
plasma flow
• Hyperfiltration
Progression of CKD
glomerular
hypertension +
hyperfiltration
hypertrophy
glomerulosclerosis
Progression of CKD Hyperfiltration
High protein intake
Lead to glomerular hyperfiltration
Loss of nephrons
= decrease of glomerular filtration
Protein-restricted diet
(+keto/amino acids supplement)
Dietary management in CKD
Initiation of a Keto Acid Therapy
Stage
1
(ml/min/1.73 m2)
Daily permitted protein
supply
Ketosteril®
supplementation
 90
Normal diet
Not required
GFR
(according to RDA: 0.75-0.8 g /kg bw)
2
60-89
Normal diet
Not required
(according to RDA: 0.75-0.8 g /kg bw)
3
30-59
Protein-restricted diet
3 x 4-8 tablets/day*
(0.3-0.4 or 0.6 g protein/kg bw)
4
15-29
Protein-restricted diet
3 x 4-8 tablets/day*
(0.3-0.4 or 0.6 g protein/kg bw)
5
< 15
- Not yet under dialysis
Protein-restricted diet
3 x 4-8 tablets/day*
(0.3-0.4 or 0.6 g protein/kg bw)
- Under dialysis
Normal diet
3 x 4-8 tablets/day*
(1.0-1.3 g protein/kg bw)
* Long-term experience: 1 tablet/5 kg body weight/day
Protein-restricted diet is recommended
Protein-restricted diet is strongly indicated
Ketosteril® Tablet
1 tablet contains:
67 mg
101 mg
68 mg
86 mg
59 mg
-ketoanalogue to isoleucine, Ca-salt
-ketoanalogue to leucine, Ca-salt
-ketoanalogue to phenylalanine, Ca-salt
-ketoanalogue to valine, Ca-salt
-hydroxy-analogue to methionine, Ca-salt
105 mg
53 mg
23 mg
38 mg
30 mg
50 mg
L-lysine-acetate
L-threonine
L-tryptophan
L-histidine
L-tyrosine
Calcium
The proven medication therapy to slow down CKD progression.
Ketosteril ®
Amino acid composition
Essential amino
acids
Non-essential amino
acids
Conditionally essential
amino acids
Histidine
Isoleucine
Leucine
Lysine
Methionine
Phenylalanine
Threonine
Tryptophan
Valine
Alanine
Aspartic acid
Asparagine
Glutamic acid
Serine
Arginine
Cysteine
Glutamine
Glycine
Proline
Tyrosine
Amino acids in Ketosteril®
Amino acids present as their corresponding keto acids (KA) in Ketosteril®
Dr. Anja Markant , 01/2006
9
How does Ketosteril work?
Conversion of -Ketoacids to corresponding amino acid
-Ketoacids conjugates to Amino to get EAA
H 3C
CH3
H 3C
CH
CH2
Transaminase
+NH2
C= O
CH3
CH
CH2
HC
COOH
COOH
-Ketoisocaproic Acid
Leucine
Patient gets amino acids without as much nitrogen load
NH2
Mechanism of KA benefits
Keto EAA
Transaminases
NEAA
EAA
Keto NEAA
1. Availability of EAA:- Improved nutritional status
2. Less nitrogen in diet
3. Endogenous nitrogen diverted to AA formation
BENEFIT
• Slowdown of CRF progression
• Metabolic and other benefits
Reduced Kidney
Load
A mixture of amino acids and ketoanalogues
The saving of nitrogen due to the transfer of the amino group to the
ketoanalogues is associated with a direct inhibition of ureagenesis.
Keto Acid Therapy
Superiority of AA/KA supplemented VLPD
SCHMICKER et al. (1986): Influence of LPD supplemented with AA and KA on the progression of CRF.
