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Chronic kidney disease: Global dimension and perspectives

Article in The Lancet · May 2013

DOI: 10.1016/S0140-6736(13)60687-X · Source: PubMed

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Global Kidney Disease 3

Chronic kidney disease: global dimension and perspectives
Vivekanand Jha, Guillermo Garcia-Garcia, Kunitoshi Iseki, Zuo Li, Saraladevi Naicker, Brett Plattner, Rajiv Saran, Angela Yee-Moon Wang,
Chih-Wei Yang

Lancet 2013; 382: 260–72 Chronic kidney disease is defined as a reduced glomerular filtration rate, increased urinary albumin excretion, or
Published Online both, and is an increasing public health issue. Prevalence is estimated to be 8–16% worldwide. Complications include
May 31, 2013 increased all-cause and cardiovascular mortality, kidney-disease progression, acute kidney injury, cognitive decline,
http://dx.doi.org/10.1016/
anaemia, mineral and bone disorders, and fractures. Worldwide, diabetes mellitus is the most common cause of
S0140-6736(13)60687-X
chronic kidney disease, but in some regions other causes, such as herbal and environmental toxins, are more
This online publication has been
corrected. The corrected version common. The poorest populations are at the highest risk. Screening and intervention can prevent chronic kidney
first appeared at thelancet.com disease, and where management strategies have been implemented the incidence of end-stage kidney disease has
on July 19, 2013 been reduced. Awareness of the disorder, however, remains low in many communities and among many physicians.
This is the third in a Series of Strategies to reduce burden and costs related to chronic kidney disease need to be included in national programmes
six papers about global for non-communicable diseases.
kidney disease
Postgraduate Institute of
Medical Education and
Introduction important effect on outcomes,2 which prompted the
Research, Chandigarh, India In 2002, the US National Kidney Foundation Kidney Kidney Disease: Improving Global Outcomes (KDIGO)
(Prof V Jha DM); George Institute Disease Outcomes Quality Initiative clinical practice Work Group on Evaluation and Management of Chronic
of Global Health, New Delhi, guidelines defined chronic kidney disease as kidney Kidney Disease to include albuminuria in the revised 2012
India (Prof V Jha); Hospital Civil
de Guadalajara, University of
damage or glomerular filtration rate lower than 60 mL/min classification.3 Causes of chronic kidney disease are also
Guadalajara Health Sciences per 1·73 m² for 3 months or longer, and proposed a included in the new scheme because they can affect
Centre, Guadalajara, Mexico classification scheme based on glomerular filtration rate.1 outcomes and the choice of treatments. Early identification
(Prof G Garcia-Garcia MD); Later analyses have shown that albuminuria also has an of chronic kidney disease is needed to prevent disease
University Hospital of the
Ryukyus, Okinawa, Japan
progression and reduce the risk of cardiovascular
(Prof K Iseki MD); Institute of morbidity and mortality. Public health approaches to
Nephrology, Peking University, Key messages enabling early identification are, therefore, receiving
Beijing, China (Z Li MD);
• Chronic kidney disease is an important cause of death and increasing attention.
University of the
Witwatersrand, Department of loss of disability-adjusted life-years worldwide, but As part of this Series on global kidney disease, we
Internal Medicine, awareness is low among patients and health-care providers examine the worldwide differences in the burden, risk
Johannesburg, South Africa
• The number of patients with chronic kidney disease is factors, and causes of chronic kidney disease in relation
(Prof S Naicker MD); Internal
expected to grow at the fastest rate in the poorest parts of to levels of socioeconomic development and health-care
Medicine (B Plattner MD,
Prof R Saran MD) and University the world, but a strong association is seen between low systems. We also review the different types of chronic
of Michigan-Kidney levels of economic development and reduced availability kidney disease encountered in various parts of the
Epidemiology and Cost Center
of renal replacement therapy world, controversies in methods of screening, and the
(Prof R Saran), University of
Michigan, Ann Arbor, MI, USA; • Variations in methods used to estimate concentrations of
Queen Mary Hospital, creatinine in serum and albuminuria affect estimation of
University of Hong Kong, Hong Search strategy and selection criteria
the number of cases of early-stage chronic kidney disease
Kong, China
(Prof A Y-M Wang MD); Kidney
• Unique causes and risk factors for chronic kidney disease, We searched PubMed and Medline for articles published in
Research Centre, Chang Gung such as exposure to herbal preparations and English between July 6, 2012, and Dec 28, 2012, with the
Memorial Hospital, Linkou, environmental factors, exist in some parts of the world terms “chronic renal failure”, “end stage renal failure”,
Taiwan (Prof C-W Yang MD); and
• Care for advanced chronic kidney disease is associated with “chronic kidney disease”, “epidemiology”, “health-care costs”,
Chang Gung University College
of Medicine, Tao-Yuan, Taiwan catastrophic health expenditure in developing countries “kidney failure, chronic/economics”, and “hemodialysis”. The
(Prof C-W Yang) • Early detection of chronic kidney disease requires following terms were used to obtain geographically specific
Correspondence to: development of cost-effective approaches relevant to the information: “developing countries OR Asia/epidemiology OR
Prof Vivekanand Jha, George local level of economic development and resources Latin America/epidemiology OR Africa south of the Sahara/
Institute for Global Health, • Integration of screening and management strategies for epidemiology OR Tropical climate OR Tropical climate/adverse
219-221 Splendor Forum, Jasola,
New Delhi, India
chronic kidney disease into national programmes for effects”. Abstracts of all the publications were reviewed. We
[email protected] non-communicable diseases can reduce the burden and selected 749 potentially relevant articles for in-depth review
cost of care of chronic kidney disease of abstracts and, where relevant, of the full text. Additional
• Because of a shortage of trained nephrologists, general references were selected from relevant articles, chapters of
practitioners must be involved in caring for patients with recent textbooks, and other web resources. Conference
chronic kidney disease presentations and position papers were also reviewed.

