Diabetic Nephropathy

Dr Kamani Wanigasuriya

Senior Lecturer in Medicine

FMS/USJP

Magnitude of the problem

• Diabetic nephropathy has become the leading cause of ESRF in the western world (40% of patients with ESRF in USA).

• Approximately, 40% of patients with diabetes develop nephropathy.

• This percentage may be even higher in Asian countries.

Magnitude of the problem

• There will be a considerable increase in ESRD patients with diabetes as world diabetic population is expected to double within the next 10 years.

Kumari, 23-years-old female

o DM type 1 since the age of 9 years. On insulin.o In 2001 (10 years after the onset of DM)

o Oedema&facial swellingo Nephrotic syndrome was diagnosed.

o No retinopathyo Renal biopsy – advanced diabetic nephropathy

with nodular sclerosiso Treatment – blood sugar control, ACEI

• 2002 – Hypertension ACEI was increased• Cr Clearance (Normal 80-120ml/min/1.732)

2001- 45 ml/min 2002 – 35.6 ml/min 2003- 34.8 ml/min 2004- 32.8 ml/min 2006- 30.0ml/min

• 24 hour urinary Pr 1200mg (Normal <200mg)

Diabetic Nephropathy

Is characterized by,

• Persistent albuminuria

• Elevated blood pressure

• Relentless decline in GFR

• High risk of CVS morbidity and mortality

Diabetic nephropathy

A review of• Risk factors

• Screening• Evidence based

approach to management

Functional ChangesElevated GFR (>120 ml1min1 1.78 m2)

Clinical Latency

Microalbuminuria (30-300 mg/24 h)

GFR is normal

Macroalbuminuria (>300mg/24 h)

(Overt Nephropathy)

ESRF

Microalbuminuria

• Measurement of UAE is now an integral aspect of routine diabetic care.

• MA is the earliest manifestation of nephropathy.

• MA is also a marker of increased cardiovascular mortality and morbidity in Type 1 and Type 2 DM.

Risk Factors for development or progression of nephropathy

• Development– Genetic– Metabolic – hyperglycaemia,duration of diabetes

– Hemodynamic – hypertension

– Other – smoking

• Progression– Metabolic – hyperglycaemia– Hemodynamic – Hypertension– Other - smoking , superimposed renal injury

Who should be screened?

Type 1Should begin after 5 years duration of

diabetesAnd annually thereafter

Type 2At the time of diagnosisAnd annually thereafter

How do you screen?A routine urinalysis should be

performed first.

If found positive for protein a quantitative measure should be done.

If negative, proceed to microalbumin estimation.

Screening for microalbuminuria

Three methods.

• Albumin to creatinine ratio in a random spot collection

• 24 hour urinary albumin excretion

• Timed (eg 4 hr or overnight) urine collection

Reagent strips may be used if above tests are not available

Should confirm with these tests later

Diagnosis of albuminuria

Urine ALB 24 hour urinary Alb

Spot test (Adjusted for U Cr)

Timed Urine (Alb excretion rate)

Normal <30mg/24h 30mg/g Cr < 20µg/min

Micro. 30-300mg /24 h

30-300 mg /g Cr

20-200 µg/min

Macro >300 mg /24 h

>300mg /g Cr

> 200 µg/min

Screening for MicroAlb (in macroalb –ve)

Microalbumin +ve

Exclude other causes&Retest

Microalbumin +ve

Repeat over 4-6weeks

No microalbumin

Repeat in 1year

Early morning urine

Microalbumin +veMicroalbumin +ve

Treat with ACEI

Transient elevations in urine albumin can occur in,

• Fever• Exercise within 24 hours

• Infection• Marked hypertension• Marked hyperglycaemia• Cardiac failure

DN or other form of renal disease?

