Series
`
`Lancet 2010; 375: 1296–309
`See Editorial page 1226
`See Comment page 1227
`This is the second in a Series of
`three papers about renal
`medicine
`Departments of Medicine and
`Community Health Sciences,
`University of Calgary, Calgary,
`AB, Canada (M T James MD,
`B R Hemmelgarn MD); and
`Department of Medicine and
`Centre for Health Economics,
`University of Alberta,
`Edmonton, AB, Canada
`(M Tonelli MD)
`Correspondence to:
`Dr Marcello Tonelli, University of
`Alberta, Department of
`Medicine, Division of
`Nephrology and Immunology,
`Clinical Sciences Building 7-129,
`Edmonton, AB, Canada T6G 2G3
`mtonelli-admin@med.
`ualberta.ca
`
`Renal Medicine 2
`Early recognition and prevention of chronic kidney disease
`
`Matthew T James, Brenda R Hemmelgarn, Marcello Tonelli
`
`Chronic kidney disease is a common disorder and its prevalence is increasing worldwide. Early diagnosis on the basis
`of presence of proteinuria or reduced estimated glomerular fi ltration rate could permit early intervention to reduce
`the risks of cardiovascular events, kidney failure, and death that are associated with chronic kidney disease. In
`developed countries, screening for the disorder is most effi cient when targeted at high-risk groups including elderly
`people and those with concomitant illness (such as diabetes, hypertension, or cardiovascular disease) or a family
`history of chronic kidney disease, although the role of screening in developing countries is not yet clear. Eff ective
`strategies are available to slow the progression of chronic kidney disease and reduce cardiovascular risk. Treatment of
`high blood pressure is recommended for all individuals with, or at risk of, chronic kidney disease. Use of
`angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers is preferred for patients with diabetic
`chronic kidney disease or those with the proteinuric non-diabetic disorder. Glycaemic control can help prevent the
`onset of early stages of chronic kidney disease in individuals with diabetes. Use of statins and aspirin is benefi cial for
`most patients with chronic kidney disease who are at high cardiovascular risk, although research is needed to ascertain
`how to best prevent cardiovascular disease in this cohort. Models of care that facilitate delivery of the many complex
`aspects of treatment simultaneously could enhance management, although eff ects on clinical outcomes need further
`assessment. Novel clinical methods to better identify patients at risk of progression to later stages of chronic kidney
`disease, including kidney failure, are needed to target management to high-risk subgroups.
`
`Introduction
`Chronic kidney disease is a common disorder that is
`associated with raised risk of cardiovascular disease,
`kidney failure, and other complications. The ageing of
`populations along with the growing global prevalence of
`diabetes and other chronic non-communicable diseases
`has
`led to corresponding worldwide
`increases
`in
`prevalence of chronic kidney disease and kidney failure.
`Strategies for early identifi cation and treatment of people
`with chronic kidney disease, who are at risk of
`cardiovascular events and progression to the end stage
`of chronic kidney disease (kidney failure), are needed
`worldwide, especially
`in countries where
`renal
`replacement is not readily available. This Review will
`discuss potential strategies for early identifi cation and
`treatment of such high-risk patients to reduce morbidity
`and mortality associated with later stages of chronic
`kidney disease.
`
`Defi nition, classifi cation, and staging
`Chronic kidney disease is defi ned by a sustained
`reduction in glomerular fi ltration rate or evidence of
`structural or functional abnormalities of the kidneys on
`urinalysis, biopsy, or imaging.1–3 A fi ve-stage classifi cation
`system for the disorder has been established by the US
`National Kidney Foundation’s Kidney Disease Outcomes
`Quality Initiative and adopted internationally by the
`Kidney Disease: Improving Global Outcomes (KDIGO)
`initiative to guide identifi cation of cases and facilitate
`management (table 1).2–5 In the clinical setting, glomerular
`fi ltration rate is generally estimated on the basis of
`creatinine concentration in serum and demographic
`features
`(age, sex, and ethnic origin) with
`the
`
`Cockcroft-Gault6 or MDRD (Modifi cation of Diet in Renal
`Disease) study7,8 equations. The severity of chronic kidney
`disease in the fi ve-stage scheme is based mainly on
`glomerular fi ltration rate (table 1), although risk of
`complications at a given rate is modifi ed substantially by
`the amount of proteinuria. The MDRD study equation
`was developed in a population with chronic kidney
`disease from the USA, and its precision and accuracy is
`reduced with increasing glomerular fi ltration rate and in
`diff erent ethnic groups.7 Unique prediction equations
`have been derived and validated for other nationalities.9,10
`Since the concentration of creatinine in serum alone
`is insensitive to early disease, identifi cation and staging
`of chronic kidney disease on the basis of estimated
`glomerular fi ltration rate was an important advance that
`facilitated both research and clinical care. Nonetheless,
`
`Search strategy and selection criteria
`
`We searched the Cochrane Library, Medline, and Embase
`up to the end of August, 2009, with the search terms “chronic
`kidney disease” or “chronic renal insuffi ciency” in
`combination with “diagnosis”, “screening”, “prevention”,
`“control”, “treatment”, or “intervention”. Largely, we selected
`publications from the past 10 years from journals with high
`impact factors but did not exclude frequently referenced and
`highly regarded older publications. We also searched the
`reference lists of articles identifi ed by this search strategy and
`selected those we judged relevant. Review articles were
`included when they provided comprehensive overviews
`beyond the scope of this Review. We did not limit by
`language or date of publication.
