12th meeting of the Mediterranean
Group for the Study of Diabetes
Casablanca – 29 April 2011
Diabetes and Nephropathy: state of
the art
Michel MARRE
− Groupe Hospitalier Bichat – Claude Bernard
Assistance Publique – Hôpitaux de Paris
− INSERM U695 – Université Paris VII, Paris
Agenda:
• Pathophysiology
• Some differences between type 1 and type 2
diabetes
• Current treatment options
• Perspectives from experimental nephrology
• Sexual transmission of kidney disease
Agenda:
• Pathophysiology
• Some differences between type 1 and type 2
diabetes
• Current treatment options
• Perspectives from experimental nephrology
• Sexual transmission of kidney disease
Diabetic Nephropathy : definition
• a glomerular disease:
proteinuria ( albuminuria)
hypertension ( or a rise in blood pressure )
reduced glomerular filtration rate
• Attributable to diabetes:
by probability: diabetic retinopathy
by morphology: kidney biopsy
Diabetic Glomerulopathy
• PAS-positive Nodules
• ( Kimmelstiel et
Wilson,Am J
Pathol,1936;12:83-95)
• Electronic Microscopy:
Basement membrane
width/ mesangial
expansion
Correlation morphology-functional (M Mauer,
J Clin Invest, 1984)
Predicting Diabetic Nephropathy
in Insulin-Dependent Patients
C. E. Mogensen, and C. K. Christensen
N Engl J Med 1984; 311:89-93
Fig. 2: Glomerular Filtration Rate (GFR)
at initial examination in 24 patients, 6
with progression and 18 without
progression.
The patients with progression had
albumin excretion rates below 70 µg per
minute
Fig. 3: Log Urinary Albumin Excretion (UAE) plotted against
Glomerular Filtration Rate (GFR) in 39 patients.
Solid circles refer to the initial examination, and open circles refer to
the follow-up examination.
Abnormal glucose metabolism, hypoxia, and
vasodilatation
HIGH GLUCOSE
Hexosamines
PKC
Polyols
CAPILLARY VASOPLEGIA
CAPILLARY HYPERTENSION
AGE
Agenda:
• Pathophysiology
• Some differences between type 1 and type 2
diabetes
• Current treatment options
• Perspectives from experimental nephrology
• Sexual transmission of kidney disease
Pressure Dependency
• May be different in type 1 vs type 2 diabetes
Bijective relationship between High
Blood Pressure and High Urinary
Albumin
• KIDNEY CULPRIT :
• A glomerular disease,
signaled by high urinary
albumin, provokes high
blood pressure
• KIDNEY VICTIM :
• Essential hypertension
affects target organs :
• >Heart : LVH
• >Kidney : albuminuria
• Type 1 Diabetes
• Essential hypertension
Excrétion Urinaire d'Albumine ( mg / 24 h )
DID
HTA
3000
300
30
3
0
80
100
120
140
160
180
200
Pression Artérielle Systolique ( mm Hg )
220
Agenda:
• Pathophysiology
• Some differences between type 1 and type 2
diabetes
• Current treatment options
• Perspectives from experimental nephrology
• Sexual transmission of kidney disease
Treatment Interventions :
• Type of intervention :
 glycemia
 blood pressure ( +/- inhibition of the ReninAngiotensin-Aldosterone System )
• Time of intervention :
 primary (normoalbuminuria stage)
 secondary (microalbuminuria stage)
 tertiary (proteinuria stage)
Normoalbuminuria Stage
Diabetes
Intervention
Glycemia
Intervention BP
ACEI(Arbs)
Type 1
Type 2
YES
YES
(DCCT)
(UKPDS,
ADVANCE)
YES
NO
(EUCLID,
DIRECT, RAS
study)
(UKPDS,
ADVANCE)
DCCT primary prevention
Over a 6.5 year period, in T1D subjects aged
13-39 years at baseline, a 30-50 % relative
risk reduction to develop microalbuminuria
for a reduction of HbA1c from 9 to 7 %.
