kidney disease
Date written: July 2012
Author: David Johnson
GUIDELINES
DIAGNOSIS
a. We recommend that chronic kidney disease (CKD) be diagnosed in all individuals on at least 2
occasions for a period of at least 3 months, irrespective of the underlying cause and on the
basis of: (1C)
an estimated or measured glomerular filtration rate <60 mL/min/1.73 m2 and/or
evidence of kidney damage (albuminuria, proteinuria, haematuria after exclusion of
urological causes, or structural abnormalities on kidney imaging tests)
Note:
These diagnostic criteria are the same for all races and gender
GFR (mL/min/1.73 m )
Description
1
2
3A
3B
4
5
90
60-89
45-59
30-44
15-29
<15 or on dialysis
Kidney damage
stage*
Urine albumin/
creatinine ratio
(mg/mmol)
24h urine
albumin
(mg/day)
Urine protein:
creatinine ratio
(mg/mmol)
24h urine
protein
(mg/day)
Normoalbuminuria
<2.5 (M)
<3.5 (F)
2.5-25 (M)
3.5-35 (F)
>25 (M)
>35 (F)
<30
<4 (M)
<6 (F)
4-40 (M)
6-60 (F)
>40 (M)
>60 (F)
<50
Microalbuminuria
Macroalbuminuria
30-300
>300
50-500
>500
*When reporting kidney function, stage (stages 1-5) is combined with kidney damage
(albuminuria/proteinuria (Norm/Micro/Macro-albuminuria)) and clinical diagnosis to fully specify
CKD stage (eg Stage 2 CKD with microalbuminuria secondary to diabetic nephropathy).
Note:
These staging criteria are the same for all races and gender.
c. We recommend that these staging criteria be used to stratify CKD patient risk and be linked
with specific management plans according to that level of risk (1C).
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Albuminuria stage
Kidney
function
stage
GFR
2
(mL/min/1.73m )
90
60-89
3a
45-59
3b
30-44
15-29
<15 or on dialysis
Normal
(urine ACR mg/mmol)
Male: < 2.5
Female: < 3.5
Not CKD unless
Microalbuminuria
Macroalbuminuria
(urine ACR mg/mmol) (urine ACR mg/mmol)
Male: 2.5-25
Male: > 25
Female: 3.5-35
Female: > 35
haematuria, structural or
pathological abnormalities
present
Risks of progressive CKD denoted as low (green), moderate (yellow), high (orange) and very high
(red).
[For specific management plans refer to Chronic Kidney Disease Management in General Practice
[1]]
Note:
For patients with CKD, the combination of a low GFR and albuminuria or proteinuria places
them at a greater risk of CKD progression at all ages, than those with just low GFR,
albuminuria or proteinuria.
2
A measured or estimated GFR <45 mL/min/1.73m is associated with increased risks of
adverse renal, cardiovascular and other clinical outcomes, irrespective of age.
d. We recommend that when CKD is initially diagnosed, to consider the underlying cause and to
pursue the diagnosis sufficiently to exclude treatable pathology, such as obstruction,
vasculitis, nephrotic syndrome and rapidly progressive glomerulonephritis (1C).
e. We recommend an early repeat of the eGFR test if there is any suspicion of an acute condition.
It is particularly important to be sure that acute kidney disease is not missed by assuming the
first abnormal eGFR represents a long-standing condition (1C).
f.
We recommend that the above criteria for CKD diagnosis and staging be applied irrespective
of age (1C).
The following diagnostic evaluation tests for CKD are always indicated:
Full blood count
Repeat (within 1 week) serum urea/electrolytes/creatinine/eGFR/albumin
Urine albumin: creatinine ratio (preferably on a first morning void, although a random urine is
acceptable)
Fasting lipids and glucose
Urine microscopy and culture
Renal ultrasound scan
ii. The following diagnostic evaluation tests for CKD are sometimes indicated:
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If patient:
Has diabetes
Has eGFR < 60 mL/min/1.73m2
Is > 40 years old
Has rash, arthritis or features of connective
tissue disease
Has pulmonary symptoms or deteriorating
kidney function
Has risk factors for HBV, HCV and HIV
Has persistent albuminuria >60-120
mg/mmol (approximately equivalent to 24hr
urinary protein >1-2 g/day)
BACKGROUND
Chronic kidney disease is a major public health problem in Australia and throughout the world. Based
on data from the AusDiab study [2], it is estimated that over 1.7 million Australian adults have at least
moderately severe kidney failure, defined as an estimated glomerular filtration rate (eGFR) less than 60
mL/min/1.73 m2. This pernicious condition is often not associated with significant symptoms or urinary
abnormalities and is unrecognized in 80-90% of cases [2-4]. CKD progresses at a rate that requires
approximately 2300 individuals each year in Australia to commence either dialysis or kidney
transplantation [5]. Furthermore, the presence of CKD is one of the most potent known risk factors for
cardiovascular disease, such that individuals with CKD have a 10- to 20-fold greater risk of cardiac
death than age- and sex-matched controls without CKD [6-8]. Developing an operational definition and
classification of the stages of CKD is therefore critically important for guiding research to provide
estimates of CKD prevalence by stage, developing a clinical action plan for evaluating and managing
each stage of CKD, and for defining individuals at increased risk of developing progressive CKD and
cardiovascular disease.
Historically, the definition of CKD has been vague, accompanied by variable and imprecise terminology
(such as chronic renal failure, chronic renal insufficiency, pre-dialysis, and pre-end-stage renal
disease), and categorised mainly by cause [9]. In principle, CKD should be diagnosed and classified
according to severity, diagnosis, treatment and prognosis, and should be readily linked to clinical
action plans to facilitate management (particularly in the primary care setting). Although the aetiology
of CKD may have important implications for management under certain circumstances, this is not the
case for the majority of CKD encountered by clinicians. Nevertheless, it remains important in all patients
when CKD is initially diagnosed to consider the underlying cause and to pursue the diagnosis
sufficiently to exclude treatable pathology, such as obstruction, vasculitis, nephrotic syndrome and
rapidly progressive glomerulonephritis. It is particularly important to be sure that acute kidney disease is
not missed by assuming the first abnormal eGFR represents a long-standing condition.
In 2002, the National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI) [10]
published a guideline on CKD covering evaluation, classification, and stratification of risk. The diagnosis
of CKD definition was based on 3 components: (1) an anatomical or structural component (markers of
kidney damage, including albuminuria), (2) a functional component (based on GFR), and (3) a temporal
component (at least 3 months duration of structural and/or functional alterations). The KDOQI
Guidelines also recommended 5 CKD stages system based on the GFR cut-points of 90 mL/min/1.73
m2 (the lower limit of normal for healthy young adults), 60 mL/min/1.73 m 2 (the threshold below which
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eGFR has been validated to have acceptable accuracy), 30 mL/min/1.73 m 2 (the threshold below which
there is broad consensus that referral to a nephrologist is generally indicated) and 15 mL/min/1.73 m2
(the upper limit at which most patients with CKD start renal replacement therapy). Because of the
limited accuracy of eGFR at normal or near-normal levels of renal function, the diagnosis of CKD at
eGFR levels above 60 mL/min/1.73 m2 required concomitant evidence of kidney damage. However, an
eGFR < 60 mL/min/1.73 m2 was considered to represent CKD, irrespective of age, gender, race or any
other factors.
There has since been broad consensus and supportive observational evidence that the diagnosis and
staging of CKD should be based on both an evaluation of kidney function (ie. estimated or measured
glomerular filtration rate (GFR) and the presence or absence of kidney damage (persistent albuminuria,
persistent proteinuria, persistent haematuria after exclusion of urological causes, or structural
abnormalities on kidney imaging tests) [10-15]. However, the use of an isolated estimated GFR
threshold of 60 mL/min/1.73 m2, uncorrected for age and gender, to define the presence of CKD even
in the absence of evidence of kidney damage has been criticised by some authors [16-18]. There has
also been criticism of the focus of current CKD diagnosis and staging systems on eGFR without
appropriate consideration of the important role of concomitant proteinuria/albuminuria for risk
stratification [19].