`
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`
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`

`Series
`
`Stage 1
`Stage 2
`Stage 3
`Stage 4
`
`is a history of established cardiovascular disease.29 In the
`developing world, infectious diseases are also important
`causes of kidney failure, including infections due to
`bacteria (tuberculosis in India and the Middle East,
`streptococcal infection in Africa), viruses (HIV and
`hepatitis B and C in Africa), and parasites (schistosomiasis
`in Africa and Latin America, leishmaniasis in Africa and
`Asia, and malaria in Africa).30 In Asia, Africa, and
`the Middle East, chronic kidney disease has been
`attributed to environmental and occupational exposure to
`
`Description
`
`–
`
`At risk
`
`1
`
`Kidney damage with normal or
`increased GFR
`Kidney damage with mildly diminished GFR
`2
`3* Moderately reduced GFR
`4
`Severely decreased GFR
`5
`End-stage renal disease (kidney failure)
`
`GFR (mL per min per
`1·73 m2)
`≥60 (with risk factors for
`chronic kidney disease)
`≥90
`
`60–89
`30–59
`15–29
`<15
`
`Modifi ed from reference 1, with permission of Elsevier. GFR=glomerular fi ltration
`rate. *UK National Institute for Health and Clinical Excellence guidelines split
`stage 3 into two subcategories (3A, GFR 45–59 mL per min per 1·73 m2; and 3B,
`GFR 30–44 mL per min per 1·73 m2) and use the suffi x (p) to denote the presence
`of proteinuria.
`
`Table 1: Stages of chronic kidney disease, as defi ned by the Kidney
`Disease Outcomes Quality Initiative
`
`14
`
`12
`
`10
`
`8
`
`revalence (%)
`
`6P
`
`4
`
`2
`
`0
`
`Age (years)
`Criteria:
`Estimated GFR
`Proteinuria
`Haematuria
`
`USA17
`1999–2004
`≥20
`
`Japan18
`2005
`≥20
`
`Spain19
`2004
`≥20
`
`Iran20
`2008
`≥14
`
`Taiwan21
`1994–2006
`≥20
`
`China9
`2008
`≥18
`
`Norway22
`1995–97
`≥20
`
`√
`ACR
`
`√
`Dipstick
`
`√
`ACR
`
`√
`Dipstick
`
`√
`Dipstick
`
`√
`ACR
`√
`
`√
`ACR
`
`Figure 1: Population-based estimates of prevalence of chronic kidney disease
`ACR=albumin-to-creatinine ratio. GFR=glomerular fi ltration rate.
`
`the existing
`to surround
`controversy continues
`classifi cation system, specifi cally with regard to its
`propensity to overestimate prevalence; its failure to fully
`incorporate prognostic information from proteinuria;
`and the potential for misclassifi cation of some people as
`having chronic kidney disease in the absence of clinically
`relevant kidney disease.11 New equations for estimation
`of glomerular fi ltration rate from serum creatinine (eg, the
`Chronic Kidney Disease Epidemiology Collaboration
`equation) show enhanced precision and accuracy,
`particularly at high rates, and could overcome some of
`these limitations.12 Although current interest exists for
`use of new markers, such as cystatin C, to detect early
`chronic kidney disease,13 or for combination of both
`serum creatinine and cystatin C for estimation equations
`to increase accuracy,14 the clinical role of such markers
`remains to be defi ned. The current chronic kidney
`disease staging system is expected to evolve in response
`to these considerations, and the KDIGO initiative held
`an international consensus conference to discuss the
`issue in late 2009.
