Seminar

Chronic kidney disease

Andrew S Levey, Josef Coresh

Chronic kidney disease is a general term for heterogeneous disorders affecting kidney structure and function. The Lancet 2012; 379: 165–80
2002 guidelines for definition and classification of this disease represented an important shift towards its recognition Published Online
as a worldwide public health problem that should be managed in its early stages by general internists. Disease and August 15, 2011
DOI:10.1016/S0140-
management are classified according to stages of disease severity, which are assessed from glomerular filtration rate
6736(11)60178-5
(GFR) and albuminuria, and clinical diagnosis (cause and pathology). Chronic kidney disease can be detected with
William B Schwartz Division
routine laboratory tests, and some treatments can prevent development and slow disease progression, reduce of Nephrology, Tufts Medical
complications of decreased GFR and risk of cardiovascular disease, and improve survival and quality of life. In this Center, Boston, MA, USA
Seminar we discuss disease burden, recommendations for assessment and management, and future challenges. We (A S Levey MD); and
Department of Epidemiology,
emphasise clinical practice guidelines, clinical trials, and areas of uncertainty.
Johns Hopkins Bloomberg
School of Public Health,
Introduction The definition of chronic kidney disease is based on Baltimore, MD, USA
Chronic kidney disease is a general term for the presence of kidney damage (ie, albuminuria) or (J Coresh PhD)
heterogeneous disorders affecting the structure and decreased kidney function (ie, glomerular filtration rate Correspondence to:
Dr Andrew S Levey,
function of the kidney. The variation in disease expression [GFR] <60 mL/min per 1·73 m²) for 3 months or more,
William B Schwartz Division
is related partly to cause and pathology, severity, and rate irrespective of clinical diagnosis (panel 1).1,10,11 Because of of Nephrology, Tufts Medical
of progression. Since the introduction of the conceptual the central role of GFR in the pathophysiology of Center, 800 Washington Street,
model, definition, and staging of chronic kidney disease complications, the disease is classified into five stages Boston, MA 02111, USA
alevey@tuftsmedicalcenter.org
10 years ago,1–4 guidelines have recommended a shift on the basis of GFR: more than 90 mL/min per 1·73 m²
from kidney disease being recognised as a life-threatening (stage 1), 60–89 mL/min per 1·73 m² (stage 2),
disorder affecting few people who need care by 30–59 mL/min per 1·73 m² (stage 3), 15–29 mL/min per
nephrologists, to a common disorder of varying severity 1·73 m² (stage 4), and less than 15 mL/min per 1·73 m²
that not only merits attention by general internists, but (stage 5). Findings from experimental and clinical
also needs a concerted public health approach for studies have suggested an important role for proteinuria
prevention, early detection, and management.4–6 Although in the pathogenesis of disease progression.12
guidelines have had an important effect on clinical Epidemiological studies have shown graded relations
practice, research, and public health, they have also between increased albuminuria and mortality and kidney
generated controversy.4,7 A Series8 in The Lancet outcomes in diverse study populations, in addition to,
emphasised early recognition and prevention of disease and independent of, low GFR and risk factors for
and described treatment recommendations. In this cardiovascular disease.13–18 In view of these findings, an
Seminar we review the framework and estimates of
disease burden; present an overview of the assessment
and management of disease; emphasise guidelines and Search strategy and selection criteria
clinical trials; and discuss the challenges that are met in We searched the database of clinical practice guidelines
the association of chronic kidney disease with ageing and in adults, which are developed and maintained by Kidney
vascular disease, management of clinical trials, Disease Improving Global Outcomes (KDIGO)9 in collaboration
development of guidelines, and public health. We focus with the five main groups that develop English-speaking
on the latest data and indicate areas of uncertainty and guidelines: Australian and New Zealand Society of
future directions for research.9 Nephrology, Caring for Australians with Renal Impairment,
Canadian Society of Nephrology, European Renal Association/
Conceptual model, definitions, and outcomes European Dialysis and Transplant Association (ERA/EDTA)
Figure 1 shows a conceptual model for the development, European Best Practice Guidelines (EBPG), National Kidney
progression, and complications of chronic kidney disease.1,4 Foundation (NFK) Kidney Disease Outcomes Quality Initiative
The model includes antecedents associated with increased (KDOQI), and United Kingdom Renal Association. We included
risk, disease stages, and complications including death. selected guidelines and consensus statements for
Risks can be categorised either as susceptibility to kidney management of cardiovascular disease risk factors and
disease because of sociodemographic and genetic factors, cardiovascular disease, drug dosing in kidney disease, and
or as exposure to factors that can lead to disease. Early acute kidney injury. For our review of clinical trials, we selected
stages of disease are often asymptomatic, are detected high-quality, high-impact clinical trial included in the
during the assessment of comorbid disorders, and can be guidelines. We focused mainly on publications from 2000 to
reversible. Rapidly progressive diseases can lead to kidney 2010, but did not exclude commonly referenced and highly
failure within months; however, most diseases evolve over regarded older publications. We also included recent trials of
decades and some patients do not progress during many promising therapeutic agents.
years of follow-up.

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Potential antecedents of CKD

Stages of CKD
Consequences of CKD Complications

Increased Kidney
Normal Damage ↓ GFR Death
risk failure

Screening CKD risk Diagnosis and Estimate Replacement

for CKD reduction; treatment; progression; by dialysis and
risk factors screening for treat comorbid treat complications; transplantation
CKD conditions; prepare for
slow progression replacement

Figure 1: Conceptual model for chronic kidney disease

Continuum of development, progression, and complications of chronic kidney disease (CKD) and strategies to improve outcomes. Thick arrows between circles
represent development, progression, and remission of CKD. Complications refer to all complications of CKD, including complications of decreased glomerular
filtration rate (GFR) and cardiovascular disease. Complications might also arise from adverse effects of interventions to prevent or treat the disease. Horizontal arrows
pointing from left to right represent the progressive nature of CKD. Dashed arrowheads signify that remission is less frequent than progression. Modified and
reproduced, with permission, from references 1 and 4.

international conference recommended modification of findings of hypertensive nephrosclerosis are often more
disease classification to indicate prognosis by the severe than expected because of the level of blood
addition of stages based on albuminuria, and an update pressure. The presence of red-blood-cell or white-blood-
of the 2002 guidelines (figure 2).19 cell casts, or specific imaging abnormalities, suggest
Kidney failure is traditionally regarded as the most another cause of kidney disease. In developing countries,
serious outcome of chronic kidney disease and symptoms common causes of chronic kidney disease also include
are usually caused by complications of reduced kidney glomerular and tubulointerstitial diseases resulting from
function. When symptoms are severe they can be treated infections and exposure to drugs and toxins.
only by dialysis and transplantation; kidney failure treated
this way is known as end-stage renal disease. Kidney Prevalence
failure is defined as a GFR of less than 15 mL/min per Many countries have surveillance programmes to
1·73 m², or the need for treatment with dialysis or monitor kidney failure treated by dialysis and
transplantation. Other outcomes include complications transplantation (figure 3).26 Incidence and prevalence
of reduced GFR, such as increased risk of cardiovascular vary because of differences in underlying diseases rates
disease, acute kidney injury, infection, cognitive and availability of government-sponsored treatment.
impairment, and impaired physical function.20–24 Incidence is now as high as 200 cases per million per
Complications can occur at any stage, which often lead to year in many countries. It is nearing 400 cases per
death with no progression to kidney failure, and can arise million in the USA, Taiwan, and some regions in
from adverse effects of interventions to prevent or treat Mexico, and has risen fastest in older individuals.
the disease. Dialysis is the main treatment method in most
countries. With average survival of 3–5 years in the
Causes USA, prevalence is nearing 1800 cases per million. In
In developed countries, chronic kidney disease is Japan and Taiwan, high survival translates to high
generally associated with old age, diabetes, hypertension, prevalence nearing 2400 cases per million. Diabetes is
obesity, and cardiovascular disease, with diabetic the main cause of kidney failure in most countries,
glomerulosclerosis and hypertensive nephrosclerosis as accounting for 40% or more of new patients.26 The USA
the presumed pathological entities; however, exact has a high incidence of disease in racial and ethnic
diagnosis is often difficult.25 Diabetic glomerulosclerosis minorities, which is probably an indicator of genetic
is characterised by slowly worsening albuminuria, and environmental factors in susceptibility, and
hypertension, and progressive decline in GFR, sometimes disparities in treatment.25,27,28
with nephrotic syndrome. Hypertensive nephrosclerosis Estimation of the burden of early stages of kidney
has no distinct markers of kidney damage, but high- disease is difficult. Prevalence estimates might be biased
normal to high concentrations of albuminuria can occur by limitation of the markers and methods that are used
after the onset of decreased GFR. Many patients with to estimate GFR and to define kidney damage. In the
diabetes and chronic kidney disease do not have typical USA, the most accurate estimates based on estimated
features of diabetic glomerulosclerosis, and pathological GFR and albuminuria of the prevalence of chronic kidney

