QJM Advance Access originally published online on May 8, 2006
QJM 2006 99(6):365-375; doi:10.1093/qjmed/hcl052
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Reviews |
Chronic kidney disease: evolving strategies for detection and management of impaired renal function
From the 1John Stevenson Lynch Renal Unit, 2Department of Biochemistry, Crosshouse Hospital, NHS Ayrshire & Arran, Kilmarnock, UK
Address correspondence to Dr Mark S. MacGregor, The John Stevenson Lynch Renal Unit, Crosshouse Hospital, NHS Ayrshire & Arran, Kilmarnock KA2 0BE. email: mark.macgregor{at}aaaht.scot.nhs.uk
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Summary |
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Nephrologists have long been concerned about late referral of patients with severe kidney disease, and resultant poor outcomes on dialysis. But there is an increasing realisation that mild to moderate chronic kidney disease is far more common than previously appreciated. Furthermore, the main consequence of chronic kidney disease is not progression to dialysis, but increased risk of cardiovascular disease. Chronic kidney disease is at least as common and important a risk factor for cardiovascular disease as diabetes mellitus. The MDRD formula is a well-validated formula to estimate glomerular filtration rate, which is now being widely implemented by clinical chemistry laboratories, and should increase the recognition of chronic kidney disease. The K/DOQI classification of chronic kidney disease has gained international acceptance and provides the structure to guide referral and management. This classification, and associated guidelines, also focus attention on areas where evidence is lacking, and which urgently require research. These current developments will substantially change and improve how chronic kidney disease is identified and managed.
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Introduction |
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The routine methods of assessing kidney function have remained unchanged for many years. An increasing realisation that renal dysfunction is under-diagnosed, and concerns about late referral to nephrologists, have led to attempts to improve both the assessment of renal function and its classification. We discuss these recent changes and likely further developments (with examples from the UK), which we believe will lead to a substantial improvement in the clinical care of people with chronic kidney disease (CKD).
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Methods |
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We searched Ovid Medline 1966–2006 January Week 2, Embase 1980–2006 week 3 and the Cochrane Database of Systematic Reviews 4th quarter 2005 for the terms ‘(MDRD or Levey) adj3 (equation or formula)’. We also reviewed articles identified in the reference lists of these articles. We supplemented the search with additional searches on the epidemiology of CKD, and by review of published guidelines on CKD. Further articles were identified from our personal reference lists. Only articles in English were selected.
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Serum creatinine is a poor measure of glomerular filtration rate |
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The excretory component of kidney function is usually assessed using serum creatinine, and is commonly measured in routine medical practice (Figure 1). For example, it was measured in 23.7% of the population in Northern Ireland in 2001,1 and in 32% of adults in a Canadian population in a single year.2 Despite being used so frequently, serum creatinine is a highly flawed measure of glomerular filtration rate (GFR). First, the rate of production of creatinine correlates with muscle mass, so patients with a low muscle mass (such as women and the elderly) will have a lower serum creatinine for any given GFR. Thus recommendations which are based on serum creatinine, such as those for the referral of patients to nephrology services,3,4 or the avoidance of metformin,5 lead to a systematic bias against women and the elderly.6 Compounding this problem, laboratories often produce reference ranges for serum creatinine which are not adjusted for sex and age, and are commonly misinterpreted by clinicians as ‘normal’ ranges. For example, a 70-year-old woman with a serum creatinine of 80 µmol/l, whose creatinine has risen to 120 µmol/l, is still within the ‘normal’ range in many laboratories, but has lost at least one third of her renal function, and probably has significant renal dysfunction. Second, the reciprocal relationship between serum creatinine and GFR renders serum creatinine insensitive to the early stages of renal dysfunction (Figure 2), particularly once laboratory and natural variability are taken into account. For example, a rise in serum creatinine from 70 µmol/l to 80 µmol/l might represent simple inter-sample variation or a genuine loss of 12.5% of GFR. Additional issues are noted in Table 1. While doctors are probably aware of these problems, it seems difficult to translate this knowledge into clinical action.