Indications for evaluating other causes of renal disease:

Proteinuria in T1 DM for fewer than 10 years or without retinopathy

Haematuria

cellular or granular casts in urine

accelerated renal damage (Decline in GFR >15ml/min per year)

Decline in GFR with ACEI therapy

Microalbuminuria

• Marker of CVS morbidity & mortality

• Indication for screening for other CVS risk factors (HT, lipids etc)

• Screen for other complications of diabetes retinopathy, neuropathy, peripheral vascular disease, IHD

DN in Sri Lankan Type 2 DMWanigasuriya & Fernando. Diabetes in Asia 2001

43.10%

27.60%

34.00%

10.30%

retinopathyP.neuro.IHDPVD

How should DN be treated?

glycaemic control

Treatment of hypertension

Treatment of proteinuria

Low protein diet

Treatment of hyperlipidaemia

Rx of CVS risk factors

Glycaemic control

• Control of blood glucose levels reduces the development of incipient nephropathy and to a lesser extent the progression to overt nephropathy.

Glycaemic control

Type 1 DM

Diabetes Control and Complications Trial (DCCT)

Intensive glycaemic control delays the onset of DN in Type 1 DM

Type 2 DM• UK Prospective Diabetes Study (UKPDS) Group

Each 1% reduction in mean HbA1c was associated with a reduction in risk of 37% for microvascular complications.

Hb A1c < 7%

Pre Prandial plasma glucose 90-130 mg/ dl(5.0–7.0 mmol/L)

Peak Post Prandial Plasma glucose

< 180 mg/dl(< 10 mmol/l)

Recommendations for blood sugar control

Treatment of hypertensionUKPDS (Type 2 DM) Each 10 mmHg decrease in mean systolic pressure

was associated with reduction of risk of 13% for micro-vascular complications.

Anti-hypertensive treatment with either β blocker or ACEI were effective on preventing the progression

of nephropathy. UKPDS BMJ 1998:317:703-13

Treatment of hypertension

• Life style modifications– Reduce Na intake, Increase exercise, limit

alcohol

• ACE inhibitors or angiotensin 11 receptor blockers

• Other antihypertensive agents as needed

ACEI in treatment of HT

Captopril Prevention Trial (The Lancet 1999;353:611-16)

MICRO-HOPE study ( Heart Outcomes Prevention Evaluation Study)

ABCD Trial

ACEI in HT –Meta analysis (Ann. Int. Med 2001, 134:370-9)

MICRO-HOPE Events Per Patient Group for Primary Endpoint* and Components

0

5

10

15

20

25Placebo Ramipril

HOPE Study Investigators. Lancet. 2000;355:253-259.

Combined primary

endpoint*

Myocardial infarction

Stroke Cardiovascular death

RR=25%P<0.001

RR=22%

P=0.01

RR=33%P=0.007

RR=37%P<0.001

Even

ts p

er

pati

en

t g

rou

p (

%)

RR=Relative risk reduction

*The occurrence of myocardial infarction, stroke or cardiovascular death

ABCD Trial CV Outcomes and Death in Hypertensive Subgroup

0

5

10

15

20

25

30

Fatal or non-fatal

MI

Non-fatal MI

Congestive heart failure

Death from CV causes

Death from any cause

MI=myocardial infarctionCV=cardiovascular

Estacio RO, et al. N Engl J Med. 1998;338:645-652.Schrier RW, Estacio RO. N Engl J Med. 2000;343:1969.

P=0.03P=0.03

Nu

mb

er

of

even

ts

P=NS P=NS

P=NS

Nisoldipine (n=235)

Enalapril (n=235)

ACEI in normotensive individuals

• Lisinopril in normotensive Type 1 DM and NA and MA ( The EUCLID Study)

- A randomized placebo controlled trial

- Little beneficial effect in those started with AER 5µg /min or less

- Those who started with MA benefited from lisinopril

- AER MA/NA 49.7% Vs 12.7%

- ACEI is effective in 2ry prevention in normotensive individuals with DM

Angiotensin type 1 receptor blockers

Angiotensin receptor blockers in DNThree trials in Type2 DM.