DCCT primary prevention
UKPDS : Microalbuminuria onset
Urine albumin >50 mg/L
Baseline
Three years
Six years
Nine years
Twelve years
Fifteen years
RR
p
0.5
0.89
0.83
0.88
0.76
0.67
0.70
0.24
0.043
0.13
0.00062
0.000054
0.033
<
Relative Risk
& 99% CI
1
2
Favours Favours
intensive conventional
Blood Pressure : Tight vs Less Tight Control
cohort, median values
180 Less tight control Tight control
mmHg
160
140
100
80
60
0
2
4
6
Years from randomisation
8
Microvascular endpoints
25%
% patients with event
Less Tight Blood Pressure Control (390)
Tight Blood Pressure Control (758)
20%
15%
10%
5%
risk reduction
37% p=0.0092
0%
0
3
6
Years from randomisation
9
UKPDS : ACEI vs -blocker
Retinopathy 2 step progression
median 1.5 years
median 4.5 years
median 7.5 years
Urine albumin > 50 mg/L
3 years
6 years
9 years
Urine albumin >300 mg/L
3 years
6 years
9 years
RR
p
0.99
0.99
0.91
0.75
0.82
0.28
1.11
0.93
1.20
0.55
0.65
0.31
1.41
0.75
0.48
0.44
0.43
0.090
Relative Risk & 99% CI
0.1
1
favours ACE favours Beta
inhibitor blocker
10
Excrétion Urinaire d'Albumine ( mg / 24 h )
DID
HTA
3000
300
30
3
0
80
100
120
140
160
180
200
Pression Artérielle Systolique ( mm Hg )
220
Microalbuminuria Stage
Diabetes
Type 1
Type 2
Type 2
No
Hypertension
YES?
No
Hypertension
YES
Hypertension
(STENO )
(UKPDS,
ADVANCE)
(UKPDS,
ADVANCE)
ACEIs/Arbs
YES
YES
YES
Non-ACEIs
NO
YES
YES
Intervention
Glycemia
YES
Intervention
Type 1, microalbuminuria, glycemia
Over 2 years, HbA1c < 7% stabilized
micoalbuminuria of T1D subjects, but no
regression was observed.
Bo Feldt-Rassmussen et al,
The Lancet,1986
Long-term Renal Outcomes of Patients With
Type 1 Diabetes Mellitus and Microalbuminuria
An Analysis of the Diabetes Control and Complications
Trial/Epidemiology
of Diabetes Interventions and Complications Cohort
Ian H. de Boer, MD, MS; Tessa C. Rue, MS; Patricia A. Cleary, MS; John M.
Lachin, ScD; Mark E. Molitch, MD; Michael W. Steffes, MD, PhD; Wanjie
Sun, MS; Bernard Zinman, MDCM; John D. Brunzell, MD; for the Diabetes
Control and Complications Trial/Epidemiology of Diabetes Interventions
and Complications Study Research Group
Arch Intern Med. 2011;171(5):412-420
Figure 1. Cumulative incidence of persistent microalbuminuria in the
Diabetes Control and Complications Trial/Epidemiology of Diabetes
Interventions and Complications study by duration of type 1 diabetes
and by Diabetes Control and Complications Trial treatment assignment.
Figure 4. Cumulative incidence of long-term renal outcomes after the development of
persistent microalbuminuria (time 0) among 325 participants in the Diabetes Control
and Complications Trial/Epidemiology of Diabetes Interventions and Complications
study by Diabetes Control and Complications Trial treatment assignment. A,
Regression to normoalbuminuria. B, Progression to macroalbuminuria. C, Impaired
glomerular filtration rate (GFR). D, End-stage renal disease (ESRD).
Type 1 Diabetes, microalbuminuria, and
ACEI

Micro
Macroalbuminuria
RRR  70 % after 2 years

Regression Micro- to Normoalbuminuria
RRR  50 % after 2 years
 The ACE Inhibitors in Diabetic Nephropathy Trialist
Group: Should all type 1 diabetic patients with
microalbuminuria receive ACE inhibitors? A metaregression analysis.
Ann Intern Med 2001, 134: 370-379
Question:
Does amelioration in function translate in
improvement in structure within the Glomeruli?
ACE inhibition and changes in
Structure/Function in type 1 diabetes:
• Rudberg S, Osterby R, Bangstad HJ,
Dahlquist G, Persson B : Effect of
Angiotensin Converting Enzyme Inhibitor or
Beta Blocker on Glomerular Structural
Changes in young Microalbuminuric Patients
with type1 (insulin-dependent) Diabetes
Mellitus, Diabetologia, 1999 ; 42 : 589-595
Type 2 Diabetes, microalbuminuria,
no Hypertension, and ACEI
Over 7 years, enalapril 10 mg daily vs
placebo ->50 % RRR of doubling doubling
plasma creatinine.