Recent guidelines in the United Kingdom published by the National Institute for Health and Clinical
Excellence (NICE) (10,11) have attempted to address these criticisms by dividing CKD stage 3 into
stages 3A and 3B (eGFR 45 to 59 mL/min/1.73 m2 and 30 to 44 mL/min/1.73 m2, respectively), and the
addition of the suffix p to CKD staging for significant proteinuria. Moreover, the Kidney Disease
Improving Global Outcomes (KDIGO) Guideline group acknowledged the limitations of the current
diagnostic criteria and classification system for CKD and published a position statement indicating that
further refinements were indicated and needed to focus on patient prognosis [20].
The objective of this guideline is to develop diagnostic and staging criteria for CKD that can readily be
linked to management strategies, such as cardiovascular and CKD risk modification, quality use of
medicines, nephrologist referral, and preparation for commencement of kidney replacement therapy.
The guideline group particularly focused on the prognostic significance of different levels of GFR, the
prognostic value of other factors, such as proteinuria, and whether changes to the current one size fits
all approach to diagnosis and classification were appropriate.
SEARCH STRATEGY
Databases searched: Text words for chronic kidney disease were combined with MeSH terms and text
words for diagnosis, classification or staging. The search was carried out in Medline (1966 3 August
2009). No language restrictions were placed on the search. The conference proceedings of the
American Society of Nephrology from 1994-2008 were also searched for trials. An updated search was
conducted in Medline (2009 June 2012). Text words and MeSH terms for chronic kidney disease
were combined with text words and MeSH terms for classification, staging and diagnosis.
Date of search/es: 3 August 2009: June 2012
GFR and albuminuria/proteinuria for the purposes of risk stratification/staging of patients with CKD; and
whether any other clinical factors (eg diabetes mellitus, hypertension, obesity, etc.) improved the
predictive value of a staging system based on GFR and albuminuria/proteinuria.
1. Kidney function (GFR)
For the purposes of staging criteria for CKD, the group primarily focused on the prognostic value of
measured GFR (mGFR) or estimated GFR (eGFR) for predicting CKD progression, cardiovascular
disease and other clinical outcomes. For a review of the evidence pertaining to the performance
characteristics of serum creatinine, measured GFR (mGFR), eGFR and cystatin C, please refer to the
CARI
Guidelines
for
Evaluation
of
Renal
Function
(http://www.cari.org.au/ckd_evaluation_function_list.php).
i.
Large population studies have consistently shown that GFR reduction below 60 mL/min/1.73 m 2
strongly and exponentially predicts increased risks of CKD progression [8, 21-26], frailty [27], disability
[27, 28], cognitive impairment [29], anaemia [28, 30], adverse reactions to renally excreted drugs [31],
falls at home [30], depression [30], cardiovascular events [21, 23, 26, 30, 32-48], cardiovascular death
[23, 30, 34, 49-56], and all-cause death [23, 25, 30, 33, 34, 37, 47, 49, 52, 53, 57]. A measured or
estimated GFR below 60 mL/min/1.73 m2 is therefore generally considered sufficient to diagnose CKD
[10-13]. For GFR values above 60 mL/min/1.73 m2, there is no consistent relationship with adverse
clinical outcomes and so the concomitant presence of kidney damage is required to diagnose CKD
under these circumstances [10-13].
ii. Does age modify the relationship between GFR and outcomes?
One of the current controversies with respect to using GFR to diagnose and stage CKD is how to take
account of the age-related decline in renal function in the elderly. After the age of 30 years, GFR
progressively declines at an average rate of 8 mL/min/1.73 m2 per decade [58]. Based on North
American data [58], it is estimated that 25% of the Australian population over the age of 70 years will
have an eGFR below 60 mL/min/1.73 m2. There is ongoing debate as to whether this age-related GFR
decline is normal or pathological. Approximately one-third of the population does not experience a
decline in GFR with age [59]. Data from the only longitudinal study to address this issue (Boston
Longitudinal Study of Ageing) [59] suggest that the decline in GFR with increasing age is largely
attributable to hypertension. Another study showed that heart failure was a significant contributing factor
[60]. The Italian Longitudinal Study on Ageing (ILSA) similarly demonstrated that age-associated
decline in renal function in elderly subjects is associated with co-existing cardiovascular diseases and
risk factors [61].
Although the elevated relative risk of death with lower GFR has been shown in a large population study
to fall with increasing age [62], a reduced GFR remains a strong predictor of all-cause and
cardiovascular mortality, even in elderly populations [27, 63-65]. In a large observational cohort study of
Department of Veterans Affairs patients who were aged 18 to 100 years and had at least one outpatient
serum creatinine measurement between 1 October 2001 and 30 September 2002 (n=2,583,911), 20%
of patients had an eGFR<60 ml/min per 1.73 m2, ranging from 3% among 18- to 44-year-olds to as high
as 49% among 85- to 100-year-olds [57]. The association of eGFR with mortality was weaker in the
elderly than in younger age groups. Whereas severe reductions in eGFR (<45-50 mL/min/1.73 m2)
were associated with an increased risk for death in all age groups, mild-moderate reductions in eGFR
(50 to 59 ml/min per 1.73 m2) were associated with an increased adjusted risk for death only among
patients who were younger than 65 years old. A subsequent study of 209,622 US veterans with eGFR <
60 mL/min/1.73 m2 by the same group [66] demonstrated that patients aged 75 years or older at
baseline comprised 47% of the overall cohort. Irrespective of age, the risk of death and end-stage renal
disease (ESRD) increased as GFR decreased. Age was a major effect modifier among patients with an
eGFR <60 mL/min/1.73 m2, such that the level of eGFR below which the risk of ESRD exceeded the
risk of death varied by age, ranging from 45 ml/min per 1.73 m 2 for 18 to 44 year old patients to 15
ml/min per 1.73 m2 for 65 to 84 year old patients. In a Norwegian cohort of 3047 patients with eGFR 3059 mL/min/1.73 m2 stratified by age (69 years, 70-79 years, >79 years), each 10 mL/min/1.73 m2
decrement in GFR was associated with a significantly increased risk of all-cause mortality (HR 2.50,
95% CI 1.89-3.31) that was independent of age and gender [22]. A community-based population study
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of 53 general practices in Great Britain involving patients 75 years and older (n=13,177) [30] showed a
graded and independent increase in all-cause and cardiovascular mortality, especially in men and those
with eGFR less than 45 mL/min/1.73 m2. In the first 2 years of follow-up, adjusted hazard ratios for allcause mortality in eGFR bands of 45 to 59, 30 to 44, and less than 30 compared with eGFR greater
than 60 mL/min/1.73 m2 were 1.13 (95% confidence interval [CI] 0.93-1.37), 1.69 (95% CI 1.26-2.28),
and 3.87 (95% CI 2.78-5.38) in men and 1.14 (95% CI 0.93-1.40), 1.33 (95% CI 1.06-1.68), and 2.44
(95% CI 1.68-3.56) in women, respectively. Hazard ratios were greater for cardiovascular mortality in
this very elderly group.
In previous recommendations [67], the Australasian Creatinine Consensus Working Group concluded
that it was premature at that time to recommend age-related decision points for eGFR, but that it was
appropriate to advise medical practitioners that in people aged 70 years and older an eGFR from 45 to
59 mL/min/1.73m2, when stable over time and unaccompanied by other evidence of kidney damage,
may be interpreted as consistent with a typical eGFR for this age and unlikely to be associated with
CKD complications. Recently, Levey et al [68] reported the findings of a collaborative meta-analysis of
45 cohorts and 1,555,332 participants from general, high-risk and kidney disease populations in which
an eGFR < 60 mL/min/1.73 m2 was associated with increased risks of all-cause mortality,
cardiovascular mortality, end-stage renal disease, acute kidney injury and progression of CKD without
consistent age interactions. In particular, for the controversial category of eGFR 45-59 mL/min/1.73 m2
with normal albuminuria, the relative hazards of all outcomes except all-cause mortality were similar
above and below the age of 65 years. These observations are not consistent with the interpretation
that decreased GFR with ageing is normal or physiological. Consequently, the Working Group
concluded that age-related decision points for eGFR are not recommended in adults.
