The Pharmaceutical Journal
Vol 276 No 7400 p570-571
13 May 2006

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Diabetes UK

Microalbuminuria — a warning sign of renal decline in diabetes patients

Microalbuminuria is a reliable indicator for diabetic nephropathy within the first 10 years of type 1 diabetes, but less reliable in older people with type 2 in whom it may be accounted for by other diseases, began Sally Marshall, professor of diabetes at the University of Newcastle on Tyne. Microalbuminuria is “an increase in urine albumin excretion above normal but below that detected by conventional dipsticks”, she said.

Detecting microalbuminuria requires sensitive immuno-assays, specific for albumin and it is expressed by the urine albumin:creatinine ratio (ACR).

About 5 per cent of those with normal albumin excretion and approximately 80 per cent of those with microalbuminuria at baseline develop proteinuria, the next stage of renal decline. Although microalbuminuria in some individuals can persist and progress to proteinuria, in others it can regress back to normal levels (high incidence in the young) and later revert back again.

For people with persistent, increasing microalbuminuria, the rate of increase is significant, whereas intermittent microalbuminuria over 10–12 years poses a relatively low risk. It is important to identify which pattern the patient is showing.

Factors influencing regression of microalbuminuria are:

· Lower baseline glycosylated haemoglobin (indicator of longer-term glycaemic control)

· Lower baseline albumin excretion rate

· Shorter duration of albuminuria

· Lower systolic blood pressure

· Lower total cholesterol

· Lower triglycerides

· Lower waist:hip ratio

“Conversely, if these factors are increasing in an individual, this may indicate an increased risk of ‘metabolic syndrome’, which encompasses insulin resistance, hypertension, central obesity, endothelial dysfunction, high triglycerides, low levels of high-density lipoprotein cholesterol and inflammation,” Professor Marshall said. And, she said, “it should perhaps be also called the microalbuminuria syndrome”.

“ Even when a person has proteinuria, tight control of blood pressure can reverse it to microalbuminuria levels for at least 3–4 years, after which there is progression back to proteinuria and eventually end-stage renal failure,” explained Professor Marshall. Her screening programme for diabetic nephropathy is built around these issues.

If the patient has stable renal control, a urine sample is taken annually. The sample, when taken, should be retrieved in the early morning. A conventional dipstick is used for a protein assay and a microalbuminuria assay is carried out on the sample to determine the urine albumin:creatinine ratio. The patient’s serum creatinine and estimated glomerular filtration rate are also determined.

If the patient screens positive for microalbuminuria, the test is repeated at least twice more. If one of the three tests taken is positive then the patient is considered “normal” and can be screened again in a year. If two out of the three are positive it is considered that the patient has microalbuminuria. The ACR is measured at several visits.

The current guidelines for confirmed microalbuminuria are to start an inhibitor of the renin-angiotensin system, control glucose levels, control BP, instigate aspirin and take measures to control cardiovascular risks and other microvascular complications.

Screening programme to identify those at risk

The pilot trials for the “Diabetes, heart disease and stroke screening programme” were evaluated at the conference by Elizabeth Goyder, clinical senior lecturer in public health medicine at the University of Sheffield. These pilots, under the guidance of the National Screening Committee, were tasked with targeting people at risk of these conditions in eight primary care trusts around the country.

Patients considered at “high-risk” were invited for screening in practices, but only those that fitted certain criteria were tested for glucose intolerance. Health care assistants, nurse practitioners, GPs, administrative and reception staff all had key roles in implementing the screening. Data collection and retrieval was a major issue for both implementation and audit of screening.

A few issues arose during the pilots. Staff found it difficult to gather information about the patients, eg, determining whether their body mass index was over 25 or whether they had been tested recently. Practice staff also thought that everyone invited for screening should be offered a test. Also, a lack of informed consent also meant that some patients had misconceptions that the screening could eliminate (rather than reduce) the risk of diabetes or complications.

Recommendations from the pilot programme were relayed by Dr Goyder. She said that due to local variation, the feasibility of screening patients in a range of settings needed to be considered. Primary care information technology also needed to be further developed. Dr Goyder said that it is also important that patients understand the implications of the results and that screening may be better understood and false reassurance avoided by using the terms “risk assessment and reduction”.

Sir Muir Gray, director of the NSC, then spoke about plans for the fully implemented “National screening programme”.

The pilots illustrate the need to ensure that anything done with diabetes is integrated with other activities designed to prevent morbidity or mortality from stroke, heart disease, and vascular disease, he said. “We need to consider everyone to be at risk of vascular disease with everyone requiring educational interventions, while some also require pharmacological interventions.”

The NSC is now working with the NHS Confederation and the National Institute of Health and Clinical Excellence to ensure a coordinated approach. During this year, two tasks will be carried out: a simple modelling of the population to be covered to make best use of resources and, a consideration of the risk factors that should be measured and how risk should be estimated for whatever population is invited.

Before the pilots started, screening for diabetes in GP practices was triggered by a variety of situations; a variety of screening and diagnostic tests were used.

Sir Muir said that priorities for 2006 are to sort out the mess, pull together all the interested groups, lay the infrastructure and draw from supporting research.

Appropriate referral to a nephrologist is essential

Late referral of people with diabetes for renal replacement therapy (RRT) is evidence of a suboptimal diabetes service, said Charlie Thomson, consultant nephrologist, North Bristol NHS Trust. More than 30 per cent of UK patients are referred within four months of needing a renal transplant. This late referral is harmful, with a high mortality and morbidity due to a poorer clinical state at presentation and a lack of vascular access. It is also associated with longer hospital stays, at a greater cost (around £30,000 per case). Emergency dialysis that is required also presents a risk of subjecting the patient to methicillin resistant Staphylococcus aureus, he said.