260 www.thelancet.com Vol 382 July 20, 2013

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cost-effectiveness, feasibility, and effects of screening Hispanic, and Native Americans in the USA, and
and prevention programmes for chronic kidney disease Indigenous Australians, South American Aborigines,
in different countries. Maori, Pacific, and Torres Strait Islanders in New Zealand,
and First Nation Canadians.8–10
Epidemiology of chronic kidney disease
Mortality Demographic characteristics
According to the 2010 Global Burden of Disease study4 The demographics of people with chronic kidney disease
chronic kidney disease was ranked 27th in the list of causes vary widely worldwide. The mean age of 9614 patients
of total number of global deaths in 1990 (age-standardised presenting with stage 3 chronic kidney disease in India
annual death rate of 15·7 per 100 000), but rose to 18th in was 51·0 (SD 13·6) years,11 whereas in 1185 patients in
2010 (annual death rate 16·3 per 100 000).4 This degree of China it was 63·6 (14·7) years.12 In India, patients with
movement up the list was second only to that for HIV and chronic kidney disease of unknown origin were younger,
AIDS. The overall increase in years of life lost due to poorer, and more likely to present with advanced chronic
premature mortality (82%) was third largest, behind HIV kidney disease than were people with known causes.11
and AIDS (396%) and diabetes mellitus (93%). An analysis Young adults aged 20–50 years in sub-Saharan Africa
of data on cause of death in the USA and Australia by Rao mainly develop chronic kidney disease owing to hyper-
and colleagues5 showed that a substantial proportion of tension and glomerulonephritis.13 In the USA, African
individuals who had died from diabetes had renal failure, American and Hispanic people reach end-stage kidney
but the cause of death was coded as diabetes without disease at younger ages than white people (mean age
complication. Reported mortality from diabetes-related 57 and 58 years vs 63 years).8
renal disease was estimated to be four to nine times less
than the actual rate. Causes
Diabetes and hypertension are the leading causes of
Incidence and prevalence chronic kidney disease in all developed and many
The incidence and prevalence of end-stage kidney disease developing countries (figure 2), but glomerulonephritis
differ substantially across countries and regions and unknown causes are more common in countries of
(figure 1). More than 80% of all patients receiving Asia and sub-Saharan Africa. These differences are related
treatment for end-stage kidney disease are estimated to mainly to the burden of disease moving away from
be in affluent countries with large elderly populations infections towards chronic lifestyle-related diseases,
and universal access to health care.6 The lower figures decreased birth rates, and increased life expectancy in
reported from poor countries are largely due to patients developed countries.14 By contrast, infectious diseases
not being accepted into renal replacement therapy (RRT) continue to be prevalent in low-income countries,
programmes, although where economies are growing, secondary to poor sanitation, inadequate supply of safe
the numbers of patients being accepted for RRT are water, and high concentrations of disease-transmitting
rising strikingly.7 Projected worldwide population vectors.15 Environmental pollution, pesticides, analgesic
changes suggest that the potential number of cases of abuse, herbal medications, and use of unregulated food
end-stage kidney disease will increase disproportionately additives also contribute to the burden of chronic kidney
in developing countries, such as China and India, where disease in developing countries.16 Rapid urbanisation and
the numbers of elderly people are expanding. This effect globalisation have accelerated the transition in south
will be enhanced further if the trends of increasing Asian and Latin American countries, which has led to
hypertension and diabetes prevalence persist, competing an overlap of disease burdens, with continued high
causes of death—such as stroke and cardiovascular prevalence of infectious diseases and an increasing
diseases—are reduced, and access to treatment improves. prevalence and severity of lifestyle disorders, such as
In contrast to clinically apparent advanced-stage chronic diabetes and hypertension.17,18 Genetic factors also
kidney disease, precise calculation of the burden of less contribute. Variations in MYH9 and APOL1 are associated
symptomatic or asymptomatic early-stage chronic kidney with non-diabetic chronic kidney disease in individuals of
disease, which accounts for 80–90% of all cases, is difficult.3 African origin.19,20
Although data on early-stage chronic kidney disease from
different parts of the world have been published (appen- Identification of chronic kidney disease See Online for appendix
dix), they are confounded by heterogeneity in the popu- Identification and staging of chronic kidney disease rely
lations screened, methods used to determine glomerular on measurement of glomerular filtration rate and
filtration rate, and proteinuria assays. The estimates are albuminuria. Calculation of actual glomerular filtration
usually based on a single-time measurement rather than rate by measurement of external filtration markers is
on sustained demonstration of abnormality. Even within cumbersome and impractical. Values are, therefore,
countries, subgroups are at increased risk of developing estimated on the basis of creatinine concentrations in
chronic kidney disease, disease progression, or both, plasma. Creatinine concentrations in serum might also
including black and Asian people in the UK, black, be affected by creatinine generation (dependent on

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Prevalence (per million population) Annual incidence (per million population)

0
500
1000
1500
2000
2500
3000
0
50
100
150
200
250
300
350
400
450
Ta Ta
iw iw
a an
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an U
Series

M SA
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J o
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o So Tu ai
Ca rea ut rke
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Au ain Cz M Israe
s ec al l
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SLANH=Sociedad Latinoamerica de NefrologÍa e HipertensiÓn.