(Microalbuminuria /Overt nephropathy/ renal impairment)

Ibersartan Diabetic Nephropathy Trial (IDNT)

The Reduction of Endpoints NIDDM with Angiotensin 11 antagonist Losartan (RENNAL)

Ibersartan Microalbuminuriai Type 2 DM (IRMA2)

Angiotensin receptor blockers in DN

ARB conclusion, ARBs prevent long-term renal damage in DN

Beneficial effects of ARBS were independent of their BP lowering effects.

Well tolerated, without significant side effects.

Recommendations- Rx of HT

In hypertensive and normotensive Type 1 diabetic patients with nephropathy ACEI are the initial agents of choice.

In Type 2, there is evidence to recommend ARBs as the drug of first choice

ß blocker, Ca channel blocker, diuretics can be added in a stepwise fashion

Target of Blood Pressure

New guidelines for good blood pressure control are;

< 130/80 mmHg (American Diabetic Association)

< 125/ 75 mmHg for patients with renal insufficiency with greater than 1g/day proteinuria.

ACEIs & ARBs- caution

hyperkalaemia in patients with renal impairment

deterioration in renal functionsevere hypotension in the presence of

bilateral renal artery stenosiscontraindicated in pregnancy

Combination theray with ACEI & ARBs. More effective?

The Candersartan and Lisinopril microalbuminuria study (CALM Study)

RCT of dual blockage of RA system in patients with HT, MA & Type 2 DM /24 weeks follow up

ConclusionCandersartan and lisinopril were effective

monotherapies for reducing MA & HTTheir combined use was well tolerated and more

effective for reducing BP & alb/creat ratio.

Issues with dual blockade

• Hyperkalaemia

• Deterioration of renal function– Low incidence reported in trials– Only short term studies– ? Real life situation

Protein restriction

Protein Restriction

• ?Effectiveness in early stages

• Protein intake of 0.8g kg-1. Day -1 is recommended in patients with overt nephropathy.

• Restriction to 0.6gkg-1. Day -1 is useful once the GFR is begin to fall.

Rx of Hyperlipidaemia

Rx of hyperlipidaemia

• American Association Guidelines– LDL ≤ 100 mg/dl– HDL > 45 mg/dl– TG ≤ 200mg/dl

Statins and RAS

• Hpercholesterolaemia induces an upregulation of vascular AT1 receptors.

• Statins directly down regulate AT1 receptor expression

• Beneficial effect in individuals with normal cholesterol levels.

Modification of CVS risk factors

• Stop smoking

• Treat hyperlipidaemia

• Correct obesity

• Dietary modifications

• Regular exercise

Intensified multifactorial intervention type 2 DM: The Steno type 2 randomised study

• Intensified multifactorial intervention in patients with type 2 diabetes and microalbuminuria slows progression to nephropathy, retinopathy and autonomic neuropathy.

Lancet1999:353:617-22

Management of ESRD

• Survival of diabetic patients after KT or on

dialysis is inferior to that of non diabetic patients

• KT has a better life expectancy than HD

• Pre-emptive transplantation gives better results

• Additional beneficial effects with SPK

transplantation eg improvement of halting the

process of microangiopathy

When to refer?

Referal to a nephrologist

• Overt nephropathy• Elevated serum creatinine >2mg/dl• Difficulty in controlling hypertension• Associated hyperkalaemia

– Early referal to nephrologist has been shown to improve the outcome of RRT

– Are we ready for the challenge ?

Conclusion• Annual screening for MA will allow identification

of DN at a point very early in its course.

• Improving glycaemic control, aggressive anti-HT

treatment and ACEI therapy will slow the

progression of nephropathy.

• Prevention in way of tight glycaemic control and

aggressive antihypertensive therapy should be the

main goal of management.

Thank you