Contr Nephrol, 53, 121-127
Keto Acid Therapy
Effect on progression
Calculated delays (in years) up to the postulated start of dialysis (5 ml/min):
VLPD + KA/AA
Teschan et al. (1998)
Ø 3.0 years
Walser et al. (1992) Ø 2.8 years
Aparicio et al. (1990)
Ø 4.6 years
Walser et al. (1993)
-
VLPD + AA
Ø 1,6 years
Ø 1.5 years
Ø 1.4 years
Keto Acid Therapy
Deferment of renal replacement
COMMON CRITERIA FOR STARTING DIALYSIS:
GFR < 10 ml/min in non-diabetic patients
GFR < 15 ml/min in diabetic patients
Design: No. of patients: n=76 (23: GFR < 10 ml/min/ 53: GFR > 10 ml/min,
who reached GFR < 10 ml/min during
treatment)
Diet:
VLPD + AA/KA + CaCO3 + vitamin preparation
Duration: Few weeks to 2 years
Outcome measure: Renal survival (interval between the time at
which GFR became less than 10 ml/min and
the date at which RRT was started)
WALSER and HILL (1999): Can renal replacement be deferred by supplemented VLPD? J Am Soc Nephrol ,10, 110-116
Keto Acid Therapy
Deferment of renal replacement
RENAL SURVIVAL for 76 patients treated with a VLPD + AA/KA
[interval between meeting Medicare criteria (GFR: < 10 ml/min) for
starting RRT and actual date of starting RRT (5.6 ± 1.9 ml/min)]
MEDIAN SURVIVAL:
353 days
WALSER and HILL (1999): Can renal replacement be deferred by supplemented VLPD? J Am Soc Nephrol ,10, 110-116
Low Protein Diet
Incidence of GFR Stop/ESRD/death in CKD
LEVEY et al. (1996): Effect of dietary protein restriction on the progression of advanced renal disease in the
Modification of Renal Disease Study. Am J Kidney Dis, 27, 652-663
Low Protein Diet
Incidence of ESRD/death in diabetic nephropathy
 A protein restriction improves prognosis in type 1 diabetic patients
with progressive diabetic nephropathy in addition to the beneficial
effect of antihypertensive treatment.
HANSEN et al. (2002): Effect of dietary protein restriction on prognosis in patients with diabetic nephropathy
Kidney Int, 62, 220-228
Metabolic acidosis in CKD
PATHOGENESIS: The kidney is no longer able to excrete
sufficient acids to neutralize the body’s
daily acid load
CHARACTERISTICS: - Decreased serum bicarbonate levels
- Decreased blood pH
Metabolic acidosis contributes to:
- Acceleration of the protein degradation
- Impaired nitrogen utilisation
- The development of renal osteodystrophy
- Decreased myocardial contractility
Metabolic acidosis causes catabolic conditions
Metabolic acidosis in CKD
METABOLIC ACIDOSIS
Bone mineral loss
• Stimulation of PTH and
osteoclast secretion
• Inhibition of osteoblasts
• Bone acts as a buffer for
hydrogen ions
• Interfering with the
activation pathway for
25 (OH) Vitamin D2
Oxidation of
Branched-chainamino acids
Decreased muscle mass
• Protein degradation
 Stimulation of
proteolytic pathways
• Resistance to insulin
and IGF-1
• Decreased albumin
synthesis
Keto Acid Therapy
Correction of metabolic acidosis
Phosphate-Calcium metabolism disorders in CKD
High phosphate
levels
P
Low calcium
levels
Ca
Phosphate-Calcium metabolism disorders in CKD
SECONDARY HYPERPARATHYROIDISM
• Phosphate retention linked to CKD plays an important role in
the pathogenesis of secondary hyperparathyroidism.
• Secondary hyperparathyroidism is a frequent and deleterious
complication in CKD.
ITS PATHOGENESIS IS DOMINATED BY TWO MECHANISMS:
• Impaired urinary excretion and accumulation of phosphate.
• Diminished synthesis of active vitamin D resulting in a
decreased absorption of calcium.
Phosphate-Calcium metabolism disorders in CKD
Progression of CRF
and decreasing GRF (< 25 ml/min)
Serum-phosphate
Serum-calcium
Increase in PTH
SEC. HYPERPARATHYROIDISM
RENAL OSTEODYSTROPHY
Therapeutic aims: - Serum-phosphate has to be decreased
a) reduction of the phosphate intake
b) binding of phosphate with drugs
- Serum-calcium has to be increased
Keto Acid Therapy
Phosphate-Calcium metabolism disorders in CKD
Design: No. of patients: n=17 (GFR  20 ml/min)
12 months
0.3 g protein/kg bw/d+ 1 tabl. Ketosteril®/5 kg bw/d
+ 1 g CaCO3 + 1,000 IU vitamin D2
300
.
25
250
2
1.5
1
200
150
100
.
05
50
0
0
initial
VLPD after 12 months
LAFAGE et al. (1992): Kidney Int, 42, 1217 - 1225
2
p < 0.01
*
Phosphate (mmol/l)
3
i-PTH (pg/ml)
Calcium (mmol/l)
Duration:
Diet:
.
15
1
.
