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Age and Ageing Advance Access originally published online on December 14, 2007
Age and Ageing 2008 37(2):179-186; doi:10.1093/ageing/afm180
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Copyright © The Author 2007. Published by Oxford University Press on behalf of the British Geriatrics Society.

Detecting chronic kidney disease in older people; what are the implications?

Paul J. Roderick1,, Richard J. Atkins2, Liam Smeeth2, Dorothea M. Nitsch2, Richard B. Hubbard3, Astrid E. Flectcher2 and Chris J. Bulpitt4

1 University of Southampton, Public Health Sciences and Medical Statistics, Southampton, UK
2 London School of Hygiene and Tropical Medicine, Epidemiology, London, UK
3 University of Nottingham, Epidemiology, Nottingham, UK
4 Imperial College Hammersmith Campus, Care of the Elderly, London, UK

Address correspondence to: Paul J. Roderick. Email: pjr{at}soton.ac.uk


   Abstract
Top
 Abstract
Introduction
 Methods
 Analysis
 Results
 Discussion
 Key points
 Conflicts on interest
 Funding
 References
 
Background: national policy is focused on early identification, referral and management of chronic kidney disease (CKD) to prevent both progression to endstage renal failure and cardiovascular disease. However, the significance of identifying CKD in older people is unclear.

Objective: to determine the frequency of CKD in older people using estimated glomerular filtration rate (eGFR), and its associations with morbidity and functional measures.

Design: observational cross-sectional analysis of baseline data from a large cluster randomised trial of health and social assessment of older people in the community.

Setting: included 53 general practices in Great Britain.

Subjects: subjects were people aged 75 and over, living in the community participating in the trial arm where systematic blood testing was undertaken.

Methods: the response rate for participation at baseline assessment of those eligible was 73% (15,536/20,934), of whom 13,109 (86%) participants had a serum creatinine measured, and an eGFR derivable using the Modification of Diet in Renal Disease formula (MDRD) in ml/min/1.73 m2. Key outcomes were the prevalence of CKD stages and their associations with morbidity and functional status.

Results: prevalence of CKD was 56.1% (95% CI 55.3–57.0) for eGFR < 60, 17.7% for eGFR < 45 (95% CI 17.1–18.4), and 2.7% (95% CI 2.4–2.9) for eGFR < 30. It was higher in older ages, females, and those with cardiovascular comorbidity and doctor-diagnosed hypertension but not with diabetes. The strength of the association with measures of morbidity and functional impairment increased as eGFR fell, especially once the eGFR was < 45. For example, the odds ratios in males for anaemia for an eGFR < 30, 30–44 and 45–59 versus reference GFR > 60 were 8.3 (5.1–13.7), 3.0 (2.1–4.2) and 1.2(0.8–1.7) respectively; similar figures for partial dependence on activities of daily living were 2.2 (1.4–3.3), 1.6 (1.2–2.1) and 1.0 (0.9–1.3) and for lack of physical activity 2.20 (1.39–3.48), 1.78 (1.37–2.32) and 1.10 (0.92–1.32).

Conclusions: an eGFR < 60 is very common in older people. An eGFR < 45 identifies a smaller sub-group of older people with significant comorbidity, impaired functional state and a high risk of potentially reversible consequences such as anaemia. The benefits of identifying older people with an eGFR > 45 need to be determined.

Keywords: chronic kidney failure, prevalence, aged


   Introduction
Top
 Abstract
 Introduction
Methods
 Analysis
 Results
 Discussion
 Key points
 Conflicts on interest
 Funding
 References
 
Acceptance (i.e. new patients starting) and prevalence of renal replacement therapy (RRT) have been rising in most developed countries [1]. The main factor has been the liberalisation of referral and acceptance of older people onto RRT. In response to the rising prevalence of RRT, national policies have focused on the prevention and early detection of chronic kidney disease (CKD) [2]. Kidney function has traditionally been assessed using serum creatinine, but this is insensitive especially in older people because serum creatinine production is dependent on the muscle mass. CKD is now assessed using the formula for estimated glomerular filtration rate (eGFR) by taking account of factors that influence the muscle mass. The Modification of Diet in Renal Disease (MDRD) equation is most widely used, based on serum creatinine, age, gender and race [3]. A new CKD classification scheme has been introduced using the eGFR [4]. In England, patients will be registered by general practices as having CKD, if the eGFR < 60 under the Quality and Outcomes Framework (QoF) scheme [5]. Whilst population screening for CKD is not recommended, there are high rates of routine and opportunistic testing for serum creatinine in older people [6]. Kidney function falls with age [7,8], but the prevalence and clinical significance of a reduced eGFR in older people is unclear [9]. In younger people, as kidney function declines, the consequences such as anaemia, symptoms and signs of uraemia including malnutrition and muscle weakness, and disturbances in mineral metabolism, occurr with increasing frequency.

