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Screening and early intervention in chronic kidney disease

In the first of two articles on CKD, consultant nephrologists Dr Richard Burden and Dr Charlie Tomson describe the evidence behind recommendations on detecting and treating CKD as early as possible. See the attached table for the UK CKD guidelines group's classification scheme and full referral advice for each stage.

In the first of two articles on CKD, consultant nephrologists Dr Richard Burden and Dr Charlie Tomson describe the evidence behind recommendations on detecting and treating CKD as early as possible. See the attached table for the UK CKD guidelines group's classification scheme and full referral advice for each stage.

Despite mounting evidence that progressive loss of kidney function can be slowed, or even prevented, by timely treatment, the incidence of established renal failure continues to rise.

Even in countries with comprehensive healthcare systems, many patients reaching established renal failure (ERF) do so without receiving any preventive treatment. Late referral of such patients is associated with increased morbidity and mortality, and removes the option of pre-emptive kidney transplantation1.

Most patients reaching ERF have progressed through earlier stages of chronic kidney disease (CKD). However, most patients with early CKD do not progress to ERF; the main risk in this group is of premature cardiovascular disease.

Both risks can be reduced by treatment of cardiovascular risk factors. The purpose of this article is to enable GPs to recognise the early features of CKD, to implement early treatment to prevent its progression and to minimise the cardiovascular risks, and to recognise the minority of patients with progressive kidney damage who will benefit from referral to a nephrologist.

The Department of Health in England has published an NSF for renal services2,3. In addition, comprehensive guidelines on the identification, management and referral of patients with CKD have recently been published in the UK4,5. Estimated glomerular filtration rate (eGFR) reporting and the inclusion of CKD in the quality framework have also resulted in a large increase in the numbers of patients classed as having CKD.

Classification of CKD

The table overleaf outlines the classification scheme adopted by the UK CKD guideline group; this is very similar to classifications used in North America6 and that proposed by an international working group – Kidney Disease: Improving Global Outcomes (KDIGO)6. Look online at for a more comprehensive version of this table and referral advice.

These schemes have been criticised for giving prominence to eGFR over other markers of kidney disease severity, such as proteinuria and systemic blood pressure. They have also triggered a debate about the extent to which a decline in GFR with age is normal, and what level of GFR should be considered ‘disease' in an elderly person.

In addition, the use of the term ‘stage' implies that there is an inevitable progression from stage 1 to stage 5, whereas in truth most CKD is non-progressive, and at least some cases of stage 5 CKD occur as a result of irreversible acute renal failure in patients whose kidney function may have been completely normal a few days before.

In the UK, a 2007 consensus statement from the Royal College of Physicians and the Renal Association suggested GFR and the presence of proteinuria could be used to identify those at stage 3 at highest risk who will need more monitoring, intervention and referral.

The stage was divided by level of GFR and the presence of proteinuria. GFR levels of 45-59 were 3A and 30-44 were 3B, presence of proteinuria being identified by the suffix p – so 3Bp has the highest risk.

Draft NICE guidelines, released last month, also suggested microalbuminuria testing should be routinely carried out in patients with CKD to quantify proteinuria.

Causes of CKD

To our knowledge, the causes of CKD stages 1–3 have not been documented comprehensively at population level with radiological and biopsy testing; hospital-based series will not be representative.

But information is available on those who start dialysis, the commonest single cause being type 2 diabetes. Atherosclerotic vascular disease affecting the major renal arteries commonly accompanies CKD in the elderly, but whether this relationship is causal – and whether progression of CKD can be prevented by revascularisation – is uncertain.

In a large proportion of patients, especially those who present late, it is impossible to give a cause. Among both patients with diabetes and those with atherosclerosis, reduced death rates following successful cardiovascular preventive measures, from ‘competing causes' such as myocardial infarction may be part of the reason for the apparent epidemic of CKD in affluent countries.

Options for detection of CKD

Diagnosis of CKD depends on one or more of the following four factors:

• evidence of structural kidney disease

• haematuria, either known to be of renal origin, or presumed to be after exclusion of other causes

• proteinuria, including so-called ‘microalbuminuria'

• eGFR less than 60ml/min/1.73m2 – preferably for two estimations at least three months apart.

In general, renal imaging to detect structural kidney disease will be confined to those with symptoms justifying investigation and those with a family history, for instance of polycystic kidney disease or reflux nephropathy. These patients constitute a small minority of patients with CKD.

