Diabetic Nephropathy

People with diabetes are at increased risk of renal atherosclerosis, urinary tract infections and papillary necrosis, but glomerular lesions cause most of the problems (e.g. from basement membrane thickening and glomerulosclerosis).

Diabetic nephropathy may be diffuse or nodular (Kimmelstiel-Wilson lesion). Early on there is an elevated glomerular filtration rate with enlarged kidneys, but the principal feature of diabetic nephropathy is proteinuria. This develops insidiously starting as intermittent microalbuminuria before progressing to constant proteinuria and occasionally nephrotic syndrome.

• Data from the UK Renal Registry in 1998 showed that diabetic nephropathy is the most common single cause of end-stage renal failure amongst adult patients starting on renal replacement therapy (16% of the total). Diabetic renal disease was recorded in 9.5% of existing patients (6.8% were recorded as type 1 and 2.7% were recorded as type 2).¹
• The prevalence of microalbuminuria in patients with type 1 diabetes at 30 years disease duration is approximately 40%.²
• The prevalence of microalbuminuria in patients with type 2 diabetes at 10 years disease duration is approximately 20-25%.²

• Microalbuminuria: albumin:creatinine ratio greater than or equal to 2.5 mg/mmol (men) or 3.5 mg/mmol (women), or albumin concentration greater than or equal to 20 mg/l.
• Proteinuria: albumin:creatinine ratio greater than or equal to 30 mg/mmol or albumin concentration greater than or equal to 200 mg/l.

• Arrange recall and annual review for people with type 1 and type 2 diabetes.
• Measure urinary albumin:creatinine ratio or albumin concentration annually. Use a first morning urine sample where practicable.
• If microalbuminuria or proteinuria is present, repeat twice more (within 1 month) to confirm.
• Measure serum creatinine annually.

• Raised albumin excretion rate in type 2 diabetes is often a sign of general vascular damage rather than specific renal damage. It is a useful arterial risk marker.
• Abnormal serum creatinine in type 2 diabetes is often due to renal arterial disease and/or diuretic therapy for cardiac failure rather than to diabetic nephropathy.
• Detection and surveillance of specific kidney problems therefore depends on identifying progression of albumin excretion rate and serum creatinine, in the absence of other causes.
• Consider a non-diabetes-related cause of renal disease (full history and examination, urinalysis, renal ultrasound, other investigations as appropriate). Other renal disease should be suspected:
  • In the absence of progressive retinopathy
  • If blood pressure is particularly high (for type 1 diabetes)
  • If proteinuria develops suddenly
  • If significant haematuria is present
  • In the presence of systemic ill health

Primary prevention

• Optimal control of blood glucose and blood pressure
• The Diabetes control and Complications Trial (DCCT) found that a reduction in mean HbA1c from 9.0% to 7.3% in people with type 1 diabetes was associated with a 39% reduction in microalbuminuria and 54% reduction in proteinuria over 6.5 years. However, no clear benefit was seen in the treatment of established microalbuminuria in people with type 1 diabetes.³
• The UKPDS also showed that a reduction in blood pressure from 154/87 to 144/82 mmHg was associated with an absolute risk reduction of developing microalbuminuria of 8% over 6 years in patients with type 2 diabetes.⁴
• For type 2 diabetes, this also means early diagnosis and therefore management before complications have already started.
• Smoking cessation

Microalbuminuria and proteinuria

• Ensure good blood glucose control (HbA1c below 6.5-7.5%, according to the individual's target).
• Measure, assess and manage cardiovascular risk factors aggressively (smoking, glucose, raised lipids, high blood pressure).
• Maintain blood pressure below 135/75 mmHg for type 2 diabetes (NICE Guidelines for type 1 diabetes state 130/80).^5,6
• Begin therapy with an appropriate ACE inhibitor for cardiovascular/renal protection. ACE inhibitors are the drug class of first choice and can arrest or reduce the albumin excretion rate in microalbuminuric normotensive diabetics, as well as reduce or prevent an increase in blood pressure.⁵ To achieve target blood pressure, use combination therapy if ACE inhibitors alone are not fully effective. Combination therapy is likely to be necessary for most patients with type 2 diabetes. ACE inhibitor therapy (and angiotensin II receptor antagonists) should be used with caution in those with:
  • Peripheral vascular disease/renovascular disease.
  • Raised serum creatinine.
• For all people with type 2 diabetes, measure serum creatinine and electrolytes 1 week after initiating ACE inhibitor therapy and each increase in dose.
• Angiotensin II receptor antagonists are an effective alternative to ACE inhibitors in slowing the progression of nephropathy in patients with type 2 diabetes.⁷ Because of a relative lack of specific evidence for their long-term benefit and because of higher cost, they are usually reserved for those patients who are intolerant of ACE inhibitors. Unlike ACE inhibitors, angiotensin II receptor antagonists do not increase bradykinin levels and therefore do not produce the dry cough or angio-oedema associated with ACE inhibitors. The two classes of drugs have equivalent effects on renal outcomes but, although evidence exists that ACE inhibitors reduce the risk of early death in patients with diabetic nephropathy, no such evidence exists for angiotensin II receptor antagonists.⁸
• Reduce protein intake with target of less than 0.8 g/kg. One Cochrane systematic review showed a slight slowing of the decline in GFR following low protein diet for six to 24 months follow-up.⁹
• Measure urine albumin and serum creatinine levels more frequently (e.g. six monthly for microalbuminuria but normal serum creatinine). The frequency will depend on the individual situation of the patient.
• Refer for diabetes specialist/nephrologist opinion if serum creatinine greater than 150 μmol/l.
• The management of chronic renal failure is discussed in a separate article.

Type 1

• Approximately 19% to 24% of patients with microalbuminuria develop diabetic nephropathy. Systolic blood pressure, glycated haemoglobin and triglycerides are significantly higher in people with type 1 diabetes who progress to diabetic nephropathy, than for those who did not.⁶
• Five year follow-up of microalbuminuric patients with type 1 diabetes showed 19% progressed to diabetic nephropathy and 33% regressed to normoalbuminuria.
• With aggressive antihypertensive therapy proteinuric type 1 patients lose glomerular filtration rate (GFR) at approximately 4 ml/min/year.²
• When proteinuria and hypertension are present the standardised mortality ratio is increased 11-fold in men and 18-fold in women.²

Type 2

• 20% of microalbuminuric type 2 patients who survive for 10 years develop proteinuria.²
• Treated proteinuric, hypertensive type 2 patients lose glomerular function at a rate of approximately 8 ml/min/year.
• Patients with microalbuminuria have a two to fourfold increase in cardiovascular morbidity and mortality.
• The 4-year mortality is 32% for microalbuminuric type 2 patients and 50% for proteinuric type 2 patients.
• When proteinuria and hypertension are present the standardised mortality ratio is increased fivefold in men and eightfold in women with type 2 diabetes.²