Diag Classification Staging ECKD

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Early Chronic Kidney Disease July 2012 Page 1 of 31

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).

Kidney function stage* GFR (mL/min/1.73 m

2) 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 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)

<30 <4 (M) <6 (F)

<50

Microalbuminuria 2.5-25 (M) 3.5-35 (F)

30-300 4-40 (M) 6-60 (F)

50-500

Macroalbuminuria >25 (M) >35 (F)

>300 >40 (M) >60 (F)

>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 (mL/min/1.73m

2)

Normal

(urine ACR mg/mmol)

Male: < 2.5

Female: < 3.5

Microalbuminuria

(urine ACR mg/mmol)

Male: 2.5-25

Female: 3.5-35

Macroalbuminuria

(urine ACR mg/mmol)

Male: > 25

Female: > 35

1 ≥90 Not CKD unless

haematuria, structural or

pathological abnormalities

present

2 60-89

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.

A measured or estimated GFR <45 mL/min/1.73m2 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 tissue disease

Anti-nuclear antibodies, Extractable nuclear antigens, Complement studies

Has pulmonary symptoms or deteriorating kidney function

Anti-glomerular basement membrane antibody, Anti-neutrophil cytoplasmic antibody

Has risk factors for HBV, HCV and HIV HBV, HCV, HIV serology

Has persistent albuminuria >60-120 mg/mmol (approximately equivalent to 24hr urinary protein >1-2 g/day)

Refer to Nephrologist for consideration of renal biopsy

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 m

2. 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 Foundation‟s 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 m

2 (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 m2 (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 m

2 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 m

2, 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 m

2 and 30 to 44 mL/min/1.73 m

2, 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 m

2 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 m

2 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 m

2. 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 m

2, 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 m

2)

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 m

2) 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 m

2 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 m

2, 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 m2 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 m

2

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 m

2. 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 m

2 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/1.73m

2, 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 m

2 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 m

2

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 m

2 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 m

2, 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 m

2 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 m

2. 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 m

2, 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 m

2, 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 m

2, -2.3, 5.9 and 24.1 for 60-74 mL/min/1.73 m

2, 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 m

2.

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 m

2 [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 m

2 12%, 70–79 ml/min/1.73 m

2 17%, 60-69 ml/min/1.73 m

2 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 m

2, 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 m

2 (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, Goodpasture‟s 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

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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 45–59 ml/min/1.73m2 (stage 3A) and

GFR 30–44 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 45–59 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.

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Stage 3 CKD should be split into two parts: - Stage 3A: GFR 45-59 (ml/min/1.73m

2)

- 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 m

2 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 “echogenic“kidneys); 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

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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 non–referred 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).

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CONFLICT OF INTEREST David Johnson has a level II b. conflict of interest for receiving speaker honoraria and advisor‟s fees from several companies related to anaemia, CKD-MBD, hypertension and cardiovascular disease between 2008 and 2012.

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84. 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.

85. Hillege HL, Fidler V, Diercks GFH et al. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation. 2002; 106: 1777-82.

86. Yuyun MF, Khaw K-T, Luben R et al. Microalbuminuria, cardiovascular risk factors and cardiovascular morbidity in a British population: the EPIC-Norfolk population-based study. European Journal of Cardiovascular Prevention & Rehabilitation. 2004; 11: 207-13.

87. Yuyun MF, Khaw KT, Luben R et al. Microalbuminuria and stroke in a British population: the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population study. Journal of Internal Medicine. 2004; 255: 247-56.

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88. Yuyun MF, Khaw K-T, Luben R et al. Microalbuminuria independently predicts all-cause 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.

89. 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.

90. 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.

91. 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.

92. 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.

93. 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.

94. 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.

95. 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.

96. 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.

97. 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.

98. 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.

99. 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.

100. 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.

101. Hemmelgarn BR, Manns BJ, Lloyd A et al. Relation between kidney function, proteinuria, and adverse outcomes. JAMA. 2010; 303: 423-9.

102. 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.

103. 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.

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104. 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.

105. 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.

106. 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.

107. 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.

108. 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.

109. 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.

110. 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.

111. 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.

112. 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.

113. 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.

114. 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.

115. 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.

116. 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 N Study design Participants Follow up Comments and results

1) Kidney Function (GFR) – ii. Does age modify the relationship between GFR and outcomes?