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an
Ne Tha nia
w
Cz Z ilan Su ce
ec ea d Ar da
h R la ge n
ep nd nt
u Au ina
M blic

Country or region
ex str

Figure 1: Annual incidence (A) and prevalence rates (B) of end-stage kidney disease in different countries
ico ia
Ve Bra Ita
ne zil ly
M Sp
zu a a
SL ela Ne ced in
A t on
Es NH Ne herl ia
to w an
n Ze ds
La ia
t a
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on a or
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Ec uba C
ua Au uba
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Ru or a
s Tu lia
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Pa liv si
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So C ine Fi via
ut hi Ve nlan
h A na ne d
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c Es ela
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au di
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an Bo ia
liv
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n Ru ia
Ba Be ya s
ng ni M C sia
lad n on h
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ua
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Uk or d
Se oon
ne Pa rain
g ra e
Gh al gu
an ay
a

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Venezuela
USA
UK
Taiwan
Sudan
Spain
South Africa
Singapore
Shanghai
Serbia
Philippines
Nigeria
New Zealand
Country or region

Netherlands
Malaysia
Japan
Italy
India
Ghana
France
Finland
Egypt
Cuba
China
Benin
Belgium
Bangladesh
Austria
Australia
Argentina
0 10 20 30 40 50 60 70 80 90 100
Proportion (%)
Diabetes CGN HT CIN RVD Inherited Others Unknown

Figure 2: Distribution of causes of chronic kidney disease worldwide

CGN=chronic glomerulonephritis. HT=hypertensive nephrosclerosis. CIN=chronic interstitial nephritis. RVD=renovascular disease.

muscle mass and dietary intake), tubular secretion, and clearance (figure 3).24 These different approaches might
extrarenal removal3 and, therefore, variations between substantially alter outcomes, as noted in the Japanese
populations are expected. The Modification of Diet in general population when two equations were used.25
Renal Disease study (MDRD) and Chronic Kidney The characteristics of the population assessed during
Disease Epidemiology Collaboration (CKD-EPI) creatine equation development can also affect accuracy. If an
equations have correction factors for African Americans. equation is developed in patients with advanced chronic
Chinese, Japanese, and Thai investigators found that the kidney disease, output values are generally low.26 If the
MDRD equation underestimated the absolute glomerular same equation were applied to the general population,
filtration rates in populations from those countries and an artificially high prevalence of low glomerular fil-
developed new equations or correction factors.21–23 The tration rates would be seen. This feature led to the
applicability of these modified equations to similar development of the CKD-EPI equation.27 The average
populations, such as the South Asians and most glomerular filtration rate reference values for the
indigenous races, has not been widely explored. MDRD and CKD-EPI cohorts assessed for equation
The accuracy of equations is affected by the reference development were 39·8 and 68·0 mL/min per 1·73 m²,
method used to measure glomerular filtration rate. The respectively. The MDRD equation showed 7·8%
MDRD and CKD-EPI equations were developed with prevalence of chronic kidney disease in the National
¹²⁵I-iothalamate clearance as the gold standard, the Health and Nutrition Examination Survey population,
Chinese MDRD equation uses ⁹⁹mTc-diethylene triamine but the CKD-EPI showed a 6·3% prevalence.27 The 2012
penta-acetic acid (⁹⁹mTc-DTPA) clearance, and the Japanese KDIGO guideline suggests use of the CKD-EPI
MDRD equation uses modified inulin clearance. In a equation to calculate estimated glomerular filtration
head-to-head comparison study, ⁹⁹mTc-DTPA clearance rates in adults.3 Specific paediatric equations, which
gave 10 mL/min per 1·73 m² higher values than did inulin require knowledge of height, should be used to estimate

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200
were 27·0% for men and 28·0% for women.28 Prevalence
Y=1·055*X+8·167 is higher in urban populations than in rural populations in
developing countries.29 The worldwide hypertension
CL-DTPA (mL/min per 1·73 m2)