To summarise, an eGFR <60 mL/min/1.73 m2 is very common in older people and predicts significantly
increased risks of adverse clinical outcomes in all age groups. An eGFR <60 mL/min/1.73 m2 should
therefore generally be considered pathological (ie. CKD) rather than physiological or age-appropriate.
iii. Does gender modify the relationship between GFR and outcomes?
There is conflicting evidence regarding the relationship between gender, GFR and outcomes.
Neugarten et al. [69] performed a meta-analysis of 68 cohort studies (11,345 patients) and concluded
that male gender was associated with a more rapid decline of GFR. A community-based, prospective
observational study of 23,534 men and women in Washington County [70] reported that the adjusted
hazard ratio (95% confidence interval) of developing CKD among women was 2.5 (0.05 to 12.0) for
normal blood pressure (BP), 3.0 (0.6 to 14.4) for high-normal BP, 3.8 (0.8 to 17.2) for stage 1
hypertension, 6.3 (1.3 to 29.0) for stage 2 hypertension, and 8.8 (1.8 to 43.0) for stages 3 or 4
hypertension compared with individuals with optimal BP. In men, the relationship was similar but
somewhat weaker than in women, with corresponding hazard ratios of 1.4 (0.2 to 12.1), 3.3 (0.4 to
25.6), 3.0 (0.4 to 22.2), 5.7 (0.8 to 43.0), and 9.7 (1.2 to 75.6), respectively. In contrast, Jafar et al. [71]
reported an increased rate of progression of CKD in women after adjusting for baseline risk factors
using a pooled database of patients with non-diabetic CKD enrolled in 11 randomized controlled trials.
With respect to overall survival, John et al. [4] observed that women with stage 3 CKD who were not
referred to a renal unit had a significantly reduced risk of all-cause mortality compared with unreferred
men (HR 0.73, 95% CI 0.65-0.82). In a Norwegian cohort of 3047 patients [22] with eGFR 30-59
mL/min/1.73 m2, female gender was associated with a significantly slower decline in GFR (regression
coefficient 0.5, 95% CI 0.20-0.81), better renal survival (HR 0.35, 95% CI 0.21-0.59) and patient
survival (HR 0.55, 95% CI 0.48-0.62). Nevertheless, in all age strata (<69, 70-79, >79 years), women
with GFR values 30-60 mL/min/1.73 m2 had significantly higher standardised incident rate ratios for
death and renal failure relative to the general population. Similar findings for cardiovascular and allcause mortality were reported in a community-based population study of 53 general practices in Great
Britain involving patients 75 years and older (n=13,177) [30].
To summarise, the available evidence suggests that the risks of CKD progression and death in patients
with early CKD may be lower for women than men, but are still significantly higher than the general
population. There is therefore no strong evidence that the diagnosis or classification of CKD should
vary according to gender.
iv. Does race modify the relationship between GFR and outcomes?
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There is no published evidence to suggest that race is a significant effect modifier for the relationship
between GFR and clinical outcomes or that the diagnosis or classification of CKD should vary
according to race.
2. Kidney Damage
There is broad consensus that evidence of kidney damage sufficient to diagnose CKD includes
persistent (3 months) albuminuria, persistent proteinuria, persistent haematuria after exclusion of
urological causes, pathological abnormalities (eg abnormal kidney biopsy) or structural abnormalities on
kidney imaging tests (eg polycystic kidneys or scarring on renal ultrasound examination) [10-15]. For
the purposes of staging criteria for CKD, the Guideline group primarily focused on the prognostic value
of kidney damage for predicting CKD progression, cardiovascular disease and other clinical outcomes.
2a. Albuminuria/Proteinuria
Albuminuria/proteinuria is common in the Australian general population. The Australian Diabetes
Obesity and Lifestyle (AusDiab) study screened stored spot (untimed) urine collections obtained from
10,596 Australian adult participants [72]. Proteinuria was present in 2.4%, whilst microalbuminuria was
detected in 6.0% and macroalbuminuria in 0.6%. These results were similar to those of the North
American National Health and Nutrition Examination Survey III (NHANES III), which found that 8.3% of
14,622 adults had microalbuminuria and 1% had macroalbuminuria [73]. When the AusDiab figures are
extrapolated to the Australian adult population, the expected numbers of individuals with proteinuria,
microalbuminuria and macroalbuminuria are 320,000, 800,000 and 80,000, respectively.
For the purposes of staging criteria for CKD, the Guideline group primarily focused on the prognostic
value of albuminuria/proteinuria for predicting CKD progression, cardiovascular disease and other
clinical outcomes. For a review of the evidence pertaining to the performance characteristics of
measures of albuminuria/proteinuria, please refer to the CARI Guidelines for Urine Protein as a
Diagnostic Test (http://www.cari.org.au/ckd_urineprot_list_pub2004.php).
i.
Large population studies have consistently shown that increasing levels of albuminuria/proteinuria
strongly predict increasing risks of CKD progression [23, 26, 74-83], cardiovascular disease [23, 26, 38,
45, 74, 82, 84-97] and all-cause death [23, 35, 80, 82, 98, 99]. These associations are independent of
the known associations of proteinuria and albuminuria with hypertension, impaired glucose metabolism,
dyslipidaemia, obesity, smoking and other cardiovascular risk factors.
The relationship between albuminuria/proteinuria and cardiovascular disease appears to be linear
without a clear threshold effect. Consequently, increased cardiovascular risk is also seen in individuals
with albuminuria levels in the high-normal range [78, 84, 85, 91].
The risk of albuminuria/proteinuria for CKD progression has been shown to extend down into the range
of microalbuminuria in an observational cohort study of 1094 African Americans with hypertensive renal
disease [77]. Similarly, in a Japanese cohort study involving 95,255 subjects, Iseki et al. [100] observed
that the 7-year cumulative incidences of end-stage renal disease (ESRD) per 1,000 subjects were 86.8
in estimated creatinine clearance (eCrCl) <50.2 mL/min, 13.6 in eCrCl 50.2-63.9 mL/min, 8.3 in eCrCl
64.0-79.3 mL/min, and 7.9 in eCrCl >79.3 mL/min in patients who had positive dipstick proteinuria
(1+), whereas they were 1.2, 0.7, 0.04, and 0.13 in those who did not have proteinuria, respectively.
ii. What is the value of combining albuminuria/proteinuria for CKD staging?
Several studies have demonstrated that combination of albuminuria/proteinuria with eGFR provides
synergistic, complementary risk stratification information for CKD patients with respect to cardiovascular
disease [26, 38, 39, 42, 91, 101-103] and CKD progression [26, 75-78, 100, 101, 104-107]. Ninomiya et
al. [26] demonstrated in a study of 10,640 patients with type 2 diabetes mellitus that individuals with
both UACR >300 mg/g and eGFR < 60 mL/min/1.73 m 2 at baseline had a 3.2-fold higher risk of
cardiovascular events and a 22.2-fold higher risk of renal events compared with individuals who had
neither of these risk factors. Farbom et al. [108] similarly demonstrated an interaction between
albuminuria and eGFR, such that the cardiovascular risk associated with microalbuminuria increased
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with declining eGFR. In the HUNT 2 study involving 65,589 adults residing in Nord-Trondelag county in
Norway [78], the adjusted hazard ratios for progression to ESRD for normal UACR, microalbuminuria
and macroalbuminuria were respectively 1.0, 27.3 and 196.3 for eGFR 60 mL/min/1.73 m 2, 23.4,
146.5 and 641.1 for eGFR 45-59 mL/min/1.73 m2, 51.9, 448.9 and 2036.0 for eGFR 30-44 mL/min/1.73
m2,, and 368.7, 2202.0 and 4146.0 for eGFR 15-29 mL/min/1.73 m2. Time-dependent receiver
operating characteristic (ROC) analyses demonstrated that considering both the UACR and eGFR
substantially improved diagnostic accuracy compared with either variable alone. Moreover,
hypertension, diabetes, male gender, smoking, depression, obesity, cardiovascular disease,
dyslipidaemia, physical activity and education did not add predictive information.