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Panel 1: Criteria for definition of chronic kidney disease

Duration >3 months on the basis of documentation • Threshold value roughly corresponds to urine dipstick values
or inference of trace or 1+, dependent on urine concentration
Duration is necessary to distinguish chronic from acute • High urinary ACR can be confirmed by urine albumin
kidney disease excretion in a timed urine collection
• Clinical assessment can indicate duration Abnormalities in urinary sediment as markers of kidney damage
• Documentation of duration is not usually available in • Red-blood-cell casts in proliferative glomerulonephritis
epidemiological studies • White-blood-cell casts in pyelonephritis or
GFR <60 mL/min per 1·73 m² interstitial nephritis
• GFR is the best overall index of kidney function in health • Oval fat bodies or fatty casts in diseases with proteinuria
and disease • Granular casts and renal tubular epithelial cells in many
• Normal GFR in young adults is about 125 mL/min per 1·73 m²; parenchymal diseases (non-specific)
GFR<15 mL/min per 1·73 m² is defined as kidney failure Imaging abnormalities as markers of kidney damage (ultrasound,
• Decreased GFR can be detected by equations to estimate CT, and MRI with or without contrast, isotope scans, angiography)
GFR that are based on serum creatinine (estimated GFR) but • Polycystic kidneys
not by serum creatinine alone • Hydronephrosis due to obstruction
• Decreased estimated GFR can be confirmed by measured GFR • Cortical scarring due to infarcts, pyelonephritis, or
Kidney damage as defined by structural abnormalities or vesicoureteral reflux
functional abnormalities other than decreased GFR • Renal masses or enlarged kidneys due to infiltrative diseases
Pathological abnormalities • Renal artery stenosis
• Clinical diagnosis is based on pathology and cause; markers • Small and echogenic kidneys (common in late stages of CKD
of kidney damage might show pathology because of many parenchymal diseases)
• Glomerular diseases (diabetes, autoimmune diseases, Renal tubular syndromes as markers of kidney damage
systemic infections, drugs, neoplasia) • Renal tubular acidosis
• Vascular diseases (atherosclerosis, hypertension, ischaemia, • Nephrogenic diabetes insipidus
vasculitis, thrombotic microangiopathy) • Barrter and Gittelman syndromes
• Tubulointerstitial diseases (urinary-tract infections, stones, • Fanconi’s syndrome
obstruction, toxic effects of drugs) • Cystinuria
• Cystic disease (polycystic kidney disease) • Familial hypomagnesaemia with hypercalciuria and
History of kidney transplantation nephrocalcinosis
In addition to pathological abnormalities in native kidneys, Excretion of urinary creatinine indicates muscle mass and varies with age, sex, race, diet,
common pathological abnormalities include: and nutritional status, and generally exceeds 1·0 g per day in healthy adults; therefore, the
numeric value for urinary ACR (mg/g) is usually less than the rate of urinary albumin
• Chronic allograft nephropathy (non-specific findings excretion (mg/day). Rates of 30–300 mg per day and >300 mg per day correspond to
of tubular atrophy, interstitial fibrosis, vascular and microalbuminuria and macroalbuminuria, respectively. Normal urine contains small
glomerular sclerosis) amounts of albumin, low-molecular-weight serum proteins, and proteins that are from
renal tubules and the lower urinary tract. In most kidney diseases, albumin is the main
• Rejection urine protein, comprising about 60–90% of total urinary protein when total protein is very
• Drug toxic effects (calcineurin inhibitors) high. Values corresponding to normal, high-normal, high, very high, and nephrotic-range
total protein are about <50, 50–150, 150–500, >500, and >3500 mg/g, respectively.
• BK virus nephropathy
GFR=glomerular filtration rate. CKD=chronic kidney disease. *Conversion factor for
• Recurrent disease (glomerular disease, oxalosis, albumin to creatinine (ACR) ratio: 1·0 mg/g=0·113 mg/mmol.
Fabry’s disease)
Albuminuria as a marker of kidney damage
Increased glomerular permeability, urine ACR >30 mg/g*
• The normal urinary ACR in young adults is <10 mg/g. Urine
ACR categories 10–29, 30–300 and >300 mg are high normal,
high, and very high, respectively. Urine ACR >2000 mg/g is
accompanied by signs and symptoms of nephrotic syndrome
(low serum albumin, oedema, and high serum cholesterol)

disease from 1999 to 2006 were about 11·5% (4·8% in prevalence of diabetes and hypertension.30 Reports from
stages 1–2 and 6·7% in stages 3–5), and 47% in people other countries8 show some variation but are mostly
older than 70 years, mostly because of reduced GFR.29 consistent with these results.
Prevalence seems to be increasing particularly in older In the USA, the ratios of prevalence of chronic kidney
individuals, and partly because of an increasing disease to incidence and prevalence of treated kidney

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No CKD
with considerations of likelihood of disease based on the
Moderate-risk CKD Albuminuria stages, description, and range (mg/g) clinical setting.
High-risk CKD Equations to estimate GFR use serum creatinine and
A1 A2 A3
Very high-risk CKD
Optimum and High Very high and
a combination of age, sex, ethnic origin, and body size
high-normal nephrotic as surrogates for the non-GFR determinants of serum
<10 10–29 30–299 300–1999 ≥2000
creatinine. These equations are more accurate for
estimation of measured GFR than is serum creatinine
High and >105 alone.34 The modification of diet in renal disease
G1
optimum (MDRD) study equation35 is reasonably accurate at
GFR stages, description, and range

90–104

75–89
eGFRs of less than 60 mL/min per 1·73 m²; however,
(mL/min per 1·73m²)

