Diag Classification Staging ECKD PDF

Diagnosis, classification and staging of chronic
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
CLASSIFICATION AND STAGING

b. We recommend that the stages of CKD should be based on the combined indices of kidney
function (measured or estimated GFR) and kidney damage (albuminuria/proteinuria),
irrespective of the underlying diagnosis (1C).
2
Kidney function stage* GFR (mL/min/1.73 m ) Description
1 90 Normal or increased GFR

2 60-89 Normal or slightly decreased GFR
3A 45-59 Mild-moderate decrease in GFR
3B 30-44 Moderate-severe decrease in GFR
4 15-29 Severe decrease in GFR
5 <15 or on dialysis End-stage kidney failure
Kidney damage Urine albumin/ 24h urine Urine protein: 24h urine
stage* creatinine ratio albumin creatinine ratio protein
(mg/mmol) (mg/day) (mg/mmol) (mg/day)
Normoalbuminuria <2.5 (M) <30 <4 (M) <50
<3.5 (F) <6 (F)
Microalbuminuria 2.5-25 (M) 30-300 4-40 (M) 50-500
3.5-35 (F) 6-60 (F)
Macroalbuminuria >25 (M) >300 >40 (M) >500
>35 (F) >60 (F)
*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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Early Chronic Kidney Disease July 2012 Page 1 of 31
Albuminuria stage
Kidney GFR Normal Microalbuminuria Macroalbuminuria

2
function (mL/min/1.73m ) (urine ACR mg/mmol) (urine ACR mg/mmol) (urine ACR mg/mmol)
stage Male: < 2.5 Male: 2.5-25 Male: > 25
Female: < 3.5 Female: 3.5-35 Female: > 35
Not CKD unless
1 90
haematuria, structural or
pathological abnormalities
2 60-89
present
3a 45-59
3b 30-44
4 15-29
5 <15 or on dialysis
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).
UNGRADED SUGGESTIONS FOR CLINICAL CARE
DIAGNOSIS
i. 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: Then carry out the following test:
Has diabetes HbA1C
Has eGFR < 60 mL/min/1.73m2 Serum calcium, phosphate, PTH, 25-
hydroxy-vitamin D and iron studies
Is > 40 years old Serum and urine electrophoresis
Has rash, arthritis or features of connective Anti-nuclear antibodies, Extractable
tissue disease nuclear antigens, Complement studies
Has pulmonary symptoms or deteriorating Anti-glomerular basement membrane
kidney function antibody, Anti-neutrophil cytoplasmic
antibody
Has risk factors for HBV, HCV and HIV HBV, HCV, HIV serology
Has persistent albuminuria >60-120 Refer to Nephrologist for consideration of
mg/mmol (approximately equivalent to 24hr renal biopsy
urinary protein >1-2 g/day)
IMPLEMENTATION AND AUDIT

Kidney Check Australia Taskforce (KCAT) education programs for primary health care providers should
incorporate the CARI Chronic kidney disease (CKD) classification system. KHA and KCAT should
commission audits of the awareness of the CARI CKD classification amongst primary health care
providers.
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
WHAT IS THE EVIDENCE?

No randomised controlled trials (RCTs) are available which address this issue. There are no RCTs of
outcomes following the application of a CKD diagnostic or staging system to the population in a primary
or institutional health care setting.
There is broad consensus that the diagnosis and staging of kidney disease should be based on 1)
kidney function; 2) kidney damage (particularly albuminuria/proteinuria); and 3) temporal factors (ie.
persistence or deterioration over time) [10-15]. There is reasonable observational cohort evidence
supporting a link between each of these factors and risk of CKD progression, cardiovascular disease
and other adverse clinical outcomes. The guideline group focused on the relationship between these
factors and clinical outcomes; the effects of age, race and gender as possible effect modifiers (and
would therefore need to be incorporated into any diagnostic or staging system); the value of combining
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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. What is the prognostic significance of GFR level in the population?
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 30-
59 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 all-
cause 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 all-
cause 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. What is the prognostic significance of albuminuria/proteinuria?
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
________________________________________________________________________________________________________________________
[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 intra-
individual 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, anti-
neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, etc), infective (hepatitis B and C, HIV),
glomerulonephritic or neoplastic aetiologies (multiple myeloma).
SUMMARY OF THE EVIDENCE

There are no RCTs on this topic. There are no randomized controlled trials or cohort studies of
outcomes following the application of a CKD staging system to the population in a primary or
institutional health care setting. In principle, CKD should be 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). GFR and albuminuria/proteinuria are strongly linked to the risks
of CKD progression and cardiovascular disease and provide synergistic, complementary risk
stratification information for CKD patients with respect to these outcomes. The predictive value of a risk
________________________________________________________________________________________________________________________
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.
WHAT DO THE OTHER GUIDELINES SAY?