`
`Epidemiology
`The prevalence of chronic kidney disease has been
`estimated in several developed countries but remains
`unknown in much of the developing world.15 Adoption
`of standard defi nitions and use of the MDRD study
`equation for estimated glomerular fi ltration rate have
`facilitated international comparisons. When chronic
`kidney disease is defi ned solely by estimated glomerular
`fi ltration rates less than 60 mL per min 1·73 m²,
`approximate prevalence is 2·5–11·2% of the adult
`population across Europe, Asia, North America, and
`Australia.15 In the USA, chronic kidney disease by this
`defi nition is over 200-fold more common than kidney
`failure treated by renal replacement therapy; this ratio is
`several-fold higher in countries of low and middle
`income with restricted access to renal replacement
`therapy.16 The prevalence of chronic kidney disease rises
`substantially (to 10·5–13·1%) when also defi ned by
`presence of microalbuminuria or macro albuminuria
`(fi gure 1).9,17–22 Up to 25–35% of people older than
`65 years meet current criteria for chronic kidney
`disease,15 although whether the decline in glomerular
`fi ltration rate represents disease or is part of the ageing
`process is controversial.23 The frequency of treated
`kidney failure, however, does increase with age in
`developed countries.24 Prevalence of chronic kidney
`disease in the USA rose from 10·0% to 13·1% between
`1988–94 and 1999–2004;25 the ageing population and
`growth in the prevalence of diabetes, hypertension, and
`obesity seem to account partly for this increase.25
`Chronic kidney disease has many potential causes,
`which vary in frequency between diff erent populations
`(fi gure 2).1 In developed countries, age, hypertension,
`diabetes, increased body-mass index, and smoking are
`associated consistently with chronic kidney disease,26–28 as
`
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`
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`

`

`Series
`
`Chronic kidney disease
`Glomerular filtration rate <60 mL per min per 1·73 m2
`for >3 months or evidence of kidney damage on
`urinalysis, kidney imaging, or biopsy
`
`Diabetic chronic kidney disease
`Diabetic nephropathy (type 1 or 2
`diabetes mellitus)
`
`
`Vascular
`With or without haematuria or
`proteinuria
`• Large-vessel disease (renal artery
` stenosis)
`• Small-vessel disease (hypertension,
` vasculitis, microangiopathy)
`
`
`Non-diabetic chronic kidney disease
`
`
`Glomerular
`Haematuria or albuminuria
`• Primary nephritis (IgA nephropathy)
`• Autoimmune disorders (connective
` tissue disease)
`• Systemic infection (bacteria, virus,
` parasite)
`• Malignant disease (solid organ,
` haematological)
`• Drugs
`• Hyperfiltration (reduced renal mass,
` obesity)
`
`Tubulointerstitial
`With or without mild proteinuria or
`pyuria
`• Autoimmune disorders (connective
` tissue disease, granulomatous
` disease)
`• Drug toxic effects (analgesics, metals)
`• Chronic infection (bacteria, virus,
` parasite)
`• Obstructive nephropathy (chronic
` urinary-tract obstruction)
`• Post-acute kidney injury
` (ischaemic/toxic injury)
`
`
`Cystic
`Evident on renal imaging
`• Polycystic kidney disease (autosomal
` dominant polycystic kidney disease)
`
`
`
`glomerular fi ltration rate are associated with excess
`cardiovascular risk.36 At any given level of kidney function,
`raised amounts of proteinuria are associated with
`increased cardiovascular morbidity and mortality.37–39 In
`patients with cardiovascular disease, diabetes, or
`hypertension, presence of chronic kidney disease
`(especially with proteinuria) is a so-called risk multiplier
`that identifi es the subset of individuals who are most
`likely to have adverse outcomes.40 Additional disorders
`that accompany chronic kidney disease include infection,41
`acute kidney
`injury,42 cognitive dysfunction,43 and
`impaired physical functioning.44
`Because availability of renal replacement therapies is
`limited in countries of low and middle income, most
`patients around the world with chronic kidney disease
`will die
`from kidney
`failure without receiving
`dialysis or transplantation.31 In developed countries,
`many more people will die from cardiovascular disease
`rather than progress to kidney failure requiring renal
`replacement.36,45,46 A low estimated glomerular fi ltration
`rate at presentation and the amount of proteinuria
`are the strongest independent risk factors for kidney
`failure.47,48 Reduction in
`level of proteinuria over
`time correlates with a slowing of the rate of decline in
`glomerular fi ltration
`rate, making proteinuria
`an
`important prognostic variable and potential
`therapeutic target.49,50
`
`Strategies for early recognition
`Early identifi cation of patients with chronic kidney disease
`is desirable because
`interventions can
`then be
`implemented to reduce risk of cardiovascular events or
`progression to kidney failure. The high prevalence of
`
`Figure 2: Classifi cation and selected examples of causes of chronic kidney disease
`
`ACR ≥30 mg/g
`
`Both
`
`Estimated GFR <60 mL per min per 1·73 m2
`
`18–30
`
`31–45
`
`46–60
`Age (years)
`
`61–75
`
`>75
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Proportion of patients (%)
`
`Figure 3: Proportions of patients with chronic kidney disease identifi ed by
`albumin-to-creatinine ratio, estimated glomerular fi ltration rate, or both
`ACR=albumin-to-creatinine ratio. GFR=glomerular fi ltration rate. Data taken
`from the US National Health and Nutrition Examination Survey, 1999–2004.