150 prevalence, when age-specific and sex-specific adjustments

are made to take into account changes in the world
population, is projected to increase to 1·56 billion by 2025.28
100
The actual number, however, might well exceed these
projections, as suggested by a Canadian Hypertension
50
Education Program Outcomes Research Taskforce study,30
which projected increases in prevalence of 25·7% and
60·0% between 1995 and 2005, respectively, in Ontario,
0 Canada, after adjustment for age and sex. Moreover, rates
0 50 100 150 200
of hypertension control are dismal. Pereira and colleagues31
CL-IN (mL/min per 1·73 m2)
showed that only 9·8% of men and 16·2% of women in
Figure 3: Relation between dual plasma sampling ⁹⁹mTc-DTPA plasma developing, and 10·8% of men and 17·3% of women in
clearance and modified renal inulin clearance developed countries had controlled hypertension.
Red dots indicate estimated glomerular filtration rate. DTPA=diethylene
Similar trends are apparent for diabetes. The worldwide
triamine penta-acaetic acid. CL-DTPA=plasma clearance of ⁹⁹mTc-DTPA.
CL-IN=renal inulin clearance. Regression line shows an intercept of 8·2 prevalence of diabetes in adults is estimated to be 6·4%,
(95% CI 3·9–12·5) and slope of 1·055 (95% CI 0·969–1·141). Reproduced from affecting 285 million people, and is expected to rise to
reference 24 by permission of Elsevier. 7·7% by 2030 (439 million cases).32 The largest increases
in prevalence are expected in developing regions (the
glomerular filtration rates in children. Older equations, Middle East, 163%; sub-Saharan Africa, 161%; India,
the most popular of which is the Cockroft-Gault for- 151%; Latin America, 148%; and China, 104%).33 Although
mula, continue to be used in some areas. diabetes is predicted to increase in all age strata, ageing
The accuracy of estimated glomerular filtration rate populations and a shift towards urbanisation will
and albuminuria assessments is affected by biases in contribute substantially. Similarly to hypertension, the
creatinine and urine albumin assays. Assays should be projections are probably conservative, and could be
calibrated against reference material traceable to isotope exceeded by the actual growth.34
dilution mass spectrometry standard.3 Several assays are The prevalence of obesity worldwide is also increasing.
used in laboratories around the world, but most do not 312 million adults worldwide were estimated to be obese
meet these standards, which probably leads to inaccuracy, at the beginning of the 21st century. Particularly alarm-
inconsistency, or both, in results. Laboratories in many ing is the increase in the number of overweight and
developing countries do not report estimated glomerular obese children. In China, the prevalence of people
filtration rate values. classified as overweight or obese increased by 49·3%
Accurate assessment of differences by ethnic origin, from 1992 to 2002.35 In contrast to the developed world,
region, or both, will require validation of existing equa- obesity in developing countries is rising in affluent and
tions for estimated glomerular filtration rate against the educated populations.36
same glomerular filtration rate reference method and
creatinine assay. In the meantime, the CKD-EPI equation Herbs
is recommended to calculate estimated glomerular Herbal medicines are widely used by rural populations in
filtration rate, with recognition of the possibility of mis- Africa and Asia and have become popular in developed
classification in some clinical settings and populations. countries.37 Nephrotoxic effects can result from consump-
tion of potentially toxic herbs, incorrect substitution of
Risk factors harmless herbs with toxic herbs, contamination with
Hypertension, diabetes mellitus, and obesity toxic compounds, such as heavy metals, or interactions
Chronic kidney disease is viewed as part of the rising between herbs and conventional treatments.38
worldwide non-communicable disease burden. Hyper- Herbs can cause acute kidney injury, tubular dysfunc-
tension, diabetes mellitus, and obesity are among the tion, electrolyte disturbances, hypertension, renal papillary
growing non-communicable diseases and are important necrosis, urolithiasis, chronic kidney disease, and uro-
risk factors for chronic kidney disease. The global preva- thelial cancer.37 Herbal causes should be considered in
lence of hypertension in adults was estimated to be about cases of unexplained kidney disease, especially in areas
26% (972 million cases) in 2000,28 with most cases where consumption of herbal preparations is high.
(639 million [66%]) being in developing countries.
Prevalence was 37%, 21%, and 20% in established market Aristolochic-acid and Balkan endemic nephropathies
economies, India, and China respectively. In Latin Aristolochic-acid nephropathy is a progressive inter-
America, 40·7% of men and 34·8% of women had stitial nephritis that leads to end-stage kidney disease and
hypertension, whereas in sub-Saharan Africa the values urothelial malignant disease. It was first reported in 1993,