Kidney Disease Outcomes Quality Initiative: Kidney Disease Outcomes Quality Initiative: [10]
Adverse outcomes of chronic kidney disease can often be prevented or delayed through early detection
and treatment. Earlier stages of chronic kidney disease can be detected through routine laboratory
measurements.
The presence of chronic kidney disease should be established, based on presence of kidney
damage and level of kidney function (glomerular filtration rate [GFR]), irrespective of diagnosis.
Among patients with chronic kidney disease, the stage of disease should be assigned based on the
level of kidney function, irrespective of diagnosis, according to the K/DOQI CKD classification
(Table 10) - Refer to Figure 1.
Chronic kidney disease has been defined according to the criteria listed in (Table 11) Refer to
Figure 2.
UK Renal Association: No recommendation.
Canadian Society of Nephrology: No recommendation.
European Best Practice Guidelines: No recommendation.
International Guidelines:
National Institute for Clinical Excellence (NICE): [11]

Refer to Figure 3.
R20 Use the suffix (p) to denote the presence of proteinuria when staging CKD.
R21 For the purposes of this classification define proteinuria as urinary albumin:creatinine ratio
(ACR) 30 mg/mmol or PCR 50 mg/mmol (approximately equivalent to urinary protein
excretion 0.5 g/24 hours)
R22 Stage 3 CKD should be split into two subcategories defined by:
GFR 4559 ml/min/1.73m2 (stage 3A) and
GFR 3044 ml/min/1.73m2 (stage 3B)
R23 At any given stage of CKD, management should not be influenced solely by age.*
* In people aged >70 years, an eGFR in the range 4559 ml/min/1.73m2, if stable over time and without
any other evidence of kidney damage, is unlikely to be associated with CKD-related complications.
Scottish Intercollegiate Guidelines Network (SIGN): [15]

