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Chronic renal failure

Epidemiology and causes of


chronic renal failure

Definitions
Progressive renal failure should be monitored by changes in
serum creatinine, from which an estimate of renal function
related to age, gender, ethnicity and possibly body weight can
be calculated. The most widely used estimate is the estimated
glomerular filtration rate (eGFR), calculated by the Modification
of Diet In Renal Disease (MDRD) equation, on which the widely
used Kidney Disease Outcomes Quality Initiative (K/DOQI)
classification of chronic kidney disease (CKD) is based.4
The term CRF is difficult to define. Some symptoms may
develop with only modest renal impairment, but failure is probably best defined as occurring when there are severe symptoms
related to uraemia which can be relieved only by RRT. This is
usually when eGFR falls to 15 ml/minute (CKD stage 5). Established renal failure (ERF), also called end-stage renal failure
(ESRF), is the irreversible deterioration of renal function to a
degree that is incompatible with life without RRT, either by dia
lysis or transplantation. Even this is variable: most nephrologists
now tend to dialyse patients at an earlier stage, when eGFR has
fallen to about 815 ml/minute, rather than wait for it to fall to
56 ml/minute as in the past.

Terry Feest

Abstract
Recent studies have shown that the prevalence of chronic renal failure
(CRF) is higher than was widely believed. The prevalence of renal
replacement therapy (RRT) is rising progressively, although the rising
incidence has stabilized in some developed countries. Needs may differ
widely between countries depending on ethnic mix, social deprivation,
prevalence of diabetes, and quality of healthcare. Diabetic nephropathy
is the single most common cause of CRF, leading to over 40% of RRT
in some countries, and will increase significantly in the next decade.
Making a precise renal diagnosis identifies reversible causes, predicts
prognosis, predicts recurrence after transplantation and aids counselling
in familial conditions. Renal failure is less common in children than in
adults, with a different spectrum of causes. Renal failure is common in
developing countries, particularly in tropical areas and in young individuals: secondary glomerular diseases related to infection are common.
RRT is an expensive but effective therapy, which will inevitably consume
increasing resources in the next decade as numbers grow and the growing
proportion of elderly patients and others with co-morbid conditions and
social problems will place greater demands on healthcare resources.

Incidence and epidemiology


There are two main sources of data on the incidence and causes
of CRF. Community-based studies give information on the prevalence and incidence of CRF, while renal registries report on the
use of RRT.
Community-based studies
Several recent studies suggest the prevalence of renal impairment is greater than was widely appreciated, especially in the
elderly (Table 1).46 The majority of these patients do not start
RRT, sometimes because their renal disease does not progress,
and other times because they die of other conditions first, mostly
cardiovascular disease for which CKD is a potent marker.7
There are fewer community-based studies of the incidence of
CRF. Three such studies from the UK show a similar pattern of
a progressive increase in incidence with age, from 58/million
population/year in 2049-year-olds to 588/million population/
year in people over 80 years old.

Keywords chronic kidney disease; chronic renal failure; diabetic


nephropathy; eGFR; renal replacement therapy

Renal replacement therapy (RRT) is an expensive but effective


treatment for chronic renal failure (CRF). In the UK, it consumes
over 2% of the NHS budget: this is predicted shortly to reach 3%.
Worldwide, the number of patients receiving RRT is increasing
progressively. The prognosis of patients starting RRT is improving annually, and as fewer die each year than start therapy, the
prevalence will continue to rise even if acceptance rates for therapy stabilize. In the UK, more than 640 patients/million population are currently receiving therapy: in the USA, this figure is
1500/million population, and in Japan 1800 patients/million. As
the prevalence of patients on RRT increases, expenditure will
increase. This will be accentuated by the growing proportion of
elderly patients and others with comorbid conditions and social
problems who place greater demands on healthcare resources.13
It is important to understand the incidence and causes of such a
major drain on healthcare resources, both for prevention of renal
failure and for planning future services for RRT.

Renal registries
International and national registries provide the largest volume
of data on RRT. There are many registry-based reports containing data on large numbers of patients, which are fairly precise
in terms of diagnosis and incidence. These are not studies of
the incidence of CRF, but of the incidence of treatment of CRF,
and thus, in addition to varying population needs, also reflect
the attitudes of nephrologists and more importantly of primary
care doctors and other physicians towards referral for nephrological opinion and treatment. Clinical thresholds for treatment
are changing: studies of physicians and nephrologists in the last
decades show a liberalization of attitudes.8

Terry Feest FRCP is Consultant Nephrologist at the Richard Bright


Renal Unit, Bristol, UK. His research interests include epidemiology,
treatment and audit of care of renal failure. Competing interests:
none declared.