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in young women who received a regimen containing a kidney disease in a substantial proportion of affected
herb later identified as Aristolochia fangchi in Belgian individuals. In Germany an outbreak was triggered by
slimming clinics.39 Epidemiological data from Taiwan and Shigatoxin-producing Escherichia coli,49 and in South
China show an association between use of herbs con- Asia, haemolytic-uraemic syndrome is frequently seen
taining aristolochic acid and chronic kidney disease.40,41 after infection with Shigella dysenteriae.50
Three clinical subtypes of aristolochic-acid nephropathy
have been classified: chronic tubulointerstitial neph- Chronic kidney disease of unknown origin
ropathy (accounting for 93·3% of cases), acute kidney Clusters of cases of chronic kidney disease of unknown
injury (4·3%), and tubular dysfunction with unchanged origin have been reported in some areas of Sri Lanka and
glomerular filtration rate (2·3%).42 The worldwide inci- India.7 The affected individuals are mainly young male
dence of aristolochic-acid nephropathy is probably higher farmers. Clinical presentation resembles that of interstitial
than initially thought. In Asian countries, where trad- nephritis. Histology shows interstitial fibrosis, tubular
itional medicines are very popular and pharmaceutical atrophy, and interstitial mononuclear-cell infiltration.51
medicines are frequently substituted or supplemented by Contamination of water, food, or both, by heavy metals,
botanical products that include herbs containing aristo- industrial chemicals, fertilisers, and pesticides has been
lochic acid.43 suspected.51 Nevertheless, in a study funded by the
Balkan-endemic nephropathy affects people living along Research and Prevention Committee of the International
the tributaries of the Danube River, and is characterised Society of Nephrology, no excess of heavy metals was
by chronic interstitial fibrosis with slow progression to found in the water in the Srikakulam district of India
end-stage kidney disease and urothelial malignant disease. (Ravishankar MS, Sevenhills Hospital, Mumbai, India,
It arises from consumption of aristolochic acid in flour personal communication).
obtained from wheat grown in fields contaminated with
Aristolochia clematitis and, therefore, is a deemed to be Awareness of chronic kidney disease
form of aristolochic-acid nephropathy.42 Despite its recognition as an important public health
issue, awareness of chronic kidney disease remains
Infections low.52,53 In a nationwide health screening programme in
HIV infection is epidemic in sub-Saharan Africa. Popu- the USA that involved around 90 000 adults at high risk
lation screening has shown kidney involvement in of chronic kidney disease, the prevalence and awareness
5–83% of HIV-infected individuals in this region.44,45 In rates were, respectively, 29·7% and 8·6% for white
the USA, HIV-associated nephropathy is seen in African respondents, 22·8% and 6·3% for African Americans,
Americans but not in white people. Despite a large HIV- 29·2% and 6·8% for Native Americans, 20·3% and
infected population, HIV-associated nephropathy is rare 11·1% for Hispanics, and 23·4% and 11·9% for Asians
in Asia.46 The differences between regions could be and Pacific Islanders.54 Awareness was higher among
explained by differential prevalence of high-risk alleles in people with advanced chronic kidney disease (overall
MYH9 and APOL1.19,20 Early initiation of antiretroviral 7·8% for stage 3 and 41·0% for stage 4) and those with
therapy reduces the burden of HIV-associated neph- diabetes, hypertension, and proteinuria.55 Furthermore,
ropathy but carries the risk of nephrotoxic effects, such use of nephrology care was low, with less than 6% of
as crystal-induced obstruction, tubular toxic effects, participants with stage 3 disease and less than 30% of
interstitial nephritis, lactic acidosis, and electrolyte those with stage 4–5 disease ever having seen a
disorders. Other specific infections that cause severe nephrologist. Studies from Taiwan reported that the
kidney lesions in populations worldwide include hepa- overall awareness rate for chronic kidney disease was
titis B and C viruses. 3·5–9·7%, and was lowest among people with low socio-
economic and educational statuses.56 In a study of
Water 2576 Uighur adults from Urumqi, China, the prevalence
Various disorders directly or indirectly related to water and awareness of chronic kidney disease were,
can cause kidney disease. High temperatures frequently respectively, 5·7% and 1·0%.57 In another study, only 8%
lead to water scarcity in tropical regions, which raises of the rural Chinese population with chronic kidney
the risk of dehydration. Flowing water might be con- disease were aware of having the disorder.58
taminated by heavy metals and organic compounds Low awareness has also been noted among health-care
leached from soil, and grain in waterlogged fields can providers. In a nationwide audit of 451 548 adults
become contaminated with harmful substances.47 Many followed up by general practitioners in Italy,53 only 17%
waterborne diseases (eg, schistosomiasis, leptospirosis, had undergone serum creatinine testing, of whom
scrub typhus, hantavirus, and malaria) affect the 16% had glomerular filtration rates lower than 60 mL/min
kidneys. Children are particularly vulnerable to acute per 1·73 m². Among these adults, chronic kidney disease
kidney injury because of diarrhoeal diseases.48 Enteric had been correctly diagnosed in only 15%. In another
infections can cause haemolytic-uraemic syndrome, study of 39 525 hypertensive patients, 23% had chronic
which eventually leads to the development of chronic kidney disease, but general practitioners diagnosed it

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correctly in only 3·9%.59 Incorrect diagnosis results in Interactions with other disorders
delayed referrals to nephrologists, which leads to missed Cardiovascular disease
opportunities to implement strategies for slowing disease Cardiovascular mortality is ten to 30 times higher in
progression, cardiovascular protection, and preparation individuals with end-stage kidney disease than in the
for RRT.60 general population when matched for age, ethnic origin,
Data suggest that increased awareness does not and sex. The association between chronic kidney disease
necessarily translate to improved outcomes. The risk of and increased risk of cardiovascular disease is observed in
progression to end-stage kidney disease and death was high-risk groups and in people in the general population
higher among people aware of their chronic kidney with low glomerular filtration rates and albuminuria.2,62,63
disease status at entry into the US Kidney Early The increased risks associated with low estimated
Evaluation programme. Adjustment for socioeconomic glomerular filtration rates and albuminuria seem to be
and clinical variables and presence of cardiovascular independent of each other. Furthermore, death seems to
disease and cancer reduced the difference, but it be a far more likely outcome than progression to end-
remained significant.61 These data, however, might have stage kidney disease in all stages of chronic kidney disease,
been confounded by selection bias. and the high death rates might reflect accelerated rates of
atherosclerosis and heart failure.64 Thus, individuals with
chronic kidney disease should be viewed as being in the
A highest risk group for cardiovascular disease. Even among
3000
dialysis patients, decline in residual kidney function is
associated with an increased risk of cardiovascular-related
2500 mortality and adverse outcomes.65 Additionally, cardio-
Prevalence of RRT (per million population)

vascular disease itself is a well recognised risk factor for

chronic kidney disease and predicts progression to end-
2000
stage kidney disease.2