`Adapted from reference 58, with permission of Elsevier.
`
`chemicals, including lead, cadmium, and mercury.31,32 The
`rapidly increasing burden of chronic non-communicable
`diseases that has been seen in many developing nations
`will probably lead to striking corresponding rises in
`prevalence of chronic kidney disease and kidney failure in
`these countries over the next two decades.30,33
`Cardiovascular disease is the leading cause of mortality
`in chronic kidney disease,34,35 and even mild reductions in
`
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`

`

`Series
`
`n
`
`Study population
`
`Background
`treatment
`
`Control
`treatment
`
`Intervention
`treatment
`
`Study
`duration
`(years)
`
`Relative risk reduction
`with intervention
`
`ACE inhibitors
`Jafar (2001)83
`
`1860
`
`Inclusion criteria
`
`Kidney function
`
`Proteinuria
`
`Non-diabetic
`chronic kidney
`disease
`
`Mean serum
`creatinine
`203 mmol/L
`
`Mean 1·8 g per day Concomitant
`antihypertensive
`drugs
`
`AASK (Agodoa;
`2001)84
`
`653
`
`African-American
`with hypertensive
`chronic kidney
`disease
`
`GFR 20–65 mL
`per min per
`1·73 m2
`
`Median
`112 mg per day
`
`ALLHAT (2005)88 31 897
`
`Hou (2006)85
`
`224
`
`NR
`
`18% with
`estimated GFR
`<60 mL per min
`per 1·73 m2
`
`Serum creatinine
`274–442 mmol/L
`
`>0·3 g per day
`
`Hypertension and
`≥1 other coronary
`disease risk factor
`(38% diabetes
`mellitus)
`Non-diabetic
`chronic kidney
`disease with
`persistent
`proteinuria
`
`Other
`antihypertensive
`drugs, plus
`randomised to
`mean arterial blood
`pressure goal of
`102–107 mm Hg or
`<92 mm Hg
`Other
`antihypertensive
`drugs to achieve
`blood pressure
`<140/90 mm Hg
`Goal blood pressure
`<130/80 mm Hg
`
`Angiotensin-receptor blockers
`TRANSCEND
`5927
`(2009)92
`
`Mean serum
`creatinine
`92 mmol/L
`
`Documented
`cardiovascular
`disease with
`end-organ damage
`(36% diabetes
`mellitus), intolerant
`of ACE inhibitors
`ACE inhibitor and angiotensin-receptor blocker combination
`ONTARGET
`Mean serum
`25 620
`Cardiovascular
`(2008)91,93
`creatinine
`disease or diabetes
`94 mmol/L
`(38% diabetes
`mellitus) with
`end-organ damage
`
`··
`
`··
`
`10% with
`microalbuminuria,
`1% with
`macroalbuminuria
`
`13% with
`microalbuminuria,
`4% with
`macroalbuminuria
`
`Placebo,
`nifedipine,
`atenolol, or
`acebutolol
`
`Amlodipine
`
`2–4
`
`3
`
`ACE inhibitor
`(captropril,
`enalapril,
`cilazapril,
`benazepril, or
`ramipril)
`Ramipril
`2·5–10 mg
`once daily
`
`Chlorthalidone
`
`Lisinopril
`10–40 mg daily
`
`4·9
`
`Other open-label
`antihypertensive
`drug
`
`Benazepril
`10 mg twice
`daily
`
`3·4
`
`Placebo
`
`Telmisartan
`80 mg daily
`
`4·7
`
`37% reduction in kidney
`failure*; 38% reduction in
`composite of doubling of
`serum creatinine or kidney
`failure
`
`38% reduction in composite
`of 50% or 25 mL per min
`per 1·73 m2 decrease in GFR,
`kidney failure, or death*
`
`No signifi cant reduction in
`kidney failure for all patients
`or in stratum with baseline
`estimated GFR <60 mL per
`min per 1·73 m2
`43% reduction in composite
`of doubling of serum
`creatinine, kidney failure, or
`death*
`
`No reduction in composite
`of doubling of serum
`creatinine, kidney failure, or
`death
`
`Telmisartan or
`ramipril alone
`
`4·7
`
`Ramipril 10 mg
`daily and
`telmisartan
`80 mg daily
`
`Increased risk of doubling of
`serum creatinine, dialysis, or
`death with combination
`
`(Continues on next page)
`
`chronic kidney disease,15 absence of symptoms until
`disease is advanced, accessibility of laboratory tests for
`diagnosis and prognostication,51 and availability of
`treatments that prevent complications suggest that
`screening for chronic kidney disease could be worthwhile.
