This section of the guideline focuses on the prevention, and the management of cardiovascular risk in those with diabetic nephropathy, detection and treatment of diabetic nephropathy, rather than renal disease(s) in those with diabetes. The guideline excludes the management of end-stage renal disease and renal replacement therapy.

5.1 Definitions

Microalbuminuria is defined by a rise in urinary albumin loss to between 30 and 300mg/day. To avoid a timed urine collection, a urinary albumin:creatinine ratio (ACR) > 2.5 mg/mmol in men and > 3.5 mg/mmol in women or a urinary albumin concentration > 20 mg/l are adequate.²¹⁵ This is the earliest sign of diabetic nephropathy and predicts increased total mortality, cardiovascular mortality and morbidity, and end-stage renal failure.

Diabetic nephropathy is defined by a raised urinary albumin excretion of >300 mg/day (indicating clinical proteinuria) in a patient with or without a raised serum creatinine level and with co-existing diabetic retinopathy. An ACR > 30mg/mmol in a spot urine sample indicates diabetic nephropathy. This represents a more severe and established form of renal disease and is more predictive of total mortality, cardiovascular mortality and morbidity and end-stage renal failure than microalbuminuria.

5.2 Prevalence and disease progression

5.2.1 TYPE 1 DIABETES

The cumulative incidence of microalbuminuria at 30 years disease duration is approximately 40%.^{216, 217, 218} For microalbuminuric patients the relative risk of developing proteinuria is 9.3 compared to normoalbuminuric patients.²¹⁹ Approximately 20% of type 1 patients develop proteinuria after a disease duration of 25 years.^216,217,218

The majority of microalbuminuric type 1 patients will progress to develop proteinuria, although some may revert to normoalbuminuria.^{220, 221} With aggressive anti-hypertensive therapy proteinuric type 1 patients lose glomerular filtration rate (GFR) at approximately 4 ml/min/year.²²² When proteinuria and hypertension are present the standardised mortality ratio is increased 11-fold in men and 18-fold in women.²²³

5.2.2 TYPE 2 DIABETES

The cumulative incidence of microalbuminuria in patients with type 2 diabetes at 10 years disease duration is approximately 20-25%.²²⁴ 20% of microalbuminuric type 2 patients who survive for 10 years develop proteinuria.²²⁵ The prevalence of proteinuria in patients with type 2 diabetes is approximately 15%.²²⁴

Treated proteinuric, hypertensive type 2 patients lose glomerular function at a rate of approximately 8ml/min/year.²²⁶

Patients with microalbuminuria have a two to fourfold increase in cardiovascular morbidity and mortality.²²⁷ The 4-year mortality of microalbuminuric type 2 patients is 32% and 50% of proteinuric type 2 patients have died within 4 years.^{228, 229} When proteinuria and hypertension are present the standardised mortality ratio is increased fivefold in men and eightfold in women with type 2 diabetes.²²³

5.3 Screening

Measurements of urinary albumin loss and serum creatinine are the best screening tests for diabetic nephropathy.²³⁰ Screening in young people is considered in section 2.5.2. Evidence level 3

All patients with diabetes should have their urinary albumin concentration and serum creatinine measured at diagnosis and at regular intervals, usually annually.

The daily variability in urinary albumin loss can be 40%. A first morning urine sample best reflects a timed collection and provides an adequate assessment of urinary albumin loss.²³⁰ Evidence level 3

Measurement of urinary albumin:creatinine ratio or urinary albumin concentration is usually measured using laboratory facilities. Commercial near-patient tests for measurement of low-level albuminuria (microalbuminuria) have adequate levels of sensitivity (>80%) and specificity (>90%).²²⁴ Evidence level 4

Urinary albumin concentration should be measured using a first morning urine sample and the urinary albumin:creatinine ratio should be measured by a laboratory method or a near-patient test specific for albumin at low concentration.

An abnormal result should be confirmed by a further further sample without delay.

5.4 Prevention of diabetic nephropathy

Risk factors for the development of diabetic nephropathy are:

• hyperglycaemia
• raised blood pressure
• baseline urinary albumin excretion
• increasing age
• duration of diabetes
• presence of retinopathy
• smoking
• genetic factors
• raised cholesterol and triglyceride levels
• male sex
• serum homocysteine levels.

In the DCCT study, a reduction in mean HbA1c from 9.0% to 7.0% was associated with a 39% reduction in the occurrence of microalbuminuria and a 54% reduction in the occurrence of proteinuria over 6.5 years in patients with type 1 diabetes.¹⁸ In UKPDS a reduction in mean HbA1c from 7.9% to 7.0% was associated with an absolute risk reduction of developing microalbuminuria of 11%, proteinuria by 3.5% and a twofold increase in serum creatinine by 2.5% over 12 years in patients with type 2 diabetes.²³¹ Evidence level 1++

Good glycaemic control (HbA1c around 7%) in patients with type 2 diabetes should be maintained to reduce the risk of developing diabetic nephropathy.

The UKPDS also showed that a reduction in blood pressure from 154/87 to 144/82 mm Hg was associated with an absolute risk reduction of developing microalbuminuria of 8% over 6 years in patients with type 2 diabetes.²³² In the HOPE study, ACE inhibitor therapy for 4.5 years in type 2 patients was associated with an absolute risk reduction of developing proteinuria of 2%.¹⁹⁸ Evidence level 1++

Tight blood pressure control (<140/80 mm Hg) in patients with type 2 diabetes should be maintained to reduce the risk of developing diabetic nephropathy.

