DIABETIC NEPHROPATHY

DIABETIC NEPHROPATHY

MAY 2013

DR RAMESH B NAIK FRCP

Causes of ESRF in Patient Starting Dialysis

UK (%)

Diabetes 30

Glomerulonephritis 12

Pyelonephritis 9

Polycystic Kidney Disease 10

Hypertension 8

Renovascular disease 6

Uncertain 17

Others 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

AgeAge

• 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% 23%

1992 17%

1993 22% 36%

2004 25-30% 40-45%

• 1985 60% type I• 1993 60% type II

Diabetic RF - Pathology

Four Stages:-

• Hypertrophy / hyperfiltration• Microalbuminuria• Diabetic glomerulosclerosis• ESRF

Microalbuminuria in GuidelinesExisting 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)

Normal <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

Microalbuminuria: both risk marker and independent risk factor

Presence of Microalbuminuria

Increased Risk of Renal Complications

Increased Risk of Cardiovascular

Events

Increased Risk of New Onset Diabetes

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

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

ANNUAL PROTEIN DIPSTICK

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 )

WHAT DO WE DO

Renal Clinic

Urine protein >1gm/24 hrs Creatinine >150mmol//litre Diagnostic uncertainty

Diabetes Clinic

Difficulty achieving BP or HbA1C Persistent dyslipidaemia


• 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%


OBESITY, DM AND THE KIDNEY

Functional changes*

Natural History of Type 2 Diabetic Nephropathy

Proteinuria

End-stage renal disease

Clinical type 2 diabetes

Structural changes†

Rising blood pressure

Rising serum creatinine levels

Cardiovascular death

Microalbuminuria

Onset of diabetes 2 5 10 20 30

Years* Renal haemodynamics altered, glomerular hyperfiltration† Glomerular basement membrane thickening , mesangial expansion , microvascular changes +/-

Prevalence of Diabetes amongst ESRF

• UK Renal Registry report 2004Comorbidity 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 dialysis50% 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

Age (years)

An

nu

al M

ort

alit

y

(%

)

0.01

0.1

1

10

100

25-34 35-44 45-54 55-64 65-74 75-84 >85

Dialysis MDialysis F

Healthy M

Healthy FFoley AJKD 1998;32:S112-9

WET GANGRENE

2/24/00 3/9/00 3/24/00Anterior Leg (SHIN)

Distal Calcific Uremic Aeteriolopathy (CUA)

CVD Mortality by Urinary Protein Excretion in Type 2 Diabetes

U-Prot = urinary protein concentration

A: U-Prot <150 mg/L B: U-Prot 150–300 mg/L C: U-Prot >300 mg/L

Months

Survival curves for

CVD mortality

1.0

0.9

0.8

0.7

0.6

0.5

00 10 20 30 40 50 60 70 80 90

A

B

COverall: p<0.001

Miettinen H et al. Stroke. 1996; 27: 2033–2039.

Valsartan lowers AER in type 2 diabetic patients with microalbuminuria

0 4 8 12 18 24

time (wks)

HbA1c (%)

Percent change of AER (%)

Mean AER(g/min)

ValsartanAmlodipine

65

25

35

45

55

8

8.2

8.4

8.6

8.8

9

2010

0-10-20-30-40-50

p<0.001 (changes in logged UEAR from baseline at week 24)

30

IRMA 2 Normalisation of Urinary Albumin Excretion

Rate at 2 years (<20 g/min)

Subjects(%)

35

45

40

30

25

20

15

10

5

0Control(n=201)

150 mg(n=195)

300 mg(n=194)

Irbesartan

24

34

21

p=0.006

Parving H-H, et al. N Engl J Med 2001; 345(12): 870-878.

31

Subjects(%)

Irbesartan

14

18

16

12

10

8

6

4

2

0Control (n=201)

150 mg(n=195)

300 mg(n=194)

9.7

5.2

14.9

RRR=39%p=0.08

RRR=70%p<0.001

IRMA 2 Primary EndpointDevelopment of Diabetic Nephropathy

Parving H-H, et al. N Engl J Med 2001; 345(12): 870-878.

IDNT: Time to Doubling of SeCr

Control defined as placeboSeCr, serum creatinine; RRR, relative risk reduction

Pat

ien

ts (

%)

Pat

ien

ts (

%)

Follow-up (months)Follow-up (months)

00 66 1212 1818 2424 3030 3636 4242 4848 5454

00

1010

2020

3030

4040

5050

6060

7070Irbesartan (n=579)Irbesartan (n=579)

Amlodipine (n=567)Amlodipine (n=567)

Control (n=569)Control (n=569)

RRR=33%RRR=33%PP=.003=.003

PP=NS=NS

RRR=37%RRR=37%PP<.001<.001

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 ESRFUS 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

Early Stage Late Stage End Stage

Microalbuminuria Proteinuria ESRD

PRIME

Kidney Disease

IRMA 2 IDNT

Cardiovascular Morbidity and Mortality

Prevention Protection

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DIABETIC NEPHROPATHY