The Medical Research Council (MRC) Trial of Assessment and Management of Older People in the Community investigated different approaches to multi-dimensional screening and management models of people aged 75 and over living in the community in a representative sample of general practices in UK [10]. Baseline data in the universal arm included routine measurement of serum creatinine. In a cross-sectional observational study, these data were used to determine the following:

(i) the frequency of different severities of CKD, and
(ii) the associations of CKD with known risk factors (such as diabetes, cardiovascular disease); with functional status, depression and cognitive function; and with the known pathophysiological consequences of CKD such as anaemia.


   Methods
Top
 Abstract
 Introduction
 Methods
Analysis
 Results
 Discussion
 Key points
 Conflicts on interest
 Funding
 References
 
Full details of the trial have been reported previously [10,11]. In brief, the trial compared two methods of multi-dimensional assessment in people aged 75 and over in 106 general practices selected from the MRC General Practice Research Framework in England, Wales and Scotland, with stratification by practice standardised mortality rates and the Jarman deprivation score. All patients aged 75 or over registered with the practices were eligible and invited to participate unless they were resident in long-stay hospitals or nursing homes or had a terminal illness. Baseline assessments were conducted during 1994–99. This article focuses on the 53 practices in the ‘universal’ arm as here all patients were offered blood tests including serum creatinine. These practices were representative of the population in terms of the all-cause standardised mortality ratio and practice Jarman deprivation index [10]. They were widely spread throughout Great Britain with a distribution reflecting population density [12]. The response rate for baseline assessment was 73.2% (15,336/20,934), non-responders were older and more likely to be female [13].

Socio-demographic information, self-reported medical history, lifestyle and medication data were obtained by nurse interviews. Socio-economic status was classified by linking the patient's postcode to the 1991 Census ward data from which the Carstairs deprivation score was derived. Diabetes was classified according to the self-report of a medical diagnosis, use of anti-diabetic medication or the presence of a high random blood glucose measurement [14]. Cardiovascular disease was based on history of either myocardial infarction or stroke. Drug use was coded into broad classes using the British National Formulary (BNF) chapter headings.

Functional measures that might reflect the consequences of uraemia were the Mini Mental State Examination (MMSE) [15], Geriatric Depression Score (GDS) [16], eight item Activities of Daily Living (ADL) and a single question on general health perception were administered. The MMSE excluded those who were unable to complete the language section, scores were categorised so that leq23 was considered to indicate cognitive impairment. A GDS score > 5 was taken as indicating depression. ADL was grouped into full activity, partially dependent (ADL ≥2), and full dependence (ADL=8). Falls history was also used as a measure of frailty; whilst multifactorial, it was hypothesised that this would be greater in those with a low eGFR, because of muscle weakness and postural effects of hypertensive treatment.

ADL constituted the following: self-washing, self-dressing, cutting of toe nails, cooking, shopping, doing light housework, walking 50 yards, going up and down the stairs and steps. For self-rated physical activity we compared ‘Not very active’ or ‘not at all’ versus ‘Very active’ and ‘Fairly active’.

Patient's height, weight, waist circumference and blood pressure (the average of two sitting measures) were measured. A non–fasting blood sample was taken. Urine dipstick was performed on all, and if positive for protein a mid-stream urine (MSU) was taken. Of the 45 local laboratories to which the samples were sent, 37 laboratories used the modified Jaffe method for serum creatinine, while seven laboratories used an enzymatic method and in one of the laboratories, the method was not known. The simple Modification of Diet in Renal Disease (MDRD) [3] was used to calculate eGFR in ml/min/1.73 m2

eGFR = 186x serum creatinine µmol/l–1.154 x age–0.203 x 1.212 if Black x 0.742 if female

For brevity this was expressed in units only. Subjects were divided into four eGFR groups with corresponding CKD stages [4] as shown in Table 1.