MEDICINE 35:8

Gender: among those with CRF, men outnumber women by at


least 1.5:1. This ratio is higher over the age of 70 years, despite
the greater longevity of women.
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2007 Elsevier Ltd. All rights reserved.

Chronic renal failure

Prevalence of chronic renal failure


Study

Year

Country

Age

Definition

NHANES III

19881994

USA

>20

eGFR
CKD stage 3
CKD stages 4 & 5
C&G eCCr
CKD stage 3
CKD stages 4 & 5
eGFR
CKD stage 3
CKD stages 4 & 5

Ausdiab

De Lusignan, et al

2002

2004

>24

Australia

UK

All

% prevalence

4.3%
0.4%
10.9%
0.3%
4.6%
0.2%

eGFR, glomerular filtration rate; CKD, chronic kidney disease; C&G eCCr, estimated creatinine clearance by Cockcroft and Gault method.

Table 1

Racial differences: in the UK and USA, the incidence of initiation of RRT in African-Caribbean and South Asian populations
in any age group is at least 35-times greater than that in a comparable Caucasian population. As these relatively young ethnic
minority populations mature over the next two decades there
will be a significant increase in demand for RRT.9 In some populations, particularly many indigenous American and Australasian
groups, the incidence of ERF is very much higher, largely due to
a combination of the effects of a massive prevalence of diabetes and hypertension.3,10 However, data from London and elsewhere indicate that other renal diseases are also more common
in the African-Caribbean and South Asian populations. Whilst
CRF is more common in areas of social deprivation, this does not
explain the high incidence of CRF in ethnic minorities.11

Causes of CRF
Precise diagnosis of the cause of renal failure is mainly of importance in identifying and treating reversible causes. It also helps
in assessing prognosis and planning for RRT, in assessing the
likelihood of recurrence of primary renal disease after renal transplantation, and in counselling families in which familial conditions,
such as polycystic kidney disease, vesico-ureteric reflux, or Alports
syndrome, occur.
The causes of ESRF in patients starting dialysis in the UK,
Germany, Australasia and three major racial groups in the USA
are listed in Table 2. In a significant percentage of patients the

Age and diagnosis-specific acceptance rates of


patients starting renal replacement therapy in the
UK, 19802001

Changing patterns: whilst the worldwide total acceptance rate


per million population for RRT is rising, in some developed
countries it has been stable in the last three years (including
USA [total 341: whites 259, blacks 996], New Zealand [110], the
Netherlands [100], Australia [95], the Scandinavian countries)
whereas in others it is still rising (Germany [194], Austria [154],
UK [105]). The pattern does not seem to be related to the acceptance rates of individual countries. In the UK, there has been
a more than fourfold increase since 1980, to an annual acceptance rate of over 105/million population/year (Figure 1) with
many more elderly and diabetic patients receiving treatment.
Patients are increasingly older. In 1982, in the UK, only 11% of
new patients were over 65 years old compared with 50% now
(Figure 2).2
The total acceptance rate needed to meet the demand for RRT
is unknown, may be rising, and will vary with the age, racial,
and social make-up of the population. Population projections
suggest an increase in over-65-year-olds during the next two
decades, which will lead to a significant increase in demand.
A study comparing the UK and Germany, where the acceptance
rates are very different, suggests that a large part of the difference
is due to differing needs related to the prevalence of diabetes
and hypertension, effectiveness of therapy for hypertension, and
perhaps differing attitudes to offering supportive care rather than
dialysis.12

MEDICINE 35:8

350

<44 years of age


4564 years of age

Rate per million population

300

250

>65 years of age


Diabetics
Total

200

150

100

50

1980
1981
1982
1983
1984
1985
1986
1987
1988
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004

Year
The annual rates are per million alive in the population in the specified
age range.

Figure 1

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2007 Elsevier Ltd. All rights reserved.

Chronic renal failure

Hypertensive renal disease


The most striking difference between the UK and the USA is the
apparent incidence of hypertensive renal disease, which appears
markedly more common in the USA. This also illustrates the
imprecision of diagnosis. The diagnosis of hypertensive renal
disease is usually made on clinical grounds and not following
biopsy, but several European biopsy studies have shown that
many such patients have underlying glomerulonephritis or other
renal disease.