`However, the role of population-based screening remains
`controversial.52 Screening for proteinuria is appealing
`because it is easy to undertake, predicts cardiovascular
`morbidity and mortality, and might be a better predictor
`of future decline in glomerular fi ltration rate than a
`reduction
`in estimated glomerular fi ltration rate.53
`However, on the basis of data from the USA, annual
`dipstick testing to detect proteinuria in all adults older
`than 50 years is not cost eff ective unless restricted to high-
`risk groups (eg, older individuals or those with diabetes or
`hypertension).54,55 Projections of an analysis from Norway
`suggested that screening for a reduction in estimated
`
`glomerular fi ltration rate would be most eff ective if
`targeted at people with hypertension, diabetes, or those
`older than 55 years of age, although risk of kidney failure
`in those detected would remain low.56 Data from the
`general US population indicate that albuminuria is the
`most typical marker of chronic kidney disease in young
`adults, whereas reduced estimated glomerular fi ltration
`rate is the most frequent abnormality in elderly people
`with the disorder (fi gure 3).57,58 Albuminuria and estimated
`glomerular fi ltration rate might have complementary
`roles in screening diff erent age groups, and use of the two
`variables together could be effi cient for identifi cation of
`people at high risk of progression to kidney failure.
`Screening with urinalysis to detect glomerulonephritis
`has been done routinely for all working adults and school-
`aged children (age 6–18 years) in Japan since the 1970s,
`and this strategy seems to have lowered the incidence of
`
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`

`Series
`
`n
`
`Study population
`
`Background
`treatment
`
`Control
`treatment
`
`Intervention
`treatment
`
`Study
`duration
`(years)
`
`Relative risk reduction
`with intervention
`
`Inclusion criteria
`
`Kidney function
`
`Proteinuria
`
`(Continued from previous page)
`Blood pressure target
`MDRD study
`840
`(1994)76
`
`Chronic kidney
`disease, excluding
`patients with
`diabetes receiving
`insulin
`
`Substudy A, GFR
`25–55 mL per
`min per 1·73 m²;
`substudy B, GFR
`13–24 mL per
`min per 1·73 m²
`
`Substudy A,
`0·9 g per day;
`substudy B,
`1·4 g per day
`
`Also randomised to
`usual or low-protein
`diet
`
`AASK (Wright;
`2002)77
`
`1094
`
`African-American
`with hypertensive
`chronic kidney
`disease
`
`GFR 20–65 mL
`per min per
`1·73 m²
`
`Mean 0·6 g per
`day
`
`REIN-2 (2005)79
`
`335
`
`Non-diabetic
`nephropathy with
`persistent
`proteinuria
`
`Creatinine
`clearance <70 mL
`per min per
`1·73 m²
`
`≥1 g per day
`
`Randomised to
`metoprolol,
`ramipril, or
`amlodipine, plus use
`of other
`antihypertensives to
`achieve blood
`pressure targets
`Ramipril
`2·5–5 mg daily
`
`Usual mean
`arterial blood
`pressure target
`≤107 mm Hg for
`patients age
`≤60 years and
`≤113 mm Hg for
`patients
`≥61 years of age
`Usual blood
`pressure goal,
`mean arterial
`blood pressure
`102–107 mm Hg
`
`Low mean
`arterial blood
`pressure target
`of 92 mm Hg
`for patients
`age 60 years
`and ≤98 mm
`Hg for patients
`≥61 years
`Lower blood
`pressure goal,
`mean arterial
`blood pressure
`≤92 mm Hg
`
`Diastolic blood
`pressure
`<90 mm Hg
`
`Addition of
`amlodipine to
`target blood
`pressure
`<130/80 mm
`Hg
`
`2·2
`
`No signifi cant reduction in
`kidney failure or death†
`
`4
`
`1·6
`
`No reduction in composite
`of 50% or 25 mL per min
`per 1·73 m² decrease in GFR
`or death*
`
`Study stopped after fi rst
`interim analysis due to
`futility; no reduction in
`kidney failure*
`
`ACE=angiotensin-converting-enzyme. AASK=African-American Study of Kidney Disease. GFR=glomerular fi ltration rate. ALLHAT=Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.