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  		Table 1. eGFR groups with corresponding CKD stages

 
For albumin, 39/45 laboratories used bromocresol green (BCG), while the rest used bromocresol purple (BCP). As the BCG assay gives higher readings than the BCP, albumin was expressed using the integer value closest to and below the lowest decile for each method. Phosphate and haemoglobin results are categorised according to the UK Renal Association Standards [18].


   Analysis
Top
 Abstract
 Introduction
 Methods
 Analysis
Results
 Discussion
 Key points
 Conflicts on interest
 Funding
 References
 
Descriptive data are presented separately for males and females, as the eGFR prevalence was very different. Associations of CKD with other variables were modelled separately on the basis of gender by using the logistic regression with each eGFR band compared with the reference band (eGFR ≥60) while controlling for age. Trends were tested using a chi-squared test across ordered eGFR bands. All analyses were conducted using Stata version 9.2 (StataCorp., Texas).

Analyses took account of the clustering effect within practices in the estimation of standard errors and P values.

All aspects of the original trial were approved by the relevant local ethics committees.


   Results
Top
 Abstract
 Introduction
 Methods
 Analysis
 Results
Discussion
 Key points
 Conflicts on interest
 Funding
 References
 
Study population
An eGFR was derivable from 13,179/15,336 (86%) who had completed the in-depth assessment. Missing data were either due to there being no blood data (e.g. the patient refused phlebotomy, had poor veins or was judged too ill to proceed with venepuncture) or had no serum creatinine result. The median age was 80.2 (IQR 77.2–84.1), and 61% were females.

Prevalence of CKD
The mean (standard deviation) of the eGFR was 62.4 (14.9) in the males and 55.8 (14.9) in the females. The median and inter-quartile range of serum creatinine in the males was 105 (93–122) µmol/l and in the females it was 90 (79–104) µmol/l.

Prevalence of a low eGFR was 2.7% for a GFR < 30, 17.7% for < 45 and 56.1% for < 60. Prevalence increased with age at all levels and was much higher in the females (Table 2).


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  		Table 2. Prevalence of CKD using eGFR (MDRD equation). Percent with 95% CI

 
Table 3 shows the associations of a low eGFR in males. There was a significant effect of age but no relationship with deprivation. Urinary abnormalities increased as GFR fell. There was a strong association between self-reported cardiovascular disease and hypertension and the drugs targeted at them, but not with diabetes, cancer or smoking. Measured blood pressure was not associated, though the BP tended to be lower in the lowest eGFR group. There was some evidence of increasing anthropometry indices with a falling GFR but not in the GFR < 30 group. NSAIDs use increased as GFR fell except in the GFR < 30 group. Anaemia and hyperphosphataemia increased once the GFR was below < 45 (as did potassium and urate, data not shown). There was some use of oral iron, but little of phosphate binders, calcium or vitamin D, and no use of erythropoetin or intravenous iron (data not shown). There was an increase in the prevalence of dependency and cognitive impairment and a fall in physical activity as the GFR fell, but no association with depression. A history of falls was higher in those with a low eGFR. Health perception was poorer with a falling GFR, though it was still perceived to be good or better in 76% of those with a GFR < 30. Proteinuria was associated with comorbidity in males: age-adjusted odds for hypertension were 1.94 (1.58–2.39), for cardiovascular disease it was 1.24 (0.98–1.56) and for diabetes it was 1.57 (1.16–2.10).


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  		Table 3. Estimated glomerular filtration rate and its associations in males—percentage and age-adjusted odds ratios compared to eGFR > 60 ml/min/1.73 m2

 
Table 4 shows the same data for the female population. Patterns were generally similar except that deprivation and diabetes were significantly associated with the eGFR, the urine changes were less apparent, the GFR < 30 group showed high anthropometry measures and NSAID use, and depression was associated with a falling eGFR. Proteinuria was also associated with comorbidity in the females: age-adjusted odds for hypertension were 1.35 (1.12–1.62); for cardiovascular disease, 1.18 (0.93–1.51); and for diabetes, 1.67 (1.22–2.27).


