1 Concepts of Renal Injury & CKD Prevention Dhavee Sirivongs, M.D. September 15, 2005 Lecture Hall 1 Faculty of Medicine, KKU.

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Concepts of Renal Injury & CKD Prevention

Dhavee Sirivongs, M.D.September 15, 2005

Lecture Hall 1Faculty of Medicine, KKU

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Early Stage CKD has been neglected?

• High compensatory kidneys• No annual check up• Clinical presentation appears at CKD V• Patients are high tolerant • No doctor concern, no GFR calculation• No public awareness• Etc.

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Concepts

• Critical mass of the kidney

• Genetic factor

• Environmental insults, include. drugs

• In-body factors: Ht

• Progressive nature of kidney disease & kidney

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CKD: pathophysiology• original insult destroyed most nephron • The rest of nephron was hypertrophy as

compensatory process • Non-immunological insults destroy glomeruli

& tubules• Immunological insults destroy glomeruli &

tubules• Proteinuria destroys the tubule via oxidation• Obstructive nephropathy induces glomerular

and intersitium invasion of wbc

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Nephron Loss to Critical number

Acute process

Chronic process

Unrecovery ARF

Trauma

Surgical

Immunological (SLE)

Metabolic (DM)

Mechanical (OU)

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Mechanisms of Renal Injury

• Immunological insults (direct) & proteinuria (indirect): SLE, NS

• Non-immuno insults (direct) & proteinuria (indirect): DM, acetaminophen, pregnancy related

• Obstructive nephropathy (tubular dilatation, jncreased luminal pressure, glomerulosclerosis

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Collagen type IV

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Lupus nephritis

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Lupus nephritis

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Lupus nephritis

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Lupus nephritis

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Obstructive nephropathy

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Nephron Loss to Critical number

Wear & Tear

Hemodynamic

Hypertrophy

Fibrotic changes

Etc.

Progressive nephron loss

CKD V

ESRD

Factors: Hypertension, Smoking, Drugs, Pre-renal

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Markers of renal injury

• Microalbuminuria/Proteinuria

• Urinary sediments: hematuria, pyuria

• Clinical index: Nocturia (poor concentrating ability), Hypertension

• FEMg ?

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Glomerular hypertension

Renal injury

Reduced number of nephrons

Systemic hypertension

SCARRING

Autoregulation*

* Lost in diabetes

Brenner, Meyer, Hostetter, N Engl J Med, 1982

A unifying hypothesis for the progressive nature of renal disease

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Proteinuria/Microalbuminuria

The current number one marker for renal injury(also the marker for CVS

morbidity/mortality)

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Proteinuria Hypertension

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PODOCYTE DYSFUNCTION IN RESPONSE TO PROTEIN LOAD

Increased glomerular permeability to proteins

ACEi / AIIRA

Podocyte protein accumulation

Proteinuria

Cytoskeleton rearrangement Gene activation

Loss of differentiated phenotype

TGF-

Slit diaphragm dysfunction

Prosclerosing activation of mesangial cells

Podocyte detachment

Foot process effacement

Permselective dysfunction

Permselective dysfunction GLOMERULOSCLEROSIS

Ang II

Abbate et al., Am J Pathol, 2002

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Mechanism of Proteinuria

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Albuminuria Hypertension

Renal deterioration

Renal InjuryTubular injury Glomerular injury

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Conclusive concept

Known cause Unknown cause

Treatable cause Diseased kidney

CKD 1

CKD 2

CKD 3

CKD 4

CKD 5

Normal kidney Markers of Kidney damage

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Life style modification

• Adequate fluid intake

• Low salt diet

• Proper protein diet

• Adequate rest

• Stop smoking

• Exercise

• Etc.

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Pharmacological approach

Angiotensin converting enzyme inhibitor (ACE-I)

Angiotensin receptor blocker (ARB)

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Concept of ACE-I/ARB Usage

ใช้�แนวคิด “เศรษฐกิจพอเพ�ยง ลดคิวาม

ฟุ้� �งเฟุ้�อ”

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REIN: ACE-I IS MORE RENOPROTECTIVE THAN

CONVENTIONAL THERAPY IN NON-DIABETIC RENAL

DISEASE

% of patients without doubling of baseline creatinine or ESRF

60

40

20

00 6 12 18 24 30

80

100

36Follow-up

P=0.02

- 40 –

- 20 –

0 –

20 –

40 –

60 –

% Reduction in

Proteinuria

Diastolic Blood Pressure (mm Hg)

100 –

90 –

80 –

70 –

60 –

Ramipril

Conventional therapy

Gisen group; Lancet 1997

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3 MONTHS PROTEINURIA REDUCTION PREDICTS LONG-TERM GFR DECLINE The REIN study

Ramipril

Overall

Conventional

* Corrected for GFR

> 3 gr/24 h

GF

R (m

l/min

/mo

nth

)

3 ye

ars

- 20

- 0.6

-0.5

- 0.4

-0.3

- 0.8

- 0.7

- 0.9

-0.20 20 40

proteinuria *( percent change vs .baseline)

3 monthsPerna et al., J Am Soc Nephrol, 2000

30

45

30

25

40

35GF

R(m

l/min

/mon

th)

