Benefits of Ketoanalogue Therapy in

Diabetic Kidney Disease

Haerani Rasyid
Makassar
Outline
• Big numbers CKD and Diabetic Kidney Disease
• Evolving Paradigm on the Natural History of DKD
• Interventions in DKD to prevent Complications and
Slow Progression of Renal Disease
• The Role of LPD and Ketoanalogue in DKD
CHRONIC KIDNEY DISEASE FACTS
CAUSE OF CHRONIC KIDNEY DISEASE
Is DKD really a Problem ?

Percentage of incident
Incidence of ESRD in2017
patients with ESKD
(pmp)
due to diabetes, 2017

Mircescu G, Garneata L et al. Romanian Renal Registry - 2017 Annual Report

*** - USRDS 2018 Annual Report
Causes of Kidney Failure in Indonesia. (datafromIRR)

Diabetic Kidney Disease

Simply stated: how diabetes causes kidney disease
DIABETES

DIABETIC
KIDNEY DISEASE

A UCLA HEALTH EDUCATIONAL SEMINAR,2017

 Natural History and Classification
of Diabetic Kidney Diseases

I II III IV V
Disease Pre Early A B
stage Renal
nephro- nephro- Overt nephropathy dialysis
failure
pathy pathy Early Late

Type I diabetes
Renal Type II
Function diabetes
Proteinuria
Blood Pressure
Proteinuria GFR
&
Blood microalbuminuria Overt proteinuria
Pressure (macroalbuminuria)

Criteria of early diagnosis Criteria of dialysis

HORMONES 2017, 16(4):351-361
 Classification of diabetic nephropathy/diabetic
kidney disease according to the Ministry of Health
and Welfare of Japan

Stage I Normoalbuminuric stage

Stage II Microalbuminuric stage
Stage IIIA Macroalbuminuric stage without renal
dysfunction
Stage IIIB Macroalbuminuric stage with renal dysfunction
Stage IV Renal failure stage
Stage V Dialysis stage
 Outline
• Epidemiology of diabetes
• Diabetic kidney disease (DKD)/End stage renal
disease (ESRD)
• Burden of DKD
 Progression of renal disease

Microalbuminuria

Overt Proteinuria

Doubling of
CV Events Creatinine
&
Death End Stage Renal
Disease
 Hyperfiltration Is The First Stageof Diabetic KidneydDsease

Diabetic Kidney Disease: Challenges, Progress, and Possibilities

Radica Z. Alicic,*† Michele T. Rooney,* and Katherine R. Tuttle; CJASN ePress. Published on July 12, 2017 as doi: 10.2215/CJN.11491116
Different pathways and networks involved in the initiation and progression of
diabetic kidneydisease

Diabetic Kidney Disease: Challenges, Progress, and Possibilities

Radica Z. Alicic,*† Michele T. Rooney,* and Katherine R. Tuttle; CJASN ePress. Published on July 12, 2017 as doi: 10.2215/CJN.11491116
 Treatments to Slow the Progression
of Chronic Kidney Disease in Adults
Risk Factor for the Development of Diabetic Kidney Disease
Diabetic Kidney Kidney Disease in
Disease Nondiabetic Kidney Disease the Transplant
Strict glycemic control
Microalbuminuria
Yesa NA Not tested
Arterial blood pressure
ACE-inhibitors or Yes Yes (greater effects in patients Not tested
angiotensin-receptor Gycaemic control
with proteinuria)
blockers
Ethnicity
Strict blood pressure Yes Yes Not tested
control Genetic predisposition
• < 130/85 mmHg (greater
effect in patients without
Hyperfiltration
proteinuria)
• <125/75 mmHg (in patients
Smoking
with overt proteinuria)
Dietary protein
Dietary protein restriction Inconclusive Inconclusive Not tested
a Prevents or delays the onset of diabetic kidney diseases. Inconclusive with regard to progression of established disease
Protein restriction
TARGET OF NUTRITION MANAGEMENT in CKD

pre-HD Progression 
Renal Failure Malnutrition 

PROBLEM : When dietary protein restrictiom…

Progression 
Malnutrition

Chronic Malnutrition 
Dialysis Mortality 
 Malnutrition (PEW) iscommon in patients with DKD
• As building blocks of protein, amino acids are important
to the health and proper function of your body. ...
• The remaining eight amino acids are considered essential
because your body cannot manufacture them. Amino acids
are involved in many bodily functions and work together to
promote health.
Now…..
Not only addresses PEW, delays progression of CKD but improves
survival and is cost effective
 NH 2
CH 3- CH - CH - COOH Protein (esensial Amino Acid)

OH
( Threonine )

