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Sheffield Kidney Institute
Diabetic Kidney Disease: Update
GKA Master Class
Istanbul 2011
Sheffield Kidney Institute
DKD: Challenging dogmas
Sheffield Kidney Institute
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
Sheffield Kidney Institute
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?
Sheffield Kidney Institute
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?
Sheffield Kidney Institute
Diabetic Nephropathy
• Microvascular
Disease
• Macrovascular
disease
Sheffield Kidney Institute
Diabetic Nephropathy Microvascular
(Hyperperfusion/Hyperfiltration)
• Other microvascular
manifestations• Onset:
– Microalbuminuria– Overt Proteinuria/Albuminuria
• Declining kidney function (CKD)
• ESRD
Sheffield Kidney Institute
Afferent arteriolar vasoconstriction
Afferent arteriolar vasodilatation
Angiotensin
II
Hyperglycemia
Sheffield Kidney Institute
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)
Sheffield Kidney Institute
Diabetic Nephropathy Macrovascular
Ischemic Disease
• Systemic Systolic Hypertension• CAD• PVD• NO / LITTLE PROTEINURIA• CKD• Declining Kidney Function
Sheffield Kidney InstituteEl Nahas, KI 2010
Sheffield Kidney Institute
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
Sheffield Kidney Institute
Microvascular Macrovascular
Diabetic Kidney Disease
AGE
Sheffield Kidney Institute
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
Sheffield Kidney Institute
Conceptual Model for DKD
CKD death CKDCKD deathdeath
ComplicationsComplicationsComplications
MICROALBUMINURIAMICROALBUMINURIA
NormalNormalNormal Increased risk
IncreasedIncreased riskrisk
Kidney failure KidneyKidney failurefailure
DamageMA
DamageDamageMAMA
GFR
GFRGFR
Sheffield Kidney Institute
Diabetic Nephropathy
• Microvascular
Disease
• Macrovascular
disease
Sheffield Kidney Institute
Steno Hypothesis
Deckert
et al. 1989
Sheffield Kidney Institute Minamino
and Komuro, 2008
Albumin
Sheffield Kidney Institute
CKD
Albuminuria
Sheffield Kidney InstituteEl Nahas, KI 2010
Sheffield Kidney Institute
Sheffield Kidney Institute
Sheffield Kidney Institute
MA Regression
BSBP
BLip
Sheffield Kidney Institute
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
Sheffield Kidney Institute
DCCT
Sheffield Kidney Institute
ACCORD
Ismail-Beigi
et al, 2010
Sheffield Kidney Institute
Sheffield Kidney Institute
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
Sheffield Kidney InstituteLewis et al 1993
Sheffield Kidney Institute
Sheffield Kidney Institute
Management of Diabetic Microvascular
Disease
Key Elements
RAASInhibition
No Smoking Lipids Control
Sheffield Kidney Institute
Afferent arteriolar vasoconstriction
Afferent arteriolar vasodilatation
Angiotensin
II
Hyperglycemia
Sheffield Kidney Institute
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
Sheffield Kidney Institute
Sheffield Kidney Institute
Sheffield Kidney Institute
Management of Diabetic Macrovascular
Disease
Key Elements
AVOIDRAAS
Inhibition!!!!
No Smoking Lipids Control
Sheffield Kidney Institute
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 Institute
Sheffield Kidney Institute
Sheffield Kidney Institute
ACEi
in Long Term DN
Suissa
et al, 2006
Sheffield Kidney Institute
ONTARGET
Mann et al, 2008
Sheffield Kidney Institute
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 InstituteEl Nahas, KI 2010
Sheffield Kidney Institute
Sheffield Kidney Institute
Sheffield Kidney Institute
Sheffield Kidney Institute Gaede
et al, 2008
STENO 2Intensive Multi-Factorial Intervention
Sheffield Kidney Institute Gaede
et al, 2008
Intensive Multi-Factorial Intervention
Sheffield Kidney Institute
Intensive Multi-Factorial Intervention
Gaede
et al, 2008
Sheffield Kidney Institute
Intensive Multi-Factorial Intervention
Gaede
et al, 2008
Sheffield Kidney Institute
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
Sheffield Kidney Institute
DKD
New Therapies
Sheffield Kidney Institute
• 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
Sheffield Kidney Institute
Sheffield Kidney Institute
Sheffield Kidney Institute
ASCEND
Mann et al, 2010
Sheffield Kidney Institute JASN,2011
Sheffield Kidney Institute
Sheffield Kidney Institute
Sheffield Kidney Institute
Sheffield Kidney Institute
VITAL
De Zeeuw
et al, 2010
Sheffield Kidney Institute
Sheffield Kidney Institute April 2011
Sheffield Kidney Institute
Sheffield Kidney Institute
• 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
Sheffield Kidney Institute
DKD: Challenging dogmas