DIABETIC NEPHROPATHY
MAY 2013
DR RAMESH B NAIK FRCP
Causes of ESRF in Patient Starting
Dialysis
UK (%)
Diabetes
Glomerulonephritis
30
12
Pyelonephritis
Polycystic Kidney Disease
9
10
Hypertension
Renovascular disease
Uncertain
Others
8
6
17
8
Acceptance Rates for RRT
• 100-120 pmp/yr in UK
• USA – Whites 185 pmp/yr
Blacks 758 pmp/yr
Total – 242 pmp/yr
Berkshire is 114 but Slough is 143 pmp/yr
Age
• 1982 11% over 65 years old
• Now 50% - will be more
• Liberalisation of attitudes
PREVALENCE OF DIABETES
Percentages
All ethnic minorities
5.6
Caribbean
5.9
All South Asians
5.9
Indian
5.5
African Asian
4.0
Pakistani
7.6
Bangladeshi
7.4
Chinese
2.2
White
2.2
Diabetic Renal Failure - Incidence
•
•
Commonest cause of ESRF & rising
Major implications for dialysis programmes
Europe
•
•
USA
1976
3%
1985
11%
1992
17%
1993
22%
36%
2004
25-30%
40-45%
1985 60% type I
1993 60% type II
23%
Diabetic RF - Pathology
Four Stages:•
•
•
•
Hypertrophy / hyperfiltration
Microalbuminuria
Diabetic glomerulosclerosis
ESRF
Microalbuminuria in Guidelines
Existing UK guidance
• Joint British Societies 2 Guidelines
(2005)
Recognise MAU, proteinuria and CKD as
TOD
CKD defined by eGFR levels
Patients with raised blood pressure and
TOD should be considered high risk and be
managed accordingly
Diabetes and TOD – BP target 130/80 mm
Hg
What is Microalbuminuria?
Definitions and prevalence
• Levels of urinary albumin above the normal
range, but lower than dipstick-positive proteinuria
below are termed microalbuminuria
• Microalbuminuria is found in:
• 5-7% of the ‘healthy’ population
• 12-30% of the hypertensive population
Morning urine
sample (mg/l)
Morning urine sample – Albumin
to Creatinine Ratio (mg/mmol)
<20
Males <2.5 Females <3.5
Microalbuminuria
20-200
Males 2.5-25 Females 3.5-25
Macroalbuminuria
(proteinuria)
>200
Males >25 Females >25
Normal
Microalbuminuria: both risk marker
and independent risk factor
Presence of Microalbuminuria
Increased Risk of
Renal Complications
Increased Risk of
New Onset Diabetes
Increased Risk of
Cardiovascular
Events
GUIDELINES FOR DIABETIC RENAL
DISEASE
Persistent Microalbuminuria earliest marker of
diabetic nephropathy
 Associated with increased risk of
 Retinopathy
 Cardiovascular disease
 Reversible in up to 50% if treated early
ANNUAL PROTEIN DIPSTICK
If negative, EMU for ACR
If ACR positive, repeat 2x within 12 weeks
If negative, repeat annually
If positive dipstick proteinuria, or positive
ACR
WE MUST DO SOMETHING
WHAT DO WE DO
 All patients (regardless of BP)
 Add ACEI/ARB (Check Renal Function)
 To maximum dose
 Lifestyle modification
 Diet (Dietician)
 Exercise
 Smoking cessation
 Glycaemic control ( HbA1C <7% )
 BP 130/80 (or 125/75 if proteinuria >1gm)
Which drugs ( CaCB Diuretics BB )


Aspirin. Statin
Metformin. Fibrates ( Avoid or Stop )
Renal Clinic
 Urine protein >1gm/24 hrs
 Creatinine >150mmol//litre
 Diagnostic uncertainty
Diabetes Clinic
 Difficulty achieving BP or HbA1C
 Persistent dyslipidaemia
DIABETIC NEPHROPATHY
•
•
•
•
•
DM more common in Europe and North America
Long induction of 20-30 years from onset DM to RF
Increased prevalence DM not impacted on numbers.
Tidal wave yet to come!
