Diabetic Nephropathy

Diabetic Nephropathy

Dr Peter Andrews

Consultant Nephrologist

St Helier Hospital, Carshalton, Surrey

Frimley Park Hospital, Surrey

Farnham HD Unit

Topics to be Covered

Demographics of diabetic renal disease Screening and diagnosis How can diabetic nephropathy be reduced?

BP control Glycaemic control

BP targets Choice of antihypertensive agents The life of a diabetic nephropath and other aspects of

management

0

50

100

150

200

250

300

84 85 86 87 88 89 90 91 92 93 94 1995

Treated ESRD Incidence for Selected Countries 1984-95

New Patients/Million Population

Year of ESRD Incidence

USA (All)

JPNUSA (White)

CAN

FRAUKAUS

POL

Incidence ESRF by Age: USA 1986-95

51

53

55

57

59

61

63

65

1986 87 88 89 90 91 92 93 94 1995

64

60Mean

Median

758640

180

1119

666

327

2968

2222

0

500

1000

1500

2000

2500

3000

Black NativeAm

Asian/PI White

Incidence Prevalence

Treated ESRD Incidence and Prevalence Rates by Race, 1993-95

Race

Rate per Million Pop./Year

Overall Rate=242 Overall Rate=909

Causes of Renal Failure

Diabetes * 23%

Renovascular disease * 21%

Chronic interstitial disease 10%

Glomerulonephritis 10%

Obstructive uropathy * 8%

Cystic disease 3%

Miscellaneous (amyloid, myeloma) 5%

Unknown 20%

Diabetes: the Growing Problem

The prevalence of diabetes is 2-3% and on the increase

>50% type II diabetics are hypertensive

20% of type II diabetics have renal involvement after 20 years

Approximately equal numbers Type I and Type II diabetics currently entering ESRF





management

Screening and Diagnosis

Screening (N Thomas) vs Opportunistic testing vs High risk testing vs Event testing

Serum creatinineo Esp when used with Cr Cl calculators / eGFRo 24 hour urine specimen

Urinary dipstick for protein +/- blood Assessment for microalbuminuria

Functional changes*

Type II Diabetic Nephropathy: a progressive disease

Proteinura

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 30Years

*Kidney size , short-term GFR long-term GFR †GBM thickening , mesangial expansion ,hypertensive changes +/-.

Importance of Microalbuminuria Technique Albustix

Early morning specimen

Infection excludedRepeated tests

AER 20-200 mol/min

Albumin/creatinine ratio >2 mg/mmol

How useful? Pro’s & cons Should it prompt referral? No!

Importance of Microalbuminuria/Proteinuria

Predicts CV mortality in DM and non-DM Predicts renal disease in DM and non-DM

PREVEND - increase in cardiovascular mortality of x1.35 for each doubling of urinary albumin excretion

Predicts morbidity Predicts end-organ damage in all important systems

If you have one bedside test, dip the urine! Stratifies risk (not an indication for referral)

Serum Creatinine

If it’s raised, its important!

If it’s normal, it may still be abnormal!

Very low threshold for referral / investigation

If only mildly elevated, still a significant predictor of vasculopathy

Measuring Renal Impairment - 1

GFR is ideal measure of renal function. Plasma creatinine is used as surrogate for GFR

Large changes in GFR correspond to small changes in creatinine until around 40% of GFR is lost

In the elderly, women and malnourished >50% of the GFR will be lost before the creatinine rises above the normal hospital range


Alternative is to measure creatinine clearance

which gives a more accurate measurement in mild

renal impairment, BUT

24 hr urine collections unreliable

Awkward to organise, especially as outpatient, therefore often not done


A better alternative is to use a formula to predict GFR

from plasma creatinine measurement eg Cockcroft-Gault:

Cr Cl ml/min = 1.23 x (140-age) x weight in kg

plasma creatinine umol/l

takes body weight into account takes into account that urinary creatinine excretion decreases with age

regardless of renal function makes allowances for smaller creatinine production in women by

replacing 1.23 with 1.04

Minor Renal Dysfunction Predicts Risk of Cardiovascular Disease

HOORN Study:

• Population based cohort, n=631

• Age 50-75 yrs

• Followed 10.2 yrs

• 5ml/min drop in GFR increased risk of CV death by 26%

Minor Renal Dysfunction Predicts Risk of Cardiovascular Disease

0

10

20

30

40

50

60

Ev

ents

per

10

00

per

son

yea

rs

creatinine<124 creatinine124-200

Outcomes catagorised by renal disease in HOPE

cardiovasculardeath

primaryoutcome

HOPE study : Patients at high risk of cardiovascular events. Mann JF Ann Intern Med 2001 134:629-36