5.5 Treatment of diabetic nephropathy

5.5.1 BLOOD PRESSURE CONTROL

Tight blood pressure control to <140/80 mm Hg minimises the progressive loss of renal function.^{198, 222, 232} Evidence level 1+

Blood pressure should be maintained <140/80 mm Hg in all patients with diabetes.

In microalbuminuric type 1 patients, mean achieved blood pressure levels on treatment with ACE inhibitor therapy of 122/73 mmHg and 122/79 mm Hg was associated with a 30% and 18% reduction in AER at 30 and 24 months, respectively.^{233, 234} In patients with type 1 diabetes and proteinuria (established diabetic nephropathy), average blood pressure levels of 130/80 mm Hg were associated with renal benefit in the context of ACE inhibitor therapy.²³⁵ Evidence level 1+

The majority of patients with diabetes will require more than one antihypertensive agent in order to achieve target blood pressure levels.

5.5.2 ACE INHIBITOR THERAPY

ACE inhibitors are more effective than other agents in reducing urinary albumin loss.²³⁶ In type 1 patients, ACE inhibitor therapy for three years was associated with a 50% reduction in a combined end-point of death, dialysis and transplantation that was independent of blood pressure.²³⁵ Meta-analysis has demonstrated an additional benefit on glomerular filtration rate independent of blood pressure change.²³⁶ Evidence level 1++

Treatment with an ACE inhibitors for 4.5 years in type 2 patients with microalbuminuria has been shown to reduce cardiovascular events by 25% in both those with normal serum creatinine levels and in those with mild renal insufficiency.^{198, 237} Most published studies have used ACE inhibitors at the higher end of their therapeutic dose ranges.^{198, 233, 234, 235, 236}

Patients with microalbuminuria or proteinuria should be commenced on an ACE inhibitor.

In the presence of significant bilateral renal artery stenosis ACE inhibitor therapy is associated with acute renal failure and should not be used.

5.5.3 ANGIOTENSIN II ANTAGONISTS

Several studies have shown the benefit of angiotensin II antagonists. In one study, 5% of microalbuminuric type 2 diabetic patients developed diabetic nephropathy when treated with an angiotensin II antagonist compared to 15% in a control group over two years.²³⁸ This effect was independent of blood pressure reduction. At the stage of diabetic nephropathy with a reduced glomerular filtration rate, 17% of type 2 patients treated with an angiotensin II antagonist doubled their serum creatinine level over 2.6 years against 25% in a comparator group.²³⁹ In a similar study 22% of type 2 patients treated with an angiotensin II antagonist doubled their serum creatinine level over 3.4 years against 26% in a comparator group.²⁴⁰ In both of these studies the renal effect was independent of blood pressure reduction. No effect of angiotensin II antagonist therapy on mortality was seen. Evidence level 1+

Patients with microalbuminuria or proteinuria should be considered for angiotensin II antagonist therapy.

5.5.4 GLYCAEMIC CONTROL

The evidence for good glycaemic control in the treatment of microalbuminuria in patients with type 1 diabetes suggests no clear benefit.²²¹ In a small study of 52 type 2 patients with microalbuminuria, two years of improved glucose control (HbA1c 7.1% vs 9.1% in the standard control group) resulted in a stabilisation of urinary albumin excretion whereas albumin excretion rates tripled in the standard control group. However creatinine clearance rates fell in both intensive and standard control groups by 17% and 12% respectively.²⁴¹ Evidence level 1+

5.5.5 DIETARY PROTEIN

Reduction of dietary protein intake to 0.6 - 0.8 g/kg per day reduces the rate of GFR loss in patients with type 1 diabetes who have proteinuria and renal function impairment.²⁴² One meta-analysis suggested that the effects of a low protein diet on the decline in the glomerular filtration rate may be greater in patients with diabetes than in those with non-diabetic causes of renal failure.²⁴³ The effect of a reduction of dietary protein on renal function in patients with type 2 diabetes is unclear. Evidence level 1++

Patients with type 1 diabetes, proteinuria and a reduced GFR should reduce dietary protein intake to 0.6 - 0.8 g/kg/day.

Patients commenced on a reduced dietary protein intake should be frequently and carefully monitored by a Registered Dietitian to ensure an adequate nutritional state.

5.5.6 REFERRAL

No evidence exists to advise on the correct time for referral to a renal clinic, however most renal physicians would prefer patients to be referred earlier rather than later.

Patients should be referred to a renal clinic if serum creatinine exceeds 150 μmol/l.

There is no direct comparative data to demonstrate the effectiveness of combined diabetes/renal clinics over conventional care in the management of patients with diabetic nephropathy.

5.5.7 MANAGEMENT OF CARDIOVASCULAR RISK FACTORS.

All stages of diabetic nephropathy are independent risk factors for cardiovascular disease.

Patients with diabetic nephropathy should be medically managed as patients with established coronary disease (i.e. beta-blockers, ACE inhibitor therapy, anti-platelet therapy and lipid lowering therapy).