O‟Hare et al (2006) [57]

2,583,911 Cohort Department of Veterans Affairs patients, aged 18 to 100yrs

Mean 3.17 ± 0.62 years

20% of patients had an eGFR <60ml/min/1.73m2

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

Moderate reductions in eGFR (50 to 59ml/min/1.73m2) were associated with

an increased adjusted risk for death in patients <65 years old

O‟Hare et al (2007) [66]

209,622 Cohort US veterans with CKD stage 3 to 5 aged 18 – 100 years old.

3.2 years Patients aged 75 years or older comprised 47% of the overall cohort at 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 age groups for different eGFR levels: eGFR 45 ml/min/1.73m

2 for 18 to 44

year old patients; 15 ml/min/1.73m2 for 65 to 84 year old patients

Among patients ≥ 85 years of age, the risk of death always exceeded he risk of ESRD

Among patients with eGFR levels <45 ml/min/1.73m2 at baseline, older

patients were less likely than their younger counterparts to experience an annual decline in eGFR > 3 ml/min/1.73m

2

Age is a major effect modifier among patient with an eGFR of <60 ml/min/1.73m

2

Eriksen et al (2006) [22]

3,047 Cohort Patients with stage 3 CKD (30 to 59 ml/min/1.73m

2) aged 20

years or older

Median 44 months

Mean estimated change in eGFR was -1.03 ml/min/1.73m2/year

73% of patients experienced a decline in GFR

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)

Each eGFR 10 ml/min/1.73m2 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 (2009) [30]

13,177 Cohort Participants aged ≥75 years old from 53 General Practices Recruited between 1994 and 1999

Median 7.3 years

There is an increase in all-cause and cardiovascular mortality risk in people ≥ 75 years of age, particularly in men and those with eGFR <45 ml/min/1.73m

2

Adjusted hazard ratios for all-cause mortality for men were:

1.13 (95% CI: 0.93 to 1.37) for eGFR 45 to 59 ml/min/1.73m2


3.87 (95% CI: 2.78 to 5.38) for eGFR < 30 ml/min/1.73m2

all compared with

______________________________________________________________________________________________________________________________________________________________________________________


Study ID N Study design Participants Follow up Comments and results eGFR > 60 ml/min/1.73m

2

Adjusted hazard ratios for all-cause mortality for women were:

1.14 (95% CI: 0.93 to1.40) for eGFR 45 to 59 ml/min/1.73m2


2.44 (95% CI: 1.68 to 3.56) for eGFR < 30 ml/min/1.73m2

all compared with eGFR > 60 ml/min/1.73m

2

Dipstick proteinuria was independently associated with all-cause mortality risk but not cardiovascular mortality risk in both sexes

Levey et al (2010) [68]

45 studies n= 1,555,332

Meta-analysis Studies included participants from the general, high-risk and kidney disease populations

N/A Incidence rates for cardiovascular disease mortality, end-stage renal disease, acute kidney injury and kidney disease progression were higher in subjects ≥65 years, whereas relative risks were higher in individuals <65 years.

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 (2000) [69]

N/A Meta-analysis included 68 studies

Studies included totalled 11,345 patients.

N/A Results indicate that men with chronic renal disease of various aetiologies show a more rapid decline in renal function compared to women

Haroun et al (2003) [70]

23,534 Prospective observational

Adult volunteers from Washington County

20 years 143 people developed CKD

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) [71]

11 studies

Meta-analysis 1,860 Participants from 11 randomised trials (recruited

Mean 2.2 years

Mean baseline SBP was greater in women than in men: 151 s 147 mmHg (P<0.001)

______________________________________________________________________________________________________________________________________________________________________________________


Study ID N Study design Participants Follow up Comments and results between 1986 and 1996) 645 females (35%)

Mean baseline urine protein (UP) excretion was lower in women compared to 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) [4]

3,822 Cohort Patients with moderate to severe CKD

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 Patients with stage 3 CKD (30 to 59 ml/min/1.73m

2) aged 20

years or older

Median 44 months

Mean estimated change in eGFR was -1.03 ml/min/1.73m2/year

73% of patients experienced a decline in GFR

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 (2003) [72]

10,596 Cross sectional People 25 years or older taking part in the Australian Diabetes, Obesity and Lifestyle Study

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 Adult participants of the Third National Health and Nutrition Examination Survey (NHANES III)

N/A 8.3% micro- and 1% macroalbuminuria were detected in the population screened

37% of participants with GFR <30ml/min/1.73m2 did no show albuminuria.