6.6% 11.4%

15.1%

22.1%

P<0.001

P<0.001

NEJM Sept 23rd 2004

Anavekar et al: VALIANT sub-study 14500 pts followed 2.14 years Below 81ml/min, each 10ml/min decrease = 1.1 x risk ratio

for death & CV outcomes The lower the GFR, the lower the use of aspirin, beta

blockade, statin, & revascularisation Go et al: 1.12 million adults followed for 2.84 years (Kaiser)

RR CV death below 60 ml/min x 1.2 RR 30 - 44 ml/min x 1.8 RR 15 - 29 ml/min x 3.2 RR <15 ml/min x 5.9

Diagnosis of Diabetic Nephropathy

Usually clinical

Rarely, renal biopsyIndications: Atypical clinical course

Absence of retinopathy

High grade proteinuria

Reasons: Exclude other pathology

Aid management

Inform prognosis

Diabetic Nephrosclerosis

Hypertensive Nephropathy


Demographics of diabetic renal disease Screening and diagnosis How can diabetic nephropathy be reduced? BP targets Choice of antihypertensive agents The life of a diabetic nephropath and other

aspects of management

How can Diabetic Nephropathy be Reduced?

DM Control NB NICE target 6.5 – 7.5%

BP Control

Optimisation of Diabetes

Long established importance in Type I DM(DCCT 1993)

Effectiveness in Type II DM - UKPDS (1998)

“The UKPDS has shown that intensive blood glucose

control reduces the risk of diabetic complications, the

greatest effect being on microvascular complications”

Glucose Control Study Summary

The intensive glucose control policy maintained a lower HbA1c

by mean 0.9 % over a median follow up of 10 years from diagnosis of type 2 diabetes with reduction in risk of:

12% for any diabetes related endpoint p=0.02925% for microvascular endpoints p=0.0099

16% for myocardial infarction p=0.05224% for cataract extraction p=0.046

21% for retinopathy at twelve years p=0.015

33% for albuminuria at twelve yearsp=0.000054

Aggregate Clinical Endpoints

Favoursconventional

0.5 1 2

0.88

0.90

0.94

0.84

1.11

0.75

0.029

0.34

0.44

0.052

0.52

0.0099

Any diabetes related endpoint

Diabetes related deaths

All cause mortality

Myocardial infarction

Stroke

Microvascular

RR p

Favoursintensive

Relative Risk& 95% CI

Effect of BP on Microvascular endpoints - incl ESRF

Tight control (< 150/85) or less tight control (< 180/105)

0%

5%

10%

15%

20%

25%

0 3 6 9

% p

atie

nts

with

eve

nt

Years from randomisation

Tight Blood Pressure Control (758)

Less Tight Blood Pressure Control (390)

risk reduction37% p=0.0092

Type II Diabetes and Hypertension:

250

225

200

175

150

125

100

75

50

0

25

< 120 120–139 140–159 160–179 180–199 200

Systolic blood pressure (mm Hg)

Cardiovascular mortality

rate/10,000 person-yr

Non-diabetic

Diabetic

Stamler J et al. Diabetes Care. 1993;16:434-444.

HOT Study: 51% RR Reduction of CV Events in DM

Hansson L et al. Lancet. 1998;351:1755-1762.

0

5

10

15

20

25

90 85 80

Major cardiovascular events/1,000 patient-years

p=0.005 for trend

mm HgTarget Diastolic Blood Pressure

Lower Blood Pressure is Associated with Slower Decline in GFR

Results of studies 3 years in patients with type 2 diabetic nephropathy.Bakris GL. Diabetes Res Clin Pract. 1998;39(suppl):S35-42.

Mean arterial pressure (mm Hg)

GFR decline(mL/min/year)

-10

-8

-6

-4

-2

098 100 102 104 106 108 110

r = 0.66; p<0.05




BHS Guidelines 2004: Optimal Targets for Treatment

Most patients <140 systolic and <85 diastolic

If high risk (DM, renal disease, organ damage) <130 systolic and <80 diastolic

If daytime ABPM or home readings, subtract 10/5 N.B. Audit target (=minimal standard) is <150/90, or

<140/80 if high risk

BP Targets

BHS V DM 130/80 140/85 BHS AuditDM 140/80 150/90

NICE DM 135/75 140/90 SIGN DM 135/75 (if nephropathy)

GMS DM 145/85 150/90

HOWEVER

Targets attained not = desired

USA - 27% achieve target Canada - 16% achieve target UK – 16% achieve target

– Reluctance to escalate therapy– cost– therapeutic drift– therapeutic nihilism

Over-use of monotherapy

Therapy requirement - UKPDS

1 2 3 4 5 6 7 80

20

40

60

80

100

% o

f pa

tient

s

LessTight Control Policy

1 2 3 4 5 6 7 8

Years from randomisation

None one two > two

Tight Control Policy

number of antihypertensive agents




Meta-regression analysis of 100 studies totaling 2494 patients with type 1 and type 2 diabetes.*p<0.05 vs calcium channel blockers.†p<0.05 vs control.Kasiske BL et al. Ann Intern Med. 1993;118:129-138.