Detecting kidney damage
In patients with diabetes, albumin/creatinine ratio may be used to exclude diabetic nephropathy
(B).
Albumin/creatinine ratio is recommended for detecting and monitoring diabetic nephropathy (C).
In patient groups with a high prevalence of proteinuria without diabetes protein/creatinine ratio
may be used to exclude chronic kidney disease (B).
In patients with established chronic kidney disease and without diabetes, measurement of
protein/creatinine ratio may be used to predict risk of progressive disease (D).
Patients with persisting isolated microscopic haematuria should be initially evaluated for urinary
tract infection and malignancy (D).
Measuring renal function
Where an assessment of glomerular filtration rate is required prediction equations should be
used in preference to 24-hour urine creatinine clearance or serum creatinine alone (C).
Classification of chronic kidney disease
To diagnose stages 1 and 2 CKD, additional evidence of kidney damage must be present, eg.
proteinuria. If proteinuria (>1 g/day or >100 mg/mmol) is present the suffix p should be added.
________________________________________________________________________________________________________________________
Stage 3 CKD should be split into two parts:
- Stage 3A: GFR 45-59 (ml/min/1.73m2)
- Stage 3B: GFR 30-44 (ml/min/1.73m2)
Patients on dialysis are classified as stage 5D.
The suffix T indicates patients with a functioning renal transplant (can be stages 1-5).
Kidney Disease: Improving Global Outcomes: [14] for Tables and Figures
I.A Definition of Chronic Kidney Disease
The K/DOQI definition of chronic kidney disease (Table 3) was accepted, with the following
clarifications:
I.A.1. Retain the term disease to convey importance. It is important that the definition use terms that
reflect an appropriate balance between emphasizing need for diagnosis and treatment as
opposed to that of labelling a risk condition as a disease. The K/DOQI definition of chronic kidney
disease as a disease is consistent with current usage of this term. The Oxford English
Dictionary (compact) defines a disease as A disorder of structure or function in a human, animal,
or plant, especially one that produces specific symptoms. Evidence in support of a disease
include clinical-pathological correlations (as defined by case series), associations with symptoms
or findings (as defined by cross-sectional analyses), and associations with outcomes (as defined
by longitudinal analyses). The use of the term disease in CKD is consistent with: (1) the need
for action to improve outcomes through prevention, detection, evaluation and treatment; (2)
providing a message for public, physician and patient education programs; (3) common usage;
and (4) its use in other conditions defined by findings and laboratory tests, such as hypertension,
diabetes, hyperlipidemia
I.A.2. Infer chronicity from documentation or presumption of kidney disease for >3 months. This
clarification allows clinical judgment about chronicity in the absence of past data on levels of GFR
or markers of kidney damage. In the future, it will be important to link the definition of chronicity
with definition of acute kidney disease.
I.A.3. Retain reduced GFR as a criterion for kidney disease. GFR is widely accepted as the best index
of kidney function. The rationale for a threshold level of GFR <60 ml/min/1.73 m2 is as follows:
It is substantially above the level associated with kidney failure
It is less than half the adult level of GFR
Lower levels are very infrequent in men or women at age <80 years
Lower levels are associated with complications of CKD
Lower levels are associated with adverse outcomes, including cardiovascular disease
morbidity and mortality in individuals with and without diabetes.
Lower levels can be detected with current estimating equations for GFR based on serum
creatinine, but not by serum creatinine alone.
I.A.4. Retain albuminuria as a marker for kidney damage. Threshold values for spot urine albumin to
creatinine ratio are discussed subsequently. The rationale for the recommended threshold (>
30mg/g) is as follows:
Threshold level is 2-3 times greater than the normal value.
Higher levels are infrequent in general population.
Higher levels are the earliest marker of kidney damage due to diabetes, glomerular diseases,
and hypertension.
Higher levels are associated with adverse outcomes, including progression of kidney disease
and cardiovascular disease in individuals with and without diabetic mellitus.
Therapies that reduce albuminuria are associated with slowing the progression of diabetic and
non-diabetic kidney disease.
I.A.5. Allow clinical judgment regarding the relevance of other markers of kidney damage. Other
markers of kidney damage include abnormalities in the urine sediment (casts, tubular epithelial
cells); abnormalities in imaging studies (polycystic kidneys, hydronephrosis, small
echogenickidneys); and abnormalities in the composition of the blood and urine that define
tubular syndromes(renal tubular acidosis, nephrogenic diabetes insipidus, Fanconi syndrome,
etc). The K/DOQI guidelines address the clinical relevance of these abnormalities based on
whether they can lead to decreased kidney function. This language is included in the definition
of CKD (Table 3).
I.A.6. Consider all kidney transplants recipients to have chronic kidney disease, irrespective of GFR
level or presence or absence of markers of kidney damage. The rationale for this is based on
________________________________________________________________________________________________________________________
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 evidence-
based, 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.
SUGGESTIONS FOR FUTURE RESEARCH

1. Prospective, longitudinal study of the predictive value of CARI CKD staging system in Australian
population (AusDiab follow-on study).
2. Prospective, longitudinal studies of the outcomes of low GFR in referred versus nonreferred
populations.
3. Determination of whether there are different predictors of progression in different populations,
thereby necessitating customization of CKD classification systems.
4. ANZDATA Registry analysis of the impact of different levels of GFR post-kidney transplant for CKD
progression and CVD outcomes.
5. Prospective longitudinal studies of the outcomes of patients with increased GFR.
6. Studies of whether chronicity can be inferred by rate of change of kidney function over intervals
shorter than 3 months (e.g. small or scarred kidneys plus GFR < 60 mL/min/1.73 m2).
________________________________________________________________________________________________________________________
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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________________________________________________________________________________________________________________________
APPENDICES
Table 1. Characteristics of included studies
Study ID N Study design Participants Follow up Comments and results

