ANDI RAHMAT HIDAYAT

HAERANI RASYID
 Background

CKD is defined as the presence renal damage (structural or

functional abnormalities of the kidney) with or without a reduction in
GFR with manifestasion :
• Patological abnormalities
• Laboratory abnormalities in blood, urine, or abnormalities in
radiology

Decrease in GFR <60 ml/min for > 3 months with or without renal
damage

Suwitro K. Buku Ajar Ilmu Penyakit Dalam jilid II. Jakarta, Indonesia: Interna Publishing. 2014:2159-65
 Background

Prevalence CKD prevalence (NHANES) in USA  11% (19.2 million)

where the prevalence of CKD stages I-IV are respectively
3.3%, 3.0%, 4.2%, 0.3% and 0.2% at end-stage.
CKD is a progressive and irreversible  renal replacement
therapy  dialysis or renal transplantation. Based on
evidence medicine, not all CKD  ESRD
Various factors affecting CKD progression  ESRD.
Intervention in earlier stage can slow the CKD progression 
Renoprotection strategy

Himmelfarb J. Chronic Kidney Disease, Dialysis, and Transplantation 3rd ed. Philadelphia: Saunders Elsevier. 2010:1:3-6
Bakri S. Makassar, 2005.
Ritz E, et.al. Evidence-Based Nephrology. Blackwell Publishing. 2009;29-41.
CKD Progression
Renoprotection Strategy
Level 1 Hypertension
Recommendation Proteinuria
Angiotensin -II
Protein intake
Hyperglycemia

Level 2 Sodium intake

Recommendation Hyperlipidemia
Smoking
NSAID
Anemia

Level 3 Hyperinsulinemia
Recommendation Homocysteinemia
Hyperphosphatemia
Hypokalemia Hebert LA, et.al. Kidney Int. 2001;59:1211-26
Hypertension
Hypertension
MDRD Study
↑ intra-glomerular
pressure

Those with minor proteinuria (< 1 gr/24

hours) had slow rate of GFR decline (3-4
Mechanical pressure to ml/min/year) in contrast with major
glomerular and proteinuria (> 3 gr/24 hrs) rapid rate of GFR
mesangial cells decline (7-14 ml/min/year) and those
derived a great benefit from aggressive
lowering BP (< 125/75 mmHg)

Maladaptive response
mediated by fibrogenic
Hebert LA, et.al. Kidney Int. 2000;57:1962-7
cytokines and Ang-II Ravera M, et.al. J Am Soc Nephrol. 2006;17:98–103
Herbert LA, et.al. Hypertension.1997; 30: 428-35
 Strategy

Pharmacological
Non pharmacological recommendation
for HT in CKD
Recommendation
• Achieve and maintain BMI 20-25 kg/m2
ACEI/ARB + ACEI/ARB +
• Sodium restriction < 90 mmol Na (< 2 diuretik + CCB diuretik + β-
ACEI/ARB +
gr/day) ACEI/ARB
diuretik
/clonidin/ β-
blocker/α-1
blocker + CCB/
minoxidil/α-1
• Physical activity for min 30 minutes a blocker blocker/clonidin

day
• Avoid drinking alcohol < 2 glass/day for
men while < 1 glass/day for women

Kidney Disease Improving Global Outcomes (KDIGO). 2012

Hebert LA, et al. Kidney Int. 2001;59:1211-26
 Proteinuria

Proteinuria is a predictive factor for CKD progression

Reducing proteinuria 1 gr/day associated with reducing GFR decline 1-

2 ml/min/year

Proteinuria precipitate tubular chemokine expression and complement

activation  inflammatory cells infiltration to interstisial and further
fibrogenesis

Abbate M, et.al. J Am Soc Nephrol. 2006;17:2974-84

Amy S, et.al. . Curr Opin Pediatr. 2010; 22(2): 161–169.
 Proteinuria

• A study using captopril for diabetic CKD  ↓ > 3.5

Herbert et.al gr/day in 16.5 subject rather than 1.5% in placebo group

• Other meta-analysis comparing using ACEI/ARB in

Meta-
analysis
diabetic and non diabetic CKD  15.73 vs 12.21 mg/d

• Study comparing Irbesartan to amlodipin in ↓ proteinuria

Lewis et.a
(IDTN Study)
33% vs 6 % vs 10% (placebo)

Herbert LA, et.al. Kidney Int. 1994 Dec;46(6):1688-93.