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The MDRD formula to estimate glomerular filtration rate |
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Measurement of GFR would avoid these problems, but formal measurements of GFR are time-consuming and expensive, and thus impractical for routine care. A formula predicting GFR (Figure 3) was derived from 1070 patients and validated in a further 528 patients being followed in the Modification of Diet in Renal Disease (MDRD) study,7 who had GFR measured by renal iothalamate clearance.8 The MDRD formula is a better estimate of GFR than those derived from 24-h urinary creatinine clearance or the Cockcroft-Gault formula.9 Formula-based estimates of GFR are now commonly referred to as eGFR (estimated GFR), to differentiate them from formally measured GFR. The MDRD formula requires age, gender, race, serum creatinine, serum urea and serum albumin. All of these parameters (except race) are readily available to the clinical chemistry laboratory, whenever serum creatinine is requested. This is a major advantage over the Cockcroft-Gault formula which requires weight, which is rarely available to the laboratory.
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Serum creatinine is usually measured by a colorimetric kinetic alkaline picrate method (based on the Jaffe reaction), or less commonly, by an enzymatic method. However, the alkaline picrate method is subject to interference from various other chromogens including ketones and glucose, leading to artificially elevated serum creatinines. Other interferents such as bilirubin may cause a reduction in serum creatinine. As a result of this, there is a high degree of variation between laboratories when compared to a standard. The creatinine assay used by the Cleveland Clinic laboratory that handled the MDRD study samples was a modified kinetic Jaffe reaction (using a Beckman Astra CX3 auto-analyser) and subject to these same interferences. Nevertheless, if a laboratory is to use the original or abbreviated MDRD formulae, adjustment of the creatinine assay against the Cleveland Clinic laboratory is important for mild and moderate renal dysfunction, though less so for more severe renal impairment.10–13 A more practical approach to standardisation is discussed below.
Different assays for albumin can also give widely varying results. Furthermore, the formula was derived in stable out-patients; as a result, the effects of acute illness on serum urea and albumin may be misleading. We, like others, therefore favour the simplified four-variable formulae (excluding urea and albumin), which sacrifice only a little accuracy.14 This approach also avoids the additional cost associated with assaying serum albumin, a major advantage given the frequency with which serum creatinine is requested.
Race is characterized as Black or non-Black. The original study included only 197 Black patients, but the validity of the formula has been subsequently confirmed in 1703 further Black patients.15 The formula has also been examined in 261 Chinese subjects.16 Although performance was satisfactory, an additional correction factor may be needed in this ethnic group, but this needs to be determined in a larger study with adequate assay calibration. The formula has not yet been adequately assessed in Indo-Asian patients with renal impairment. It has been validated to some extent in the elderly,17–19 diabetics,20 patients with advanced heart failure,21 renal transplant patients,22–24 patients with systemic sclerosis25 and in the obese.26 Several of these authors have pointed out that this formula is not sufficiently precise for research studies. The MDRD formula performs poorly in children, and should not be used. In 198 children, the MDRD eGFR markedly over-estimated GFR as measured by inulin clearance (mean difference 21 ml/min/1.73 m2) and the individual differences were widely dispersed (95%CI >100 ml/min/1.73 m2).27 In children, some recommend the use of the Schwartz28 or the Counahan-Barrett29 equations (both of which require height), whilst others prefer age-related ranges for serum creatinine.
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The K/DOQI classification of chronic kidney disease |
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 TopSummaryIntroductionMethodsSerum creatinine is a...The MDRD formula to... The K/DOQI classification of... CKD stages 1 and...CKD stage 3: a...CKD stages 4 and...Next stepsConclusionsReferences |
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In the USA in 2002, the Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation established a classification of CKD,30 which has become increasingly accepted by the international nephrology community31 (Table 2). This classification defines CKD as a GFR <60 ml/min/1.73 m2 or a GFR
60 ml/min/1.73 m2 together with the presence of kidney damage, present for 3 months. Clearly, use of this classification requires clinicians to measure or estimate GFR, which the MDRD formula now readily allows. The term CKD is beginning to replace less well-defined terms such as chronic renal failure or insufficiency, although debate still continues.32 Using this classification and the MDRD method to estimate GFR, worryingly large prevalences of CKD have been found in population-based surveys.33,34 While the prevalences quoted in Table 2 are based on data from the USA, similar data are beginning to appear from the UK,6,35,36 and elsewhere.37,38
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CKD stages 1 and 2: early kidney disease |