Age and gender distribution of patients starting


renal replacement therapy in the UK, 2004
700

Males
Females

Rate per million population

600

All UK

500

400

Diabetic nephropathy
Diabetic nephropathy is the most common cause of ESRF in
developed countries, constituting 46% in the USA, 41% Japan,
40% New Zealand, 34% Germany, 30% Australia, 18% in the
UK and 15% in Norway. This variation probably reflects both
a variation in the incidence of diabetes and a variation of the
willingness of physicians to offer dialysis to patients with many
diabetic complications. The diabetic ESRF population is increasingly elderly, with type II diabetics outnumbering type I by over
10:1 in some countries.14,15

300

200

100

90+

8588

8084

7579

6574

5559

6064

5054

4549

4044

3539

3034

2529

2024

Glomerulonephritis
Many forms of glomerulonephritis progress to CRF. Despite the
many recent advances in understanding the underlying mechanisms of disease, relatively few forms of glomerulonephritis have
been shown in controlled trials to respond to currently available
therapies.

Age group
Figure 2

diagnosis is uncertain; many of these patients present with


renal failure with two small kidneys and no further clues to the
aetiology. Renal biopsy can be dangerous and unhelpful in these
circumstances. In the UK, uncertain diagnosis is more common
in those aged over 65 years (28%) than in younger patients
(16%).2,3,13

Other important causes of CRF


It is important to exclude less common but potentially reversible causes of CRF. The majority are not associated with heavy
proteinuria. These include renovascular disease (which may be

Causes of established renal failure in patients starting renal replacement therapy


Country/Year

UK 2004

Germany
2004

Australia
2004

New Zealand
2004

USA 20002004

White

Diabetes
Glomerulonephritis
Pyelonephritis/
reflux
Polycystic kidney
disease (PKD)
Hypertension
Renovascular
disease
Uncertain
Missing data

Black

Native American

pmp

pmp

pmp

pmp

pmp

pmp

pmp

18.0
10.4
7.0

18.9
10.9
7.4

34.0
12.0
8.0

66.0
23.3
15.5

30.0
25.0
3.0

28.5
23.8
2.9

40.0
24.0
3.0

44.0
26.4
3.3

44.6
8.4
0.6

115.5
21.8
1.6

43.6
7.1
0.1

434.3
70.7
1.0

73.1
7.5
0.4

271.2
27.8
1.5

5.4

5.7

5.0

9.7

7.0

6.7

5.0

5.5

2.8

7.3

1.0

10.0

0.7

2.6

5.5
7.5

5.8
7.9

<4
22.0

42.7

13.0
n.a.

12.4

16.0
n.a.

17.6

21.1
2.6

54.6
6.7

33.8
0.4

336.6
4.0

8.0
0.4

29.7
1.5

23.0
9.2

24.2
9.7

9.0
n.a.

17.5
-!

7.0
n.a.

6.7
-!

5.0
n.a.

5.5
-!

4.5
1.0

11.7
2.6

3.1
1.0

30.9
10.0

2.5
0.2

9.3
0.7

Pmp, annual incidence per million population.


Note how percentages of the total may be misleading with regard to the annual incidence per million population (e.g. as the annual incidence of RRT in Black
Americans is nearly ten times that in the UK, the low percentage of PKD in them actually represents a higher annual incidence pmp than in the UK).

Table 2

MEDICINE 35:8

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2007 Elsevier Ltd. All rights reserved.

Chronic renal failure

unmasked by the use of ACE inhibitor drugs), acute interstitial


nephritis and other drug reactions, use of non-steroidal antiinflammatory drugs (NSAIDs), and renal vasculitis in which
rapid diagnosis enables effective therapy. Obstructive uropathy
must always be considered; prostatic disease is the most common
cause of renal impairment in elderly men.