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 <30ml/min/1.73m

2 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 –

______________________________________________________________________________________________________________________________________________________________________________________


Study ID N Study design Participants Follow up Comments and results [77] hypertensive renal disease

(GFR 20 – 65 mL/min/1.73m2) (mean) mL/min/1.73m

2 per year faster GFR decline was observed (P<0.001)

For each 10-mL/min/1.73m2 lower baseline GFR, an associated mean ±SE

0.38±0.08 –mL/min/1.73m2 per year greater mean GFR decline occurred (P<0.001)

Iseki et al (2004) [100]

95,255 Cohort Japanese adults older than 20 years, participated in a screening project held by the Okinawa General Health Maintenance Association

7 years Seven-year cumulative incidences of ESRD per 1,000 subjects were: 86.8 in CrCl I (<50.2mL/min), 13.6 in CrCl II (50.2 to 63.9mL/min); 8.3 in CrCl III (64.0 to 79.3 mL/min) and 7.9 in CrCl IV (≥79.4 mL/min) in patients who had proteinuria. These levels were lower for patients without proteinuria: 1.2, 0.7, 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 (2009) [26]

10,640 Cohort Participants aged ≥ 55 years with type 2 diabetes

4.3 years (mean)

938 (8.8%) of patients experienced a cardiovascular event and 107 (1.0%) 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 (2008) [108]

10,881 Cohort Swedish and Norwegian hypertensive patients taking part in the Nordic Diltiazem Study.

4.5 years Increased creatinine (P<0.001) and decreased GFR (P=0.001) were independent risk factors for the primary end points: fatal and non-fatal myocardial infarction, stroke and other cardiovascular deaths

There was a significant interaction between microalbuminuria and eGFR (P=0.04) in prediction of the primary end points.

Hallan et al (2009) [78]

65,589 Cohort Adults ≥ 20 years who took part in the Nord-Trondelag Health (HUNT 2) Study

10.3 years 124 patients progressed to ESRD

The adjusted hazard ratios for progression to ESRD for Normal ACR, microalbuminuria and macroalbuminuria were:

1.0, 27.3 and 196.3 respectively for eGFR ≥ 60 ml/min/1.73m2;

23.4, 146.5 and 641.1 for eGFR 45 to 59 ml/min/1.73m2;

51.9, 448.9 and 2036 for eGFR 30 to 44 ml/min/1.73m2;

368.7, 2202 and 4146 for eGFR 15 to 29 ml/min/1.73m2.

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

______________________________________________________________________________________________________________________________________________________________________________________


Study ID N Study design Participants Follow up Comments and results (2007) [91] part in the Nord-Trondelag

Health (HUNT 2) Study person-years for: 1. optimal UACR (urinary albumin creatinine ratio) [<5 mg/g in men and <7

mg/g in women] 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/1.73m2

iii) -0.3 (-2.4 to 0.9) for eGFR 45 – 59 mL/min/1.73m2

iv) 0.1 (-3.6 to 4.3) for eGFR < 45 mL/min/1.73m2

2. high normal UACR [5 to 19 mg/g in men and 7 to 29 mg/g in women] i) 0.6 (-0.3 to 2.4) for eGFR ≥ 75 mL/min/1.73m

2


iii) 1.9 (0.02 to 8.1) for eGFR 45 – 59 mL/min/1.73m2


3. microalbuminuria [20 to 199 mg/g in men and 30 to 299 mg/g in women]. i) 0.6 (-0.6 to 3.2) for eGFR ≥ 75 mL/min/1.73m

2


iii) 1.0 (-0.1 to 4.0) for eGFR 45 – 59 mL/min/1.73m2

iv) 4.1 (0.9 to 13.6) for eGFR < 45 mL/min/1.73m2

For participants ≥70 years, the absolute excess cardiovascular deaths/1000 person-years for: 1. optimal UACR 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/1.73m2



2. high normal UACR i) 13.6 (-0.2 to 50.1) for eGFR ≥ 75 mL/min/1.73m

2




3. microalbuminuria i) 8.4 (-4.2 to 41.9) for eGFR ≥ 75 mL/min/1.73m

2

ii) 24.1 (2.8 to 84.5) for eGFR 60 to 74 mL/min/1.73m2

iii) 26.6 (4.5 to 85.3) for eGFR 45 – 59 mL/min/1.73m2


Reduced kidney function and microalbuminuria are risk factors for cardiovascular death. Independent of each other and traditional risk factors