05
0
p < 0.05
*
Phosphate-Calcium metabolism disorders in CKD
Parameters
(mean + SD)
Normal range
Before 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 (µg/ml)
10 - 60
168 ± 101
83 ± 68 (b)
Alk. Phophatase (IU/l)
30 - 120
88 ± 45
86 ± 38
Osteocalcin (µg/ml)
3.7 - 6.9
40 ± 29
31 ± 25
25 OH Vitamin D (µg/ml)
12.5 - 60
49.5 ± 29.3
79.1 ± 36.5 (a)
Results are expressed as mean + SD:
LAFAGE et al. (1992): Kidney Int, 42, 1217 - 1225
(a) p < 0.05; (b) p < 0.01; (c) p < 0.001
Glucose metabolism in CKD
Abnormalities in glucose metabolism affect more than
50% of patients with CKD:
• HYPERINSULINAEMIA
due to
a.) Insulin resistance
b.) Decrease in insulin clearance rate
(REASON: Impairment in insulin metabolism in liver and muscles by
uraemic toxins which interfere with insulin degradation and insulin
action)
• HYPERGLYCAEMIA/GLUCOSE INTOLERANCE
(Abnormal glucose tolerance tests)
due to
a.) Increased hepatic glucose production
b.) Reduced peripheral glucose metabolism (insulin resistance)
Keto/amino acid supplemented (V)LPD
Insulin clearance rate
Design: No of patients/healthy controls:
n =17/10
GFR:
14.6  2.9 ml/min
Dietary regime: VLPD (0.3 g protein/kg bw/day) + KA/AA + CaCO3
Duration:
3 months
healthy
controls
GIN et al. (1994): Am J Clin Nutr, 59, 663-666
Keto-diet Improved insulin sensitivity
Pts with type II diabetes, 3 month follow up
Before
After Ketodiet
Glucose infused mg/m2/min
450
p<0.01
p<0.01
400
350
p<0.01
300
250
200
400
800
Insulin level mcU/ml
Daily insulin requirements decreased from 38.3 to 28.2 units (p < 0.01)
Gin et al, Nephron 1991;57:411-415
Keto Acid Therapy
Overall improvement of glucose metabolism
INCREASE OF THE INSULIN CLEARANCE RATE (~ 30%)
1)
 Reduction of the plasma insulin levels (20-30%) 2)
IMPROVEMENT OF THE PERIPHERAL INSULIN SENSITIVITY/
CORRECTION OF THE GLUCOSE TOLERANCE TEST 2) 3)
 Restoration of the peripheral glucose metabolism (stimulation of
glucose storage and oxidation)
 Reduction of the endogenous glucose production
POSSIBLE MECHANISMS:
- Reduction of uraemic toxins (peptides) derived from alimentary
proteins
- Correction of metabolic acidosis
1) GIN
et al. (1994): Am J Clin Nutr, 59, 663-666; 2) RIGALLEAU et al. (1997): Kidney Int, 51, 1222-1227;
3) APARICIO et al. (1989) Kidney Int, 36, 231-235
Lipid metabolism in CKD
Common features 1)-3)
• HYPERTRIGLYCERIDAEMIA
(due to the impairment of triglyceride hydrolysis)
• DYSLIPOPROTEINAEMIA
- Decrease in HDL-cholesterol (most important antiatherogenic factor!
 Cholesterol – released from extra-hepatic tissues is transported via HDL
to the liver for excretion in bile
- Increase of apolipoprotein C III
 Inhibits the hydrolysis of triglycerides
- Decrease in apolipoprotein A I (integral part of HDL)
 Activates the enzyme which is responsible for esterification of free
plasma cholesterol
1) 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
Keto Acid Therapy
Overall improvement of lipid metabolism
 Significant improvement of the serum lipid profile
- Correction of hypertriglyceridaemia (211 ± 139 vs. 154 ± 102 mg/dl; p < 0.05) 2)
- Increase in serum apolipoprotein A I (1.73 ± 0.05 vs. 1.82 ± 0.06 g/l; p < 0.025) 1)
- Increase in HDL-cholesterol (35.1 ± 8.1 vs. 45.7 ± 12.2 mg/dl; p < 0.005) 2)
POSSIBLE MECHANISMS:
- Modification of food intake (reduced food intake from animal origin, mainly
saturated fatty acids)
 Reduction of plasma lipid fraction 1)
- Correction of endocrine parameters (reversal of hyperparathyroidism, restoration
of blood testosterone levels in male uraemics, improvement of thyroid hormone levels) 2)
1) BERNARD
et al. (1996): Miner Electrolyte Metab, 22, 143-146; 2) CIARDELLA et al. (1988): Contr Nephrol, 65, 72-80;
ATTMAN and ALAUPOVIC (1991): Nephron, 51,401-410
3)
Meta-analysis
PEDRINI et al.(1996) : Effect of dietary protein restriction on
the progression of diabetic and nondiabetic renal disease.