M. Ravid et coll, Arch Int Med, 1996
Type 2 Diabetes, microalbuminuria,
Hypertension, and ACEI
Still controversial; let’s look at UKPDS
Any diabetes related endpoint
Diabetes related deaths
All cause mortality
RR
p 0.5
1.10 0.43
1.27 0.28
1.14 0.44
Myocardial infarction
Stroke
Microvascular
1.20 0.35
1.12 0.74
1.29 0.30
Relative Risk
& 95% CI
1
2
>
>
Favours Favours
ACE inhibitor Beta blocker
Joint effects of blood pressure lowering
and intensive glucose control
New or worsening
nephropathy
Hazard ratios
Favours
Per-Ind
BP arm
Annual event rate %
Favours
Placebo
Relative risk
reduction (95% CI)
18% (-1 to 32)
All participants
Standard
18% (-7 to 37)
Intensive
17% (-12 to 38)
0.5
1.0
1.2
1.02
1.0
2.0
Hazard ratio
RRR 33%, P=0.005
0.8
Favours Favours
Intensive Standard
Glucose arm
Relative risk
reduction (95% CI)
19%
All participants
(2 to 34)
Placebo
20% (-4 to 39)
Per-Ind
18% (-9 to 39)
0.5
1.0
Hazard ratio
2.0
0.82
0.84
0.6
Standard
0.68
Intensive
Placebo
Per-Ind
P for interaction=0.93
Microalbuminuria in Type II Diabetes with
Hypertension
PREVENTION of PROTEINURIA
- ACEI (ramipril) : Micro-HOPE, GERSTEIN et al,
Lancet 2000
- AT1R antagonist (irbesartan) : IRMA,
PARVING et al, NEJM 2001, 345: 870-878
The matter of the dose
Parving HH et al. NEJM, 345, 12: 870-8
Proteinuria Stage
Diabetes
Type 1
Type 2
Glycemia
NO
YES
Intervention
YES
YES
ACEIs-Arbs
Lewis 1993
Lewis, Brenner, 2001
Intervention
Proteinuria, Type 1 Diabetes, and ACEI
•
Subjects with Type 1 Diabetes and Proteinuria, Captopril vs
Placebo:
RRR  50 % for doubling of serum creatinine, ESRD,
and/or death
•
Ed. LEWIS et coll, NEJM, 1993
•
A confirmation of Björk et al study comparing enalapril to
metoprolol (BMJ, 1992)
Proteinuria, Type II Diabetes, and Arbs
- Irbesartan vs placebo :
20 % RRR
vs amlodipine : 23 % RRR
(E. LEWIS et coll, NEJM, 2001, 345: 851-860)
- Losartan vs placebo :
16 % RRR
( B.M. BRENNER et coll, NJM, 2001, 345: 861-869)
Lewis EJ et al. NEJM, 2001, 345: 851-860
Brenner BM et al. NEJM, 3001, 345: 861-869
Brenner BM et al. NEJM, 3001, 345: 861-869
Association between urinary albumin exretion and
cardiovascular risk in diabetes
CV Risk
X 10
Renal
Insufficiency
X5
Proteinuria
X2
Microalbuminuria
0
2
diagnostic du
diabète
5
10
20
30
Years
Risk of CV death by albuminuria at baseline and achieved
during follow-up in ADVANCE
At baseline
Hazard ratio (95% CI)
Normo
During follow-up
Micro
Normo
Macro
Micro
Macro
5.0
4.0
3.0
2.0
p for trend <0.0001*
p for trend <0.0001*
1.0
0.7
3
30
300
Baseline UACR (μg/mg)
3
30
300
Achieved UACR (μg/mg)
*Adjusted for age, sex, HbA1c, serum lipids, BMI,
smoking, alcohol use, and study drug
Left ventricular mass regression (SECURE)
732 randomised patients. Follow-up : 1.5-2.2 years
10
8
6
4
2
8.21%
7.86%
Placebo
Ramipril 2.5mg
Ramipril 10mg
p=0.039
0
-2
-4
-6
-3.53%
Ramipril 2.5mg : no effect on left ventricular mass ;
no effect on atherosclerosis progression
CONCLUSION
• HIGH DOSES of ACEIs or Arbs are necessary to
reduce CV Risk in Diabetic subjects
• Dissociation of the renal vs CV effects?