Lifestyle of increasing inactivity and high calorie
intake favours development of T2DM in genetically
susceptible individuals
• Ageing population has exposed more individuals to
risk, decreasing mortality from CV causes means
more survive to get ESRF
Genetic Factors are Important
• Some Ethnic groups have higher incidence of
DM and diabetic nephropathy
• AA and native Americans in USA, A-C in
Caribbean and UK, South Asians worldwide,
every Polynesian population
• Higher incidence of older people in some
regions of Germany e.g. in lower Neckar
region 50% of dialysis population
ESRD IN DIABETES[2009]
A. New pts with DM developing ESRD 44% in USA and
25% in UK
B. Incident no. of patients in USA 355 pmp cf 110pmp in
UK
C. No. of prevalent patients rising. 572000 on ESRD RX
[half DM] in USA; 50000 in UK [17.5% DM]
D. Survival with ESRD and DM at 1 yr on dialysis
2002 76%
2009 84%
DIABETIC NEPHROPATHY
OBESITY, DM AND THE KIDNEY
Natural History of Type 2
Diabetic Nephropathy
Clinical type 2 diabetes
Functional changes*
Structural changes†
Rising blood pressure
Microalbuminuria
Proteinuria
Rising serum
creatinine levels
End-stage
renal disease
Cardiovascular death
Onset of diabetes
2
5
10
Years
* Renal haemodynamics altered, glomerular hyperfiltration
† Glomerular basement membrane thickening , mesangial expansion , microvascular changes +/-
20
30
Prevalence of Diabetes amongst ESRF
• UK Renal Registry report 2004
Comorbidity at start of RRT
% incidence
Cardiovascular disease
24.7
Cerebrovascular disease
11.7
Peripheral vascular disease 14.2
Diabetes (not cause of ESRF) 7.4
Diabetic nephropathy
18.8
Diabetes (either category)
26.1
No comorbidity
38.7
Mortality in Diabetic ESRF
• 5 year survival on dialysis 20%
• 5 year survival on transplantation 75-80%
• Causes of death
• CVS disease 50%
• Infection 15-20%
• Withdrawal from dialysis 20%
• Mailloux et al.JASN 1993;3(9)
 65% of patients were >61 years at start of dialysis
 50% of patients had diabetes and/or renovascular
disease
Mortality in Diabetic ESRF
• Joanna Johnson et al.NDT
1999;14:2156-64
• Quantitative metaanalysis
• RR of death in dialysis patients
•
•
•
•
1.029 with each year of increasing age
1.59 with cardiovascular disease
1.58 with peripheral vascular disease
1.91 with diabetes
• UK Registry report 2004 –RR of death
at 1year was 1.65 with diabetes
Epidemiology of Cardiovascular Disease in
Haemodialysis
Patients
100
10
1
0.1
0.01
25-34
35-44
45-54
55-64
65-74
75-84
>85
Age (years)
Dialysis M
Dialysis F
Healthy M
Healthy F
Foley AJKD 1998;32:S112-9
WET GANGRENE
Distal Calcific Uremic Aeteriolopathy (CUA)
2/24/00
3/9/00
Anterior Leg (SHIN)
3/24/00
CVD Mortality by Urinary Protein
Excretion in Type 2 Diabetes
A: U-Prot <150 mg/L
B: U-Prot 150–300 mg/L
C: U-Prot >300 mg/L
1.0
Survival
curves for
CVD
mortality
0.9
A
0.8
B
0.7
0.6
0.5
0
U-Prot = urinary protein concentration
C
Overall: p<0.001
0 10 20 30 40 50 60 70 80 90
Months
Miettinen H et al. Stroke. 1996; 27: 2033–2039.
Valsartan lowers AER in type 2 diabetic
patients with microalbuminuria
65
Mean AER
(g/min)
55
45
35
25
Percent change
of AER (%)
Valsartan
Amlodipine
20
10
0
-10
-20
-30
-40
-50
p<0.001 (changes
in logged UEAR from
baseline at week 24)
9
8.8
HbA1c (%)
8.6
8.4
8.2
8
0
4
8
12
time (wks)
18
24
IRMA 2
Normalisation of Urinary Albumin Excretion
Rate at 2 years (<20 g/min)
45
p=0.006
40
35
Subjects
(%)
34
30
25
20
21
24
15
10
5
0
Control
(n=201)
150 mg
(n=195)
300 mg
(n=194)
Irbesartan
30
Parving H-H, et al. N Engl J Med 2001; 345(12): 870-878.
IRMA 2 Primary Endpoint
Development of Diabetic Nephropathy
18
16
14
14.9
Subjects 12
(%)
10
RRR=70%
p<0.001
RRR=39%
p=0.08
9.7
8
6
5.2
4
2
0
Control
(n=201)
150 mg
(n=195)
300 mg
(n=194)
Irbesartan
31
Parving H-H, et al. N Engl J Med 2001; 345(12): 870-878.
IDNT: Time to Doubling of SeCr
70
Irbesartan (n=579)
RRR=37%
P<.001 RRR=33%
Amlodipine (n=567)
P=.003
P=NS
Control (n=569)
60
Patients (%)
50
40
30
20
10
0
0
6
12
18
24
30
36
Follow-up (months)
42
48
54
Control defined as placebo
SeCr, serum creatinine; RRR, relative risk reduction
Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.
Summary
• Diabetic Nephropathy accounts for
significant proportion of ESRF
• Increasing number of sick older
diabetics
• Mortality higher compared to non
diabetics
• Early intervention important to reduce
complications associated with disease
Dialysis related problems
• Difficult vascular access
• Haemodynamic instability due to autonomic
neuropathy
• Increased infection
• Unpredictable blood sugars
•
•
•
•
•
Increased insulin sensitivity
Increased insulin degradation
Increased insulin secretion
Decreased clearance of oral hypoglycemics
Hyperglycemia from PD dialysate( 83 mmol/L in
1.36%)
• Weight gain on PD
Prevalence of Diabetes amongst ESRF
• Proportion of diabetics amongst ESRF
 US 45%
 Germany 36 %
 Australia 22%
• Increasing proportion of Type 2Diabetes entering
RRT (+11.9% annually data from European registry
1991-1999)
• Increasing number of older patients due to better
survival
• Incidence of ESRF decreasing amongst Type 1
diabetes- Nishimura et al AJKD 2003;42(1)
Time Course of Type 2 Diabetic
Renal Disease
PRIME
Prevention
Protection
IRMA 2
IDNT
Microalbuminuria
Proteinuria
ESRD
Cardiovascular Morbidity and Mortality
Early Stage
Late Stage
Kidney Disease
End Stage