Lewis EJ, et.al. N Engl J Med. 2001;345 :851–60
Angiotensin II
Kidney Disease Improving Global Outcomes (KDIGO). 2012
JNC 8 committee
 Protein Intake
Protein restriction in CKD

GFR Protein intake (gr/kg/day)

(ml/min)
Protein overload  hemodinamic
change intra-glomerullar  ↑ intra-
> 60 No need
glomerullar pressure 0.6-0.8 gr/KgBB/day, including ≥ 0.35
25-60 gr/KgBB/day high biological protein
0.6-0.8 gr/KgBB/day, including ≥ 0.35
gr/KgBB/day high biological protein
5-25
↑ Protein  ↑ Hydrogen, phosphate, or additional 0.3 gr essential amino
sulfat, other unorganic ion excreted acid or ketoacid
to ren  accumulation of nitrogen < 60 0.8 gr/KgBB/day (+1 gr protein/gr
and other unorganic ion  uremia
(nephrotic proteinuria or additional 0.3 gr
syndrome) essential amino acid or ketoacid )

Suwitro K. Buku Ajar Ilmu Penyakit Dalam jilid II. Jakarta, Indonesia: Interna Publishing. 2014:2159-65
 Maintaining nitrogen
balance

Decrease uremic
intoxication

Reducing proteinuria
and amino-aciduria

Reducing
hyperphosphatemia

Correcting metabolic
acidosis

Increase essential
amino acid

Increase nutritional
status
Teplan V. Nefroloji Derjisi. 2004;13 (1) 3-7
 Hyperglycemia
Diabetes is the most etiology of CKD worldwide,
25-40% in T1DM and T2DM

Chronic hyperglycemia  glomerullar

hypertrophy, hyperfiltration and hypertension

Good glycemic control  microvascular

complication (↓ albuminuria and GFR)

KDIGO  A1c 7% to prevent CKD progression,

while lower A1c  ↑ hypoglycemia and mortality

Stage III-V CKD  high risk for hypoglycemia

Kidney Disease Improving Global Outcomes (KDIGO). 2012 due to ↓ gluconeogenesis and ↓ renal clearance
Neto PA, et.al. JNephrol. 2013;26(4): 629-35
 Hyperglycemia

Dose adjustments for oral hypoglycemic drugs in CKD

Class Drugs CKD GFR 50-80 CKD GFR 50-80 CKD GFR < 30
Sulfonilurea Glimepiride 1 mg/day 1 mg/day 1 mg/day
Gliclazide No adjusting dose
Glipizide No adjusting dose
Meglitinide Nateglinid 60 mg/day 60 mg/day Tidak
direkomendasi
DPP4I Linagliptin No adjusting dose
Sitagliptin 100 mg/day 50 mg/day 25 mg/day
Saxagliptin 5 mg/day 2.5 mg/day 2.5 mg/day
Vildagliptin 50 mg/day Tidak direkomendasi
TZD Pioglitazone No adjusting dose
Alfa
Glucosidase Acarbose No adjusting Not recommended
Inhibitor dose
Biguanide Metformin Contraindicated when Cr serum > 1.5
Neto PA, et.al. JNephrol. 2013;26(4): 629-35
 Sodium Intake
High sodium intake :
-↑ Blood pressure
-Glomerular hyperfiltration  ↑ proteinuria
-RAAS activated

In a randomized study against the African with CKD and hypertension

treated by salt restriction <5 gr/day significantly reduced protein
excretion by 19% and led to a decrease in 8 mmHg systolic blood
pressure and 3 mmHg diastolic to placebo.

KDIGO
Restriction of sodium intake <90 mmol (<2 g / day) was equivalent to the
restriction of <5 grams of salt per day
Hiddo J, et.al. Dial. Transplant. 2012;27 (9): 3435-42
Swift PA, et al. Hypertension 2005; 46: 308–12
Hyperlipidemia
• Hyperlipidemia  atherosclerosis, glomerulosclerosis, fibrosis

• LDL-C is an independent factor  CKD progression

• By controlling lipid serum  prevent CKD progression in diabetic and non

diabetic CKD

• HMGCoA (Statin)  anti inflammatory effect

• Zoja et.al  ACEI and statin combination  antiproteinuria effect

• CKD  LDL-C < 100 mg/dl and TG < 150 mg/dl

Hyperlipidemia

KDIGO CKD with age ≥ 50 years, GFR <60 ml/min/1.73 m2 (G3a-G5) that
have not been treated with dialysis or transplantation is
recommended using statin or statin-ezetimibe combination

CKD with age ≥ 50 years, GFR ≥ 60 ml /min/1.73 m2 (G1-G2)

recommended using statins

CKD with age 18-49 years who have not received dialysis or a
transplant is recommended the use of statins when there are
circumstances as follows: (1) history of coronary disease (2) diabetes
mellitus (3) a history of stroke (4) estimate the next 10 years the
incidence of death myocardial infarction due to coronary or> 10%
 Smoking