G2 Mild bias and imprecision are increased at high eGFRs. The

60–74
chronic kidney disease epidemiology collaboration
G3a Mild-moderate 45–59 (CKD-EPI) equation29,36,37 has less bias at high eGFRs
G3b 30–44
and is more accurate for predicting adverse outcomes
Moderate-severe
than is the MDRD equation, and can be used to report
G4 Severe 15–29 eGFRs greater than 60 mL/min per 1·73 m². However,
G5 Kidney failure <15 imprecision in the high range makes eGFRs less useful
to classify chronic kidney disease stages 1 and 2, identify
Figure 2: Prognosis of chronic kidney disease by GFR and albuminuria hyperfiltration, and monitor GFR decline. Both
Colours show how adjusted relative risk is ranked for five outcomes from a meta-analysis of general population equations assign ethnic origin as either black (African
cohorts: all-cause mortality, cardiovascular mortality, kidney failure treated by dialysis and transplantation, acute
kidney injury, and progression of kidney disease. For categories with GFR >15 mL/min per 1·73 m² and albuminuria
American) versus white, or other. Modifications of these
<2000 mg/g, ranks were averaged across outcomes. Mean rank numbers: 1–8=green, 9–14=pink, 15–21=orange, equations for use in individuals from China and Japan
and 22–28=red. For categories with GFR <15 or albuminuria >2000 (corresponding to nephrotic range have been reported.38 Widespread implementation of
albuminuria), ranks were extrapolated on the basis of results from a meta-analysis of chronic kidney disease equations to estimate GFR will need assessment in
cohorts. Column and row labels are combined to be consistent with the agreed number of GFR and albuminuria
stages.22 Albuminuria=albumin-to-creatinine ratio (ACR) 1·0 mg/g=0·113 mg/mmol. Reproduced with permission
other races, ethnic origins, and geographical regions.
from Kidney International and Kidney Disease Improving Global Outcomes.19 Confirmation of reduced eGFR by measurement of
GFR (clearance of creatinine or exogenous filtration
markers) is warranted when decisions are dependent
failure are about 200 to 1 and 50 to 1, respectively, which on accurate knowledge of GFR—eg, determination of
shows the high so-called competing risk of death caused eligibility for kidney donation or dose adjustment of
by cardiovascular disease, especially in older patients. toxic drugs that are excreted by the kidneys.39 Cystatin C
This finding emphasises the need for treatments to can have more advantages compared with creatinine
reduce risk of cardiovascular disease and to slow because its non-GFR determinants are less affected by
progression of chronic kidney disease. Risks of both race and muscle wasting, and because it is more
mortality and kidney failure are associated with GFR predictive of subsequent cardiovascular disease and
and concentration of albuminuria. Figure 4 shows US mortality.40 The non-GFR determinants of serum
prevalence estimates by eGFR and urinary albumin to cystatin C are poorly understood, and the use of two or
creatinine ratio. The proportion of participants with more markers in a panel might be needed to more
chronic kidney disease in the groups at moderate, high, accurately estimate GFR.41,42
and very high risk (as categorised in figure 2) is about Although markers of kidney damage show underlying
73%, 18%, and 9%, respectively, representing a pathological changes, they are non-specific for clinical
prevalence in the general population of about 10%, 2%, diagnosis (panel 1). The presence of one or more of these
and 1%, respectively. markers for 3 months or more is sufficient to identify
chronic kidney disease. Albuminuria is the most
Detection and assessment frequently assessed marker in clinical practice and
Panel 2 provides a five-step guide to the detection and epidemiological studies. Historically, total urinary protein
assessment of chronic kidney disease, which can be has been ascertained because of ease of measurement,
accomplished by routine laboratory tests. Although GFR especially with the urine dipstick, but cannot be
is difficult to measure, it can be estimated from serum standardised. Although albumin assays are expensive,
creatinine. Creatinine assays are now traceable to measurement of an albumin to creatinine ratio in
reference methods, and estimated GFR (eGFR) is now untimed spot urine has many advantages and is
routinely reported in more than 75% of clinical recommended by guidelines.43,44 A urinary albumin to
laboratories in the USA.31 Because serum creatinine is creatinine ratio of more than 30 mg/g (3·4 mg/mmol) is
commonly measured, reporting of eGFR allows chronic defined as high (panel 1); sex-specific and race-specific
kidney disease to be detected and has led to increased ratios have been proposed because of variation in
referrals to nephrologists.32,33 However, as with other creatinine excretion, but are difficult to implement. Rate
diagnostic tests, reduced eGFR should be interpreted of albumin excretion in a timed urine collection can be

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used for confirmation when clinical diagnosis needs

Morelos (Mexico) Taiwan*
more accurate measurement. Although in this Seminar Jalisco (Mexico) Japan*
we use the term albuminuria rather than proteinuria, the Taiwan* USA
USA Belgium, French speaking
loss of other serum proteins might be important in the Japan* Belgium, Dutch speaking
pathogenesis of kidney disease and its complications. Turkey Canada
Clinical diagnosis is categorised according to pathology Luxembourg* Israel
Greece Hong Kong
and cause of disease (panel 1, panel 2). Because chronic Belgium, French speaking Chile
kidney disease is mostly detected as decreased eGFR Israel France†
Belgium, Dutch speaking Greece
during assessment and management of other medical South Korea South Korea
conditions, clinical diagnosis is generally established by Czech Republic* Jalisco (Mexico)
Uruguay Uruguay
recognition of the clinical setting and markers of kidney Hungary‡ Spain
damage. A thorough review of the history, including Canada Austria
comorbid disorders and drug use, family history, Croatia Morelos (Mexico)
Chile Croatia
laboratory assessment, and ultrasound imaging are Hong Kong Sweden
usually sufficient to reach a presumptive diagnosis. Bosnia and Herzegovina Netherlands
Brazil* Denmark
Biopsy of the kidney or invasive imaging procedures are Austria Scotland
usually used only for selected patients in whom a France† Norway
definitive diagnosis would result in a change in either Argentina§ Australia
Malaysia New Zealand
treatment or prognosis. Poland UK¶
Spain Finland
Denmark Argentina
Management Sweden Turkey
Concepts Netherlands Malaysia
Treatments for chronic kidney disease can prevent Australia Poland
New Zealand Hungary‡
development, slow progression, reduce complications of Norway Bosnia and Herzegovina
decreased GFR, reduce risk of cardiovascular disease, UK¶ Luxembourg
Scotland Czech Republic*
and improve survival and quality of life. Data from the Thailand Iceland
US renal data system25 show a decreasing incidence of Romania Thailand
Finland Romania
kidney failure in some high-risk groups—eg, in young Philippines Brazil*
people with diabetes—suggesting beneficial effects of Iceland Russia
these interventions. Despite these remarkable advances, Russia Bangladesh*
Bangladesh* Philippines
the detection, assessment, and management of chronic
0 200 400 600 0 600 1200 1800 2400
disease are not fully understood. Incidence per million population Prevalence per million population
Disease management is based on clinical diagnosis
Figure 3: Incidence and prevalence of end-stage renal disease26
and stage according to GFR and albuminuria.
Incidence and prevalence of kidney failure treated by dialysis or transplantation (end-stage renal disease) in 2008.
Identification of clinical diagnosis allows for specific Data are only for countries for which relevant information was available. All rates are unadjusted. Average survival
therapy that is directed at the cause and pathological with treated kidney failure in each country can be computed from the ratio of prevalence to incidence. *Data from
processes. Thereafter, disease stage can be used to Bangladesh, Brazil, Czech Republic, Japan, Luxembourg, and Taiwan are dialysis only. †Data for France are from
13 regions in 2005, 15 in 2006, 18 in 2007, and 20 in 2008. ‡Latest data for Hungary are from 2007. §Data for
guide non-specific therapies to slow progression and
Argentina from before 2008 are dialysis only. ¶UK=England, Wales, and Northern Ireland (data for Scotland are
reduce the risk of complications. Stage-based recom- reported separately).
mendations are cumulative—ie, recommendations for
late stages include recommendations for early stages.
Guidelines for stage-based recommendations have generalists and non-nephrology specialists. Referral is
simplified the management of chronic kidney disease generally recommended for stage 4 disease, but early
(table 1, webappendix pp 1–10); however because of an referral is recommended for patients with very high See Online for webappendix
inadequate evidence base, thresholds for stage-based concentrations of albuminuria or with complications of
testing and treatment are uncertain. Despite many decreased GFR that are difficult to manage.45
clinical trials, important clinical questions are
unanswered (table 2, webappendix pp 11–19). Many Slowing progression of chronic kidney disease and
trials have been underpowered or have relied on reduction of albuminuria
surrogate rather than clinical outcomes. Other trials The mean rate of age-related decline in GFR is
have been difficult to interpret because of findings for 0·75–1·00 mL/min per 1·73 m² every year after the age
both benefits and harms. of 40 years.34 The decline in chronic kidney disease is
Practice models for the care of patients with chronic highly variable—fast rates are noted in patients with high
kidney disease will probably vary according to the concentrations of albuminuria, diabetes, or hypertension,
availability of nephrologists and other specialists. Not all and racial and ethnic minority groups in the USA.1 No
patients need referral to nephrologists; many common generally accepted definition of fast progression is
problems can be managed with existing guidelines by available. We believe that a decline of more than