1) Kidney Function (GFR) ii. Does age modify the relationship between GFR and outcomes?
2
OHare et al 2,583,911 Cohort Department of Veterans Affairs Mean 3.17 20% of patients had an eGFR <60ml/min/1.73m
(2006) [57] patients, aged 18 to 100yrs 0.62 years Association of eGFR with mortality was weaker in the elderly than in younger
age groups
Severe reductions in eGFR were associated with increased risk for death in
all age groups
2
Moderate reductions in eGFR (50 to 59ml/min/1.73m ) were associated with
an increased adjusted risk for death in patients <65 years old
OHare et al 209,622 Cohort US veterans with CKD stage 3 3.2 years Patients aged 75 years or older comprised 47% of the overall cohort at
(2007) [66] to 5 aged 18 100 years old. baseline and accounted for 28% of the ESRD at follow up
Irrespective of age, both death and ESRD increased as eGFR decreased
The risk of ESRD exceeding the risk of death varies between the different
2
age groups for different eGFR levels: eGFR 45 ml/min/1.73m for 18 to 44
2
year old patients; 15 ml/min/1.73m for 65 to 84 year old patients
Among patients 85 years of age, the risk of death always exceeded he risk
of ESRD
2
Among patients with eGFR levels <45 ml/min/1.73m at baseline, older
patients were less likely than their younger counterparts to experience an
2
annual decline in eGFR > 3 ml/min/1.73m
Age is a major effect modifier among patient with an eGFR of <60
2
ml/min/1.73m
2
Eriksen et al 3,047 Cohort Patients with stage 3 CKD (30 Median 44 Mean estimated change in eGFR was -1.03 ml/min/1.73m /year
2
(2006) [22] to 59 ml/min/1.73m ) aged 20 months 73% of patients experienced a decline in GFR
years or older Female gender was associated with slower decline in GFR (regression
coefficient 0.5 mL/min/1.73m2 (95%CI: 0.2 to 0.81; P=0.001); better patient
survival HR 0.55 (95%CI: 0.48 to 0.62; P<0.0001); and renal survival HR
0.35 (95%CI: 0.21 to 0.59; P<0.0001)
2
Each eGFR 10 ml/min/1.73m decrement was significantly associated with
an increased risk of renal failure (HR 2.50, 95%CI: 1.89 3.31, P <0.0001)
and death (HR 1.25, 95%CI: 1.14 1.37, P <0.0001)
Roderick et al 13,177 Cohort Participants aged 75 years Median 7.3 There is an increase in all-cause and cardiovascular mortality risk in people
2
(2009) [30] old from 53 General Practices years 75 years of age, particularly in men and those with eGFR <45 ml/min/1.73m
Recruited between 1994 and Adjusted hazard ratios for all-cause mortality for men were:
1999 2
1.13 (95% CI: 0.93 to 1.37) for eGFR 45 to 59 ml/min/1.73m
2
2
3.87 (95% CI: 2.78 to 5.38) for eGFR < 30 ml/min/1.73m all compared with
______________________________________________________________________________________________________________________________________________________________________________________
2
eGFR > 60 ml/min/1.73m
Adjusted hazard ratios for all-cause mortality for women were:
2
1.14 (95% CI: 0.93 to1.40) for eGFR 45 to 59 ml/min/1.73m
2
2
2.44 (95% CI: 1.68 to 3.56) for eGFR < 30 ml/min/1.73m all compared with
2
eGFR > 60 ml/min/1.73m
Dipstick proteinuria was independently associated with all-cause mortality
risk but not cardiovascular mortality risk in both sexes
Levey et al 45 Meta-analysis Studies included participants N/A Incidence rates for cardiovascular disease mortality, end-stage renal disease,
(2010) [68] studies from the general, high-risk and acute kidney injury and kidney disease progression were higher in subjects
n= kidney disease populations 65 years, whereas relative risks were higher in individuals <65 years.
1,555,332 The relative hazards (with the exception of all-cause mortality), were similar
for ages above and below 65 years.
The increased risk for all outcomes for eGFR<60ml/min/1.73m2 without
consistent age interactions is not consistent with the interpretation that
decreased GFR with aging is normal or physiological
iii) Does gender modify the relationship between GFR and outcomes?
Neugarten et al N/A Meta-analysis Studies included totalled N/A Results indicate that men with chronic renal disease of various aetiologies
(2000) [69] included 68 11,345 patients. show a more rapid decline in renal function compared to women
studies
Haroun et al 23,534 Prospective Adult volunteers from 20 years 143 people developed CKD
(2003) [70] observational Washington County The adjusted hazard ratio for women was:
2.5 (95% CI: 0.05 to 12.0) for normal BP
3.0 (95% CI: 0.6 to 14.4) for high-normal BP
3.8 (95% CI: 0.8 to 17.2) for stage 1 hypertension
8.8 (95% CI: 1.8 to 43.0) for stags 3 or 4 hypertension compared with women
with optimal BP
The adjusted hazard ratio for men was:
1.4 (95% CI: 0.2 to 12.1) for normal BP
3.3 (95% CI: 0.4 to 25.6) for high-normal BP
9,7 (95% CI: 1.2 to 75.6) for stags 3 or 4 hypertension compared with men
with optimal BP
Current cigarette smoking was also significantly associated with risk of CKD
in both men and women (HR in women 2.9 [95%CI: 1.7 to 5.0] and in men
2.4 [HR 1.5 to 4.0])
Stage 1 hypertension (23%) and cigarette smoking (31%) were the main
attributable risk factors of CKD in this population
Jafar et al (2003) 11 Meta-analysis 1,860 Participants from 11 Mean 2.2 Mean baseline SBP was greater in women than in men: 151 s 147 mmHg
[71] studies randomised trials (recruited years (P<0.001)
______________________________________________________________________________________________________________________________________________________________________________________
between 1986 and 1996) Mean baseline urine protein (UP) excretion was lower in women compared to
645 females (35%) men: 1.3 vs 2.1g.day (P< 0.001)
After adjusting for baseline variables and changes in SBP and UP during
follow-up the relative risk for the doubling of baseline serum creatinine or
onset of end-stage renal disease was 1.36 (95% CI: 1.06 to 1.75) for women
compared with men
John et al (2004) 3,822 Cohort Patients with moderate to Mean 31.3 Male sex, low GFR, and non-referral were associated with poor outcomes
[4] severe CKD months 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
2
Eriksen et al 3,047 Cohort Patients with stage 3 CKD (30 Median 44 Mean estimated change in eGFR was -1.03 ml/min/1.73m /year
2
(2006) [22] to 59 ml/min/1.73m ) aged 20 months 73% of patients experienced a decline in GFR
years or older Female gender was associated with slower decline in GFR (regression
coefficient 0.50, 95%CI: 0.20 to 0.81, P=0.001), and better patient survival
(HR 0.55, 95%CI: 0.48 to 0.62, P<0.0001) and better renal survival (HR 0.35,
95%CI: 0.21 to 0.59, P<0.0001)
2) Kidney Damage
Atkins et al 10,596 Cross sectional People 25 years or older N/A Albuminuria was strongly correlated with total protein excretion in the elderly,
(2003) [72] taking part in the Australian as well as those with diabetes, hypertension, obesity and renal impairment (P
Diabetes, Obesity and < 0.001)
Lifestyle Study 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) 14,622 Cross sectional Adult participants of the Third N/A 8.3% micro- and 1% macroalbuminuria were detected in the population
[73] National Health and Nutrition screened
2
Examination Survey (NHANES 37% of participants with GFR <30ml/min/1.73m did no show albuminuria.
III) Non-albuminuric renal insufficiency was most evident in the ages of 60 to 79;
34% of diabetics and 63% of non-diabetic hypertensives with GFR
2
<30ml/min/1.73m also showed no albuminuria
i) What is the prognostic significance of albuminuria/proteinuria?