Dipstick haematuria is known to be present in about 4% of the adult population, of whom at least 50% can be shown to have glomerular disease – most commonly IgA nephropathy or thin basement membrane nephropathy.

However, progressive loss of GFR among subjects found to have microscopic haematuria of renal origin is extremely rare if GFR is initially normal and proteinuria is absent, and for this reason screening for renal disease using tests for haematuria is not recommended.

Any degree of proteinuria, including microalbuminuria, is associated with an increased risk of cardiovascular disease and, at least for patients with diabetes, with an increased risk of progressive kidney disease. Which test to use for detection of proteinuria depends on the balance between cost and utility.

For patients with diabetes, the observation that ACE inhibitors and/or ARBs can reduce and even reverse microalbuminuria – and that this translates into prevention of progressive CKD – justifies laboratory testing. This is usually using albumin:creatinine ratios on early morning urine samples.

Microalbuminuria can also frequently be detected among non-diabetic members of the general population, is associated with hypertension and atherosclerosis, and can similarly be reversed by ACE inhibitors or ARBs. However, there is as yet no hard evidence that selective treatment of non-diabetic microalbuminuric patients with these drugs results in long-term benefit.

Among patients with CKD, more marked proteinuria (that is, more than 1g/day or a protein:creatinine ratio of more than 100) is strongly predictive of progressive loss of GFR, and there is clear evidence that ACE inhibitors or ARBs reduce the risk of progression.

Use of prediction formulae to estimate GFR has revolutionised the approach to detection and treatment of CKD in the community over the past few years.

The UK guidelines recommend the use of the four-variable ‘MDRD' formula. This formula has the advantage that – unlike some methods – knowledge of the patient's weight is not required, as the estimate it gives is ‘normalised' to body surface area, as is the convention for isotopic measurements of GFR. Most UK laboratories report an eGFR using this formula every time they report serum creatinine. This strategy alone will greatly increase the recognition of CKD in the community, necessitating a coherent strategy for management of all the patients in whom CKD is newly recognised.

The strategy has also refocused attention on marked variations between laboratories in the calibration of creatinine assays.

Epidemiology of CKD

Two large population-based studies of the prevalence of CKD are available. Figures from the National Health and Nutrition Survey in the USA gave an estimate of 11%, based on eGFR and albumin excretion.

A survey in Australia also included haematuria as a diagnostic criterion; here the estimated prevalence of CKD was 16%.

There are no equivalent population-based epidemiological studies from the UK, but studies based on laboratory testing, which underestimate prevalence, are consistent with these figures.

These studies have changed our perception of CKD, which was previously thought to be relatively rare. Patients with CKD are predominantly elderly. CKD is less common among people of white European descent than among those from ethnic minority populations.

In the UK, it is three to four times more common among the Afro-Caribbean and South Asian population, in whom hypertension and diabetes respectively are largely responsible for the difference.

The risk of premature death, particularly from cardiovascular disease, is greatly increased among people with CKD, partly because classical cardiovascular risk factors (hypertension, sedentary lifestyle, obesity, cigarette smoking, dyslipidaemia) promote the development and progression of CKD.

It is uncertain whether CKD itself is an independent risk factor that accelerates the progression of atherosclerosis via the operation of novel CKD-specific risk factors.

The association between CKD and cardiovascular disease may be due to different mechanisms in people with albuminuria but normal GFR, and in those with reduced GFR with or without albuminuria.

Both groups have been excluded from many of the randomised controlled trials on which recommendations for lipid-lowering therapy are based, so it remains uncertain whether CKD should be an indication for such therapy if it would otherwise not be indicated.

Management and referral of CKD

Most patients with CKD have co-existing conditions, particularly diabetes and hypertension. Only a small minority progress to stage 5, but detection and timely referral is extremely important.

Specialist input also adds value in some other groups, but for most patients with CKD, specialist referral is neither practicable nor necessary.

Dr Richard Burden is a consultant nephrologist at Nottingham City Hospital and Dr Charlie Tomson is a consultant nephrologist at Southmead Hospital, Bristol

This is an extract from ABC of Kidney Disease, Blackwell Publishing ISBN 978-1-4051-3675-4

Dipstick haematuria is present in 4% of the population Dipstick haematuria is present in 4% of the population Classification scheme adopted by the UK CKD guideline group Classification scheme adopted by the UK CKD guideline group

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