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  		Table 4. Estimated glomerular filtration rate and its associations in females—percentage and age-adjusted odds ratios compared to eGFR > 60 ml/min/1.73 m2

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Analysis
 Results
 Discussion
Key points
 Conflicts on interest
 Funding
 References
 
We investigated the prevalence and associations of CKD in a large study of older people aged 75 and above, from practices representative of the mortality and deprivation indices of the United Kingdom. Over half of the older people had a eGFR < 60 (stage 3–5 CKD), and prevalence was substantially higher in the females. More severe degrees (eGFR < 45) were much less common with only 3% having an eGFR < 30 (CKD stage 4–5). Moreover, such people had stronger associations with comorbidity and its treatment, functional and cognitive impairment and potentially reversible consequences of the loss of kidney function such as anaemia. Classification of an eGFR < 60 may therefore be too broad for clinical purposes in older people. Using our age–sex specific prevalence figures, we estimated that approximately 2.5 million older people in the United Kingdom would have an MDRD eGFR < 60, and nearly 130,000 an eGFR < 30. Whilst there are no guidelines advocating a population screening of older people, as blood testing is more common in the older people, a large number with an eGFR < 60 will be identified [2]. In England, they will contribute to the denominator for the QoF for CKD in primary care and may influence the general practice workload in attaining the QoF targets for CKD [5].

Whilst there are limited directly comparable age specific figures our prevalence figures are high. In the NHANES III study: the prevalence of an eGFR < 60 and an eGFR < 30 in those aged 70+ were 25.9% and 1.3% respectively; in the Ausdiab study in those aged 65+, the prevalences were 55% and 1.7% respectively; and in a Norwegian health survey in those aged 70+, prevalence of an eGFR < 60 was 18.7% [7, 8, 19]. Prevalence will be higher if the Cockcroft Gault formula is used [(as in Ausdiab, and as we also found data not shown)] as this may underestimate a true GFR in the elderly [20]. There are limitations to the assessment of kidney function, some of which are common to all these cross-sectional studies. A single measure of serum creatinine may misclassify some patients who have an acute deterioration as chronic, though in this study those with an acute illness would probably not have attended trial assessments. The MDRD formula was not validated in the older people and should therefore be used with caution. The higher prevalence in older females may indicate that the gender adjustment is too great in older females, although there is no evidence of any significant bias in older females as seen in the validation studies [20]. Ideally serum creatinine assays should be calibrated to the original MDRD laboratory. The modified Jaffe method was the most commonly used method to measure serum creatinine in our study, but we have no data on how the 45 local laboratories compared to the MDRD laboratory's modified Jaffe assay. This might have contributed to our high prevalence figures, although the exclusion of older people in nursing homes, the greater non-response of the older groups and the fact that missing blood tests were partly due to frailty would all tend towards an underestimate of the CKD prevalence.

Cardiovascular risk reduction is the prime reason for identification of most people with an eGFR < 60 as this is the main outcome of CKD [17, 19], and in many cases the kidney function in CKD is stable [21, 22]. We found an increasing frequency of cardiovascular comorbidity and its associated medications, such as aspirin, as the GFR fell (although the association with statins, which were not widely used at that time was only significant in women). These findings were expected to classify CKD as an important independent risk factor for CVD [23, 24]. Interestingly, as found in the studies of younger people, there was an inverse association of the socio-economic status with CKD (though it was significant only in women probably due to greater power) [25]. However, despite strong evidence of the causal link of diabetes and hypertension with CKD and the growing evidence that obesity and smoking are important risk factors for CKD, we found few associations with these, probably due to reverse causality and/or survivor effects. It is not clear what additional interventions to reduce cardiovascular risk would be added from knowledge of an eGFR < 60. Whilst CVD risk increases once the eGFR is <60, it rises sharply once the eGFR is below 45, supporting the argument that the focus here should be on the older people [17, 19].

Whilst there is a well-recognised decline in kidney function with age, this is not a benign phenomenon as several adverse pathophysiological consequences manifested including anaemia, phosphate retention, low serum albumin, secondary hypertension, hyperkalaemia and uricaemia. Most did not occur until the eGFR was below 45 and rose sharply in those with a GFR <30. A fall in the eGFR was also associated with decline in physical function and activity, and cognitive impairment. This may be a direct consequence of CKD and/or because of clustering of comorbidity. These support studies that show associations of a low eGFR with malnutrition, frailty and low physical heath in older people [26–28]. One potential benefit of identifying the GFR is better dosing of drugs excreted by the kidney and avoidance of nephrotoxic drugs; of interest was the increased use of NSAIDs in females with a low GFR. Proteinuria, a recognised marker of kidney damage and of vascular risk, was associated with a declining eGFR especially in the males, with vascular comorbidity and risk factors. However the prognostic significance of both the eGFR and proteinuria need to be established in older people.

