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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

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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
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


Treated ESRD Incidence for Selected Countries 1984-95

New Patients/Million Population

USA (All)

JPN

USA (White)

CAN

AUS

FRA

UK

POL

Year of ESRD Incidence



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

Rate per Million Pop./Year

Overall Rate=242

Overall Rate=909

Race


Causes of renal failure
Causes of Renal Failure 1993-95

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
Diabetes: the Growing Problem 1993-95

  • 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


Topics to be covered1
Topics to be Covered 1993-95

  • 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


Screening and diagnosis
Screening and Diagnosis 1993-95

  • Screening(N Thomas) vs

  • Opportunistic testing vs

  • High risk testing vs

  • Event testing

  • Serum creatinine

    • Esp when used with Cr Cl calculators / eGFR

    • 24 hour urine specimen

  • Urinary dipstick for protein +/- blood

  • Assessment for microalbuminuria


Type ii diabetic nephropathy a progressive disease
Type II Diabetic Nephropathy: a progressive disease 1993-95

Clinical type 2 diabetes

Functional changes*

Structural changes†

Rising blood pressure

Microalbuminuria

Proteinura

Rising serum creatinine levels

End-stage renal disease

Cardiovascular death

Onset of diabetes

2

5

10

20

30

Years

*Kidney size ­, short-term GFR ­, long-term GFR .

†GBM thickening ­, mesangial expansion ­,hypertensive changes +/-.


Importance of microalbuminuria
Importance of Microalbuminuria 1993-95

  • Technique Albustix

    Early morning specimen

    Infection excluded

    Repeated tests

  • AER 20-200 mmol/min

  • Albumin/creatinine ratio >2 mg/mmol

  • How useful? Pro’s & cons

  • Should it prompt referral? No!


Importance of microalbuminuria proteinuria
Importance of Microalbuminuria/Proteinuria 1993-95

  • 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
Serum Creatinine 1993-95

  • 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
Measuring Renal Impairment - 1 1993-95

  • 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


Measuring renal impairment 2
Measuring Renal Impairment - 2 1993-95

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


Measuring renal impairment 3
Measuring Renal Impairment - 3 1993-95

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
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 disease1
Minor Renal Dysfunction Predicts Risk of Cardiovascular Disease

P<0.001

P<0.001

22.1%

15.1%

11.4%

6.6%

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


Nejm sept 23rd 2004
NEJM Sept 23rd 2004 Disease

  • 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
Diagnosis of Diabetic Nephropathy Disease

  • Usually clinical

  • Rarely, renal biopsy

    Indications: Atypical clinical course

    Absence of retinopathy

    High grade proteinuria

    Reasons: Exclude other pathology

    Aid management

    Inform prognosis




Topics to be covered2
Topics to be Covered Disease

  • 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
How can Diabetic Nephropathy be Reduced? Disease

  • DM Control NB NICE target 6.5 – 7.5%

  • BP Control


Optimisation of diabetes
Optimisation of Diabetes Disease

  • 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 Disease

  • 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=0.029

    • 25% for microvascular endpoints p=0.0099

    • 16% for myocardial infarction p=0.052

    • 24% for cataract extraction p=0.046

    • 21% for retinopathy at twelve years p=0.015

    • 33% for albuminuria at twelve years p=0.000054



risk reduction Disease37% p=0.0092

Effect of BP on Microvascular endpoints - incl ESRFTight control (< 150/85) or less tight control (< 180/105)


Type ii diabetes and hypertension

250 Disease

225

200

175

150

125

100

75

50

25

0

Type II Diabetes and Hypertension:

Non-diabetic

Diabetic

Cardiovascular mortality rate/10,000 person-yr

< 120

120–139

140–159

160–179

180–199

³ 200

Systolic blood pressure (mm Hg)

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


Hot study 51 rr reduction of cv events in dm
HOT Study: 51% RR Reduction of CV Events in DM Disease

25

20

Major cardiovascular events/1,000 patient-years

15

p=0.005 for trend

10

5

0

90

85

80

mm Hg

Target Diastolic Blood Pressure

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


Lower blood pressure is associated with slower decline in gfr
Lower Blood Pressure is Associated with Slower Decline in GFR

Mean arterial pressure (mm Hg)

98

100

102

104

106

108

110

0

r = 0.66; p<0.05

-2

GFR decline(mL/min/year)

-4

-6

-8

-10

Results of studies ³ 3 years in patients with type 2 diabetic nephropathy.

Bakris GL. Diabetes Res Clin Pract. 1998;39(suppl):S35-42.


Topics to be covered3
Topics to be Covered GFR

  • 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


Bhs guidelines 2004 optimal targets for treatment
BHS Guidelines 2004: GFROptimal 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
BP Targets GFR

  • BHS V DM 130/80 140/85

  • BHS Audit DM 140/80 150/90

  • NICE DM 135/75 140/90

  • SIGN DM 135/75 (if nephropathy)

  • GMS DM 145/85 150/90


However
HOWEVER GFR

  • 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



Topics to be covered4
Topics to be Covered GFR

  • 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


Are all agents equal in terms of renoprotection

0.40 GFR

0.20

0.00

-0.20

-0.40

-0.60

Are all agents equal in terms of renoprotection?

Proteinuria

Albuminuria

Log change from baseline

*

ACE inhibitors

Calcium channel blockers

Beta-blockers

Control

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.


Use of ace inhibitors arb in crf
Use of ACE Inhibitors / ARB in CRF GFR

  • 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



Why do ace arb inhibitors protect
Why do ACE / ARB Inhibitors Protect ? GFR

  • 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%


GLOMERULUS GFR

Angiotensin

Angiotensin

afferent arteriole

efferent arteriole

JGA

Capillary loops and mesangial cells

Proximal tubule


Suggested protocol
Suggested Protocol GFR

  • 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
ACEI and Decline in Renal Function GFR

  • 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
ACE combined with AII antagonists GFR

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

  • 5-7 mmHg reduction in BP with dual therapy

  • Great care over potassium


Ace combined with aii antagonists1
ACE combined with AII antagonists GFR

  • CALM study (BMJ 2000;321:1440)

    • ACE vs AIIRA vs combination

    • 199 pts, crossover, blinded study, 24 wk study

    • BP reduction > in combination group than monotherapy(16.3 vs 10.4/10.7 mmHg)

    • Greater reduction in proteinuria (50% vs 24/39%)


Ace combined with aii antagonists2
ACE combined with AII antagonists GFR

  • 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


Topics to be covered5
Topics to be Covered GFR

  • 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


The life of a diabetic nephropath
The Life of a Diabetic Nephropath GFR

  • 0-10 years Well

    Hyperfiltration

  • 10-14 years Microalbuminuria

  • 14-20 years Proteinuria

    Pathlogy

    Deteriorating GFR

  • ESRF


The life of a diabetic nephropath1
The Life of a Diabetic Nephropath GFR

  • 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
Adjunctive Measures - General GFR

  • 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
Adjunctive Measures II - Renal GFR

  • 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
Coronary Calcification in ESRF GFREarly intervention is critical


Summary
Summary GFR

  • 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


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