Lea et al (2005) 1,094 Cohort African Americans with 3.8 years For each 2-fold higher proteinuria level, a mean SE 0.54 0.05
______________________________________________________________________________________________________________________________________________________________________________________
2
[77] hypertensive renal disease (mean) mL/min/1.73m per year faster GFR decline was observed (P<0.001)
2
(GFR 20 65 mL/min/1.73m2) For each 10-mL/min/1.73m lower baseline GFR, an associated mean SE
0.380.08 mL/min/1.73m2 per year greater mean GFR decline occurred
(P<0.001)
Iseki et al (2004) 95,255 Cohort Japanese adults older than 20 7 years Seven-year cumulative incidences of ESRD per 1,000 subjects were: 86.8 in
[100] years, participated in a CrCl I (<50.2mL/min), 13.6 in CrCl II (50.2 to 63.9mL/min); 8.3 in CrCl III
screening project held by the (64.0 to 79.3 mL/min) and 7.9 in CrCl IV (79.4 mL/min) in patients who had
Okinawa General Health proteinuria. These levels were lower for patients without proteinuria: 1.2, 0.7,
Maintenance Association 0.04 and 0.13 for the respective CrCl categories.
As CrCl category decreased, the adjusted hazard ratio for the risk of
developing ESRD was 4.4 (95%CI: 3.4 to 5.6; P<0.0001)
Subjects with a low CrCl who had proteinuria were at high risk of developing
ESRD
ii) What is the value of combining albuminuria/proteinuria for CKD staging?