`NR=not reported. TRANSCEND=Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease. ONTARGET=Ongoing Telmisartan Alone and in combination with Ramipril
`Global Endpoint Trial. MDRD=Modifi cation of Diet in Renal Disease. REIN=Ramipril Effi cacy In Nephropathy. *Primary endpoint of study. †Secondary endpoint of study.
`
`Table 2: Randomised controlled trials of prevention or early intervention for non-diabetic chronic kidney disease
`
`kidney failure secondary to glomerulo nephritis.59 In the
`USA, the National Kidney Foundation’s Kidney Early
`Evaluation Program (KEEP) is a community-based
`initiative that recruits adults at high risk of chronic
`kidney disease for a health-screening questionnaire and
`measurement of serum creatinine, urine microalbumin,
`and albumin-to-creatinine
`ratio.58,60 This
`targeted
`approach has been successful for identifi cation of an
`enriched population with chronic kidney disease for
`follow-up with a doctor or at a local public health centre.60
`Mass screening for kidney disease might also be feasible
`in developing countries,61 although the health and
`economic eff ects of such programmes need further
`evaluation.61 If screening is done, health systems must be
`able to provide appropriate medical care for individuals
`with newly detected chronic kidney disease.52
`Diagnostic testing for chronic kidney disease is
`advocated for several groups of patients who seek
`medical attention for other reasons,52 especially those
`with diabetes, hypertension, cardiovascular disease,
`structural renal-tract disease, autoimmune diseases with
`potential for kidney involvement, and a family history of
`chronic kidney disease or hereditary kidney disease.62–64
`A risk score based on information available routinely
`(ie, age, sex, hypertension, diabetes, cardiovascular
`disease, anaemia) has been developed to enhance
`
`identifi cation of individuals with occult chronic kidney
`disease in the USA,29 but similar methods are not
`available for other populations.
`Automated reporting of estimated glomerular fi ltration
`rate has been initiated in laboratories worldwide to
`facilitate early detection of chronic kidney disease,65
`although its role remains contentious.66,67 Introduction of
`reporting of estimated glomerular fi ltration rate,
`accompanied by education of doctors, increased the
`recognition of chronic kidney disease from 27% to 85%
`of cases.68 Although automated reporting of estimated
`glomerular fi ltration rate boosts the number of referrals
`to nephrologists, with the greatest rises in women, elderly
`people, and individuals with stage 3 chronic kidney
`disease,69,70 it might also lead to unnecessary referrals and
`overwhelm health
`resources. Whether automatic
`estimated glomerular fi ltration rate reporting enhances
`care of high-risk individuals and clinical outcomes is
`under investigation.71
`
`Prevention and intervention
`Initial management of chronic kidney disease entails
`identifi cation of reversible disorders (such as urinary-tract
`obstruction, infection, or autoimmune disease) that could
`respond to specifi c treatment and lead to stabilisation or
`improvement in kidney function. Irrespective of underlying
`
`1300
`
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`
`MPI EXHIBIT 1143 PAGE 5
`
`

`

`Series
`
`n
`
`Study population
`
`Background
`treatment
`
`Control treatment
`
`Intervention treatment
`
`Study
`duration
`(years)
`
`Relative risk reduction with
`intervention
`
`Inclusion
`criteria
`
`Kidney function Proteinuria
`
`ACE inhibitors
`Lewis
`(1993)96
`
`409
`
`100% type 1
`diabetes
`
`Serum
`creatinine
`<221 mmol/L
`
`≥500 mg
`per day
`
`Placebo
`
`Target blood
`pressure
`<140/90 mm Hg
`
`Captopril 25 mg three times
`daily
`
`Mean
`94 mmol/L
`
`32% micro-
`albuminuria
`
`..