Are all agents equal in terms of renoprotection?

Log change from

baseline

0.40

0.20

0.00

-0.20

-0.40

-0.60 *†

ProteinuriaAlbuminuria

ACE inhibitors

Calcium channel blockers

Beta-blockers

Control

Use of ACE Inhibitors / ARB in CRF

• In diabetics, ACE inhibitors / ARB reduce the progression of microalbuminuria to overt proteinuria, and also slow the decline in GFR

• IRMA, RENAL studies

– numbers reaching end stage reduced 23%

– doubling of serum creatinine reduced by up to 35% in dose-dependent fashion

BHS Indications & Contraindications for Drug Treatment

Indications Contra-indications

DrugClass

Compelling Possible Possible Compelling

-blockers prostatism dyslipidaemia posturalhypotension

urinaryincontinence

ACEI heart failure

LVD

Type 1 DMnephropathy

chronic renaldisease

Type 2 DMnephropathy

renalimpairment

PVD

pregnancy

RAS

AIIA ACEI cough heart failure

intolerance

PVD pregnancy

RAS

Why do ACE / ARB Inhibitors Protect ?

• ACE inhibitors / ARBs lower intraglomerular pressure and are more effective at doing this than most other anti-hypertensive agents

• Degree of proteinuria varies directly with intraglomerular pressure - ACE inhibitors lower proteinuria by 35%-40%

afferent arteriole efferent

arteriole

Proximal tubule

GLOMERULUS

JGA

AngiotensinAngiotensin

Capillary loops and mesangial cells

Suggested Protocol

• Type I diabetic with any sign of nephropathy should be on an ACE inhibitor/ARB regardless of BP

• Type II diabetic with microalbuminuria should be on ACE inhibitor/ARB as first line treatment for BP if > 120/70

• Type II diabetic with overt nephropathy should be on ACE inhibitor/ARB

• Anyone with CRF, high BP should be treated with ACE/ARB as first line treatment (goal of 130/80 or lower)

• Anyone with CRF and protein > 1g ? ACE/ARB whatever BP

ACEI and Decline in Renal Function

• Drop in intraglomerular pressure may drop GFR

• Rise of 10-20% in serum creatinine is common and should not result in ACE being stopped unless the rise continues

• One review found that an initial rise in creatinine correlated with slower rate of long-term renal dysfunction

ACE combined with AII antagonists

Until recently, little published experience; no large, long-term outcome trials

5-7 mmHg reduction in BP with dual therapy

Great care over potassium


CALM study (BMJ 2000;321:1440)

o ACE vs AIIRA vs combinationo 199 pts, crossover, blinded study, 24 wk studyo BP reduction > in combination group than

monotherapy(16.3 vs 10.4/10.7 mmHg)o Greater reduction in proteinuria (50% vs 24/39%)


CHARM Lancet Sept 2003

Additional cardio-protection Both diabetic and non-diabetic populations

Increased incidence cough (15-20%)Care re K+

? Spironolactone better alternative

? Cost-effective to prescribe





management

The Life of a Diabetic Nephropath

0-10 years Well

Hyperfiltration 10-14 years Microalbuminuria 14-20 years Proteinuria

Pathlogy

Deteriorating GFR ESRF

The Life of a Diabetic Nephropath

ESRF Options PD 5 years HD 10 years Cadaveric renal transplant 8-10

years Living donor renal transplant 12-18 years Isolated pancreas transplant ? SKP transplant ?

Adjunctive Measures - General

Smoking - under-recognised, independent effect up to 50%

Protein - MDRD - yes and no

Lipids - not proven to affect nephropathy Aspirin - A/A

However, sensible primary prevention

Adjunctive Measures II - Renal

Volume control Weight reduction Preservation of veins for dialysis access Early referral for education and consideration of

transplantation Calcium & Phosphate homeostasis

Bone protection Deleterious cardiac effects of XS PTH Vascular calcification

Coronary Calcification in ESRF Early intervention is critical

Summary

Demographics of diabetic renal disease Screening and diagnosis Mx of Diabetic Nephropathy

BP control Glycaemic control BP targets

Choice of antihypertensive agents Adjunctive care for DN Importance of CKD wrt atherosclerosis

Documents

Diabetic Nephropathy