O
(CH - CH - CH - C - COO) Ca
3 3 2
Ketoanalogue
CH
3
alpha - Keto analogue of Leucine
What about the effect ofKetoanalogue with low proteindiet?
Beneficial effects of Ketoanalogue supplemented protein-restricteddiets
•Delay the time to dialysis
•May slow progression of glomerular filtration rate
decline
•Decreases uremic toxins
•Better blood pressure control
•Reduces proteinuria
•Improves insulin sensitivity
•Improves lipid profile, oxidative and inflammatory status
•Improves calcium-phosphate metabolism
•Correction of metabolic acidosis
•Prevents malnutrition
Evidence Based Medicine..
Aparicio et al, Seminars in Dialysis 2013
 COMPARATION OF CREATININE SERUM LEVEL
BETWEEN KETOANALOG AND EAA
IN UREMIC PATIENTS WITH LOW PROTEIN DIET

Creatinine serum (mg/100 ml)

0.4 g protein/BW+ EAA

0.4 g protein/BW + Ketoanalog

Month

SCHMICKER et al. (1986): Influence of LPD supplemented with AA and KA on the progression of CRF.
Contr. Nephrol., 53, 121-127
 • Comparison of 149 diabetic with 300 non-diabetic patients
• Diabetic patients had a higher BMI, were older and had a higher
About 50% of the casesscore
comorbidity remained dialysis-free
(Charlson Index) 2 years after the first finding of e-GFR
(estimated
• 3glomerular
main low filtration rate)were
protein diets < 15 mL/min, and
offered to all1patients
year after reaching e-GFR < 10
mL/min. In patients
• 0.6 with
g/ kgtype 2 diabetes,
BW/day higher proteinuria
with protein-free food was associated with mortality
and initiation
• 0.6 – 0.8 g/ kg BW/day, vegan of dialysis.
• *sVLPDrestricted
In conclusion, moderately LPDs allow
was only employed similar
in a few cases results in diabetic and non non-
• Adherence to diabetic patients
diet was with similar
very good (mean comorbidity
0.47g/kg BW/day), low
rate of discontinuation (<2%)
• 39.6% of diabetic patients chose a vegan supplemented diet

Nutrients 2016, 8, 649

 Result study

In advanced DKD and severe proteinuria, sLPD was associated with :

- 70% reduction in proteinuria

- Better blood pressure control
- 5 times reduction in the rate of decline in eGFR
 Keto Acid Therapy on Proteinuria
Design: No of patients: n = 50
GFR: 25-35 ml/min/1.73 m2 (diabetic nephropathy)
Diet: Group I: LPD + Ketosteril® + ACEi (perindopril: 4 mg/d)
Group II: LPD + ACEi (perindopril: 4 mg/d)
Duration: 12 months

4
Proteinuria (g/24h)

1 Group I (LPD+ KA + ACEi)

Group II (LPD + ACEi)
0
0 2 6 8 10 12
Months
Teplan et al. (2003): Klin Bioch Met 11, 70-73
What Is The ExtraBenefit of TheUse of ketoacids?
Comparison of cost/patient, sVLPD vsDialysis

€ 29,634.72
€ 21,180 € 6500 € 28,952.82
euros

€ 682
€ 5,069.80

sVLPD € 19,188.14

Scalone L, et al. Cost-benefit analysis of supplemented very low-protein diet versus dialysis in elderly CKD5
patients. Nephrol Dial Transplant 2010:25:907–913
 Survivalcurveas PPanalysisofsVLPDvs dialysis
100

80

Survival Probability (%)

Diet

60

40
Dialysis

20
Log-Rank test for non-inferiority: p = 0.001
Log-Rank test for superiority: p = 0.6
0
0 12 24 36 48
Months
Brunori G, et al. Efficacy and safety of a very-low-protein diet when postponing dialysis in the elderly: A prospectiverandomized
multicenter controlled study. American Journal of Kidney Diseases, Vol 49, No 5 (May), 2007: pp569-580
Event-freesurvivalrateof patientson sVLPDvs LPD

Garneata L, Corbu-Stancu A, Dragomir D, Stefan G, Mircescu G. Very low protein diet supplemented with
ketoanalogues of essential amino acids in chronic kidney disease could slow the lost of renal function – a
randomized controlled trial
T

“Fornow, ketoacids sLPD THANK YOU

seems to be underutilized
and maybe even needed
to start at the
earliest stage
of
Diabetic Kidney Disease
instead of CKD stage3-5.”
KEYTAKE AWAYS
• CKD is increasing worldwide
• DKD is still the most common cause of CKD
• Changing concepts in pathophysiology of DKD
focuses on early prevention of complications
• PEW is common in DKD and has impact on CVD and survival
• The Metabolic Benefits of Dietary Intervention in Diabetic
Kidney Disease is as important in early stages of the disease as it
is in late CKD stage
• The role of KETOACIDS not only addresses PEW, delays
progression of CKD but improves survival and is cost effective.