A previous study in the same population [91] also demonstrated that reduced eGFR and
microalbuminuria were potent risk factors for cardiovascular death, independent of each other and
traditional risk factors. The combined variable improved cardiovascular risk stratification at all age
levels, but particularly in elderly persons (>70 years) where the predictive power of traditional risk
factors was attenuated. For individuals under 70 years, the absolute excess cardiovascular deaths per
1000 person-years for optimal UACR (< 5 mg/g in men and < 7 mg/g in women), high normal UACR (5
to 19 mg/g in men and 7 to 29 mg/g in women) and microalbuminuria (20 to 199 mg/g in men and 30 to
299 mg/g in women) were respectively 0, 0.6 and 0.6 for eGFR 75 mL/min/1.73 m2, 0.1, 0.5 and 0.8
for 60-74 mL/min/1.73 m2, -0.3, 1.9 and 1.0 for eGFR 45-69 mL/min/1.73 m2, and 0.1, 1.3 and 4.1 for
eGFR mL/min/1.73 m2. For elderly individuals (> 70 years), the absolute excess cardiovascular deaths
per 1000 person-years for optimal UACR, high normal UACR and microalbuminuria were respectively
0, 13.6 and 8.4 for eGFR 75 mL/min/1.73 m2, -2.3, 5.9 and 24.1 for 60-74 mL/min/1.73 m2, 12.8, 8.0
and 26.6 for eGFR 45-69 mL/min/1.73 m2, and 4.2, 31.9 and 26.6 for eGFR mL/min/1.73 m2.
To summarise, eGFR and albuminuria provide synergistic, complementary risk stratification information
for CKD patients with respect to cardiovascular disease and CKD progression. Their predictive value is
not appreciably enhanced by consideration of other clinical and laboratory variables.
2b. Haematuria
In the AusDiab study [2], haematuria was detected on initial dipstick testing in 5.2% (95% CI 4.3-6.1). A
confirmed finding of haematuria by microscopy or repeat dipstick testing on a midstream sample of
urine was found in 4.6% of participants, and was more common in women than men. Haematuria was
observed to be predictive of developing ESRD in 106,177 Japanese patients (50,584 men and 55,593
women) who participated in community-based mass screening between April 1983 and March 1984
(adjusted odds ratio 1.18, 95% CI 1.06 to 1.32, P = 0.002) [74]. However, the predictive value of
haematuria was no longer significant after including serum creatinine in the model (odds ratio, 1.13;
95% CI, 0.95 to 1.36).
2c. Structural abnormalities on renal ultrasound imaging
Ultrasound is the optimal first line test for renal imaging in patients with CKD and assists with the
identification of obstructive uropathy, renal scarring, renal asymmetry, renal artery stenosis and
polycystic kidney disease [15]. Large observational cohort studies examining the utility of ultrasound
screening for abdominal/renal cancers in the asymptomatic general population in Japan [109], USA
[110] and Germany [111] have incidentally detected obstructive uropathy in 0.13-0.34% of
examinations. Filipas et al. [111] additionally reported incidentally detected renal calculi in 2.14% and
renal asymmetry in 0.4%.
There are no studies on the usefulness of renal ultrasound alone in the diagnosis, risk stratification or
staging of CKD. Currently, renal ultrasonography is only recommended in patients once the diagnosis
of CKD is established.
3. Temporal changes in kidney function and/or damage
Diagnosis of CKD requires establishment of chronicity of reduced GFR and/or kidney damage. There is
broad consensus that reduced GFR and/or kidney damage should be demonstrated to be persistent for
at least 3 months [10-15].
The extent of 'false positive' error rates associated with a single reduced eGFR value (<60 mL/min/1.73
m2) in epidemiological studies is not known with precision, but may be as high as 30% in some studies
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[22]. In patients with a confirmed eGFR <60 mL/min/1.73 m2, the vast majority (80%) of patients will not
experience a decline in eGFR > 2 mL/min/1.73 m2 over the ensuing 3-5 years [8, 57]. Similar findings
are observed across age categories (<70, 70-80, >80 years) [8]. Stability of reduced eGFR over time,
predicts a lower level of cardiovascular risk compared with progressive decline in eGFR, but is still
greater than patients with eGFR >60 mL/min/1.73 m2 [57].
Isolated proteinuria without any evidence of renal or systemic disease or urine sediment abnormality
may be the initial manifestation of serious CKD or may represent a temporary or non-progressive
kidney abnormality of little long-term clinical significance. Transient isolated proteinuria in the primary
care setting is most commonly seen in relation to febrile or other acute medical illnesses (especially
seizure, heart failure, urinary tract infection and acute kidney injury). In such cases, albuminuria is
generally mild, and short-lived (< 3 months). In a prospective study involving 241 participants, the intraindividual coefficients of variation of the ACR in a first morning void and 24-h timed urine collection
were approximately 19% [112]. There is broad consensus that persistent albuminuria/proteinuria
signifying the presence of CKD requires the demonstration of albuminuria/proteinuria on at least 2
occasions over a 3 month period [10-15]. Reductions in proteinuria following commencement of
antiproteinuric therapy for CKD (e.g. angiotensin converting enzyme inhibition) have been associated
with reduced risks of both CKD progression and cardiovascular disease.
4. Other diagnostic evaluations in patients with CKD
In addition to the abovementioned investigations to diagnose the presence of CKD, other investigations
are often warranted to evaluate the potential complications of CKD and/or potential underlying causes
for which specific treatment might be warranted. Assessment of fasting lipids is warranted in view of the
greatly heightened risk of cardiovascular events in patients with CKD [21, 23, 26, 32-44] and the fact
that lipid lowering therapy with statins and ezetimibe has been shown in a large randomised controlled
trial to reduce the risk of cardiovascular events in patients with CKD[113], Similarly, evaluation of
albumin, bicarbonate, calcium, phosphate, PTH and haemoglobin are warranted, particularly in more
advanced CKD, based on population studies demonstrating significant increases in the prevalence of
hypoalbuminaemia, acidosis, hypocalcaemia, hyperphosphataemia, hyperparathyroidism and anaemia
as GFR declines[114]. For example, in a study of 30,528 participants in the US National Health and
Nutrition Examination Survey (NHANES) conducted in 1988-1994 and 1999-2006, the prevalence of
hyperparathyroidism was 9.1%, 11.1%, 28.2%, and 72.5% for CKD stages 1, 2, 3 and 4,
respectively[114]. Similarly, a prospective, community-based, non-interventional, prospective cohort
study of 1814 patients (SEEK study) observed increasing prevalence of hyperparathyroidism with
declining GFR (>80 ml/min/1.73 m2 12%, 7079 ml/min/1.73 m2 17%, 60-69 ml/min/1.73 m2 21%,
<60 ml/min/1.73 m2 56%)[115].Hypocalcaemia and hypophosphataemia generally became apparent at
eGFR values below 45 ml/min/1.73 m2 (at eGFR values< 20 ml/min/1.73 m2, the risks were 15% and
30%, respectively). 25-hydroxy-vitamin D deficiency prevalence remained stable until eGFR values fell
below 30 ml/min/1.73 m2 (14% in stage 3 CKD and 26% in stage 4 CKD) [115]. Based on the study of
a nationally representative sample of 15,625 noninstitutionalized adults aged 20 years and older,
participating in NHANES III, the prevalence of anaemia has also been shown to increase from 1% in
stage 2 CKD to 9% in stage 3 CKD to 33% in stage 4 CKD among men and to 67% among women in
stage 4 CKD.[116] . Finally, depending on the clinical setting, it may be appropriate to screen for certain
treatable conditions causing CKD, including autoimmune (eg SLE, Goodpastures disease, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, etc), infective (hepatitis B and C, HIV),
glomerulonephritic or neoplastic aetiologies (multiple myeloma).
stratification system based on combined eGFR and albuminuria staging is not appreciably enhanced by
incorporation of other clinical and laboratory variables. Because of high intra-individual variation in both
eGFR and albuminuria, the diagnosis of CKD requires confirmation of a low eGFR and/or albuminuria
on at least 2 occasions over a 3 month period.
damage to native kidneys, presumed damage to the kidney transplant based on studies of
protocol biopsies, and need for life-long care caused by complications of prior CKD.