1500 Acute kidney injury

Patients with chronic kidney disease are at an increased
risk of acute kidney injury.66 A transient increase in
1000 serum creatinine of as little as 27 μmol/L increases the
risk of death.67 Acute kidney injury might occur with the
500
use of several medications, such as non-steroidal anti-
inflammatory drugs, several antibiotics, and angiotensin-
converting-enzyme inhibitors, and, therefore, chronic
0 kidney disease must be taken into account when drugs
0 5000 10 000 15 000 20 000 25 000 30 000 35 000 40 000 45 000 50 000
are being prescribed to enable adjustment or complete
Per-person GNI by purchasing power parity (international $)
avoidance of specific drugs.
B A meta-analysis of 13 cohort studies confirmed that
450 GDP per person (international $) 10 000 acute kidney injury is an important risk factor for chronic
Prevalent dialysis
9000 and end-stage kidney disease.68 Severe, long, and repeated
Dialysis prevalence (per million population)

400
episodes of acute kidney injury increase the risk of
8000
GDP per person (international $)

350 progression of chronic kidney disease,69–71 which suggests

7000 a bi-directional risk relation. Despite different initial
300
6000 presentations and expression over time, chronic kidney
250
5000 disease and acute kidney injury should be viewed as parts
200 of the same clinical syndrome related to reduced
4000
glomerular filtration rates.
150
3000
100 2000 Socioeconomic effects and economic
50
implications
1000
The risk of chronic kidney disease is bi-directionally
0 0 affected by level of economic development. Poverty
1980 1982 1984 1986 1988 1990 1992 1994 1986 1988 2000 2002
Year increases the risk of disorders that predispose chronic
kidney disease to develop or progress, and worsens
Figure 4: Relation between prosperity and access to RRT and dialysis outcomes in those who already have chronic kidney
(A) Patients receiving RRT worldwide in relation to GNI, based on purchasing power parity (converted to constant
2005 international $). (B) Patients receiving dialysis in relation to GDP in Malaysia from 1980 to 2003. Use of
disease. Prosperity increases access to RRT (figure 4). In
dialysis increased with increasing GDP. RRT=renal replacement therapy. GNI=gross national income. GDP=gross eastern European countries, the number of centres
domestic product. providing dialysis and transplantation has risen rapidly,

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as has the number of patients accepted for RRT in countries where treatment requires out-of-pocket spend-
countries or regions that have undergone political and ing. Patients frequently have to travel long distances, often
economic liberalisation.72 These effects might be reversed with families, to receive specialised care.80 Most patients
in times of conflict.73 with end-stage kidney disease have complications at
An analysis of National Health and Nutrition Examin- presentation and need emergency admission to hospital
ation Survey data showed that poverty is associated with and dialysis.60 An analysis of the costs of treatment for
an increased risk of proteinuria even after correction for 50 consecutive patients with end-stage kidney disease who
age, sex, ethnic origin, education, obesity, hypertension, underwent highly subsidised kidney transplantations in a
diabetes, decreased glomerular filtration rate, and medi- public-sector hospital in India showed that 82% experi-
cation use.74 People in the lowest socioeconomic quartile enced financial crisis during treatment and more than
are at a 60% greater risk of progressive chronic kidney half (56%) of patients lost their jobs (unpublished).
disease than are those who are in the highest quartile.75 An
interaction between ethnic origin and poverty has also Prevention and screening
been shown in minority and indigenous groups in many Prevention
developed countries.8 Effective strategies can slow progression of chronic
Chronic kidney disease imposes substantial economic kidney disease and reduce the risk of cardiovascular
burden on affected individuals, especially in developing mortality. Foremost are control of blood pressure, prefer-
countries. Their families experience direct loss of income ably with agents that block the renin–angiotensin path-
and changes in consumption patterns because of the way, and good glycaemic control.3 Lipid-lowering therapy,
spending of household finances on care and welfare costs. irrespective of the starting cholesterol concentration,
About 2–3% of the health-care expenditure in developed lowers the incidence of major atherosclerotic events in
nations is used to provide treatment for patients with end- patients with chronic kidney disease,82 although no
stage kidney disease even though they account for only evidence supports the use of statins to slow loss of renal
0·1–0·2% of the total population; in 2010 treatment costs function. Correction of acidosis is thought to slow decline
accounted for 6·3% of the Medicare budget in the USA,76 in glomerular filtration rate,83 but requires confirmation.
4·1% of the total health-care budget in Japan in 1996, and A cheap and easily applicable approach is to achieve
3·24% of national health expenditure in South Korea in optimum intake of salt and protein.3 Finally, self-
2004.77 The economic costs associated with milder forms management and support groups can improve lifestyle
of chronic kidney disease are even higher. USA Medicare and dietary habits, knowledge of the disease, and
expenditures on chronic kidney disease patients in 2007 adherence to treatment, and might improve anthropo-
exceeded US$60 billion, which was 27% of the total metric indices and glycaemic and blood-pressure
Medicare budget. Acute kidney injury costs a further control.84 The cost-effectiveness of a self-management
$10 billion per year.78 The Australian Institute of Health intervention for people with stage 3 chronic kidney
and Welfare estimated that the total health expenditure on disease is currently being investigated in a randomised
chronic kidney disease in 2000–01 was AUS$647 million. clinical trial.85 A multidisciplinary approach is needed to
The estimated cost of chronic kidney disease to the UK implement treatment strategies.3
National Health Service in 2009–10 was £1·44–1·45
billion, which is about 1·3% of all health spending; more Screening
than half this sum was spent on RRT, which was provided Cost-effectiveness
to only 2% of the population with chronic kidney disease.79 The best way to screen people to identify who will bene-
Most people in developing countries have no access to fit most from preventive measures is disputed. Current
health insurance, which makes care for end-stage kidney recommendations suggest screening individuals with
disease unaffordable.80 A session of haemodialysis costs diabetes, hypertension, cardiovascular disease, structural
US$100 in Nigeria.15 This amount is twice the minimum diseases of the renal tract, autoimmune diseases with
monthly wage paid to federal government workers. The potential for kidney involvement, and family history of
annual cost of dialysis treatment in China is around kidney disease, during routine primary health encounters.1
US$14 300 per patient. Although the Chinese Govern- Screening for chronic kidney disease is cost effective in
ment plans to institute insurance schemes, patients in people with diabetes. Models have shown that addition of
rural areas would still have to pay 35–45% of the cost, screening for proteinuria followed by use of angiotensin-
which will be prohibitive for most people.81 In India, the converting-enzyme inhibitors in people with abnormal
cost of a dialysis session varies from US$20 to $60, proteinuria values reduced costs and the cumulative
dependent on the type of facility.80 Some Indian states incidence of end-stage kidney disease, and improved life
have started schemes to provide free RRT to the poor, but expectancy.86 Similar findings were seen in an economic
coverage is limited.7 assessment of the Reduction in Endpoints with the
Care of people with chronic kidney disease, particularly Angiotensin Antagonist Losartan study.87 Cost effectiveness
those who present for the first time with advanced disease, of screening for chronic kidney disease in the general
leads to catastrophic personal health expenditure in population, however, is unclear. Two studies done in the