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have not shown beneficial effects on disease progression,

Albuminuria stages, description, and range (mg/g) and some have suggested an increased risk of acute
A1 A2 A3 kidney injury. The absence of benefit probably indicates
Optimum High- High Very
the low risk of progression to kidney failure corresponding
normal high All to lower concentrations of albuminuria in studies of
<10 10–29 30–299 >300
cardiovascular disease than in studies of chronic kidney
disease.50–52 Until further studies are done, these
High and >105 23·6% 5·7% 1·9% 0·1% 31·4% interventions should be recommended for patients with
G1
optimum high concentrations of albuminuria (threshold for
GFR stages, description, and range

90–104 20·0% 4·7% 1·7% 0·3% 26·7%

75–89
urinary albumin to creatinine ratio between 30 mg/g and
17·3% 4·1% 1·6% 0·2% 23·0%
(mL/min per 1·73m²)

G2 Mild 300 mg/g). ACE inhibitors and ARBs in high doses or

60–74 8·2% 2·7% 1·3% 0·1% 12·2% with other agents that inhibit the renin-angiotensin
G3a Mild-moderate 45–59 2·5% 1·1% 0·8% 0·2% 4·7% system are effective to reduce albuminuria, but have not
G3b 30–44
been tested in long-term trials in populations with
Moderate-severe 0·6% 0·4% 0·4% 0·2% 1·5%
chronic kidney disease.53–56
G4 Severe 15–29 0·1% 0·1% 0·1% 0·1% 0·4% Previous clinical trials of intensive glycaemic control
G5 Kidney failure <15 0·0% 0·0% 0·0% 0·1% 0·1% (mean achieved glycosylated haemoglobin [HbA1c]
7%–8%) showed a benefit in slowing the development of
All 72·2% 18·8% 7·8% 1·3% 100·0%
diabetic kidney disease, but did not enrol sufficient
Figure 4: Prevalence of chronic kidney disease in the USA by GFR and albuminuria
patients with kidney disease at baseline to assess the
Grey shading=CKD defined by glomerular filtration rate (GFR) or albuminuria (13·8%). Cells show the proportion of effect on disease progression. Clinical trials of high-
adult population in the USA. Data from the National Health and Nutrition Examination Survey (NHANES III intensity therapy (target HbA1c <6·0% or <6·5%) have
1999–2000, 2001–02, 2003–04, and 2005–06 (N=18 026). GFR is estimated with the CKD-EPI equation and included increased numbers of patients with kidney
standardised serum creatinine. Albuminuria is established by one measurement of albumin-to-creatinine ratio
(ACR); thus proportions for GFR >60 mL/min per 1·73 m² exceed those reported elsewhere.29 Values in cells might
disease at baseline and have shown a slow rise in
not total to values in margins because of rounding. Category of very high albuminuria includes nephrotic range. albuminuria, but inconclusive effects on GFR decline,
For eGFRs of 45–59 ml/min per 1·73 m², percentages estimated with the CKD-EPI equation for urine ACR and an increased risk of hypoglycaemia. Despite much
categories <10, 10–29, 30–299, and >300 mg/g (2·5%, 1·1%, 0·8%, 0.·2%, and 4·7% [subtotal], respectively) are interest in restriction of dietary protein (<0·8 g/kg per
lower than for the same categories in the MDRD study equation (3·6%, 1·4%, 0·9%, 0·2%, and 6·1% [subtotal],
respectively).
day), clinical trials have so far been inconclusive.
Treatments to slow the decline in GFR also reduce
4 mL per min per year is fast; at this rate, the interval albuminuria, and the relation between albuminuria
from onset of chronic kidney disease stage 3 to kidney reduction and subsequent GFR decline is strong.
failure would be 12 years or less. Mechanisms of Nonetheless, whether albuminuria is on the causal
progression probably differ according to clinical diagnosis pathway to GFR decline and whether targeting
(eg, diabetic kidney disease vs non-diabetic kidney albuminuria is important in modification of therapy is
disease, disease with vs without proteinuria, and genetic uncertain.57–59 In practice, serial measurements of
vs acquired diseases). Nonetheless, substantial evidence albumin to creatinine ratio and eGFR can be used to
from experimental models shows that some mechanisms monitor disease progression and guide therapy. However,
are independent of the initial cause of disease, and variability can occur over time because of fluctuations in
provide several biomarkers and treatment targets for disease activity and treatment; therefore, a long period of
interventions to slow progression, induce remission of observation might be needed to assess the rate of
disease, and potentially regenerate healthy tissue.12,46–48 progression. Development of risk prediction instruments
Consistent with these findings are several interventions for kidney failure might be helpful to guide clinical
that slow progression in human beings. decisions, but few instruments are available.60–62
The most consistent benefit is noted with use of
angiotensin-converting-enzyme (ACE) inhibitors and Prevention of complications from decreased GFR
angiotensin-receptor blockers (ARBs), usually in Threats to patient safety
association with diuretic drugs, in patients with high Chronic kidney disease has been recognised as a
concentrations of albuminuria. Some trials show potential risk factor for medical errors.63 Furthermore,
favourable effects of a lower than usual target blood acute kidney injury is a frequent complication of medical
pressure (<130/80 mm Hg vs <140/90 mm Hg) in patients errors and can potentially accelerate progression to
with high concentrations of albuminuria. Unfortunately, kidney failure.20,21
these trials included few participants older than 70 years; Decreased GFR is associated with altered
therefore, the generalisability of their findings to the pharmacokinetics and pharmacodynamics of many
large number of older patients with chronic kidney drugs, leading to an increased risk of toxic effects if the
disease is not known.49 Clinical trials of these interventions dose is not appropriately adjusted. Patients with decreased
for risk reduction of cardiovascular disease in older GFR are also at an increased risk of complications from
populations who were not selected for kidney disease administration of intravenous fluid—eg, fluid overload

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and electrolyte disturbances—and of complications from

agents that are used in diagnostic angiography, including Panel 2: Five-step guide for the detection and assessment
iodinated contrast (acute kidney injury) and gadolinium of chronic kidney disease
(nephrogenic systemic fibrosis). Guidance for adjustment 1 Recognition of increased risk of CKD
of drug doses has traditionally been based on serum • Increased susceptibility to CKD (ie, old age, family history,
creatinine or creatinine clearance as estimated by the history of acute kidney injury, member of ethnic or racial
Cockcroft-Gault equation.64 A study65 has suggested that minority in the USA, reduced nephron mass [history of
GFR estimates from the MDRD study equation would be nephrectomy, low birthweight], genetic traits)
as accurate; however, estimates that are adjusted for body • Exposure to diseases or conditions that cause CKD—ie, risk
surface area should be unadjusted for accurate dosing in factors for CVD (hypertension, diabetes, obesity), CVD,
patients with very large or small body size. Recognition autoimmune disease (systemic lupus erythematosus,
of decreased GFR is fundamental to appropriate drug vasculitis), infections (bacteria, HBV, HCV, HIV,
dosing. Several studies66 have investigated the value of schistosomiasis, malaria), drugs or toxins (NSAID,
linking laboratory reporting of serum creatinine or eGFR iodinated radiographic contrast, aristolochic acid)
to computerised entry of prescription orders, with
variable success. 2 Testing for CKD
Many commonly used drugs and procedures can • Measure serum creatinine to estimate GFR
potentially cause acute kidney injury, and patients with • Measure urinary albumin
decreased GFR have an increased risk of drug-induced • Search for other markers of kidney damage that are
injury.67 Avoidance of non-steroidal anti-inflammatory specific to the risk (urine sediment, imaging
drugs (NSAIDs), phosphorus-based enemas, and abnormalities, or renal tubular syndromes)
iodinated contrast is recommended if possible. Acute • Confirmatory tests (if indicated)
kidney injury is a risk after iodinated contrast is 3 Detection of CKD
aggravated by depletion of extracellular fluid, and • GFR <60 mL/min per 1·73 m² (measured or estimated)
guidelines recommend administration of saline or • Kidney damage (pathological abnormalities, markers, or
bicarbonate, with or without N-acetylcysteine, before history of kidney transplantation)
contrast procedures. • Duration >3 months (documented or inferred)