`
`Placebo
`
`Ramipril
`
`Placebo
`
`Placebo
`
`Trandalopril or trandalopril
`plus verapamil
`
`Perindopril 4 mg plus
`indapamide 1·25 mg
`
`Placebo or
`amlodipine
`
`Irbesartan 75–300 mg daily
`
`2·6
`
`Placebo
`
`Losartan 50–100 mg daily
`
`3·4
`
`3
`
`4·5
`
`3·6
`
`4·3
`
`50% in composite of death,
`dialysis, and transplantation; 48%
`reduction in risk of doubling of
`serum creatinine*
`27% reduction in new overt
`nephropathy
`
`Delayed onset of new
`microalbuminuria by factors of 2·6
`(for trandalopril plus verapamil)
`and 2·1 (for trandalopril)*
`
`21% reduction in composite of new
`microalbuminuria, doubling of
`serum creatinine to ≥200 mmol/L,
`renal replacement therapy, or death
`due to renal disease†
`
`20% (vs placebo) and 23%
`(vs amlodipine) reductions in
`composite of doubling of serum
`creatinine concentration, kidney
`failure, or death*
`16% reduction in composite of
`doubling of serum creatinine,
`kidney failure, or death*
`
`HOPE
`(2000)100
`
`BENEDICT
`(2004)101
`
`2272
`
`1204
`
`100% type 2
`diabetes
`(subgroup)
`100% type 2
`diabetes
`
`Normal
`
`Serum
`creatinine
`<133 mmol/L
`
`ADVANCE
`(2007)103
`
`11 140
`
`100% type 2
`diabetes
`
`Mean serum
`creatinine
`87 mmol/L
`
`26% micro-
`albuminuria
`
`Angiotensin-receptor blockers
`IDNT
`1715
`100% type 2
`(2001)98
`diabetes
`
`Serum
`creatinine
`<265 mmol/L
`
`≥900 mg per
`24 h
`
`RENAAL
`(2001)97
`
`1513
`
`100% type 2
`diabetes
`
`Serum
`creatinine
`<265 mmol/L
`
`>500 mg
`per day
`
`IRMA
`(2001)99
`
`590
`
`100% type 2
`diabetes
`
`DIRECT
`(2009)104
`
`5231
`
`64% type 1
`diabetes,
`36% type 2
`diabetes
`
`100% micro-
`albuminuria
`
`Normal
`
`Serum
`creatinine
`≤113 mmol/L in
`men,
`≤97 mmol/L in
`women
`Serum
`creatinine
`<110 mmol/L in
`women,
`<130 mmol/L in
`men
`
`Additional
`antihypertensive
`drugs to target
`blood pressure
`120/80 mm Hg
`Other
`anti hypertensive
`drugs at
`discretion of
`doctor
`
`Other
`antihypertensive
`drugs targeting
`blood pressure
`<135/85 mm Hg
`Other
`antihypertensive
`drugs targeting
`blood pressure
`<140/90 mm Hg
`Other
`antihypertensive
`drugs targeting
`blood pressure
`<135/85 mm Hg
`
`Other
`anti hypertensive
`drugs if blood
`pressure
`>140/90 mm Hg
`
`Placebo
`
`Irbesartan 150 mg or 300 mg
`daily
`
`2
`
`39% (for 150 mg) and 70%
`(for 300 mg) reductions in new
`overt nephropathy*
`
`Placebo
`
`Candesartan 16–32 mg daily
`
`4·7
`
`No reduction in incidence of new
`microalbuminuria†
`
`(Continues on next page)
`
`cause, typical goals of manage ment for all patients with
`chronic kidney disease include prevention of cardiovascular
`events and reduction of the rate of progression of the
`disorder (thereby delaying or preventing kidney failure and
`other complications). Many clinical trials have been
`undertaken solely in patients with non-diabetic chronic
`kidney disease (table 2) or in those with diabetic chronic
`kidney disease (table 3). Pharmacological therapy for these
`two groups is discussed below.