I.A.7 Do not include cause of kidney disease in definition of CKD. Identification of the cause of kidney
disease is one of the goals of evaluation of CKD, and may lead to changes in management of
CKD. However, CKD can be detected without knowledge of its cause, ascertainment of the
cause may require specialized knowledge and procedures not available to the vast majority of
clinicians who encounter and can detect CKD. Importantly, the cause of CKD cannot always be
determined despite extensive evaluation. Thus, it is not practical to include the cause of CKD as
part of the definition. However, CKD can be classified by cause, as described below.
1.B Classification of Chronic Kidney Disease (Table 4)
In principle, CKD could be classified according to severity, diagnosis, treatment and prognosis.
Classification systems can be simple or complex. The choice of a classification system depends on
answers to several questions:
To whom is the classification system addressed?
Can we build a system that is useful to most clinicians, with additional complexity that is useful to
some?
Can the classification system be linked to Action Plans? An action plan should be evidencebased, but modifiable based on considerations for different populations, and individualized based
on patient circumstances.
I.B.1. Retain classification based on severity. There was agreement with initial classification based on
level of GFR, using GFR estimating equations. This initial classification is simple, and can be
linked to Action Plans. Because of imprecision of GFR estimates at higher range of GFR, it may
be difficult to distinguish Stages 1 and 2. Alternative terms such as stage, class, or grade can
vary depending on local interpretation and language.
I.B.2. Add classification based on treatment by dialysis or transplantation. This is necessary to link with
clinical care and policy, especially regarding reimbursement. To this end use the following suffix:
T for all kidney transplant recipients, at any level of GFR (CKD Stages 1-5).
D for dialysis, for CKD stage 5 for patients treated by dialysis. Irrespective of the level of
GFR at which dialysis is initiated, all patients treated by dialysis are CKD Stage 5D.
I.B.3. Encourage further consensus development on classification by cause of kidney disease. Clinical
evaluation for CKD should include elucidation of the cause of disease. As discussed above,
cause of disease cannot be ascertained in all cases. Classification based on cause of disease
would be desirable, but would require a uniform taxonomy that does not currently exist. This
would be an important area for further consensus development.
I.B.4. Further research is necessary to allow classification by prognosis. Stratification of risk for the
major outcomes of CKD (loss of kidney function and CVD) are be based in part, on level of GFR
(CKD stage), and cause of kidney disease (Figure 2A). Other factors are also important and
could be considered in risk stratification, such as magnitude of albuminuria (Figure 2B). It is likely
that these and other risk factors contribute differentially to the risk of different outcomes (Table 5).
Research is needed to elucidate.
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July 2012
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CONFLICT OF INTEREST
David Johnson has a level II b. conflict of interest for receiving speaker honoraria and advisors fees
from several companies related to anaemia, CKD-MBD, hypertension and cardiovascular disease
between 2008 and 2012.
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July 2012
Page 13 of 31
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
________________________________________________________________________________________________________________________
Early Chronic Kidney Disease
July 2012
Page 14 of 31
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
Eckardt K-U, Berns JS, Rocco MV et al. Definition and classification of CKD: the
debate should be about patient prognosis--a position statement from KDOQI and
KDIGO. American Journal of Kidney Diseases. 2009; 53: 915-20.
Fox CS, Larson MG, Leip EP et al. Predictors of new-onset kidney disease in a
community-based population. JAMA. 2004; 291: 844-50.
Eriksen BO and Ingebretsen OC. The progression of chronic kidney disease: a 10year population-based study of the effects of gender and age. Kidney International.
2006; 69: 375-82.
So WY, Kong APS, Ma RCW et al. Glomerular filtration rate, cardiorenal end points,
and all-cause mortality in type 2 diabetic patients. Diabetes Care. 2006; 29: 204652.
Johnson ES, Thorp ML, Platt RW et al. Predicting the risk of dialysis and transplant
among patients with CKD: a retrospective cohort study. American Journal of Kidney
Diseases. 2008; 52: 653-60.
Johnson ES, Thorp ML, Yang X et al. Predicting renal replacement therapy and
mortality in CKD. American Journal of Kidney Diseases. 2007; 50: 559-65.
Ninomiya T, Perkovic V, de Galan BE et al. Albuminuria and kidney function
independently predict cardiovascular and renal outcomes in diabetes. Journal of the
American Society of Nephrology. 2009; 20: 1813-21.
Shlipak MG, Stehman-Breen C, Fried LF et al. The presence of frailty in elderly
persons with chronic renal insufficiency. American Journal of Kidney Diseases.
2004; 43: 861-7.
Roderick PJ, Atkins RJ, Smeeth L et al. Detecting chronic kidney disease in older
people; what are the implications? Age & Ageing. 2008; 37: 179-86.
Kurella M, Chertow GM, Fried LF et al. Chronic kidney disease and cognitive
impairment in the elderly: the health, aging, and body composition study. Journal of
the American Society of Nephrology. 2005; 16: 2127-33.
Roderick PJ, Atkins RJ, Smeeth L et al. CKD and mortality risk in older people: a
community-based population study in the United Kingdom. American Journal of
Kidney Diseases. 2009; 53: 950-60.
Corsonello A, Pedone C, Corica F et al. Concealed renal failure and adverse drug
reactions in older patients with type 2 diabetes mellitus. Journals of Gerontology
Series A-Biological Sciences & Medical Sciences. 2005; 60: 1147-51.
Vanholder R, Massy Z, Argiles A et al. Chronic kidney disease as cause of
cardiovascular morbidity and mortality. Nephrology Dialysis Transplantation. 2005;
20: 1048-56.
Go AS, Chertow GM, Fan D et al. Chronic kidney disease and the risks of death,
cardiovascular events, and hospitalization. New England Journal of Medicine. 2004;
351: 1296-305.
Tokmakova MP, Skali H, Kenchaiah S et al. Chronic kidney disease, cardiovascular
risk, and response to angiotensin-converting enzyme inhibition after myocardial
infarction: the Survival And Ventricular Enlargement (SAVE) study. Circulation.
2004; 110: 3667-73.
McCullough PA, Jurkovitz CT, Pergola PE et al. Independent components of
chronic kidney disease as a cardiovascular risk state: results from the Kidney Early
Evaluation Program (KEEP). Archives of Internal Medicine. 2007; 167: 1122-9.
Patel UD, Young EW, Ojo AO et al. CKD progression and mortality among older
patients with diabetes. American Journal of Kidney Diseases. 2005; 46: 406-14.
Bax L, Algra A, Mali WPTM et al. Renal function as a risk indicator for
cardiovascular events in 3216 patients with manifest arterial disease.
Atherosclerosis. 2008; 200: 184-90.
________________________________________________________________________________________________________________________
Early Chronic Kidney Disease
July 2012
Page 15 of 31
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
Brantsma AH, Bakker SJL, de Zeeuw D et al. Extended prognostic value of urinary
albumin excretion for cardiovascular events. Journal of the American Society of
Nephrology. 2008; 19: 1785-91.
Parikh NI, Hwang S-J, Larson MG et al. Chronic kidney disease as a predictor of
cardiovascular disease (from the Framingham Heart Study). American Journal of
Cardiology. 2008; 102: 47-53.
Nickolas TL, Khatri M, Boden-Albala B et al. The association between kidney
disease and cardiovascular risk in a multiethnic cohort: findings from the Northern
Manhattan Study (NOMAS). Stroke. 2008; 39: 2876-9.
Coceani M, Carpeggiani C, and L'Abbate A. Comparative prognostic value of
glomerular filtration rate estimating formulas in ischaemic heart disease. European
Journal of Cardiovascular Prevention & Rehabilitation. 2008; 15: 423-7.
Foster MC, Hwang S-J, Larson MG et al. Cross-classification of microalbuminuria
and reduced glomerular filtration rate: associations between cardiovascular disease
risk factors and clinical outcomes. Archives of Internal Medicine. 2007; 167: 138692.
Shara NM, Resnick HE, Lu L et al. Decreased GFR estimated by MDRD or
Cockcroft-Gault equation predicts incident CVD: the strong heart study. Journal of
Nephrology. 2009; 22: 373-80.