Ninomiya et al 10,640 Cohort Participants aged 55 years 4.3 years 938 (8.8%) of patients experienced a cardiovascular event and 107 (1.0%)
(2009) [26] with type 2 diabetes (mean) experienced a renal event.
The multivariable-adjusted hazard ratio for cardiovascular events was 2.48
(95%Ci: 1.74 to 3.52) for every 10-fold increase in baseline urinary albumin-
to-creatinine ratio (UACR) and 2.2 (95%CI: 1.09 to 4.43) for every halving of
baseline eGFR, after adjustment for regression dilution.
Patients with both UACR >300mg/g and eGFR<60ml/min/1.73m2 at baseline
had a 3.2-fold higher risk for cardiovascular events and a 22.2-fold higher risk
for renal events compared with patients with neither of these risk factors.
Farbom et al 10,881 Cohort Swedish and Norwegian 4.5 years Increased creatinine (P<0.001) and decreased GFR (P=0.001) were
(2008) [108] hypertensive patients taking independent risk factors for the primary end points: fatal and non-fatal
part in the Nordic Diltiazem myocardial infarction, stroke and other cardiovascular deaths
Study. There was a significant interaction between microalbuminuria and eGFR
(P=0.04) in prediction of the primary end points.
Hallan et al 65,589 Cohort Adults 20 years who took 10.3 years 124 patients progressed to ESRD
(2009) [78] part in the Nord-Trondelag The adjusted hazard ratios for progression to ESRD for Normal ACR,
Health (HUNT 2) Study microalbuminuria and macroalbuminuria were:
2
1.0, 27.3 and 196.3 respectively for eGFR 60 ml/min/1.73m ;
2
23.4, 146.5 and 641.1 for eGFR 45 to 59 ml/min/1.73m ;
2
51.9, 448.9 and 2036 for eGFR 30 to 44 ml/min/1.73m ;
2
368.7, 2202 and 4146 for eGFR 15 to 29 ml/min/1.73m .
Time-dependent receiver operating characteristic analysis (ROC) showed
that urinary albumin-to-creatinine ratio and eGFR substantially improved
diagnostic accuracy
Hallan et al 9,709 Cohort Adults 20 years who took 8.3 years For participants <70 years, the absolute excess cardiovascular deaths/1000
______________________________________________________________________________________________________________________________________________________________________________________
(2007) [91] part in the Nord-Trondelag person-years for:
Health (HUNT 2) Study 1. optimal UACR (urinary albumin creatinine ratio) [<5 mg/g in men and <7
mg/g in women]
2
i) 0 (reference) for eGFR 75 mL/min/1.73m
2
ii) 0.1 (-1.6 to 2.4) for eGFR 60 to 74 mL/min/1.73m
2
iii) -0.3 (-2.4 to 0.9) for eGFR 45 59 mL/min/1.73m
2
iv) 0.1 (-3.6 to 4.3) for eGFR < 45 mL/min/1.73m
2. high normal UACR [5 to 19 mg/g in men and 7 to 29 mg/g in women]
2
i) 0.6 (-0.3 to 2.4) for eGFR 75 mL/min/1.73m
2
2
iii) 1.9 (0.02 to 8.1) for eGFR 45 59 mL/min/1.73m
2
3. microalbuminuria [20 to 199 mg/g in men and 30 to 299 mg/g in women].
2
2
2
iii) 1.0 (-0.1 to 4.0) for eGFR 45 59 mL/min/1.73m
2
iv) 4.1 (0.9 to 13.6) for eGFR < 45 mL/min/1.73m
For participants 70 years, the absolute excess cardiovascular deaths/1000

person-years for:
1. optimal UACR
2
i) 0 (reference) for eGFR 75 mL/min/1.73m
2
ii) -2.3 (-20.1 to 9.6) for eGFR 60 to 74 mL/min/1.73m
2
2
2. high normal UACR
2
2
2
2
3. microalbuminuria
2
2
ii) 24.1 (2.8 to 84.5) for eGFR 60 to 74 mL/min/1.73m
2
iii) 26.6 (4.5 to 85.3) for eGFR 45 59 mL/min/1.73m
2
Reduced kidney function and microalbuminuria are risk factors for

