Diabetic Kidney Disease: Update GKA Master Class Istanbul 2011 · Type 1 and Type 2 DN have the...

Sheffield Kidney Institute

Diabetic Kidney Disease: Update

GKA Master Class

Istanbul 2011


DKD: Challenging dogmas


Old Dogmas

• Type 1 and Type 2 DN have the same natural history

• Microalbuminuria

is an early stage of DN

• Tight Glycemia

control delays ESRD

• ACEi/ARBs

are the treatment of choice for all diabetics with kidney disease


Case study 1

• 42 year old with history of type1 DM• BP: 142/96mmHg• Serum Creatinine

210umol/l

• eGFR

= 32ml/min• Proteinuria

2.9g/24h

• PCR = 290mg/mmol • ACR = 200mg/mmol

• What is the treatment of choice?


Case study 2• 76 year old man• Hypertension for 18 years• Known IHD and intermittent claudication• Type 2 DM since 2003• BP: 178/86mmHg• Serum Creatinine

210umol/l

• eGFR

= 32ml/min• Proteinuria: 0.8g/24h• PCR: 80mg/mmol• ACR: 60mg/mmol

• What is the treatment of choice?


Diabetic Nephropathy

• Microvascular

Disease

• Macrovascular

disease


Diabetic Nephropathy Microvascular

(Hyperperfusion/Hyperfiltration)

• Other microvascular

manifestations• Onset:

– Microalbuminuria– Overt Proteinuria/Albuminuria

• Declining kidney function (CKD)

• ESRD


Afferent arteriolar vasoconstriction

Afferent arteriolar vasodilatation

Angiotensin

II

Hyperglycemia


0

20

40

60

80

100

120

140

160

0 5 10 15 20 25 300

2

4

6

8

10

12

14

16

Course of Diabetic Nephropathy Natural History

ProteinuriaGFR

Clinically silent Clinically manifest

Cre

atin

ine

clea

ranc

e (m

L/m

in)

Microalbuminuria

Prot

einu

ria(g

/24

h)

Duration of diabetes (years)


Diabetic Nephropathy Macrovascular

Ischemic Disease

• Systemic Systolic Hypertension• CAD• PVD• NO / LITTLE PROTEINURIA• CKD• Declining Kidney Function

Sheffield Kidney InstituteEl Nahas, KI 2010


0

20

40

60

80

100

120

140

160

0 5 10 15 20 25 300

2

4

6

8

10

12

14

16

Course of Diabetic Nephropathy Natural History

GFR

Clinically silent Clinically manifest

Cre

atin

ine

clea

ranc

e (m

L/m

in)

Microalbuminuria

Prot

einu

ria(g

/24

h)

Duration of diabetes (years)

Microalbuminuria

Albuminuria


Microvascular Macrovascular

Diabetic Kidney Disease

AGE


Old Dogmas




• Tight Glycemia

control delays ESRD

• ACEi/ARBs



Conceptual Model for DKD

CKD death CKDCKD deathdeath

ComplicationsComplicationsComplications

MICROALBUMINURIAMICROALBUMINURIA

NormalNormalNormal Increased risk

IncreasedIncreased riskrisk

Kidney failure KidneyKidney failurefailure

DamageMA

DamageDamageMAMA

GFR

GFRGFR


Diabetic Nephropathy

• Microvascular

Disease

• Macrovascular

disease


Steno Hypothesis

Deckert

et al. 1989

Sheffield Kidney Institute Minamino

and Komuro, 2008

Albumin


CKD

Albuminuria





MA Regression

BSBP

BLip


Old Dogmas




• Tight Glycemia

control delays ESRD

• ACEi/ARBs



DCCT


ACCORD

Ismail-Beigi

et al, 2010



Old Dogmas




• Tight Glycemia

control delays ESRD

• ACEi/ARBs


Sheffield Kidney InstituteLewis et al 1993



Management of Diabetic Microvascular

Disease

Key Elements

RAASInhibition

No Smoking Lipids Control


Afferent arteriolar vasoconstriction

Afferent arteriolar vasodilatation

Angiotensin

II

Hyperglycemia


CKD management guidelinesParameter Target Agent used

BP 130/80 mmHg or 125/75 in DM and those with proteinuria.