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Stage 1 CKD patients have essentially a normal or elevated GFR, while stage 2 patients have a mildly reduced GFR. Patients cannot be put in these disease categories simply on the basis of an eGFR, as it must also be demonstrated that they have kidney damage (defined in Table 2). As Clase and colleagues point out, it is important not to label these people as having a disease without good reason.32 As a result of the need to demonstrate kidney damage, estimates of population prevalence are not as reliable as those for stages 3 and 4 CKD. However, stage 1 and stage 2 are estimated to have prevalences of 3.3% and 3.0%, respectively.34 Currently, it is not clear what risks, if any the mild renal impairment in stage 2 CKD carries per se (vide infra). Furthermore, the MDRD formula is less reliable in patients with normal renal function or mild renal failure,20,22,27,39–44 partly because of the inverse relationship between creatinine and GFR discussed above, but also because the formula was derived from patients with renal disease, relatively few of whom had a GFR
60 ml/min/1.73 m2. While one group have created a formula to be used across the full spectrum of renal function,44 the precision of their estimate remains suspect. We therefore regard it as unhelpful to report eGFR in stage 1 and 2 CKD, and would simply report: ‘eGFR 60 ml/min/1.73 m2’. The National Kidney Disease Education Program of the National Institutes of Health, and CARI (Caring for Australians with Renal Impairment) also take that position, whereas UK guidelines recommend reporting eGFR up to 90 ml/min/1.73 m2.45
The key issue in this group of patients then becomes identification of the presence of kidney damage (e.g. proteinuria, polycystic kidneys, obstructive uropathy) and whether renal function is likely to decline. A review of these markers, and in particular proteinuria, is beyond the scope of this review, but patients who are clearly progressing, or are at significant risk of progressing (e.g. proteinuria >1 g/day, poorly controlled blood pressure, certain underlying diagnoses) should be promptly referred to nephrologists. In other words, these patients should continue to be managed as they currently are, based in part on guidelines on the referral and management of diabetic nephropathy,3,46 proteinuria47 and haematuria.48 We would however, highlight the importance of declining renal function, as evidenced by a rising serum creatinine (even within the laboratory reference range), which warrants prompt investigation, to exclude reversible causes. Although serum creatinine is a poor estimator of the absolute level of GFR, it is a good method for monitoring changes in GFR within an individual. This is because the within-individual biological variability of serum creatinine is low (coefficient of variation, CV, 4.3%),49 as is the variation due to the assay (typically CV 
2%). Thus a change in serum creatinine of >15% is likely to be significant, and not due to simple biological and analytical variation.50 If it is essential to know the GFR (e.g. in potential live kidney donors), we would still use formal isotopic GFR measurements, rather than predictive formulae based on serum creatinine.
One important issue is whether or not mild reductions in GFR are a normal part of ageing. The prevalence of mild renal impairment certainly increases dramatically with age.33,34 Several studies have suggested that GFR declines after the age of 30–40 years at 0.6–1.1 ml/min/year.51–53 Thus an individual who started adult life with a normal GFR of 120 ml/min/1.73 m2, might decline to 70 ml/min/1.73 m2 by the age of 80 years. Most of these studies are somewhat flawed, in that they were cross-sectional, and did not exclude patients with health problems. However, the Baltimore Longitudinal Study of Aging identified a subgroup of subjects with no hypertension or renal disease, in whom renal function did not decline, at least as judged by creatinine clearance.54 Similar data were found in a Scandinavian population using EDTA clearances, though over a shorter follow-up.55 Thus it would seem that age-related decline in renal function is not inevitable, at least in those without significant co-morbidity.56 As in the general population, it remains unclear whether mildly reduced renal function is of clinical significance in the elderly.
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CKD stage 3: a new cardiovascular risk factor |
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Patients with stage 3 CKD have significant renal impairment and are probably the very group in whom renal failure is poorly recognised.6,57 In patients with progressive renal failure, it is desirable to institute treatment to delay the need for dialysis. There is good evidence to support the efficacy of such measures in proteinuric patients.7,58,59 The earlier these measures are implemented, the greater their success. Patients with progressive disease or at significant risk of progression are probably best managed by nephrologists.60–62 The natural history of renal impairment in non-proteinuric patients, however, is not well-defined, and will depend at least in part on the underlying cause of renal damage. The large majority of these patients will not progress sufficiently to require dialysis,63,64 which given the population prevalence of 4–5% is fortunate.
However, patients with stage 3 CKD have substantially increased cardiovascular risk compared to patients with better renal function, with a 43–100% increased risk of cardiovascular events65,66 and most of them will therefore die as a result of cardiovascular disease before ever needing dialysis.63,64 Increased cardiovascular risk appears to start increasing as GFR declines below 75 ml/min/1.73 m2.66 This estimate is based on studies, most of which used the the Cockcroft-Gault or MDRD formulae to estimate GFR, and no confidence interval for this cut-point was presented. Given the issues around serum creatinine assays and estimated GFR discussed above, and given that most of the patients informing this estimate had cardiovascular disease or cardiovascular risk factors, we remain unsure whether this cut-point of 75 ml/min/1.73 m2 applies to the general population. Thus while some believe cardiovascular risk is increased in stage 2 CKD, we remain unconvinced. We are convinced, however, of the increased risk in stage 3 CKD.