Ann Intern Med,124,627-632
Protein-restricted diets
Effect on progression in non-diabetic CKD patients
PEDRINI et al. (1996): Ann Intern Med, 124, 627-632
Protein-restricted diets
Efficacy in delaying the need of dialysis (non-diabetics)
Study
Year
Treatment
renal death/n
IHLE et al
JUNGERS et al
KLAHR et al
LOCATELLI et al
MALVY et al
ROSMAN et al
WILLIAMS et al
Total (95%CI)
1989
1987
1994
1991
1999
1989
1991
Control
OR
renal death/n
4 / 34
5 / 10
18 / 291
21 / 230
11 / 25
30 / 130
12 / 33
13 / 38
7/9
27 / 294
32 / 226
17 / 25
34 / 117
11 / 32
101 / 753
141 / 741
(95 % CI)
0,1
0,2
1
5
 Reducing protein intake in patients with CKD reduces the occurence of renal death
by 40% compared with higher/unrestricted protein intake
FOUQUE et al. (2003): The Cochrance Library, Volume 1
10
Keto Acid Therapy
Effect on progression in diabetic CKD patients
 Dietary protein restriction significantly reduces the risk of decline
in GFR or creatinine clearance in patients with diabetic nephropathy.
PEDRINI et al. (1996): Effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases:
a meta-analysis. Ann Intern Med, 124, 627-632
Keto/amino acid supplemented (V)LPD
Outcome of nutritional status
DESIGN: No of patients: n = 10
GFR:
Diet:
Duration:
13.2  4.8 ml/min
VLPD (0.3 g protein/kg bw/d) + Ketosteril® + CaCO3
12 months
RESULTS:
Study begin
Study end
BMI (kg/m2)
TSF (mm)
AMC (cm)
Albumin (g/l)
Prealbumin (g/l)
Transferrin (g/l)
24.6 ± 2.9
14.5 ± 7.3
30.9 ± 2.1
40.7 ± 7.4
0.39 ± 0.08
2.16 ± 0.5
24.7 ± 3.3
15.7 ± 8.1
31.1 ± 2.4
40.5 ± 4.7
0.44 ± 0.06
2.02 ± 0.40
GFR (ml/min/1.73 m2)
Creatinine (mg/l)
13.2 ± 4.8
44.1 ± 11.1
12.1 ± 6.6
48.4 ± 14.5
CHAUVEAU et al. (1999): Am J Kidney Dis, 34, 500-507
Keto/amino acid supplemented (V)LPD
Effects on serum transferrin levels
Serum Transferrin (g/l)
4
Study Begin
Study End
3
2
1
0
No of patients
Duration (months)
Aparicio et
al. (1988)
Vetter et al.
(1990)
16
6
37
12
Herselman
et al. (1995)
11
9
Walser et al.
(1993)
5
4
Teplan et al.
(2001)
35
36
Prakash et
al. (2004)
18
9
Keto/amino acid supplemented (V)LPD
Effects on serum albumin levels
Study begin
Study end
60
Serum Albumin (g/l)
50
40
30
20
10
0
Aparicio et
al. (1988)
No of patients
Duration (months)
16
6
Vetter et
al. (1990)
37
12
Walser et
al. (1993)
5
4
Barsotti et
al. (1998)
21
6
Teplan et
al. (2000)
20
12
Di Iorio et
al. (2003)
10
18
Prakash et
al. (2004)
18
9
BENEFICIAL EFFECTS OF A
KETOSTERIL®SUPPLEMENTED VLPD
Reduction of uremic symptoms.
Slowing or arrest of the progression of renal failure.
Prevention of degradation of body protein.
Reduction of the daily urinary protein loss.
Normalisation of the carbohydrate metabolism.
Correction of disturbances in the calcium and phosphate
metabolism, secondary hyperparathyroidism and renal
osteodystrophy.
Improvement of the disturbed serum lipid profile.
Delay Onset of Dialysis
BENEFICIAL EFFECTS OF A
KETOSTERIL®SUPPLEMENTED VLPD
•
•
•
•
Reduce Uremic Symptoms
Prevent the Progressive Loss of Renal Function
Delay Onset of Dialysis
Improves Nutritional Status and Produces a Positive Nitrogen
Balance
• Improves the Insulin Sensitivity In Diabetic Nephropathy
• Improves Renal Osteodystrophy
• Reduce the Frequency of Dialysis
Chronic renal failure can
never be cure!!!
Only the speed of
progression can be
influenced
Caring for Kidney ,Caring for Life