Weiner DE, Tabatabai S, Tighiouart H et al. Cardiovascular outcomes and all-cause
mortality: exploring the interaction between CKD and cardiovascular disease.
American Journal of Kidney Diseases. 2006; 48: 392-401.
Bello AK, Hemmelgarn B, Lloyd A et al. Associations among estimated glomerular
filtration rate, proteinuria, and adverse cardiovascular outcomes. Clinical Journal of
The American Society of Nephrology: CJASN. 2011; 6: 1418-26.
Di Angelantonio E, Chowdhury R, Sarwar N et al. Chronic kidney disease and risk
of major cardiovascular disease and non-vascular mortality: prospective population
based cohort study. BMJ. 2010; 341: c4986.
Ford I, Bezlyak V, Stott DJ et al. Reduced glomerular filtration rate and its
association with clinical outcome in older patients at risk of vascular events:
secondary analysis. PLoS Medicine / Public Library of Science. 2009; 6: e16.
Ravera M, Noberasco G, Re M et al. Chronic kidney disease and cardiovascular
risk in hypertensive type 2 diabetics: a primary care perspective. Nephrology
Dialysis Transplantation. 2009; 24: 1528-33.
Hillege HL, Nitsch D, Pfeffer MA et al. Renal function as a predictor of outcome in a
broad spectrum of patients with heart failure. Circulation. 2006; 113: 671-8.
Nag S, Bilous R, Kelly W et al. All-cause and cardiovascular mortality in diabetic
subjects increases significantly with reduced estimated glomerular filtration rate
(eGFR): 10 years' data from the South Tees Diabetes Mortality study. Diabetic
Medicine. 2007; 24: 10-7.
Kurth T, de Jong PE, Cook NR et al. Kidney function and risk of cardiovascular
disease and mortality in women: a prospective cohort study. BMJ. 2009; 338:
b2392.
Cheng T-YD, Wen S-F, Astor BC et al. Mortality risks for all causes and
cardiovascular diseases and reduced GFR in a middle-aged working population in
Taiwan. American Journal of Kidney Diseases. 2008; 52: 1051-60.
Chien K-L, Hsu H-C, Lee Y-T et al. Renal function and metabolic syndrome
components on cardiovascular and all-cause mortality. Atherosclerosis. 2008; 197:
860-7.
Deo R, Fyr CLW, Fried LF et al. Kidney dysfunction and fatal cardiovascular
disease--an association independent of atherosclerotic events: results from the
________________________________________________________________________________________________________________________
Early Chronic Kidney Disease
July 2012
Page 16 of 31
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
Health, Aging, and Body Composition (Health ABC) study. American Heart Journal.
2008; 155: 62-8.
Deo R, Lin F, Vittinghoff E et al. Kidney dysfunction and sudden cardiac death
among women with coronary heart disease. Hypertension. 2008; 51: 1578-82.
Tonelli M, Wiebe N, Culleton B et al. Chronic kidney disease and mortality risk: a
systematic review. Journal of the American Society of Nephrology. 2006; 17: 203447.
O'Hare AM, Bertenthal D, Covinsky KE et al. Mortality risk stratification in chronic
kidney disease: one size for all ages? Journal of the American Society of
Nephrology. 2006; 17: 846-53.
Coresh J, Astor BC, Greene T et al. Prevalence of chronic kidney disease and
decreased kidney function in the adult US population: Third National Health and
Nutrition Examination Survey. American Journal of Kidney Diseases. 2003; 41: 112.
Lindeman RD, Tobin J, and Shock NW. Longitudinal studies on the rate of decline
in renal function with age. Journal of the American Geriatrics Society. 1985; 33:
278-85.
Fliser D, Franek E, Joest M et al. Renal function in the elderly: impact of
hypertension and cardiac function. Kidney International. 1997; 51: 1196-204.
Baggio B, Budakovic A, Perissinotto E et al. Atherosclerotic risk factors and renal
function in the elderly: the role of hyperfibrinogenaemia and smoking. Results from
the Italian Longitudinal Study on Ageing (ILSA). Nephrology Dialysis
Transplantation. 2005; 20: 114-23.
Raymond NT, Zehnder D, Smith SCH et al. Elevated relative mortality risk with
mild-to-moderate chronic kidney disease decreases with age. Nephrology Dialysis
Transplantation. 2007; 22: 3214-20.
Fried LP, Kronmal RA, Newman AB et al. Risk factors for 5-year mortality in older
adults: the Cardiovascular Health Study. JAMA. 1998; 279: 585-92.
Shlipak MG, Heidenreich PA, Noguchi H et al. Association of renal insufficiency with
treatment and outcomes after myocardial infarction in elderly patients. Annals of
Internal Medicine. 2002; 137: 555-62.
Manjunath G, Tighiouart H, Coresh J et al. Level of kidney function as a risk factor
for cardiovascular outcomes in the elderly. Kidney International. 2003; 63: 1121-9.
O'Hare AM, Choi AI, Bertenthal D et al. Age affects outcomes in chronic kidney
disease. Journal of the American Society of Nephrology. 2007; 18: 2758-65.
Mathew TH, Johnson DW, Jones GRD et al. Chronic kidney disease and automatic
reporting of estimated glomerular filtration rate: revised recommendations. Medical
Journal of Australia. 2007; 187: 459-63.
Levey AS, de Jong PE, Coresh J et al. The definition, classification and prognosis
of chronic kidney disease: a KDIGO Controversies Conference report. Kidney
International. 2011; 80: 17-28.
Neugarten J, Acharya A, and Silbiger SR. Effect of gender on the progression of
nondiabetic renal disease: a meta-analysis. Journal of the American Society of
Nephrology. 2000; 11: 319-29.
Haroun MK, Jaar BG, Hoffman SC et al. Risk factors for chronic kidney disease: a
prospective study of 23,534 men and women in Washington County, Maryland.
Journal of the American Society of Nephrology. 2003; 14: 2934-41.
Jafar TH, Schmid CH, Stark PC et al. The rate of progression of renal disease may
not be slower in women compared with men: a patient-level meta-analysis.
Nephrology Dialysis Transplantation. 2003; 18: 2047-53.
________________________________________________________________________________________________________________________
Early Chronic Kidney Disease
July 2012
Page 17 of 31
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
Atkins RC, Briganti EM, Zimmet PZ et al. Association between albuminuria and
proteinuria in the general population: the AusDiab Study. Nephrology Dialysis
Transplantation. 2003; 18: 2170-4.
Garg AX, Kiberd BA, Clark WF et al. Albuminuria and renal insufficiency prevalence
guides population screening: results from the NHANES III. Kidney International.
2002; 61: 2165-75.
Iseki K, Ikemiya Y, Iseki C et al. Proteinuria and the risk of developing end-stage
renal disease. Kidney International. 2003; 63: 1468-74.
Ishani A, Grandits GA, Grimm RH et al. Association of single measurements of
dipstick proteinuria, estimated glomerular filtration rate, and hematocrit with 25-year
incidence of end-stage renal disease in the multiple risk factor intervention trial.
Journal of the American Society of Nephrology. 2006; 17: 1444-52.
Keane WF, Zhang Z, Lyle PA et al. Risk scores for predicting outcomes in patients
with type 2 diabetes and nephropathy: the RENAAL study. Clinical Journal of The
American Society of Nephrology: CJASN. 2006; 1: 761-7.
Lea J, Greene T, Hebert L et al. The relationship between magnitude of proteinuria
reduction and risk of end-stage renal disease: results of the African American study
of kidney disease and hypertension. Archives of Internal Medicine. 2005; 165: 94753.
Hallan SI, Ritz E, Lydersen S et al. Combining GFR and albuminuria to classify
CKD improves prediction of ESRD. Journal of the American Society of Nephrology.
2009; 20: 1069-77.
van der Velde M, Halbesma N, de Charro FT et al. Screening for albuminuria
identifies individuals at increased renal risk. Journal of the American Society of
Nephrology. 2009; 20: 852-62.