The National Service Framework for Renal Services, standard 2, states that “all children, young people and adults approaching established renal failure are to receive timely preparation for renal replacement therapy”, said Dr Thomson. A referral should be made, where possible, at least one year before the anticipated start of dialysis, and patients should be put on the national transplant list within six months of the anticipated dialysis start date, if clinically appropriate.

Since the disease takes a long time to get to this “end stage”, there is no need for crash landing people into hospital at the last minute, said Dr Thomson. People with diabetic nephropathy from socially deprived areas are more likely than those from less deprived areas to be referred late, he said.

Reliable detection of people likely to require RRT involves checking for abnormal albumin excretion (via annual urinalysis) in patients without clinical proteinuria. Monitoring for a reduced glomerular filtration rate (GFR) should also be conducted (via an annual measurement of serum creatinine) and referral guidelines and service agreements should be followed.

Dr Thomson discussed the added value that outpatient visits can offer patients with chronic kidney disease. Clinics can help patients with the management of immunosuppressive drugs (eg, in patients with systemic vasculitis, systemic lupus erythematosus and glomerulonephritis), the management of renal bone disease, the management of renal anaemia, the investigation and treatment of renal vascular disease (using angiography, angioplasty and stents), the management of diuretic drugs in nephrotic syndrome, the use of fourth-line antihypertensive drugs and preparation for RRT. Although, Dr Thomson added: “People with chronic kidney disease are more likely to die than require dialysis.”

Dr Thomson expressed his frustration that his clinics were full of “unselective, no-added-value, early-stage referrals” that should have been dealt with in primary care. Patients arrive without having had their blood pressure and creatinine levels checked, he said. On top of this, nearly all annual reviews should be performed by GPs, not in the outpatients clinic. Incomplete correspondence is also an issue, he said; it is difficult to determine the full list of medicines a patient is taking.

Dr Thomson believes joint clinics, where a physician from another specialty sits in (unless for training) are a waste of expertise since one consultant is able to manage the problems.

Because many people suffer from multiple conditions, the Department of Health has set up a new board, which embraces stroke, coronary heart disease, diabetes and renal disease, with a shared agenda of prevention, awareness raising and risk management. There are now also clear CKD referral guidelines for the UK.

Dr Thomson clarified why reporting of the estimated glomerular filtration rate (eGFR) had been introduced. There is a non-linear relationship between GFR and creatinine, the production of the latter being dependent on muscle mass, he said. Since eGFR varies with the kidney function, a knowledge of the patient’s weight is not required and eGFR can be normalised to 1.73m2. “This greatly improves the recognition of CKD,” he said.

Dr Thomson said recommendations for preventing CKD in diabetes were annual urinalysis and calculation of the albumin excretion rate and eGFR, consideration of other causes of microalbuminuria, especially in type 1 diabetes of more than five years and, testing for haematuria in people with abnormal albumin or protein excretion.

Recommended therapy for diabetes patients with CKD includes the use of lipid-lowering drugs, antihypertensive drugs and lifestyle changes. Dr Thomson recommended including angiotensin converting enzyme inhibitors (ACEIs) or angiotensin 2 receptor antagonists (ARBs) for all people with microalbuminuria or proteinuria.

With regard to the use of an ACEI or ARB in chronic kidney disease, Dr Thomson gave the following advice: creatinine and potassium should be checked before commencing therapy, within two weeks after starting and after the dose has been increased. If the patient’s serum creatinine rises by greater than 20 per cent, it should be rechecked and discussed with a nephrologist. Drugs should not be stopped unless it is advised. If potassium is greater than 6.0mmol/L, non-steroidal anti-inflammatory drugs should be stopped, potassium-sparing diuretics reduced or stopped, loop diuretics reduced if there is a possibility of over-diuresis and ACEIs or ARBs stopped if hyperkalaemia persists.

He said that patients should be referred to nephrologists if:

· eGFR falls >=15 per cent over 12 months with widespread atherosclerosis

· eGFR falls >=15 per cent within two months of starting the ACEI or ARB

· There is unexplained hypokalaemia with hypertension

· The patient has refractory hypertension (< 150/90 despite taking three drugs)

· There is increasing proteinuria without retinopathy

· The patient has nephrotic syndrome

· The patient has haematuria with proteinuria or a GFR<60

· The patient is suffering from stage three CKD, with anaemia and hyperparathyroidism

· The patient is suffering stage four or five CKD (GFR<30)

The detection of CKD in patients with diabetes mellitus is not difficult, said Dr Thomson. In most people early CKD can safely be managed in primary care with input from specialist diabetes services. Timely referral with markers of potentially treatable CKD and those with stage 4 CKD, will greatly improve outcomes, he concluded.

Diabetes in aged care — an “area in need”

Alan Sinclair, consultant geriatrician and diabetologist at Warwick University, said that care homes are still “an area in need”, with prescribing patterns potentially dangerous in diabetes, examples being the excessive use of neuroleptics and beta-blockers being underused for post-myocardial infarction. Less hypoglycaemia is reported in the cognitively impaired with diabetes, possibly because the “hypos” are not being recognised by staff, he said. As many as 25 per cent of residents could have diabetes and 50 per cent a major glucose abnormality. Diabetes UK is in the process of revising its care home guidelines. These should include the use of care plans, adequate staff training, integrated care, clinic audits and diabetes screening every two years. Diagnosed residents are to be included on the local diabetes register.

What pharmacists who met at the conference want Diabetes UK to focus on over the coming year

· More pharmacy funded-research, to illustrate how the pharmacist’s contribution is unique

· Promotion of the pharmacist’s role, with case studies in Diabetes UK publications

· Raising the profile of the role of pharmacists with GPs and local support teams