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USA88,89 showed that targeted annual microalbuminuria targeting of populations only on the basis of previously
screening, relative to no screening, was cost effective only described risk factors in all regions might miss groups at
in people older than 50 years and with diabetes, risk of chronic kidney disease where these features are not
hypertension, or both: cost-effectiveness ratios per quality- the most common causes. The Asian Forum of Chronic
adjusted life-year were US$21 000 for those with diabetes, Kidney Disease Initiative has suggested the addition of
$55 000 for those hypertension, and $155 000 for those region-specific high-risk groups for screening, such as
with neither diabetes nor hypertension.89 people exposed to harmful herbal preparations or environ-
Treatment with fosinopril in people with urinary mental factors.92 Haematuria raises the risk of developing
albumin excretion rates of 15–300 mg per day and blood advanced chronic kidney disease, including end-stage
pressure lower than 160/100 mm Hg in the Prevention of kidney disease, in some parts of the world.93,94 Substantial
Renal and Vascular Endstage Disease intervention trial,90 proportions of individuals in developing countries have
done in the Netherlands, cost €16 700 per life-year gained, undiagnosed hypertension and diabetes and could be
with a 56% probability of being under the Netherlands overlooked by a risk-factor strategy. Population-based
cost-effectiveness threshold of €20 000.The proportion approaches that integrate screening for chronic kidney
would increase to 91% if only people with urinary albumin disease with cardiovascular health programmes have the
excretion higher than 50 mg per day were treated. Limiting advantage of increasing health awareness in countries
of screening to individuals older than 50 years or 60 years without advanced health systems.
also improved cost-effectiveness. The other issue is the definition of cost-effectiveness.
Analyses of the cost-effectiveness of using estimated According to the WHO Commission on Macro-
glomerular filtration rate to identify patients who will economics and Health, the cost-effectiveness of an
benefit most from treatment are scarce. Simulation intervention depends upon the local gross domestic
modelling data from Canada showed that compared with product. Interventions are classified as highly cost
no screening, population-based screening by estimated effective (the cost of the intervention per disease-
glomerular filtration rate in the general population cost adjusted life-year saved is less than the gross domestic
CAN$22 600 for people with diabetes and $572 000 for product per person), cost-effective (one to three times
those without diabetes per quality-adjusted life-year the gross domestic product per person), or not cost
gained.91 Thus, only screening in people with diabetes by effective (more than three times the gross domestic
this method seemed cost effective. Data are insufficient, product per person).95 The 2010 per-person gross
however, to make generalisations. domestic product and cost-effectiveness thresholds for
different regions of the world are shown in the table.
Worldwide application Estimates are confounded by the variation in costs of
Most population-based screening approaches have been tests, interventions, or both, across countries. Therefore,
undertaken in developed nations. The applicability of these an intervention that is cost-effective in one region
strategies to populations around the world is unclear. might not be somewhere else. Cost-effectiveness studies
Because risk factors are not the same worldwide, the should, therefore, be done in all regions. Interventions
targeted towards unique risk factors, such as use of
herbs, or environment or lifestyle factors, might be
Per-person GDP* Cost-effectiveness
more cost effective than screening for proteinuria or
threshold
estimated glomerular filtration rate in affected areas.
North America 41 399 124 196
High-income countries 33 185 99 555
Integration into national programmes
European Union 27 696 83 089 Notwithstanding the controversies, screening and
East Asia and Pacific (all income levels) 8724 26 171 management programmes for chronic kidney disease,
Latin America and Caribbean 10 180 30 540 diabetes, hypertension, and cardiovascular disease must
Middle East and north Africa 9491 28 473 be implemented, particularly in developing countries.
Upper-middle-income countries 8724 26 171 The training of local experts, implementation of manage-
Europe and Central Asia (developing only) 10 645 31 935 ment plans, and the establishing of partnerships between
East Asia and Pacific (excluding Japan, South Korea, and 6006 18 017 the local community, caregivers, governments, non-
Singapore)
governmental organisations, and the pharmaceutical
Lower-middle-income countries 3169 9508
industry will all be required.96 Methods should suit local
South Asia 2771 8314 needs, and factors such as health awareness and avail-
Sub-Saharan Africa 2037 6112 ability of human and material resources should be taken
Low-income countries 1141 3422 into account.
Values are given as constant 2005 international $. GDP=gross domestic product. *Annual GDP per person, based on Benefits from prevention strategies have already been
purchasing power parity. seen in several countries. A kidney health promotion
project was started in Taiwan in 2003, with a budget of
Table: Thresholds for cost-effectiveness of interventions worldwide in 2010, by income group or region
US$15·0 million per year. The components included a