cardiovascular death. Independent of each other and traditional risk factors
2b) Haematuria
Chadban et al 11,247 Cross-sectional Australian adults aged 25 N/A Haematuria was detected initially (dipstick test), in 5.2% of cases (95%CI: 4.3
(2003) [2] years and over 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
______________________________________________________________________________________________________________________________________________________________________________________
haematuria
Iseki et al (2003) 106,177 Cohort 20 to 98 year old Japanese 17 years 420 people (246 men and 174 women) entered the ESRD program
[74] participants in mass screening Haematuria was predictive of developing ESRD, adjusted odds ratio 1.18
(1983 -1984) (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)
3. Temporal changes in kidney function and/or damage
Witte et al (2009) 241 Cohort Participants in the Prevention Regression analysis showed that the albumin / creatinine ratio (ACR) in a
[112] of Renal and Vascular End- first morning void best agreed with 24-hr urinary albumin excretion (UAE)
stage Disease (PREVEND) Prevalence of microalbuminuria determined by data from a first morning void
(7.5%, whether by UAC or ACR) nearly equalled the prevalence of
microalbuminuria determined by 24-hr UAE (10%)
Prevalence was higher when determined by spot urine samples (25.4% for
UAC and 22.4% for ACR; both P<0.001 versus 24-h UAE)
The intra-individual coefficients of variation of the ACR in a first morning void
and 24-hr UAE were similar (19%)
Measurement of albuminuria in a first morning void, preferably as the ACR, is
more reliable than a spot urine sample to diagnose and monitor
microalbuminuria
4. Other diagnostic evaluations

Baigent et al 9,270 RCT Patients 40 years of age with 4.9 years 17% proportional reduction in major atherosclerotic events, 526 (11.3%) in
(2011)[113] (4,650 = CKD (3,023 on dialysis, 6,240 the S+E group vs 619 (13.4%) in the placebo group. RR 0.83; 95%CI: 0.74 -
(SHARP Study) treatment not) 0.94; log-rank P=0.0021
4,620 = Patients were randomly Significant reductions in non-haemorrhagic stroke 131 vs 174, (RR 0.75;
placebo) assigned to simvastatin 95%CI: 0.60 0.94, P=0.01) and arterial revascularization procedures 284 vs
(20mg) plus ezetimibe (10mg) 352 (RR 0.79; 95%CI: 0.68 0.93, P=0.0036) for the S+E and placebo
(S+E) group or to placebo. groups, respectively.
Multicentre study, 18 Incidence of non-fatal myocardial infarction or death from coronary heart
countries, 380 hospitals. disease was non-significantly lower in the S+E group 213 (4.6%) vs 230
(5.0%); RR 0.92; 95%CI: 0.76 1.11, P=0.37.
Risk of myopathy was 2/10,000 patients/ year of treatment
No evidence of excess risk of hepatitis, gallstones, cancer or death from non-
vascular causes.
Inker et al 30,528 Survey Participants in the US National N/A The prevalence of CKD complications for stages 1, 2, 3 and 4 CKD
(2012)[114] Health and Nutrition respectively, were:
Examination Survey (1988- Hyperparathyroidism: 9.1%, 11.1%, 28.2% and 72.5%
1994 and 1999-2006) Anaemia: 6.7%, 6.5%, 14.9% and 51.5%
Acidosis: 16.4%, 9.2%, 11.6% and 31.5%
Hyperphosphataemia: 7.4%, 6.4%, 9.2% and 23.0%
Hypoalbuminaemia: 2.6%, 4.0%, 4.3% and 7.5%
Hypertension: 34.1%, 64.8%, 73.4% and 82.1%
Astor et al 15,625 Survey Participants in the third N/A The prevalence of anaemia in men (Hb <12 g/dL) increased from 1%
______________________________________________________________________________________________________________________________________________________________________________________
2
(2002)[116] National Health and Nutrition (95%CI: 0.7% -2%) at an eGFR level of 60mL/min/1.73m to 9% (95%CI:4%-
2
Examination Survey (NHANES 19%) at an eGFR level of 30mL/min/1.73m and to 33% (95%CI: 11%-67%)
2
III). Non-institutionalised adults at an eGFR level of 15mL/min/1.73m
20 years and older. The prevalence increase of anaemia (Hb <11 g/dL) was similar in women
except that it increased to 67% (95%CI: 30%-90%) at an eGFR of
2
15mL/min/1.73m
______________________________________________________________________________________________________________________________________________________________________________________
Table 1 Characteristics of included randomised trials
Study ID N Study Design Setting Participants Intervention Intervention Follow Comments

