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

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

GFR
(ml/min/1.73 m2)

Daily permitted protein

supply

Ketosteril
supplementation

90

Normal diet

Not required

(according to RDA: 0.75-0.8 g /kg bw)

60-89

Normal diet

Not required

(according to RDA: 0.75-0.8 g /kg bw)

30-59

Protein-restricted diet

3 x 4-8 tablets/day*

(0.3-0.4 or 0.6 g protein/kg bw)

15-29

Protein-restricted diet

3 x 4-8 tablets/day*

(0.3-0.4 or 0.6 g protein/kg bw)

< 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

How does Ketosteril work?

Conversion of -Ketoacids to corresponding amino acid

-Ketoacids conjugates to Amino to get EAA

H3 C

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)
3.0 years
Walser et al. (1992) 2.8 years
Aparicio et al. (1990)
4.6 years
Walser et al. (1993)
-

VLPD + AA
1,6 years
1.5 years
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 bodys
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

2.5

250

2
1.5
1

200
150
100

0.5

50

initial

VLPD after 12 months

LAFAGE et al. (1992): Kidney Int, 42, 1217 - 1225

p < 0.01
*

Phosphate (mmol/l)

1.5

i-PTH (pg/ml)

Calcium (mmol/l)

Duration:
Diet:

0.5

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 (g/ml)

10 - 60

168 101

83 68 (b)

Alk. Phophatase (IU/l)

30 - 120

88 45

86 38

Osteocalcin (g/ml)

3.7 - 6.9

40 29

31 25

25 OH Vitamin D (g/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
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
1)

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

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
1)

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)
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
1)

3)

2)

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

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)

Study Begin
Study End

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

S erum A lbum in
(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
KETOSTERILSUPPLEMENTED 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
KETOSTERILSUPPLEMENTED 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