Pavkov ME, Knowler WC, Hanson RL et al. Predictive power of sequential
measures of albuminuria for progression to ESRD or death in Pima Indians with
type 2 diabetes. American Journal of Kidney Diseases. 2008; 51: 759-66.
Yoshida T, Takei T, Shirota S et al. Risk factors for progression in patients with
early-stage chronic kidney disease in the Japanese population. Internal Medicine.
2008; 47: 1859-64.
Hoy WE, Wang Z, VanBuynder P et al. The natural history of renal disease in
Australian Aborigines. Part 2. Albuminuria predicts natural death and renal failure.
Kidney International. 2001; 60: 249-56.
Berrut G, Bouhanick B, Fabbri P et al. Microalbuminuria as a predictor of a drop in
glomerular filtration rate in subjects with non-insulin-dependent diabetes mellitus
and hypertension. Clinical Nephrology. 1997; 48: 92-7.
Klausen K, Borch-Johnsen K, Feldt-Rasmussen B et al. Very low levels of
microalbuminuria are associated with increased risk of coronary heart disease and
death independently of renal function, hypertension, and diabetes. Circulation.
2004; 110: 32-5.
Hillege HL, Fidler V, Diercks GFH et al. Urinary albumin excretion predicts
cardiovascular and noncardiovascular mortality in general population. Circulation.
2002; 106: 1777-82.
Yuyun MF, Khaw K-T, Luben R et al. Microalbuminuria, cardiovascular risk factors
and cardiovascular morbidity in a British population: the EPIC-Norfolk populationbased study. European Journal of Cardiovascular Prevention & Rehabilitation.
2004; 11: 207-13.
Yuyun MF, Khaw KT, Luben R et al. Microalbuminuria and stroke in a British
population: the European Prospective Investigation into Cancer in Norfolk (EPICNorfolk) population study. Journal of Internal Medicine. 2004; 255: 247-56.
________________________________________________________________________________________________________________________
Early Chronic Kidney Disease
July 2012
Page 18 of 31
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
Yuyun MF, Khaw K-T, Luben R et al. Microalbuminuria independently predicts allcause and cardiovascular mortality in a British population: The European
Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population study.
International Journal of Epidemiology. 2004; 33: 189-98.
Yuyun MF, Khaw K-T, Luben R et al. A prospective study of microalbuminuria and
incident coronary heart disease and its prognostic significance in a British
population: the EPIC-Norfolk study. American Journal of Epidemiology. 2004; 159:
284-93.
Brown MJ, Palmer CR, Castaigne A et al. Morbidity and mortality in patients
randomised to double-blind treatment with a long-acting calcium-channel blocker or
diuretic in the International Nifedipine GITS study: Intervention as a Goal in
Hypertension Treatment (INSIGHT). Lancet. 2000; 356: 366-72.
Hallan S, Astor B, Romundstad S et al. Association of kidney function and
albuminuria with cardiovascular mortality in older vs younger individuals: The HUNT
II Study. Archives of Internal Medicine. 2007; 167: 2490-6.
Irie F, Iso H, Sairenchi T et al. The relationships of proteinuria, serum creatinine,
glomerular filtration rate with cardiovascular disease mortality in Japanese general
population. Kidney International. 2006; 69: 1264-71.
Madison JR, Spies C, Schatz IJ et al. Proteinuria and risk for stroke and coronary
heart disease during 27 years of follow-up: the Honolulu Heart Program. Archives of
Internal Medicine. 2006; 166: 884-9.
Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S et al. Urinary albumin
excretion. An independent predictor of ischemic heart disease. Arteriosclerosis,
Thrombosis & Vascular Biology. 1999; 19: 1992-7.
Agrawal B, Berger A, Wolf K et al. Microalbuminuria screening by reagent strip
predicts cardiovascular risk in hypertension. Journal of Hypertension. 1996; 14:
223-8.
Brantsma AH, Bakker SJL, Hillege HL et al. Cardiovascular and renal outcome in
subjects with K/DOQI stage 1-3 chronic kidney disease: the importance of urinary
albumin excretion. Nephrology Dialysis Transplantation. 2008; 23: 3851-8.
Bouchi R, Babazono T, Nyumura I et al. Is a reduced estimated glomerular filtration
rate a risk factor for stroke in patients with type 2 diabetes? Hypertension Research
- Clinical & Experimental. 2009; 32: 381-6.
Gullion CM, Keith DS, Nichols GA et al. Impact of comorbidities on mortality in
managed care patients with CKD. American Journal of Kidney Diseases. 2006; 48:
212-20.
Brenner BM, Cooper ME, de Zeeuw D et al. Effects of losartan on renal and
cardiovascular outcomes in patients with type 2 diabetes and nephropathy. New
England Journal of Medicine. 2001; 345: 861-9.
Iseki K, Kinjo K, Iseki C et al. Relationship between predicted creatinine clearance
and proteinuria and the risk of developing ESRD in Okinawa, Japan. American
Journal of Kidney Diseases. 2004; 44: 806-14.
Hemmelgarn BR, Manns BJ, Lloyd A et al. Relation between kidney function,
proteinuria, and adverse outcomes. JAMA. 2010; 303: 423-9.
Nerpin E, Ingelsson E, Riserus U et al. The combined contribution of albuminuria
and glomerular filtration rate to the prediction of cardiovascular mortality in elderly
men. Nephrology Dialysis Transplantation. 2011; 26: 2820-7.
van der Velde M, Matsushita K, Coresh J et al. Lower estimated glomerular filtration
rate and higher albuminuria are associated with all-cause and cardiovascular
mortality. A collaborative meta-analysis of high-risk population cohorts. Kidney
International. 2011; 79: 1341-52.
________________________________________________________________________________________________________________________
Early Chronic Kidney Disease
July 2012
Page 19 of 31
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
Berhane AM, Weil EJ, Knowler WC et al. Albuminuria and estimated glomerular
filtration rate as predictors of diabetic end-stage renal disease and death. Clinical
Journal of The American Society of Nephrology: CJASN. 2011; 6: 2444-51.
Hoefield RA, Kalra PA, Baker PG et al. The use of eGFR and ACR to predict
decline in renal function in people with diabetes. Nephrology Dialysis
Transplantation. 2011; 26: 887-92.
Tonelli M, Muntner P, Lloyd A et al. Using proteinuria and estimated glomerular
filtration rate to classify risk in patients with chronic kidney disease: a cohort study.
Annals of Internal Medicine. 2011; 154: 12-21.
Ohashi Y, Sakai K, Tanaka Y et al. Reappraisal of proteinuria and estimated GFR
to predict progression to ESRD or death for hospitalized chronic kidney disease
patients. Renal Failure. 2011; 33: 31-9.
Farbom P, Wahlstrand B, Almgren P et al. Interaction between renal function and
microalbuminuria for cardiovascular risk in hypertension: the nordic diltiazem study.
Hypertension. 2008; 52: 115-22.
Mizuma Y, Watanabe Y, Ozasa K et al. Validity of sonographic screening for the
detection of abdominal cancers. Journal of Clinical Ultrasound. 2002; 30: 408-15.
Malaeb BS, Martin DJ, Littooy FN et al. The utility of screening renal
ultrasonography: identifying renal cell carcinoma in an elderly asymptomatic
population. BJU International. 2005; 95: 977-81.
Filipas D, Spix C, Schulz-Lampel D et al. Screening for renal cell carcinoma using
ultrasonography: a feasibility study. BJU International. 2003; 91: 595-9.
Witte EC, Lambers Heerspink HJ, de Zeeuw D et al. First morning voids are more
reliable than spot urine samples to assess microalbuminuria. Journal of the
American Society of Nephrology. 2009; 20: 436-43.
Baigent C, Landray MJ, Reith C et al. The effects of lowering LDL cholesterol with
simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart
and Renal Protection): a randomised placebo-controlled trial. The Lancet. 2011;
377: 2181-2192.
Inker LA, Tonelli M, Hemmelgarn BR et al. Comparison of Concurrent
Complications of CKD by 2 Risk Categorization Systems. American journal of
kidney diseases : the official journal of the National Kidney Foundation. 2012; 59:
372-381.