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ban on herbs containing aristolochic acid, public-aware- limited capacity to provide expensive treatments, such as
ness campaigns and education of patients, funding for dialysis and transplantation, and few or non-existent
research into chronic kidney disease, and the setting up nephrology training programmes have led to shortages
of teams to provide integrated care. In 2007, a programme in care.105 Globalisation has increased migration of
of integrated care for patients before they developed end- health-care professionals, including nephrologists, from
stage kidney disease was also introduced in Taiwan, with developing to developed countries. The numbers of
an annual budget of US$1·5 million per year.56 The nephrology nurses and dialysis technicians are also
Cuban Ministry of Public Health has implemented a insufficient worldwide.
national programme that supports epidemiological Detection and prevention programmes for chronic
research, continuing education for nephrologists, family kidney disease also require substantial manpower
doctors, and other health professionals, and reorientation resources. Although leadership must be provided by
of primary health care towards increased nephrology nephrologists, most cases of non-progressive chronic
services, surveillance, and intervention.97 Similar pro- kidney disease could be managed by general practitioners.
grammes have been established in Uruguay98 and Chile.99 Nephrology referral can be reserved for patients with
In Mexico, the Ministry of Health has set up a network of advanced-stage chronic kidney disease, rapidly declining
health services against chronic renal disease.100 The cost kidney function, persistent proteinuria, uncontrolled
of implementing this network is estimated to have been hypertension, or diabetes. Educational interventions in
$US50 million. The goal is to have reduced the number low-income countries increase the clinical competence of
of patients with end-stage kidney disease by 50% by 2025. general practitioners.106 After an educational intervention,
According to official reports, the annual incidence of end- family doctors used more angiotensin antagonists and
stage kidney disease in Taiwan declined from a peak of statins.106 In Chile, consistent improvement in outcomes
432 per million of the population in 2005, to a 361 per was noted in patients treated by a general practitioner, with
million of the population in 2010.76 The programme has kidney function being stabilised in 56%.99
resulted in savings of US$36 million per year, owing to
reduced dialysis costs and improved quality of life.101 In Conclusions
Uruguay, the average annual growth in the incidence and Chronic kidney disease is a global public health issue
prevalence of end-stage kidney disease declined from with different features to take into account in different
1·6% and 5·4%, respectively, in 1994–2003, to 0·13% and parts of the world. The burden of chronic kidney disease
1·6% in the following decade.76,102 In Chile, the annual is rising worldwide, as shown by increases in attributable
incidence and prevalence of end-stage kidney disease deaths and incidence and prevalence of end-stage kidney
were lowered after the introduction of a prevention disease. Chronic kidney disease and its complications,
programme, from 13·3% and 14·5%, respectively, in which involve most organ systems, can be prevented, but
2005–08 to 1·9% and 4·6% in 2009–10.76 This outcome is awareness and use of accurate methods are needed to
notably better than the 10% incidence drop intended by enable timely diagnosis. Cost-effectiveness of preventive
the Chilean health authorities for 2020. Nevertheless, approaches must be assessed in relation to the local
these official country statistics remain to be indepen- levels of economic development and resources. Preven-
dently validated, and what the overall effects of these tion programmes will function best as part of national
programmes will be is difficult to judge. non-communicable disease strategies, with the involve-
ment of general practitioners.
Nephrology resources Contributors
The resources for nephrology care remain critically low All authors contributed equally to the content of the paper, the
in many parts of the world. Even in developed countries, researching of data, and the writing of the paper. VJ reviewed and edited
the paper before submission and all authors approved the final version.
nephrologists are frequently in short supply. In Latin
America the number of nephrologists varies from 1·7 per Conflicts of interest
AY-M has received grants from AbbVie, Baxter, and Sanofi Renal, and
million of the population in Honduras to 53·9 per speaker honoraria from Baxter, Fresinius Kabi, Roche Diagnostics,
million of the population in Uruguay.103 In Asia, the and Sanofi Renal. All other authors declare that they have no conflicts
range is from 0·2 per million of the population in Burma of interest.
and Indonesia to 5·0 per million of the population in References
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