Some consequences such as mineral metabolism disorders and anaemia are amenable to intervention [29]. Not unexpectedly, there was little evidence of treatment of these disorders in this age group, particularly in those using erythropoietin for anaemia, at the time of the study recruitment in the 1990s. Recent NICE guidance in the United Kingdom has supported the treatment of renal anaemia with a therapeutic target Hb11–12 g/dl [30]. Extrapolating our data, there would be nearly 190,000 people, aged 75 or over with a GFR <60 and a Hb < 11 g/dl in the United Kingdom, and 30,000 with an eGFR <30. Not all would have renal anaemia, but the proportion will rise as the GFR falls. There is uncertainty as to the cost effectiveness of identification of anaemia in older people with a low GFR.

Our data are derived from a large nationally representative study of very old people who had a systematic assessment by trained research nurses, using validated instruments. The overall response rate and availability of serum creatinine data was high. However, the findings presented are cross-sectional, so causation cannot be inferred nor prognostic significance derived. There were no data on ethnicity, though the ethnic proportion in this age group is small. Use of each practice's local laboratory and non-fasting sampling introduces variation in the serum creatinine measure and hence in the eGFR, which would have tended to reduce the strength of any associations.

Our findings suggest that we need to be more specific in identifying sub-groups of people at higher risks of progression or of CVD in older people with CKD stage 3 (eGFR < 60). We found that over half of the older population were categorised as ‘diseased’ at this level, and this was highest among the females. The predicted adverse consequences of the loss of kidney function, some reversible, occurred with an increasing frequency when the eGFR fell below 45. Moreover, in studies of all ages, the risk of progression of kidney disease and CVD risk increases once the eGFR is < 45. A low eGFR (below 45 and especially below 30) is an important finding in older people as it identifies a potentially vulnerable group of older people who could be considered for further investigation, referral or intervention.


   Key points
Top
 Abstract
 Introduction
 Methods
 Analysis
 Results
 Discussion
 Key points
Conflicts on interest
 Funding
 References
 

  • National policy is focused on early identification, referral and management of CKD to prevent both progression to endstage renal failure and cardiovascular disease.
  • In England, in the Quality and Outcomes Framework, GPs are paid to identify the CKD stage 3–5 (eGFR < 60 ml/min/1.73 m2) as indicated by an estimated GFR. CKD prevalence increases with age, but the significance of detecting CKD in older people is unclear.
  • CKD stage 3–5 is extremely common in people aged 75+ and its management would generate a substantial health care workload.
  • The prevalence of more severe CKD is much less (eGFR < 45) but is more strongly associated with comorbidity (and its treatment), functional and cognitive impairment, and potentially reversible consequences of the loss of kidney function such as anaemia.
  • The threshold for active identification and intervention for CKD should be re-considered in older people.


   Conflicts on interest
Top
 Abstract
 Introduction
 Methods
 Analysis
 Results
 Discussion
 Key points
 Conflicts on interest
Funding
 References
 
There were no conflicts of interest.


   Funding
Top
 Abstract
 Introduction
 Methods
 Analysis
 Results
 Discussion
 Key points
 Conflicts on interest
 Funding
References
 
Project grant from Kidney Research UK R/34/1/05. KRUK had no role to play in any aspect of the study.


   References
Top
 Abstract
 Introduction
 Methods
 Analysis
 Results
 Discussion
 Key points
 Conflicts on interest
 Funding
 References
 

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  20. Froissart M, Rossert J, Jacqout C, et al. Predictive performance of the Modification of Diet in Renal Disease and Cockroft-Gault equations for estimating renal function. J Am Soc Nephrol (2005) 16:763–73.[Abstract/Free Full Text]
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  26. Garg AX, Blake PG, Clark WF, et al. Association between renal insufficiency and malnutrition in older adults: results from the NHANES III. Kidney International (2001) 60:1867–84.[CrossRef][Web of Science][Medline]
  27. Schlipak MG, Stehman-Breen C, Fried LF, et al. The presence of frailty in elderly persons with chronic renal insufficiency. Am J Kidney Dis (2004) 43:861–7.[CrossRef][Web of Science][Medline]
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Received 23 April 2007; accepted in revised form 7 September 2007.


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G. Lippi, G. Targher, G. L. Salvagno, M. Montagnana, and G. C. Guidi
Detecting of chronic kidney disease in older people by the MDRD and MCQ formulas
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