Diabetic Nephropathy:
The scenario has been transformed
by interventions over the past
decades
Microalbuminuria in type 1
Diabetes:
From the 1980’s to the 2000’s
Predicting Diabetic Nephropathy
in Insulin-Dependent Patients
C. E. Mogensen, and C. K. Christensen
N Engl J Med 1984; 311:89-93
Fig. 1: Urinary Albumin Excretion during Initial and Follow-up Studies
in 43 Male Diabetics Reexamined after 7 to 14 Years.
The mean follow-up period ( S.D) was 10.4  3 years
Long-term Renal Outcomes of Patients With
Type 1 Diabetes Mellitus and Microalbuminuria
An Analysis of the Diabetes Control and Complications
Trial/Epidemiology
of Diabetes Interventions and Complications Cohort
Ian H. de Boer, MD, MS; Tessa C. Rue, MS; Patricia A. Cleary, MS; John M.
Lachin, ScD; Mark E. Molitch, MD; Michael W. Steffes, MD, PhD; Wanjie
Sun, MS; Bernard Zinman, MDCM; John D. Brunzell, MD; for the Diabetes
Control and Complications Trial/Epidemiology of Diabetes Interventions
and Complications Study Research Group
Arch Intern Med. 2011;171(5):412-420
Figure 3. Prevalence of normoalbuminuria, microalbuminuria, and
macroalbuminuria by time following the diagnosis of incident persistent
microalbuminuria (time 0) among 325 participants in the Diabetes
Control and Complications Trial/Epidemiology of Diabetes Interventions
and Complications study. Ellipsis indicates not applicable; RAAS, reninangiotensin-aldosterone system.
Proteinuria in type 1 Diabetes:
From the 1980’s to the 2000’s
Effect of antihypertensive treatment on kidney function
in diabetic nephropathy
HANS-HENRIK PARVING, ALLAN R ANDERSEN, ULLA M SMIDT,
EVA HOMMEL, ELISABETH R MATHIESEN, PER A SVENDSEN
BMJ, 1987, Jun 6;294(6585):1443-7
FIG 1-Average course of mean arterial blood pressure,
glomerular filtration rate, and albuminuria before (0)
and during (0) long term effective antihypertensive
treatment of nine insulin dependent diabetic patients
who had nephropathy.
FIG 2-Individual courses of glomerular filtration
rate before (0) and during (0) antihypertensive
treatment. *Patient in case 4 died from acute
myocardial infarction, and patient in case 11 was
insufficiently treated.
Figure 2. Cumulative incidence of long-term renal outcomes after the
development of persistent microalbuminuria (time 0) among 325
participants in the Diabetes Control and Complications
Trial/Epidemiology of Diabetes Interventions and Complications study.
ESRD indicates end-stage renal disease; GFR, glomerular filtration rate.
Figure 4. Cumulative incidence of long-term renal outcomes after the development of
persistent microalbuminuria (time 0) among 325 participants in the Diabetes Control
and Complications Trial/Epidemiology of Diabetes Interventions and Complications
study by Diabetes Control and Complications Trial treatment assignment. A,
Regression to normoalbuminuria. B, Progression to macroalbuminuria. C, Impaired
glomerular filtration rate (GFR). D, End-stage renal disease (ESRD).
Microalbuminuria in type 2
Diabetes:
From the 1980’s to the 2000’s
Microalbuminuria predicts clinical proteinuria
and early mortality in maturity-onset diabetes
Mogensen CE
N Engl J Med. 1984 Feb 9;310(6):356-60.
Table 2: Numbers of patients with and without
clinical proteinuria during observation period.
Table 3: Numbers of patients alive in 1983, according to
albumin concentration and duration of diabetes.
Table 5: Causes of death in study subjects, 1973 to 1983,
expressed as percentages.
Risk of CV death by albuminuria at baseline and achieved
during follow-up in ADVANCE
At baseline
Hazard ratio (95% CI)
Normo
During follow-up
Micro
Normo
Macro
Micro
Macro
5.0
4.0
3.0
2.0
p for trend <0.0001*
p for trend <0.0001*
1.0
0.7
3
30
300
Baseline UACR (μg/mg)
3
30
300
Achieved UACR (μg/mg)
*Adjusted for age, sex, HbA1c, serum lipids, BMI,
smoking, alcohol use, and study drug
Agenda:
• Pathophysiology
• Some differences between type 1 and type 2
diabetes
• Current treatment options
• Perspectives from experimental nephrology
• Sexual transmission of kidney disease
Abnormal glucose metabolism, hypoxia, and
vasodilatation
HIGH GLUCOSE
Hexosamines
PKC
Polyols
CAPILLARY VASOPLEGIA
CAPILLARY HYPERTENSION
AGE
Blocking the abnormal glucose
metabolism in target organs of
microangiopathy, including kidney
•
•
•
•
Blocking AGE formation/RAGE action
Blocking Polyol Pathway
Blocking PKC subtypes
Blocking TGF beta
• ...excellent demonstrations in animal models;
no clinical translation
What’s New with Blockade of
the RAAS?
