Nephropathy

Diabetic nephropathy is the commonest cause of end stage renal disease in the western world. Diagnosis is made on a clinical and biochemical grounds, typically the presence of diabetes for 10-20 years or more, a progressive deterioration in renal function associated with worsening proteinuria, no haematuria, and usually other microvascular complications such as retinopathy or neuropathy. The mainstay of management is anti-hypertensive therapy with ACE-inhibitors and/or angiotensin receptor blockers. Eventually dialysis or transplantation are necessary in a proportion of cases.

Prevention

What are the main strategies for prevention of nephropathy?

The prevention of nephropathy relies on good glycaemic control and effective treatment of hypertension where this is present.

The importance of good glycaemic control was convincingly demonstrated by the original DCCT and UKPDS trials for T1DM and T2DM respectively. Subsequent investigations have supported these findings.

What glycaemic targets should be applied?

The 'one-size-fits-all' strategy of using a single HbA1c target for the whole diabetic population is a blunt approach and it is increasingly recognised that inidividualised targets should be set with each patient.

The fundamental challenge is that the lower the HbA1c, the more frequent hypoglycaemia will be. Thus for a newly diagnosed patient who is adapting well to life with diabetes and is actively engaging with education and other aspects of self management, setting a target of 6.5% (48 mmol/mol) without experiencing unacceptably frequent hypoglycaemia is a realistic aim.

However, for a 75-year-old patient with a ten-year history of T2DM and an HbA1c of 9% (75 mmol/mol), attempting reduction to 6.5% (48 mmol/mol) will probably confer no survival advantage and may even increase mortality rate as shown by the recent ADVANCE, ACCORD and VADT trials.

Other examples of groups where caution should be applied regarding zealous reduction of HbA1c include the advanced elderly (for example over 80-years-old, and younger if significant comorbidity is present), those with frequent hypoglycaemia and hypoglycaemia unawareness and those who have had diabetes for many decades and have developed autonomic neuropathy, gastroparesis and other comorbidity that render coping with hypoglycaemia especially difficult.

What blood pressure target should be applied?

Control of blood pressure has been shown to be an effective way of reducing the risk of nephropathy.

There is also evidence that treatment with ACE inhibitors and with angiotensin receptor blockers (ARBs) has beneficial effects on nephropathy, over and above systemic blood pressure, which is thought to be due to control of intra-glomerular hypertension.

There is a relative paucity of convincing data as to what BP targets should be aimed for, NICE recommends BP<140/80 mm Hg for people with T2DM. Many diabetologists will aim for a lower blood pressure target in patients with microalbuminuria (see Management section below).

We do know from the recent ACCORD-BP study that in patients with T2DM who are at increased cardiovascular risk, over-zealous BP lowering (target <120/80) conferred no survival benefit and some increased risk.

Are there any other strategies for prevention of nephropathy?

More recently, some evidence supporting the use of fibrates (specifically fenofibrate) has emerged for the prevention of nephropathy (FIELD study). These data relate to the prevention of nephropathy in T2DM. It should however be emphasised that this has not yet become widely accepted practice and has not as yet been incorporated into the major national guidelines.

Other research has shown that a combined approach of intensive simultaneous control of hyperlipidaemia, blood pressure and glycaemia in T2DM (STENO 2 study) also produces a modest risk reduction of nephropathy.

Management

Disease progression

Diabetic nephropathy follows a predictable natural history in which the kidney starts leaking small quantities of albumin into the urine (so called 'microalbuminuria', proteinuria that is below the detection threshold of urinalysis sticks).

This progresses to overt proteinuria (which can even advance to nephrotic range proteinuria) and eventually GFR falls and progresses remorselessly to end stage renal disease.

Management of this process revolves around early detection and aggressive blood pressure management to slow progression as much as possible.

Blood pressure control

Once microalbuminuria has developed, a lower blood pressure target should be pursued and NICE recommends 130/80 mm Hg at this stage. However, in the elderly or others at risk of falls and/or postural hypotension then clinical judgment should be used in applying these targets.

There is a significant evidence base that ACE inhibitors and ARBs are the drugs of choice for management of hypertension in patients with microalbuminuria and in those with overt proteinuria.

However, UKPDS clearly demonstrated that multiple agents will often be required to adequately control hypertension in T2DM. Current guidelines recommend that after ACE inhibitor or ARB, the next class of drug to be added should be a calcium channel blocker, then a thiazide diuretic, then an alpha blocker or beta blocker in a sequential manner.

In patients with microalbuminuria and normal blood pressure, there is some evidence supporting the use of ACE inhibitors and ARBs but care (i.e. lowest possible dose) must be exercised not to cause symptomatic hypotension.

Patient understanding and feedback

Other aspects of management include: 

1. Checking that the patient is not on nephrotoxic drugs, such as NSAIDS.

2. Reviewing metformin therapy. Once the Cr is above 150 micromol/L and/or the eGFR is below 30 ml/min then metformin should be stopped.

3. Discussing the situation with the patient so that they are aware of what is happening, what the likely prognosis is, warning them to avoid non-steroidals and so on.

When should a patient be referred to a nephrologist? 

Referral to a nephrologist should be made when renal replacement is looming on the horizon (i.e. CKD stage 4, eGFR < 30 ml/min). 

However, referral should be made earlier if GFR is deteriorating fast or if there is any doubt about the diagnosis.

Obviously not all renal impairment in patients with diabetes is due to diabetic nephropathy. Warning signs to alert the physician to a non-diabetic aetiology of renal impairment include renal dysfunction out of proportion to the patient’s other microvascular complications (for example, diabetic nephropathy in the complete absence of retinopathy is unusual); rapidly progressing renal impairment of recent onset; and, the presence of haematuria, as diabetic nephropathy is an unusual cause of haematuria.

Diabetesbible is for health professionals