Uraemic complications 4 Evaluation of clinical diagnosis for implementation

Many of the disorders associated with uraemia are of specific therapy
generally asymptomatic and can first be identified at • Diabetic kidney disease (type 1 or type 2)
GFRs of less than about 60 mL/min per 1·73 m².1 These • Non-diabetic kidney disease (glomerular diseases other
disorders are more common as GFR declines, and when than diabetic kidney disease, vascular diseases,
GFR is 15–30 mL/min per 1·73 m² the frequency is about tubulointerstitial diseases, or cystic diseases)
75% for hypertension; 50% for anaemia; 20% for • Kidney disease in recipients of kidney transplants
hyperparathyroidism, hyperphosphataemia, and acidosis; 5 Assessment of stage for implementation
and 5–10% for hypocalcaemia and low serum of stage-based non-specific therapy
albumin.1,25,45,68 Fatigue, weakness, frailty, and decreased • GFR stages
health-related quality of life are common but non-specific, • Albuminuria stages
and might be caused by comorbid disorders.
Impairments in renal excretory and endocrine function CKD=chronic kidney disease. CVD=cardiovascular disease. HBV=hepatitis B virus.
HCV=hepatitis C virus. NSAID=non-steroidal anti-inflammatory drug. GFR=glomerular
parallel reductions in GFR, leading to complex disorders filtration rate.
that are characterised by solute retention, hormone
deficiencies or resistance, and compensatory responses
in other organ systems.69 For each disorder, these nitric-oxide deficiency.70 Although restriction of dietary
abnormalities are markers of disease severity and targets sodium reduces blood pressure in experimental models,
for intervention. Observational studies1 provide strong adherence is low in clinical practice. All antihypertensive
evidence for associations of markers with clinical drugs seem to be effective in lowering blood pressure,
outcomes. Clinical trials have shown that several but several agents, including a diuretic, are usually
interventions are successful in ameliorating the necessary to reach the target level. The optimum level of
abnormalities in the markers (table 2), but evidence is blood pressure and selection of antihypertensive agents
scarce for long-term effectiveness for clinical endpoints to reduce risk of cardiovascular disease are controversial.
for many therapies. Guidelines suggest a lower than usual target for blood
Hypertension is attributed to salt retention and pressure(<130/80 mm Hg vs <140/90 mm Hg), but no
increased vascular tone due to a failure to suppress the adequately powered randomised trials of chronic kidney
sympathetic nervous system and renin-angiotensin disease have been done to test this hypothesis.51,52 The
system, inhibition of sodium-potassium ATPase, and main findings from the action to control cardiovascular

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Rationale Target population Examples*

Reduction of the risk of CKD Interventions for modifiable factors that can All adults Prevention, detection, and treatment of
cause or increase susceptibility to kidney hypertension and diabetes
disease
Early detection of CKD Laboratory testing to detect presence of Adults at increased risk of CKD (hypertension, Urinary albumin-to-creatinine ratio as a marker of
asymptomatic disease diabetes, clinical CVD, family history of kidney kidney damage, serum creatinine to estimate GFR
failure, or age >60 years)
Identification of the clinical diagnosis Specific therapy directed at the clinical All patients with CKD See panel 1
(cause and pathology) diagnosis
Slowing the progression of CKD and of Non-specific therapies, irrespective of the cause All patients with CKD (high priority in ACE inhibitors or ARBs for patients with
albuminuria of CKD patients with high-risk CKD) albuminuria, low blood-pressure goal
Prevention of complications of Avoiding toxic effects of drugs and Patients with CKD stages 3–5 Drug dosing based on eGFR; avoiding NSAIDs,
decreased GFR: threats to patient safety drug-induced AKI iodinated radiographic contrast, phosphate-based
bowel preparation, gadolinium (CKD stages 4–5);
prevention of contrast AKI with isotonic saline or
bicarbonate
Prevention of complications of Therapy directed at altered pathophysiology Patients with CKD stages 3–5 (more often in ESA and iron for anaemia; vitamin D and phosphate
decreased GFR: uraemic complications stages 4–5) binders for CKD-MBD; appropriate energy intake for
malnutrition; referral to nephrologists
Treatment of the nephrotic syndrome Non-specific therapies, irrespective of the cause Patients with urine ACR >2000 mg/g ACE inhibitors or ARBs, restriction of dietary sodium,
of CKD diuretics, statins, consider anticoagulation
Improvements in the outcomes of Preparation and timely initiation of kidney Patients with CKD stages 4–5 (more often in Modality selection for dialysis; access placement for
dialysis and transplantation replacement therapy stage 5) haemodialysis; recipient selection for
transplantation; donor selection for transplantation;
adequate dialysis dose; improved
immunosuppression for transplantation;
complications associated with decreased GFR and
albuminuria after transplantation
Reduction of the risk of CVD Treatment of CVD risk factors and clinical CVD All patients with CKD (high priority in CKD as the highest risk group for blood pressure, lipids
patients with high-risk CKD)

For references see table 1, webappendix pp 1–10. CKD=chronic kidney disease. CVD=cardiovascular disease. GFR=glomerular filtration rate. ACE=angiotensin-converting enzyme. ARB=angiotensin-receptor blocker.
AKI=acute kidney injury. eGFR=estimated GFR. NSAID=non-steroidal anti-inflammatory drug. ESA=erythropoietin-stimulating agent. CKD-MBD=CKD-mineral and bone disorders. ACR=albumin-to-creatinine
ratio. *References to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines9 if available, and to other guidelines and consensus statements if no KDIGO guideline is available.

Table 1: Overview of strategies for prevention, detection, evaluation, and management to improve outcomes of chronic kidney disease in adults

risk in diabetes (ACCORD) trial did not show an lower, quality of life is poorer, and transfusion is needed
advantage of low systolic blood pressure on cardiovascular more often than for patients with earlier stages of
disease events in patients with type 2 diabetes, but chronic kidney disease.82
analyses in the subgroup with chronic kidney disease are Mineral and bone disorders in chronic kidney disease
not yet available. The systolic blood pressure intervention are characterised by abnormalities in serum concentrations
trial (SPRINT) will test this hypothesis in non-diabetic of calcium, phosphorus, 1,25-dihydroxycholecalciferol, and
patients with chronic disease. parathyroid hormone; abnormalities in bone morphology;
Anaemia is caused mainly by decreased production of and vascular calcification.83 Phosphate retention and
erythropoietin by the peritubular cells, and bone- deficiency of 1,25-dihydroxycholecalciferol seem to be the
marrow unresponsiveness to erythropoietin, indicating main causes of hyperparathyroidism and hypocalcaemia,
systemic inflammation, increased hepcidin production and can be treated by decreased phosphorus intake (with
by the liver, and decreased iron availability for restriction of dietary protein) and phosphate-binding drugs
erythropoiesis.71 Treatment with exogenous erythrocyte- (calcium carbonate, lanthanum carbonate, and sevelamer).
stimulating agents (ESA) raises haemoglobin, reduces Hyperparathyroidism can also be treated by exogenous
the need for transfusions, and improves quality of life 1,25-dihydroxycholecalciferol and vitamin D analogues,
and exercise capacity.72,73 However, treatment with ESA and calcimimetics. Although these measures can reduce
to target haemoglobin concentrations of 130 g/L or the severity of osteitis fibrosa cystica, they do not reduce
more (achieved mean concentrations >110 g/L or the incidence of fractures. 1,25-dihydroxycholecalciferol
120 g/L) has been consistently associated with high and calcium-containing phosphate binders have a greater
rates of cardiovascular disease, especially in patients risk of hypercalcaemia than do non-calcium-containing
who are ESA-hyporesponsive.74–81 Clinical decision phosphate binders, and might induce low-turnover
making should balance risks and benefits and usually osteomalacia and vascular calcification. However, the
favours ESA administration in patients undergoing long-term consequences of these effects are not
dialysis in whom haemoglobin concentrations are known. Fibroblast growth factor (FGF)-23—a bone-derived