As patients with CKD 3 represent approximately 4–5% of the population, it is unlikely that they can all be managed by nephrologists. Management revolves around vigorous treatment of hypertension, particularly with blockade of the renin-angiotensin system, to a blood pressure <130/80 mmHg (<125/75 mmHg if proteinuria >1 g/day is present), and treatment of other cardiovascular risk factors, all of which falls easily within the purview of primary care. Whether the standard interventions for these risk factors are effective in this patient group is uncertain, as most pharmaceutical trials exclude patients with renal dysfunction as a matter of course. A post hoc analysis of pooled data from three large trials in patients who had had, or were at high risk of, cardiovascular events (independent of their CKD) suggests a mortality benefit from pravastatin (40 mg daily) in patients with CKD stage 3 (2.3% absolute risk reduction);67 however, specific prospective trials in this population are awaited.68 To our knowledge, there are no prospective studies demonstrating mortality benefit from lowering of blood pressure or use of aspirin in this population. In a post hoc subgroup analysis of the HOPE study,69 patients with a creatinine clearance 
65 ml/min and high cardiovascular risk (independent of their CKD) had a 3.6% absolute risk reduction in mortality if randomized to ramipril. Whether this was due to the small degree of blood pressure reduction, or to blockade of the renin-angiotensin system, is unclear.
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CKD stages 4 and 5: the complexity of severe chronic kidney disease |
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It is estimated that 0.4% of the population have stage 4 or 5 CKD, although the estimate of stage 5 prevalence was extrapolated from the prevalence of dialysis and transplant patients in the USA, and may not be accurate in most other countries, which have far fewer dialysis patients.34 These patients have marked disruption to normal physiology, causing complications such as renal anaemia and renal osteodystrophy that require specialist management. These are also the stages at which preparations for dialysis and transplantation are required. Late referral of patients with advanced renal failure to nephrologists compromises the preparations for dialysis and subsequent survival of those patients,70,71 and is more costly than timely referral.72 There is wide variation in the incidence and prevalence of treated end-stage renal disease in different industrialised countries. For example, the UK has a low prevalence of patients on renal replacement therapy,73 and the assumption is that these ‘missing’ patients are either never identified and/or referred to nephrologists. Even patients who are unsuitable for dialysis (or are unwilling to undergo it) will benefit from management of their anaemia and bone disease, and potentially from palliative care.74 Thus referral of virtually all such patients to renal services should be considered. The MDRD formula may be less reliable at the lowest levels of renal function,75 which is unsurprising, as tubular secretion and extra-renal routes may contribute as much as 50% of creatinine excretion at these levels,76–78 and additionally the decline in nutritional status may also affect the validity of the formula.79 However, the key issue in stages 4 and 5 is recognising that the patient has sufficiently severe renal impairment to warrant nephrological attention. Even for the nephrologist, precise estimation of the level of GFR in stage 5 CKD is relatively unimportant, as there is no evidence to support starting dialysis purely on the basis of GFR.80,81
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Next steps |
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Implementing the MDRD formula
So what needs to be done to improve the care of patients with renal impairment? A first step would be to encourage all biochemistry laboratories to report MDRD eGFR whenever a serum creatinine is requested and the GFR is <60 ml/min/1.73 m2. The National Service Framework for Renal Services has recently recommended that all English biochemistry laboratories should report formula-based estimates of GFR,82 and this should be implemented by most UK laboratories as of 1 April 2006. Similar initiatives are ongoing worldwide. Reporting of eGFR (using the less accurate and less convenient Cockcroft-Gault formula) improves recognition of renal impairment in primary care,57 is easy to implement, and is virtually cost-free. However, it would be helpful in the future to establish a national or international creatinine calibration standard, analogous to that achieved for glycosylated haemoglobin, and efforts are ongoing internationally.83 As the standard will eventually be a true measure of creatinine (isotope dilution-mass spectrometry, ID-MS), this will involve recalibration of the original MDRD formula,84 or derivation of a new formula. Practical implementation issues were recently reviewed by Lamb and colleagues.85 It is important that laboratories use the appropriate version of the MDRD formula, depending on their efforts to standardise the serum creatinine assay. In the UK, for example, the ID-MS-traceable MDRD formula is recommended,84 and each laboratory will be provided with an assay-specific correction factor from a national quality assurance scheme, based on an international reference preparation of creatinine and an international reference ID-MS laboratory. Further validation of the MDRD formula in other populations such as Asians would also be of value. Improvement of the creatinine assay to reduce interferences would also be welcome.86 Whilst these refinements are certainly desirable, it is important that they do not lead to delays in implementation, as even the current formula without calibration will benefit patients more than the status quo. As noted above, laboratories will rarely know the race of the patient. In areas with significant Black and non-Black populations, one approach is to always report two eGFRs, one for Black and one for non-Black patients. In areas with more homogeneous populations, it may make more sense to report one value only, as long as clinicians are aware of the issue.