2b) Haematuria

Chadban et al (2003) [2]

11,247 Cross-sectional Australian adults aged 25 years and over

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

______________________________________________________________________________________________________________________________________________________________________________________


Study ID N Study design Participants Follow up Comments and results haematuria

Iseki et al (2003) [74]

106,177 Cohort 20 to 98 year old Japanese participants in mass screening (1983 -1984)

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)

3. Temporal changes in kidney function and/or damage

Witte et al (2009) [112]

241 Cohort Participants in the Prevention of Renal and Vascular End-stage Disease (PREVEND)

Regression analysis showed that the albumin / creatinine ratio (ACR) in a first morning void best agreed with 24-hr urinary albumin excretion (UAE)

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 (2011)[113] (SHARP Study)

9,270 (4,650 = treatment 4,620 = placebo)

RCT Patients ≥ 40 years of age with CKD (3,023 on dialysis, 6,240 not) Patients were randomly assigned to simvastatin (20mg) plus ezetimibe (10mg) (S+E) group or to placebo. Multicentre study, 18 countries, 380 hospitals.

4.9 years 17% proportional reduction in major atherosclerotic events, 526 (11.3%) in the S+E group vs 619 (13.4%) in the placebo group. RR 0.83; 95%CI: 0.74 - 0.94; log-rank P=0.0021

Significant reductions in non-haemorrhagic stroke 131 vs 174, (RR 0.75; 95%CI: 0.60 – 0.94, P=0.01) and arterial revascularization procedures 284 vs 352 (RR 0.79; 95%CI: 0.68 – 0.93, P=0.0036) for the S+E and placebo groups, respectively.

Incidence of non-fatal myocardial infarction or death from coronary heart 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 (2012)[114]

30,528 Survey Participants in the US National Health and Nutrition Examination Survey (1988-1994 and 1999-2006)

N/A The prevalence of CKD complications for stages 1, 2, 3 and 4 CKD respectively, were:

Hyperparathyroidism: 9.1%, 11.1%, 28.2% and 72.5%

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%

______________________________________________________________________________________________________________________________________________________________________________________


Study ID N Study design Participants Follow up Comments and results (2002)[116] National Health and Nutrition

Examination Survey (NHANES III). Non-institutionalised adults 20 years and older.

(95%CI: 0.7% -2%) at an eGFR level of 60mL/min/1.73m2

to 9% (95%CI:4%-19%) at an eGFR level of 30mL/min/1.73m

2 and to 33% (95%CI: 11%-67%)

at an eGFR level of 15mL/min/1.73m2

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

15mL/min/1.73m2

______________________________________________________________________________________________________________________________________________________________________________________


Table 1 – Characteristics of included randomised trials

Study ID (author, year)

N Study Design Setting Participants Intervention (experimental group)

Intervention (control group)

Follow up (months)

Comments

Other diagnostic evaluations


9,270 Randomised controlled clinical trial

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 3,023 patients on dialysis, 6,240 not on dialysis

Three arms initially to test for the safety of adding Ezetimibe. Thus one arm was simvastatin only for 1 year.

Table 2a – Methodological quality of randomised trials

Study ID (author, year)

Method of allocation concealment *

Blinding Intention-to-treat analysis †

Loss to follow up (%)

Comments ‡ (participants) (investigators) (outcome

assessors)

Other diagnostic evaluations


Computer-generated

Yes Yes Yes Yes 2 +

* 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 (Ø); poorly (–).

______________________________________________________________________________________________________________________________________________________________________________________


Table 3a – Results and quality rating for dichotomous outcomes

Outcomes Study ID (author, year)

Intervention group (no. of patients with events/no. of patients exposed)

Control group (no. of patients with events/no. of patients exposed)

Relative risk (RR) [95% CI]

Risk difference (RD) [95% CI]

Importance**

Death from cardiovascular causes


Simvastatin+E 91 / 4630

90 / 4620 1.01 [0.76, 1.35] 0.00 [-0.01, 0.01] Critical

Non-fatal myocardial infarction


Simvastatin+E 134/ 4630

159 / 4620 0.84 [0.67, 1.05] -0.01 [-0.01, 0.00] Important

Any non-haemorrhagic Stroke


Simvastatin+E 131/ 4630

174/ 4620 0.75 [0.60, 0.94] -0.01 [-0.02, -0.00] 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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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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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.

Documents

Diag Classification Staging ECKD