ALISKIREN: let’s wait and see…
Potential mechanisms
of ACE inhibition
Angiotensin I
Bradykinin
ACE/
Kininase II
Angiotensin II
Degradation
products
ACE Inhibitor
Angiotensin II
Bradykinin
B2 receptor
Microcirculation:
flow, pressure,
inflammation, sclerosis
B1 receptor
Nitric oxide
Henriksen EJ et al. J Cell Physiol. 2003;196:171-9.
Kallikrein protects against microalbuminuria
in experimental type 1diabetes
Bodin S, Chollet C, Goncalves-Mendes N, Gardes J, Pean F,
Heudes D, Bruneval P, Marre M, Alhenc-Gelas F, Bouby N
Kidney Int, 2009, 76: 395-403
Albumin excretion in Kallikrein-null
streptozotocin-induced diabetic mice
Histopathology of kidneys in 12-month-old male WT, B2R-null, BRKO, Akita, B2R-null-Akita, and
BRKO-Akita mice.
Kakoki M et al. PNAS 2010;107:10190-10195
©2010 by National Academy of Sciences
Agenda:
• Pathophysiology
• Some differences between type 1 and type 2
diabetes
• Current treatment options
• Perspectives from experimental nephrology
• Sexual transmission of kidney disease
Fetal exposure to maternal type 1
diabetes is associated with renal
dysfunction at adult age
C Abi-Khalil, F Travert, S Fetita, F Rouzet, R Porcher, JP
Riveline, S Hadjadj, E Larger, R Roussel, P Vexiau, D Le
Guludec, JF Gautier, M Marre
Diabetes, 59 2631 2636 2010
Introduction
• A reduced number of nephrons may cause
hypertension and cardio-renal risk in general
population (Brenner et al. Kidney Int. 1983, Keller et
al N Engl J Med 2008)
Moderate hyperglycemia reduces global angiogenesis in
an experimental model of chicken chorioallantoid
membrane (Larger et al. Diabetes 2004)
Rats exposed to hyperglycemia during their fetal
development have a reduced number of nephrons,, an
altered nephrogenesis and a predisposition to
hypertension later in adulthood (Amri et al. Diabetes
1999 and 2001;Nehiri et al. Diabetes 2008)
Aim of the work
• To investigate whether intra-uterine exposure to
hyperglycemia during fetal development in
humans influenced renal function during
adulthood:
• To study renal vasculature in Offspring of Type 1 Diabetic
Mothers (OT1DM) vs Controls: Offspring of Type 1
Diabetic Fathers (OT1DF)
• Renal Functional Reserve (RFR): Glomerular Filtration
Rate (GFR) and Effective Renal Plasma Flow (ERPF)
before and after intravenous Amino Acid (AA) infusion
Study design
Bolus, then continuous I.V. infusion of 123I-Hippurate and
51Cr-EDTA
A.A. (5 mg/kg/min)
S1
S2
S3
S4
S5
S6
plasma
T
0
30
60
75
90
105
120
135
150
165
180
195
210 (min)
urine
Urine
1
Urine
2
 Basal:
Urine
3
mean of 2nd and 3rd periods
Stimulated: mean of 5th and 6th periods
 RFR = (Stimulated-Basal) / Basal
Urine
4
Urine
5
Urine
6
GFR changes
Offspring of fathers
150
150
125
125
GFR (mL/min)
GFR (mL/min)
Offspring of mothers
100
100
75
75
50
50
Basal
Stimulated
Relative changes: +8(13), p= 0.019
Basal
Stimulated
Relative changes: +19(17), p= 0.002
Inter-group changes p= 0.009
Summary and conclusion
• Reduced renal functional reserve in offspring
of TID mothers
• The present data may be the expression of a
reduced number of nephrons due to the
impact of moderate hyperglycemia on
angiogenesis during foetal development
Thank You for Your Attention!