Models of care for chronic kidney disease
Whilst reporting the eGFR will have no cost impact, clearly subsequent changes in referral patterns could disrupt specialist services if unplanned. Therefore, another key step will be the development and promulgation of referral and therapy guidelines based on eGFR. We believe however, that reporting of stage 4 and 5 CKD should be introduced as soon as possible, given that most of these patients should be attending renal services. As stage 3 CKD is so common, it will require considerably more preparation before introducing eGFR reporting, but clearly the potential benefits affect far more patients, so strenuous efforts should be made. K/DOQI have produced extensive guidelines on CKD, and also web-based tools to assist clinicians.30 Evidence-based referral and management guidelines have also been produced by the Renal Association and the Royal College of Physicians of London.45 A concise version is available,87 and web-based tools are being developed. Various models of care for stage 3 CKD are being developed around the world.88,89 For example, in the UK, CKD-related financial incentives will be incorporated into the Quality Outcomes Framework of the General Medical Services contract on 1 April 2006.90 Up to 27 out of 1000 points will be available to general practitioners for maintaining a register of CKD stages 3–5 (6 points), monitoring blood pressure (6 points) and achieving a blood pressure target of <140/85 mmHg (11 points). Use of angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers is also rewarded (4 points). These primary care targets should increase the recognition and treatment of CKD in the UK. Disappointingly, monitoring of renal function and urinary protein are not part of the targets. The impact on health service costs of improved identification and treatment of CKD is unclear, and will depend on the relative effects on delaying the need for dialysis, identifying unmet need for dialysis and delaying cardiovascular deaths.
Future developments?
Clearly, further research is required, particularly in stage 3 CKD, both on the natural history of the renal impairment in these patients, and on appropriate interventions to protect renal function and to reduce cardiovascular events. However, simple recognition of these patients’ renal impairment will be of value, so that it continues to be monitored for progression. As many of these patients will be managed in primary care, regional shared-care registers of patients may be of value, and there is much to be learned from the experience gained in the diabetic community.91 We feel it is essential to extend the national registries of end-stage renal disease patients to all stage 4 and 5 patients. This will facilitate comparative audit of whether patients receive dialysis, if and when appropriate, and whether non-dialytic management (including expensive drugs such as erythropoiesis-stimulating agents and calcimimetics) is effective and efficient. There has been an inexorable rise in the incidence of end-stage renal disease since the inception of chronic haemodialysis in 1960.92 In the UK, most of the increase has been due to the relaxation of selection criteria for dialysis, although the rising prevalence of diabetes and changing race of the population raise concerns about changes in the true incidence. National registries of stage 4 and 5 patients would allow us to ascertain more closely the genuine incidence of end-stage renal disease and monitor the future trends and success in altering those trends. It will also facilitate comparison between countries. Of course, only patients who have blood taken would appear in such a registry. While 32% of a Canadian population had serum creatinine checked in one year, this rose to 54% in those aged over 65 years (66% in our catchment population, Figure 1), the group most at risk of CKD.2 Studies are beginning to assess whether we should also be actively screening for renal impairment in selected populations such as hypertensives, the elderly or relatives of patients with renal disease.93
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Conclusions |
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A new serum creatinine-based formula, the MDRD formula, allows a better estimate of GFR. This has facilitated the creation and implementation of a new classification of CKD, and the development of primary care management guidelines. Implementation of these changes will probably reduce the late presentation of patients requiring dialysis, but more importantly, allows the identification of a significant proportion of the population at markedly increased risk of cardiovascular disease. We believe these changes will lead to substantial improvements in the care of millions of affected patients worldwide.
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References |
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