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phosphaturic hormone—is secreted in response to usually not sufficient to increase intake. Inflammation
phosphorus intake, inhibits production of 1,25-dihydroxy- might be partly due to underlying systemic vascular
cholecalciferol, and is associated with cardiovascular disease and to retained solutes. Clinical trials are
disease. Increased FGF-23 in chronic kidney disease might underway with exercise training and agents to promote
be an alternative mechanism for mineral and bone anabolism, such as human growth hormone and
disorders and a new target for interventions.84 ghrelin.87–90 Signs of peripheral nervous system and
Malnutrition and inflammation frequently coexist in CNS disorders include peripheral neuropathy, restless
chronic kidney disease.85,86 Decreased energy intake is leg syndrome, sleep disorders, and cognitive
an important causal factor, but dietary interventions are impairment.69 Retained toxins are thought to have a role

Surrogate outcomes* Clinical outcomes

Measures Trial results Measures Trial results
Kidney disease progression in CKD stages 1–4
ACE inhibition and ARB vs other Decline in GFR and Slow decline in GFR (strong Time to kidney failure Beneficial effect in patients with
antihypertensive regimens albuminuria effect in patients with high high baseline albuminuria
baseline albuminuria);
reduction in albuminuria
Low vs usual blood pressure target Decline in GFR and Slow decline in GFR in patients Time to kidney failure Beneficial effect after long-term
albuminuria with high baseline albuminuria; follow-up in patients with high
reduction in albuminuria baseline albuminuria;
harm for target SBP<120 mm Hg
in type 2 diabetes
More vs less intensive glycaemic Decline in GFR and Inconsistent effects on GFR Time to kidney failure Not enough events; harm for
control in diabetes albuminuria decline; reduction in albuminuria target HbA1c<6·0–6·5% in type 2
diabetes
Low protein diet with or without Decline in GFR and Inconclusive effect on GFR Time to kidney failure Insufficient events
aminoacid or ketoacid albuminuria decline; reduction in albuminuria
supplements vs usual protein diets
Statins vs placebo Decline in GFR and Slow decline in GFR in some Time to kidney failure Insufficient events in small trials,
albuminuria trials; reduction in albuminuria generally non-significant
outcomes in largest trial
Sodium bicarbonate vs Decline in GFR, Slow decline in GFR; improved Time to kidney failure Beneficial effect in one small trial
standard care nutritional status nutritional status
Paricalcitol vs placebo Decline in GFR and No effect on GFR decline; greater Time to kidney failure Not tested
albuminuria decline in albuminuria
Somatostatin vs placebo in PKD Decline in GFR, cyst No effect on GFR decline; small Time to kidney failure Not tested
growth effect on cyst growth
mTOR inhibitors vs placebo or Decline in GFR and cyst No effect on GFR decline; small Time to kidney failure Not tested
standard care in PKD growth effect on cyst growth
Anaemia in CKD stages 4–5
ESA with high vs low haemoglobin Need for blood Decreased need for transfusions CVD and mortality, No benefit for mortality;
target transfusions quality of life probable harm for CVD
ESA vs placebo Need for blood Decreased need for transfusions CVD and mortality; Beneficial effect on quality of life;
transfusions quality of life no benefit for mortality;
probable harm for CVD
Mineral and bone disorders in CKD stages 4–5
Vitamin D or analogues vs other Parathyroid hormone Lower concentrations of Fractures Not tested
agents parathyroid hormone
Cinacalcet vs other agents Parathyroid hormone Lower concentrations of Fractures Not tested
parathyroid hormone
Sevelamer vs calcium-containing Vascular calcification Reduced increase in vascular CVD and mortality No beneficial effect
phosphorus binders calcification
Dialysis delivery in CKD stage 5D†
Early vs usual initiation of dialysis Uraemic symptoms Few symptoms Mortality No benefit
High vs low dialysis dose Hospital admissions No difference CVD and mortality No benefit
High vs low dialysis membrane flux Hospital admissions No difference CVD and mortality No benefit
Short daily (6 days per week) vs Left ventricular mass Improved left ventricular mass Quality of life Beneficial effect on self-assessed
usual (3 days per week) physical function
haemodialysis
(Continues on next page)

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Surrogate outcomes* Clinical outcomes

Measures Trial results Measures Trial results
(Continued from previous page)
Cardiovascular disease in CKD stage 5D†
Antihypertensive agents vs .. .. CVD and mortality Beneficial effect in a
placebo or conventional agents meta-analysis
Statins vs placebo .. .. CVD and mortality No benefit on total mortality;
beneficial effect on
atherosclerotic CVD events
Folic acid and B vitamins vs .. .. CVD and mortality No benefit
placebo
Graft survival in CKD stages 1–5T†
Tacrolimus vs ciclosporin Acute rejection Few acute rejections Long-term graft Not tested
survival
Antilymphocyte antibodies and Acute rejection Few acute rejections Long-term graft Not tested
low-dose calcineurin inhibitor vs survival
standard-dose calcineurin inhibitor
for induction
Mycophenolate mofetil vs placebo Acute rejection Fewer acute rejections Long-term graft Not tested
or azathioprine survival
mTOR inhibitors vs calcineurin Acute rejection, GFR Equivalence for acute rejection, Long-term graft Not tested
inhibitors higher GFR survival
Costimulatory blockade Acute rejection, GFR Equivalence for acute rejection, Long-term graft Not tested
(betalacept) vs calcineurin higher GFR survival
inhibitors

For references see table 2, webappendix pp 11–19. CKD=chronic kidney disease. ACE=angiotensin-converting enzyme. ARB=angiotensin-receptor blocker. GFR=glomerular
filtration rate. SBP=systolic blood pressure. PKD=polycystic kidney disease. ESA=erythropoietin-stimulating agent. CVD=cardiovascular disease. mTOR=mammalian target of
rapamycin. *GFR decline that is ascertained from doubling of baseline serum creatinine is accepted as a surrogate for progression of kidney disease in clinical trials to slow
progression. This doubling roughly corresponds to halving of baseline GFR with new onset of CKD stage 3 in patients with CKD stages 1–2 at baseline, or new onset of CKD stage 4
in patients with CKD stage 3 at baseline. Acute rejection ascertained from biopsy is accepted as a surrogate for graft failure in clinical trials of transplant immunosuppression.
Surrogate outcomes do not include direct effects of interventions (eg, effects of blood pressure for antihypertensive agents, serum urea nitrogen for low protein diets or higher
dialysis dose, LDL cholesterol for statins, haemoglobin for ESA or iron, phosphorus for phosphorus binders, middle-molecular-weight solutes for high-flux dialysers,
homocysteine for folic acid, or immunological measures for immunosuppressive therapy). †D or T after CKD stage refers to treatment with dialysis or transplantation.