Levin A, Bakris GL, Molitch M et al. Prevalence of abnormal serum vitamin D, PTH,
calcium, and phosphorus in patients with chronic kidney disease: results of the
study to evaluate early kidney disease.[Erratum appears in Kidney Int. 2009
Jun;75(11):1237]. Kidney International. 2007; 71: 31-8.
Astor BC, Muntner P, Levin A et al. Association of kidney function with anemia: the
Third National Health and Nutrition Examination Survey (1988-1994). Archives of
Internal Medicine. 2002; 162: 1401.
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APPENDICES
Table 1. Characteristics of included studies
Study ID
Study design
Participants
Follow up
1) Kidney Function (GFR) ii. Does age modify the relationship between GFR and outcomes?
2
OHare et al
(2006) [57]
2,583,911
Cohort
Mean 3.17
0.62 years
OHare et al
(2007) [66]
209,622
Cohort
3.2 years
Eriksen et al
(2006) [22]
3,047
Cohort
Median 44
months
Roderick et al
(2009) [30]
13,177
Cohort
Median 7.3
years
______________________________________________________________________________________________________________________________________________________________________________________
Early Chronic Kidney Disease
July 2012
Page 21 of 31
Study ID
Study design
Participants
Follow up
45
studies
n=
1,555,332
Meta-analysis
N/A
iii) Does gender modify the relationship between GFR and outcomes?
Neugarten et al
(2000) [69]
N/A
Haroun et al
(2003) [70]
23,534
Jafar et al (2003)
[71]
11
studies
Meta-analysis
included 68
studies
Prospective
observational
N/A
20 years
Meta-analysis
Mean 2.2
years
Mean baseline SBP was greater in women than in men: 151 s 147 mmHg
(P<0.001)
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Early Chronic Kidney Disease
July 2012
Page 22 of 31
Study ID
Study design
Participants
Follow up
John et al (2004)
[4]
3,822
Cohort
Mean 31.3
months
Male sex, low GFR, and non-referral were associated with poor outcomes
Women who were not referred to a renal unit had a significantly reduced risk
of all-cause mortality compared with unreferred men (HR 0.73, 95% CI: 0.65
to 0.82, P<0.001
Cardiovascular disease, cancer and infection were the most common causes
of death
Eriksen et al
(2006) [22]
3,047
Cohort
Median 44
months
2) Kidney Damage
Atkins et al
(2003) [72]
10,596
Cross sectional
N/A
Albuminuria was strongly correlated with total protein excretion in the elderly,
as well as those with diabetes, hypertension, obesity and renal impairment (P
< 0.001)
Albuminuria was detected in 6.8% (95%CI: 5.5 to 8.1%) of participants and
proteinuria in 2.4% (95%CI: 1.6 to 3.1%)
Albuminuria detection consisted of 6.1% micro- and 0.7% macroalbuminuria
Albuminuria performed well as a screening test for proteinuria: sensitivity
91.7% (95%CI: 87.7 to 94.5%), specificity 95.3% (95%CI: 94.9 to 95.7%) and
negative predictive value 99.8% (95%CI: 99.7 to 99.9%)
However among those with proteinuria, 8% excreted albumin within the
normal range
Garg et al (2002)
[73]
14,622
Cross sectional
N/A
3.8 years
1,094
Cohort
______________________________________________________________________________________________________________________________________________________________________________________
Early Chronic Kidney Disease
July 2012
Page 23 of 31
Study ID
Study design
[77]
Iseki et al (2004)
[100]
95,255
Cohort
Participants
Follow up
(mean)
7 years
10,640
Cohort
4.3 years
(mean)
Farbom et al
(2008) [108]
10,881
Cohort
4.5 years
Hallan et al
(2009) [78]
65,589
Cohort
10.3 years
Hallan et al
9,709
Cohort
8.3 years
______________________________________________________________________________________________________________________________________________________________________________________
Early Chronic Kidney Disease
July 2012
Page 24 of 31
Study ID
Study design
(2007) [91]
Participants
Follow up
2b) Haematuria
Chadban et al
(2003) [2]
11,247
Cross-sectional
N/A
Haematuria was detected initially (dipstick test), in 5.2% of cases (95%CI: 4.3
to 6.1%)
Haematuria was confirmed in 4.6% of cases (95%CI: 3.8 to 5.4%) by
microscopy or repeat dipstick, and was more common in women than in men
Age, gender and hypertension were independently associated with
______________________________________________________________________________________________________________________________________________________________________________________
Early Chronic Kidney Disease
July 2012
Page 25 of 31
Study ID
Study design
Participants
Follow up
Iseki et al (2003)
[74]
106,177
Cohort
17 years
420 people (246 men and 174 women) entered the ESRD program
Haematuria was predictive of developing ESRD, adjusted odds ratio 1.18
(95%CI: 1.06 to 1.32; p=0.002). However the OR was no longer significant
when serum creatinine was included in the model 1.13 (95%CI: 0.95 to 1.36)
4.
241
Cohort
Baigent et al
(2011)[113]
(SHARP Study)
9,270
(4,650 =
treatment
4,620 =
placebo)
RCT
4.9 years
Inker et al
(2012)[114]
30,528
Survey
N/A
Astor et al
15,625
Survey
N/A
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Early Chronic Kidney Disease
July 2012
Page 26 of 31
Study ID
(2002)[116]
Study design
Participants
National Health and Nutrition
Examination Survey (NHANES
III). Non-institutionalised adults
20 years and older.
Follow up
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Early Chronic Kidney Disease
July 2012
Page 27 of 31
Study Design
Setting
Participants
Intervention
(experimental
group)
Intervention
(control
group)
Follow
up
(months)
Multicentre, (UK,
Germany, Australia,
China, France,
Denmark, Thailand,
Sweden, Norway,
Czech Republic,
Poland,
Netherlands,
Finland, USA,
Malaysia, Canada
and New Zealand)
CKD patients
aged 40 years
or older whether
or not on
dialysis.
Simvastatin
(20mg) plus
Ezetimibe
(10mg) daily
dose
Matching
placebo
4.9 years
Comments
9,270
Randomised
controlled
clinical trial
Method of
allocation
concealment *
Blinding
(participants)
(outcome
assessors)
Intentionto-treat
analysis
Loss to
follow up
(%)
Comments
(investigators)
Yes
Yes
Yes
Yes
Computergenerated
* Choose between: central; third party (e.g. pharmacy); sequentially labelled opaque sealed envelopes; alternation; not specified.
Choose between: yes; no; unclear.
Quality score How successfully do you think the study minimised bias? Choose between: very well (+); okay (); poorly ().
______________________________________________________________________________________________________________________________________________________________________________________
Early Chronic Kidney Disease
July 2012
Page 28 of 31
Study ID (author,
year)
Intervention group
(no. of patients
with events/no. of
patients exposed)
Death from
cardiovascular
causes
Non-fatal myocardial
infarction
Baigent et al
(2011)[113]
(SHARP Study)
Baigent et al
(2011)[113]
(SHARP Study)
Baigent et al
(2011)[113]
(SHARP Study)
Simvastatin+E
91 / 4630
Control group
(no. of patients
with events/no.
of patients
exposed)
90 / 4620
Risk difference
(RD) [95% CI]
Importance**
Critical
Simvastatin+E
134/ 4630
159 / 4620
Important
Simvastatin+E
131/ 4630
174/ 4620
Critical
Methodological quality, consistency across studies and directness of the evidence (generalisability/applicability).
** The GRADE system uses the following 3 categories to rank the importance of end points:
critical for decision making
important but not critical for decision making
not important for decision making (of lower importance to patients)
*
NA not applicable
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July 2012
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Figure 1.
National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation,
classification, and stratification. American Journal of Kidney Diseases. 2002; 39: S1-266.
Figure 2.
National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation,
classification, and stratification. American Journal of Kidney Diseases. 2002; 39: S1-266.
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Early Chronic Kidney Disease
July 2012
Page 30 of 31
Figure 3.
National Collaborating Centre for Chronic Conditions, Chronic kidney disease: National clinical guideline for early
identification and management in adults in primary and secondary care. 2008, Royal College of Physicians:
London.
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July 2012
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