`
`Pharmacological treatment of non-diabetic chronic
`kidney disease
`Treatment of hypertension is the mainstay of management
`to slow the progression of chronic kidney disease and
`reduce cardiovascular risk.72 Observational work has
`
`indicated an increased risk of progression of chronic
`kidney disease and of kidney failure as blood pressure
`rises above 130/80 mm Hg.73–75 The current recommended
`blood pressure target for patients with chronic kidney
`disease is 125–135/75–85 mm Hg, but all guidelines
`advocate a goal
`lower than that for the general
`population.1,4,5 Findings of the MDRD76 and AASK
`studies77 did not show substantial reductions in incidence
`of kidney failure or death, or decline of glomerular
`fi ltration rate when a lower mean arterial blood pressure
`of 92 mm Hg (equivalent to <125/75 mm Hg) was
`targeted. Although some suggestion of benefi t has been
`made with such goals in specifi c subgroups (eg, patients
`with proteinuria >1 g per day)75,76 or with extended follow-
`up,78 this outcome remains uncertain. The REIN-2 study
`
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`
`1301
`
`MPI EXHIBIT 1143 PAGE 6
`
`

`

`Series
`
`n
`
`Study population
`
`Background
`treatment
`
`Control treatment
`
`Intervention treatment
`
`Study
`duration
`(years)
`
`Relative risk reduction with
`intervention
`
`Inclusion
`criteria
`
`Kidney function Proteinuria
`
`(Continued from previous page)
`Glycaemic control
`DCCT
`1441
`(2000)109
`
`100% type 1
`diabetes
`
`Mean creatinine
`clearance
`129 mL per min
`
`Normal or
`micro-
`albuminuria
`
`Diet and exercise
`education
`
`Insulin twice daily
`
`Kumamoto
`study
`(1995)110
`
`110
`
`100% type 2
`diabetes
`
`Serum
`creatinine
`<132 mmol/L
`
`<300 mg
`per day
`
`..
`
`1–2 daily injections
`intermediate-
`acting insulin
`
`UKPDS
`(1998)95
`
`3867
`
`100% type 2
`diabetes
`
`Serum
`creatinine
`<175 mmol/L
`
`1·9%
`proteinuria
`
`Dietary advice
`
`Maintain fasting
`blood glucose
`<15 mmol/L with
`sulphonylurea or
`insulin, plus
`metformin if obese
`
`Insulin ≥3 times daily targeting
`blood glucose <6·7 mmol/L
`preprandial, <10 mmol/L
`postprandial, and HbA1c <6%
`≥3 times daily injections rapid-
`acting and intermediate-acting
`insulin targeting fasting blood
`glucose <7·7 mmol/L,
`postprandial blood glucose
`<11 mmol/L, HbA1c about 7·0%
`Fasting blood glucose
`<6 mmol/L, preprandial
`blood glucose 4–7 mmol/L with
`sulphonylurea, insulin
`
`6·5
`
`6
`
`10
`
`34% reduction in new
`microalbuminuria and 56%
`reduction in new albuminuria†
`
`70% reduction in new
`microalbuminuria or new
`nephropathy
`
`30% and 42% non-signifi cant
`reductions in new
`microalbuminuria†
`
`ACE=angiotensin-converting-enzyme. HOPE=Heart Outcomes Prevention Evaluation. BENEDICT=Bergamo Nephrologic Diabetes Complications Trial. ADVANCE=Action in Diabetes and Vascular disease:
`preterax and diamicron-MR Controlled Evaluation. IDNT=Irbesartan in Diabetic Nephropathy Trial. RENAAL=Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan. IRMA=Irebesartan
`in patients with type 2 Diabetes and Microalbuminuria. DIRECT=Diabetic Retinopathy Candesartan Trials. DCCT=Diabetes Control and Complications. HbA1c=glycosylated haemoglobin. UKPDS=UK
`Prospective Diabetes Study. *Primary endpoint of study. †Secondary endpoint of study.
`
`Table 3: Randomised controlled trials of prevention or early intervention for diabetic chronic kidney disease
`
`examined the eff ect of addition of a non-dihydropyridine
`calcium-channel blocker to background treatment with
`an angiotensin-converting-enzyme inhibitor to achieve a
`lower-than-usual target blood pressure of less than
`130/80 mm Hg. The study was terminated after the fi rst
`interim analysis when data indicated that the combined
`intervention to achieve lower blood pressure would not
`show a reduction in the primary outcome of kidney
`failure.79 Whether achievement of reduced levels of blood
`pressure with alternative antihypertensive combinations,
`or maintenance of these levels of blood pressure for a
`prolonged period, can further preserve kidney function
`remains unclear.78
`Angiotensin-converting-enzyme inhibitors are the best-
`studied agents for slowing the progression of non-
`diabetic kidney disease. Their eff ectiveness has been
`shown most clearly in individuals with proteinuric
`chronic kidney disease, and they are recommended as
`fi rst-line treatment in this sub