(author, (experimental (control up
year) group) group) (months)
Other diagnostic evaluations
Baigent et al 9,270 Randomised Multicentre, (UK, CKD patients Simvastatin Matching 4.9 years 3,023 patients on dialysis,
(2011)[113] controlled Germany, Australia, aged 40 years (20mg) plus placebo 6,240 not on dialysis
(SHARP clinical trial China, France, or older whether Ezetimibe Three arms initially to test
Study) Denmark, Thailand, or not on (10mg) daily for the safety of adding
Sweden, Norway, dialysis. dose Ezetimibe. Thus one arm
Czech Republic, was simvastatin only for 1
Poland, year.
Netherlands,
Finland, USA,
Malaysia, Canada
and New Zealand)
Table 2a Methodological quality of randomised trials
Study ID Method of Blinding Intention- Loss to Comments

(author, year) allocation (participants) (investigators) (outcome to-treat follow up
concealment * assessors) analysis (%)
Other diagnostic evaluations
Baigent et al Computer- Yes Yes Yes Yes 2 +
(2011)[113] generated
(SHARP Study)
* 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 ().
______________________________________________________________________________________________________________________________________________________________________________________
Table 3a Results and quality rating for dichotomous outcomes
Outcomes Study ID (author, Intervention group Control group Relative risk (RR) Risk difference Importance**
year) (no. of patients (no. of patients [95% CI] (RD) [95% CI]
with events/no. of with events/no.
patients exposed) of patients
exposed)
Death from Baigent et al Simvastatin+E 90 / 4620 1.01 [0.76, 1.35] 0.00 [-0.01, 0.01] Critical
cardiovascular (2011)[113] 91 / 4630
causes (SHARP Study)
Non-fatal myocardial Baigent et al Simvastatin+E 159 / 4620 0.84 [0.67, 1.05] -0.01 [-0.01, 0.00] Important
infarction (2011)[113] 134/ 4630
(SHARP Study)
Any non- Baigent et al Simvastatin+E 174/ 4620 0.75 [0.60, 0.94] -0.01 [-0.02, -0.00] Critical
haemorrhagic Stroke (2011)[113] 131/ 4630
(SHARP Study)
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
______________________________________________________________________________________________________________________________________________________________________________________
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.
_______________________________________________________________________________________________________________________________
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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Diagnosis, classification and staging of chronic

CLASSIFICATION AND STAGING

1 90 Normal or increased GFR

Kidney GFR Normal Microalbuminuria Macroalbuminuria

UNGRADED SUGGESTIONS FOR CLINICAL CARE

IMPLEMENTATION AND AUDIT

Date of search/es: 3 August 2009: June 2012

WHAT IS THE EVIDENCE?

1. Kidney function (GFR)

i. What is the prognostic significance of GFR level in the population?

Albuminuria/proteinuria is common in the Australian general population. The Australian Diabetes

i. What is the prognostic significance of albuminuria/proteinuria?

The relationship between albuminuria/proteinuria and cardiovascular disease appears to be linear

ii. What is the value of combining albuminuria/proteinuria for CKD staging?

2c. Structural abnormalities on renal ultrasound imaging

3. Temporal changes in kidney function and/or damage

4. Other diagnostic evaluations in patients with CKD

SUMMARY OF THE EVIDENCE

WHAT DO THE OTHER GUIDELINES SAY?

UK Renal Association: No recommendation.

Canadian Society of Nephrology: No recommendation.

European Best Practice Guidelines: No recommendation.

National Institute for Clinical Excellence (NICE): [11]

Scottish Intercollegiate Guidelines Network (SIGN): [15]

SUGGESTIONS FOR FUTURE RESEARCH

1. Johnson D, Mathew T, Ludlow M et al, Chronic Kidney Disease (CKD) Management

Study ID N Study design Participants Follow up Comments and results

i) What is the prognostic significance of albuminuria/proteinuria?

ii) What is the value of combining albuminuria/proteinuria for CKD staging?

For participants 70 years, the absolute excess cardiovascular deaths/1000

Reduced kidney function and microalbuminuria are risk factors for

4. Other diagnostic evaluations

Study ID N Study Design Setting Participants Intervention Intervention Follow Comments

Table 2a Methodological quality of randomised trials

Study ID Method of Blinding Intention- Loss to Comments

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