4 Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of


chronic kidney disease and decreased kidney function in the adult
US population: Third National Health and Nutrition Examination
Survey. Am J Kidney Dis 2003; 41: 112.
5 Chadban SJ, Briganti EM, Kerr PG, et al. Prevalence of kidney
damage in Australian adults: The AusDiab kidney study. J Am Soc
Nephrol 2003; 14(suppl 2): S13138.
6 de Lusignan S, Chan T, Stevens P, et al. Identifying patients with
chronic kidney disease from general practice computer records.
Fam Pract 2005; 22: 23441.
7 Keith DS, Nichols GA, Gullion CM, Brown JB, Smith DH. Longitudinal
follow-up and outcomes among a population with chronic kidney
disease in a large managed care organization. Arch Intern Med
2004; 164: 65963.
8 McKenzie JK, Moss AH, Feest TG, Stocking CB, Siegler M. Dialysis
decision making in Canada, the United Kingdom, and the United
States. Am J Kidney Dis 1998; 31: 1218.
9 Roderick PJ, Raleigh VS, Hallam L, Mallick NP. The need and
demand for renal replacement therapy in ethnic minorities in
England. J Epidemiol Community Health 1996; 50: 33439.
10 Hoy W. Renal disease in Australian Aborigines. Nephrol Dial
Transplant 2000; 15: 129397.
11 Caskey FJ, Roderick P, Steenkamp R, et al. Social deprivation and
survival on renal replacement therapy in England and Wales. Kidney
Int 2006; 70: 213440.
12 Caskey FJ, Schober-Halstenberg HJ, Roderick PJ, et al. Exploring the
differences in epidemiology of treated ESRD between Germany and
England and Wales. Am J Kidney Dis 2006; 47: 44554.
13 McDonald S, Excell L. Australia and New Zealand Dialysis and
Transplant Registry 28th Annual Report. 2005. (Available at:
www.anzdata.org.au)
14 Muntner P, Coresh J, Powe NR, Klag MJ. The contribution of
increased diabetes prevalence and improved myocardial infarction
and stroke survival to the increase in treated end-stage renal
disease. J Am Soc Nephrol 2003; 14: 156877.
15 Lippert J, Ritz E, Schwarzbeck A, Schneider P. The rising tide of
ESRF from diabetic nephropathy type II and epidemiological
analysis. Nephrol Dial Transplant 1995; 10: 46267.

Renal failure in children


Renal failure is much less common in children than in adults; the
annual incidence is about 6/million population. The causes differ markedly from adult practice. Dysplastic kidneys and reflux
nephropathy are relatively common and there are many more
hereditary diseases, of which cystinosis is one of the most important. Haemolytic uraemic syndrome is relatively common in children, although the majority recover renal function. Other forms
of glomerulonephritis are less common than in adults and often
do not lead to renal failure until adult life.

Renal failure in developing countries


Renal failure is common in developing countries, particularly in
tropical areas and in young individuals. Secondary glomerular
diseases related to infection are common.
Socioeconomic and local environmental factors determine the
pattern of disease. HIV nephropathy is a growing problem. In
many countries, post-streptococcal glomerulonephritis remains a
common problem. In endemic areas, Schistosoma haematobium
may cause obstructive uropathy, and S. mansoni causes several
types of glomerulopathy, including mesangiocapillary glomerulonephritis that often progresses to CRF. Plasmodium malariae
and hepatitis B cause membranous and membranoproliferative
glomerulonephritides, which may progress to CRF. Amyloidosis
secondary to various chronic infections is another common cause
of nephrotic syndrome and renal failure; it is usually secondary
to tuberculosis in India, and to leprosy in Papua New Guinea.
The incidence of HIV nephropathy is increasing.
The incidence of CRF in developing countries could be reduced
by improved economic conditions and eradication of endemic
infections. In these areas, dialysis is unaffordable for all but the
very wealthy; survival depends on early transplantation. There
is commonly a lack of cadaver donors leading to pressure on
relatives and friends to become living donors, and a trade in paid
organ donation.

Practice points
Numbers of patients on renal replacement therapy are
rising, with an increasing proportion elderly: this has major
implications for resources
The incidence of CRF increases with age and is at least threeto five-fold higher in many ethnic minority populations
Making a precise renal diagnosis identifies reversible causes,
predicts prognosis, predicts recurrence after transplantation
and aids counselling in familial conditions
Renal failure is less common in children than in adults and
the spectrum of causes differs

References
1 Feest TG, Rajamahesh J, Byrne C, et al. Trends in adult renal
replacement therapy in the UK: 19822002. QJM 2005; 98: 2128.
2 Ansell D, Feest T, Rao R, Williams A, Winearls C. UK Renal Registry
8th Annual Report. 2005. (Available at: www.renalreg.com)
3 US Renal Data System. USRDS 2006 Annual Data Report: Atlas of
end-stage renal disease in the United States. USRDS, 2006.
(Available at: www.usrds.org)

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2007 Elsevier Ltd. All rights reserved.

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