• Smoking is an independent risk factor for CKD progression

• Cohort study  every 5 ciggaretes associated with an increase of 27

ummol/l Cr serum in 3 years

• Gas and particle containing in ciggaretes  endotel dysfunction,

growth factor activation, oxidative stress, platelets aggregation, lipid
metabolism disorder

Orth SR, et.al. Clin J Am Soc Nephrol. 2008;3: 226–236

 NSAID

• NSAID  AKI and CKD Progression

• NSAID  ↓ Prostaglandin  renal blood flow ↓

• It is recommended not using NSAID regularly in CKD patient, Using

NSAID once or twice a week considered to be save for CKD
patients or using other type of analgetic

Plantinga L, et.al. Ann Fam Med. 2011;9(5):423-30.

 Anemia

•Anemia is an early complication in CKD.

•Anemia  tissue hypoxia (including renal) 

tubulointerstisial injury

•Several studies have shown that early intervention

of anemia can slow the progression of CKD

Vanrenterghem WH,et.al. Nephrol Dial Transplant. 2007:22(3):20–26

 Anemia

 Rossert et al studied the effects of early  In the CREATE study the higher Hb
anemia intervention in 155 PGK target of 13-15 g / dl did not reduce
patients with LFG 15-50 ml / min cardiovascular risk as well as
divided into two groups ie groups with improved kidney function
high Hb (11-12 g / dl) and lower Hb (9-
 So that target of Hb about 11-12 is
10 g / dl ) Found that those with higher
recommended in CKD patients
Hb had a much lower LFG decline
than those with lower Hbs (0.058 vs
0.081 ml / min / month)

Vanrenterghem WH,et.al. Nephrol Dial Transplant. 2007:22(3):20–26

Rossert J, Levin, et.al. Am J Kidney Dis 2006;47: 738–750
 Hyperinsulinemia

Insulin resistence is a risk factor for CVD

High insulin plasma and high TG  glomerular

sclerosis  fibrosis and glomerular hyperfiltration

Weight loss and exercise can reduce the insulin

resistence

Hebert LA, et.al. Kidney Int. 2001;59:1211-26

 Hyperhomocysteinemia

Hyperhomocysteinemia in advance stage  decrease LFG

Hyperhomocysteinemia  risk factor for atherothrombosis

and microalbuminuria in DKD due to endothel injury and
oxidative stress

Folic acid 5-10 mg , B6 and B12  reduce homocysteine level

in plasma

Hebert LA, et.al. Kidney Int. 2001;59:1211-26

 Hyperphosphatemia

• Change in bone mineral metabolism due to impaired phosphat

and calcium homeostasis found in early stage of CKD

• Hyperphosphatemia  risk factor for CKD progression

• In Meta-analysis study  every increase 1 mg of phosphat

associated increase 36% risk of ESRD

Lezaic V, et.al. Clin Nephrol. 2009 Jan;71(1):21-9.

 Hyperphosphatemia
• High phosphate level in plasma  tubular damage, intestisial
fibrosis, endothelial dysfunction, calcium deposition in cardiac
valve

• KDIGO recommend to maintain the normal level phosphate in

plasma

• Achieving normal level phosphate  diet and phosphate

binding

Lezaic V, et.al. Clin Nephrol. 2009 Jan;71(1):21-9.

 Phosphate Binding
Agent Dosage/day

Aluminium Hidroksida 1.425-2.85 gr

Kalsium Sitrat 1.5-3.0 gr

Magnesium Karbonat 0.7-1.4 gr

Kalsium Karbonat 3-6 gr

Kalsium Asetat 3-6 gr

Lanthanum Karbonat 3 gr

Savelamer-HCL 4.8-9.6 gr

Savelamer Karbonat 4.8-9.6 gr

Kidney Disease Improving Global Outcomes (KDIGO). 2012
 Hypokalemia

Long term hypokalemia  induce TGF-β  growth factor and matrix

production factors  interstisial fibrosis

In cohort study  hypokalemia is risk factor for CKD progression

 82% annual decrease of LFG and increase proteinuria

Long term hypokalemia  ADPKD

Wang HH, et.al. Plos one. 2013; 8(7).

CONCLUSION

A variety of complex mechanisms are involved in the progression of CKD

Some risk factors can be easily eliminated with prevention strategies,

others require aggressive treatment and tight control

Renoprotective strategy is aimed at interventions on various risk factors

based on a proven and classified progression of kidney disease progression
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