Table 2: Summary of selected randomised trials for chronic kidney disease

in these disorders, and intensive dialysis is some- Dialysis and transplantation

times associated with amelioration. No specific thera- The high cost of dialysis and transplantation restrict their
pies have yet been developed for these neurological availability worldwide, and many patients with kidney
manifestations. failure die without treatment. In 2008, Medicare payments
in the USA were US$77 506 for haemodialysis, $57 639
Treatment of nephrotic syndrome for peritoneal dialysis, and $26 668 for transplantation per
Nephrotic syndrome is one of the main clinical person per year.94 Observational studies suggest that
presentations of glomerular disease (panel 1), indicating referral to nephrologists before the onset of kidney failure
the pathophysiological effects of losses of large is associated with an increased rate of transplantation,
quantities of urinary albumin and other serum proteins, and reduced mortality and cost after the onset of dialysis;
such as immunoglobulins, growth factors, components however, findings from a clinical trial95 did not show a
of the complement, and coagulation cascades. The benefit of early initiation of dialysis. Early referral also
clinical manifestations are related to the underlying enables informed decision making about modality by
clinical diagnosis and severity of proteinuria.91–93 patients, creation of vascular access for haemodialysis,
Irrespective of cause, patients with nephrotic syndrome and identification of living donors for transplantation
might have disabling symptoms from fluid retention, before the onset of kidney failure.
and are at increased risk of infectious, metabolic, and First-year survival with a functioning graft after
thrombotic complications, and acute kidney injury. deceased donor transplantation now exceeds 90%.
Non-specific therapy includes ACE inhibitors or ARBs However, the rate at 10 years is less than 40%, which is
to reduce proteinuria, restriction of dietary sodium and caused partly by nephrotoxic effects of calcineurin
diuretics for oedema, statins to reduce hyperchol- inhibitors and death with graft function attributed to
esterolaemia, and possibly anticoagulants to reduce the cardiovascular disease.25 Clinical trials focus on low
risk of deep-vein thrombosis. doses of these agents in combination with other

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immunosuppressive agents to reduce nephrotoxic effects are associated with an increased risk of cardiovascular
and risk of cardiovascular disease, and to prevent graft mortality, de-novo and recurrent cardiovascular events,
rejection. Observational studies show that reduced GFR and subclinical cardiovascular disease. Pathophysio-
and albuminuria are risk factors for graft loss and logical links between cardiovascular and chronic kidney
mortality in recipients of kidney transplants.96,97 disease include a high prevalence of traditional and
Guidelines for non-specific therapy to slow progression non-traditional risk factors, including hypertension;
of kidney disease and to prevent complications of fluid overload; electrolyte, acid-base, and mineral
decreased GFR and albuminuria are based largely on disorders; anaemia; dyslipidaemia; inflammation;
observational data and extrapolation of trials of diseases increased oxidative stress; and prothrombotic
in the native kidneys. Transplantation is mostly limited stimuli.108–110 However, these associations do not prove
by a scarcity of donor organs. Although preliminary causation. Other possible explanations are the high
experience with donor exchange programmes or prevalence of shared risk factors for both diseases, and
recipient desensitisation shows promising results in reverse causation, because cardiovascular disease is
overcoming ABO and HLA incompatibilities, logistical now recognised as a risk factor for GFR decline.111,112
obstacles need to be overcome before these activities can Many guidelines now recommend that patients with
be used worldwide.98,99 chronic kidney disease be considered in the highest-risk
Patients’ survival in long-term dialysis is substantially group for subsequent cardiovascular events, and that
lower than survival for transplant recipients, even after most effective interventions for reducing the risk of
selection and case-mix bias have been accounted for. cardiovascular disease in the general population should
Improvements in age-adjusted survival of patients on also be applied to patients with chronic kidney disease.
dialysis have occurred during the past decade in Few clinical trials have been specifically designed to
association with adoption of new technologies and assess clinical outcomes after interventions for risk factors
measures of clinical performance, including increased for cardiovascular disease and for clinical cardiovascular
doses of dialysis, partial correction of anaemia, and disease in people with chronic kidney disease. However,
control of hyperphosphataemia.25 However, clinical trials treatment for patients with risk factors for cardiovascular
of single interventions have not shown improved survival. disease is effective in early stages of chronic kidney
One trial100 showed improvement in left ventricular mass disease, and in trials of cardiovascular disease, the
and physical function with frequent haemodialysis, subgroup with chronic kidney disease seems to benefit as
perhaps indicating improved fluid and blood-pressure much or more than the subgroup without disease from
control. Cardiovascular disease is the leading cause of intensive reduction in risk factors for cardiovascular
death, but the relation of traditional risk factors—such as disease and intensive management of clinical disease.113–115
blood pressure, serum LDL cholesterol, and body-mass These findings suggest that patients with early stages of
index—to mortality is complex, with increased risk at chronic kidney disease might be more similar to the
both low and high levels. These paradoxical relations general adult population, in whom one intervention for
seem to indicate confounding by disease severity, cardiovascular disease can improve mortality, than to
malnutrition and inflammation, and unmeasured patients with kidney failure treated by dialysis.
comorbid disorders. Although a meta-analysis101 of trials
of antihypertensive agents has shown reduced mortality, Controversies and challenges
the optimum agents and blood pressure targets were not Association with ageing and vascular disease
identified. Two moderately large trials of statins102,103 did Ageing and vascular disease are associated with low GFR
not show reduction in total mortality despite substantial and high albuminuria, and whether the present definition
lowering of serum LDL cholesterol; however, the study of leads to overdiagnosis of chronic kidney disease has been
heart and renal disease protection (SHARP) trial104 questioned, particularly for older individuals.116,117 The
showed reduced atherosclerotic events. The failure of magnitude and cause of these associations are not well
statins to reduce overall mortality could indicate heart understood and are important topics for research; however,
failure or arrhythmias as the main mechanism for death some evidence suggests that low GFR and high
from cardiovascular disease, rather than atherosclerosis. albuminuria are not normal and that the term kidney
Improvements in mortality in patients on dialysis will disease is appropriate. First, the age-related decline in
probably need several interventions. GFR is associated with abnormalities in kidney structure
and function, which cannot be distinguished from
Reductions in risk of cardiovascular disease abnormalities caused by disease.118–120 Second, the kidney is
Cardiovascular disease is considered separately from a highly vascular organ; therefore kidney disease cannot
other complications of chronic kidney disease because be distinguished from kidney involvement in a systemic
it is the most frequent outcome of chronic kidney vascular disease as has been suggested.121 Third, increased
disease, and because chronic kidney disease is a risk evidence has indicated that decreased GFR and
factor for cardiovascular disease.105–107 Studies of several albuminuria are associated with high risks of mortality
populations show that low GFR and high albuminuria and kidney outcomes in both old and young individuals.15–18