Start with ACEI or ARBs if proteinuria or DM microalbuminuria –

caution in the elderly and those with atherosclerosis. Monitor eGFR within 1-2 weeks of initiation, review if eGFR decreases by ≥15%, stop at ≥25%.

Proteinuria Lowest achievable ACEi/ ARBs

sCholesterol Refer to national guidelines

Lifestyle Standard CV risk reduction measures, including salt restriction

Avoid NSAIDs, COX2s and radiocontrast agents

Sheffield Kidney InstituteJASN, 2011




Management of Diabetic Macrovascular

Disease

Key Elements

AVOIDRAAS

Inhibition!!!!

No Smoking Lipids Control


CKD management guidelinesParameter Target Agent used

BP 130/80 mmHg or 125/75 in DM and those with proteinuria.

Start with ACEI or ARBs if proteinuria or DM microalbuminuria –

caution in the elderly and those with atherosclerosis. Monitor eGFR within 1-2 weeks of initiation, review if eGFR decreases by ≥15%, stop at ≥25%.

Proteinuria Lowest achievable ACEi/ ARBs

sCholesterol Refer to national guidelines

Lifestyle Standard CV risk reduction measures, including salt restriction

Avoid NSAIDs, COX2s and radiocontrast agents




ACEi

in Long Term DN

Suissa

et al, 2006


ONTARGET

Mann et al, 2008


Conceptual Model for CKD

CKD death CKDCKD deathdeath

ComplicationsComplicationsComplications

Screening Screening for CKDfor CKD

risk factors:risk factors:diabetesdiabetes

hypertensionhypertensionage >60age >60

family historyfamily historyUS ethnic US ethnic minoritiesminorities

CKD riskCKD risk reduction;reduction;

Screening forScreening for CKDCKD

DiagnosisDiagnosis & treatment;& treatment;

Treat Treat comorbidcomorbid

conditions;conditions; Slow Slow

progressionprogression

EstimateEstimate progression;progression;

TreatTreat complications;complications;

Prepare forPrepare for replacementreplacement

ReplacementReplacement by dialysisby dialysis

& transplant& transplant

NormalNormalNormal Increased risk

IncreasedIncreased riskrisk

Kidney failure KidneyKidney failurefailureDamageDamageDamage

GFR

GFRGFR

Sheffield Kidney InstituteAhmed, A. K. et al, 2011

Changes in eGFR

after stopping ACEi/ARB in patients with advanced CKD





Sheffield Kidney Institute Gaede

et al, 2008

STENO 2Intensive Multi-Factorial Intervention

Sheffield Kidney Institute Gaede

et al, 2008

Intensive Multi-Factorial Intervention



Gaede

et al, 2008



Gaede

et al, 2008


Old Dogmas




• Tight Glycemia

control delays ESRD

• ACEi/ARBs



DKD

New Therapies


• Vasoactive

substances– Renin

antagonsist

DN

– Endothelin

antagonists

DN• Growth Factors/Hormones antagonists:

– TGF-1:

Neutralising antibodies, DN

– GH:

Antagonist/Somatostatin

DN• Signal Transduction manipulations:

– PKC:

Ruboxistaurin

DN– PPAR

agonists

Glitazones

DN

• ECM Modulators:– Heparinoids:Sulodexide

DN

– LMW heparin

DN– MMP inhibitors

XL784

DN

• Anti-Fibrotics

(miscellaneous):– Pirfenidone

DN




ASCEND

Mann et al, 2010

Sheffield Kidney Institute JASN,2011





VITAL

De Zeeuw

et al, 2010


Sheffield Kidney Institute April 2011



• Vasoactive

substances– Renin

antagonsist

DN

– Endothelin

antagonists

DN• Growth Factors/Hormones antagonists:

– TGF-1:

Neutralising antibodies, DN

– GH:

Antagonist/Somatostatin

DN• Signal Transduction manipulations:

– PKC:

Ruboxistaurin

DN– PPAR

agonists

Glitazones

DN

• ECM Modulators:– Heparinoids:Sulodexide

DN

– LMW heparin

DN– MMP inhibitors

XL784

DN

• Anti-Fibrotics

(miscellaneous):– Pirfenidone

DN


DKD: Challenging dogmas

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Diabetic Kidney Disease: Update GKA Master Class Istanbul 2011 · Type 1 and Type 2 DN have the...

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