RamiprilRamipril

GFR = -0.44 ± 0.54

GFR = -0.10 ± 0.50

GFR = -0.81 ± 1.12 GFR = -0.14 ± 0.87

RamiprilConventional

CORE FOLLOW-UP

Ruggenenti et al., Lancet, 1998

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3 4 5 years-2 - 1 0 1 2

Mogensen et al., 1976* PA 200/120 mmHg

Glo

mer

ular

Filt

ratio

n R

ate

(ml/m

in/1

.73s

qm)

treatment *

GFR 20 ml/year

GFR 2 ml/year40

60

80

100

20

0DYALISIS

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Decrease in Mean Blood

Pressure (mm Hg)

+ 2 –

0 –

- 2 –

- 4 –

- 6 –

- 8 –

- 9 –

- 10 –

+ 40 –

+ 20 –

0 –

- 20 –

- 40 –

- 60 –

% Reduction in

Proteinuria

p <.001

% with Doubling of

Baseline Creatinine+ ESRD+ death

0

25

50

75

100

0 1 2 3 4

Losartan

Conventional therapy

Brenner et al, N Engl J Med., 2001.

NS

RENAAL: ARB IS BETTER THAN CONVENTIONAL

THERAPY IN TYPE 2 DIABETIC NEPHROPATHY

+ 19

- 45-9.2 -9.6

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6 MONTHS PROTEIN/CREATININE RATIO REDUCTION PREDICTS RENAL AND CARDIOVASCULAR EVENTSThe RENAAL study

ESRD

CV events

Heart failure

0.4 0.60.2 0.8 1 1.2

RENAAL Study group, 2002

Hazard ratio (95 % C.I.)

Decreased risk Increased risk

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Prevention of progression and remission strategies for chronic kideny diseases

• Stop activities of the insult(s)

• Save the the rest of nephrons

– Life style modification eg. Stop smoking

– Pharmacological approach, to control hypertension, intraglomerular pressure, protein/microalbuminuria

Ideal drugs: ACEI, ARB

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ISN: Activities on CKD prevention

• Canada: Symposium on CKD prevention yearly since 2002

• Mexico 2003: The Ensenada Conference on Renal Disease in Minorities Groups, with Emphasis on the Americas

• Italy 2004: Bellago conference: Prevention of Renal Disease in the Emerging World: Toward global Health Equity

• Hong Kong 2004: CKD Prevention• Pre-congress WCN 2005, Singapore

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ISN: Prevention strategies

• Detecting those at risk of developing CKD• Preventing the onset of CKD in susceptible individuals

by altering lifestyle• Detecting those with early stage CKD• Preventing progression of CKD by intervention• Developing and applying diagnostic guidelines including

albuminuria and estimated GFR as well as therapeutic guidelines

• Raising awareness with the general public, policymakers and physicians

• Creating funds and facilities for global assistances

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กิ�จกิรรม CKD prevention ในไทย

• คิณะอน�กิรรมกิารป้�องกิ นไตวายเร#$อร ง สมาคิมโรคิไตฯ • แผนงานป้�องกิ นภาวะไตวายแบบบ+รณากิาร• ส มมนาอาย�รแพทย-โรคิไต• แนวป้ฏิบ ตเพ#/อช้ะลอกิารเส#/อมของไต• อบรมวทยากิรพยาบาล• โคิรงกิารศ1กิษาอ ตรากิารเส#/อมของไต• อบรมแพทย-และพยาบาลใน5 พ#$นท�/ใน5 ภาคิ 22-23

กิย . 48

• เผยแพร2คิวามร+ �ให้�กิ บป้ระช้าช้น 5 ธคิ. 48

กิลุ่� มวิ�จ�ยโรคไตเร��อร�ง คณะแพทยศาสตร ม.ขอนแกิ น กิ อต��งต��งแต ปี# พ.ศ . 2544

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End of the session

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Loss of Kidney Mass

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A META-ANALYSIS IN 840 TYPE 1 AND TYPE 2 DIABETIC PATIENTS WITH INCIPIENT AND OVERT NEPHROPATHY AND PRESERVED RENAL FUNCTION

Cha

nge

in p

rote

inur

ia (

%)

Change in GFR (%/year)

Modified from Weidmann et al., Nephrol Dial Transpl, 1995

0

- 20

- 40

- 60

- 80

- 100

+ 20

-20 0-16 -12 -8 -4 +4 +8 +12 +16-100 -50

Nifedipine (n=75)

Diuretics and/or beta-blockers

(n=213)

CCBs, except nifedipine

(n=63)

ACE inhibitors (n=489)

Baseline parameters:

- mean GFR: 83 ml/min

- mean proteinuria: 2.4 g/24 h

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Cause/Etiology

Pre-clinical evidences

Clinical evidences

Lab. evidences

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NEPHRON NUMBER IN 10 MIDDLE-AGED WHITE HYPERTENSIVES AND 10 MATCHED NORMOTENSIVES

Keller et al., N Engl J Med, 2003

Mean glomerular volume (10-3/mm3)

Nephron number per kidney

(x 1

,000

)

HP0

1,000

1,500

2,000

2,500

500

N

6.5 2.8

706 (626-802)

1,429 (1,130-1,627)

*

* p < 0.001

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HALTING THE PROGRESSION OF CHRONIC NEPHROPATHIES:The negleted issue of residual proteinuria

Lowest< 1.5 g/24 h

Middle1.5 - 3.5 g/24 h

Highest≥3.5 g/24 h

0

0.25

0.50

0.75

1.00G

FR

(m

l/min

/mon

th)

3 ye

ars

Ruggenenti et al., J Am Soc Neph, 2000

Tertiles Proteinuria

Residual proteinuria (6 months)