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As in diabetes, hypertension, or hypercholesterolaemia, delivery of adequate doses of haemodialysis.130,131 Many

the selection of the threshold value for disease definition guidelines now target all stages of chronic kidney disease
should balance the risk of identification of low-risk and the most common clinical diagnoses (table 1), and
individuals versus the benefit of early detection of high- many recommendations have been incorporated into
risk individuals. Although studies of risks and benefits are measures of clinical performance in patients undergoing
necessary, they are limited by insufficient knowledge dialysis.132 The main responsibility for developing
about the full range of complications and effectiveness of guidelines for chronic kidney disease has now been
interventions to treat chronic kidney disease.122 assumed by Kidney Disease Improving Global Outcomes
(KDIGO)—a global not-for-profit foundation dedicated to
Clinical trials improving the care and outcomes of patients with kidney
To improve outcomes for chronic kidney disease, new disease worldwide.133,134 KDIGO guidelines rate the
treatments will need to be translated into clinical practice strength of recommendations and evidence with rigorous
and public health. and well accepted methods.135 The rationale for worldwide
Nephrology has the fewest number of clinical trials of development of guidelines is that chronic kidney disease
major specialties123 and, not surprisingly, few treatments is a global health problem, methods need to be
have been shown to enhance clinical outcomes (table 2). standardised for guideline development, and the scientific
These factors are the substantial challenges in clinical and evidence-base are independent of geographical
trials of chronic kidney disease. First, the average rate of location or national borders. However, guidelines should
progression of most kidney diseases is slow, needing a be implemented locally because of variations in cause
long period of follow-up or a large study population and prevalence of disease, standards of medical practice,
to test the effectiveness of interventions to slow and public health priorities for resource allocation.
progression. Death from cardiovascular disease is a
competing event, especially in older patients with early Chronic kidney disease as a public health problem
stages of chronic kidney disease in whom the rate of The increased prevalence of kidney failure and early
death far exceeds the rate of kidney failure. Second, the stages of chronic kidney disease, and the high costs and
high prevalence of comorbid disorders in patients with poor outcomes of treatment constitute a worldwide
chronic kidney disease suggests that multifaceted public health threat. Costs for dialysis and transplantation
interventions and coordination of medical care might are increasing alongside costs for other chronic diseases.136
be needed to improve outcomes. The design, The ageing of the population and the obesity epidemic
management, and interpretation of trials of complex mean that this disease will probably be a threat to both
interventions is difficult; however, some have been developed and developing nations for the foreseeable
reported.124–126 Third, despite the large number of uraemic future. Through remarkable progress in laboratory
complications in chronic kidney disease, most patients investigation and clinical trials, treatment is now available
do not have specific symptoms until late stages of that can be tailored to the risk of adverse outcomes on
disease, and few studies have recorded patient-reported the basis of GFR and albuminuria. Testing can detect
outcomes.127 However, pivotal clinical trials for drug early stages of disease, and the same methods that are
development need a clinical endpoint that is an indicator used in clinical practice can be used to screen populations
of how a patient survives or feels. A doubling of serum at increased risk. Public health interventions are available
creatinine has been accepted as surrogate endpoint for to improve the treatment and prevent the development of
progression of chronic kidney disease, but a change in hypertension and diabetes. Thus, methods to reduce the
GFR that is smaller than this change in serum creatinine burden of chronic kidney disease are available, and
is not accepted.57,59 Changes in serum creatinine are not many countries are beginning to develop public health
sensitive to the early decline in GFR, which limits drug strategies for this disease.
development to patients with severe disease. Re- Recommendations for prevention include improve-
evaluation of whether some asymptomatic disease ments in surveillance, screening, education, and
complications might be considered as clinical endpoints awareness, which are directed at three target populations:
in chronic kidney disease could be worthwhile. people with or at increased risk of chronic kidney
disease; providers, hospitals, and clinical laboratories;
Guidelines and the general public.137,138 Low awareness of chronic
Clinical practice guidelines are systematically developed kidney disease in all three groups probably indicates the
statements that assist practitioners and patient decisions absence of symptoms and low familiarity with the new
about appropriate health care for specific clinical guidelines for definition and classification. To increase
circumstances. Implementation of rigorously developed awareness, the International Society of Nephrology and
evidence-based guidelines can reduce variability of care, International Federation of Kidney Foundation
improve patient outcomes, and ameliorate deficiencies inaugurated World Kidney Day in 2006,139 to be marked
in health-care delivery.128,129 The first guidelines in in March every year to communicate that kidney disease
nephrology were developed in 1993 and focused on the is common, harmful, and treatable. Screening

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programmes for kidney disease have been launched in 10 Vassalotti JA, Stevens LA, Levey AS. Testing for chronic kidney
many locations, which confirm a high prevalence of disease: a position statement from the National Kidney Foundation.
Am J Kidney Dis 2007; 50: 169–80.
decreased GFR and albuminuria in association with a 11 Stevens LA, Levey AS. Current status and future perspectives
high burden of risk factors for cardiovascular disease.140 for CKD testing. Am J Kidney Dis 2009; 53 (suppl 3): S17–26.
However, studies141–144 have suggested that screening is 12 Remuzzi G, Benigni A, Remuzzi A. Mechanisms of progression
and regression of renal lesions of chronic nephropathies and
not cost effective for reducing kidney failure or all-cause diabetes. J Clin Invest 2006; 116: 288–96.
mortality except in high-risk populations—eg, old 13 de Jong PE, Curhan GC. Screening, monitoring, and treatment
people with diabetes or hypertension. With a wide range of albuminuria: public health perspectives. J Am Soc Nephrol 2006;
17: 2120–26.
of outcomes and a focus on high-risk target populations,
14 Hemmelgarn BR, Manns BJ, Lloyd A, et al, for the Alberta Kidney
cost-effectiveness of screening might be improved. Disease Network. Relation between kidney function, proteinuria,
Chronic kidney disease is one of several chronic and adverse outcomes. JAMA 2010; 303: 423–29.
diseases affecting mostly older people and leading to a 15 Matshushita K, van de Velde M, Astor BC, et al, for the Chronic
Kidney Disease Prognosis Consortium. Association of estimated
substantially increased risk of cardiovascular disease. glomerular filtration rate and albuminuria with all-cause and
Coordination of public health efforts for chronic kidney cardiovascular mortality in general population cohorts:
disease and other chronic diseases will probably be the a collaborative meta-analysis. Lancet 2010; 375: 2073–81.
16 van der Velde M, Matsushita K, Coresh J. Lower estimated
most efficient strategy. Reorganisation of delivery of care glomerular filtration rate and higher albuminuria are associated with
to treat older people and others with various chronic all-cause and cardiovascular mortality. A collaborative meta-analysis
diseases efficiently will probably be necessary, as will of high-risk population cohorts. Kidney Int 2011; 79: 1341–52.
17 Gansevoort RT, Matshushita K, van de Velde M, et al, for the
cooperation at all levels of governmental and private Chronic Kidney Disease Prognosis Consortium. Lower estimated
organisations. Assessment of the effectiveness of public GFR and higher albuminuria are associated with adverse kidney
health strategies will be important to guide progress. outcomes. A collaborative meta-analysis of general and high-risk
population cohorts. Kidney Int 2011; published online Feb 2.
Contributors DOI:10.1038/ki.2010.531.
ASL did the literature search and wrote the first draft of the Seminar 18 Astor BC, Matsushita K, Gansevoort RT, et al. Lower estimated
with assistance from JC. Both authors interpreted the retrieved glomerular filtration rate and higher albuminuria are associated with
publications and planned and revised the Seminar. mortality and end-stage renal disease. A collaborative meta-analysis
of kidney disease population cohorts. Kidney Int 2011; 79: 1331–40.
Conflicts of interest
19 Levey AS, de Jong PE, Coresh J, et al. The definition, classification
ASL has received payment for editorial board membership from the
and prognosis of chronic kidney disease: a KDIGO Controversies
National Kidney Foundation (NKF), and grant support from NKF and Conference report. Kidney Int 2010; published online Dec 8.
Amgen. JC declares that he has no conflicts of interest. DOI:10.1038/ki.2010.483.
Acknowledgments 20 Hsu CY, Ordoñez JD, Chertow GM, Fan D, McCulloch CE, Go AS.
We thank Mark J Sarnak, Katrin L Uhlig, Lesley A Stevens, The risk of acute renal failure in patients with chronic kidney
Ashish Upadhyay, and Joe Eustace for reviewing early versions of the disease. Kidney Int 2008; 74: 101–07.
Seminar; Aghogho Okparavero for helping to prepare the Seminar; and 21 James MT, Hemmelgarn BR, Wiebe N, et al, for the Alberta Kidney
Stephen Juraschek and Brad C Astor for providing data for figure 4. Disease Network. Glomerular filtration rate, proteinuria, and the
incidence and consequences of acute kidney injury: a cohort study.
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