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Definition,
incidence and
prevalence
Classification
Screening
Management
The authors
DR COLIN McCLINTOCK
renal unit, Royal Prince Alfred
Hospital, Camperdown, NSW.
DR ALAN CASS
renal division, The George
Institute for International Health,
Camperdown, NSW.
Chronic
KIDNEY DISEASE
ASSOCIATE PROFESSOR
STEVE CHADBAN
renal unit, Royal Prince Alfred
Hospital, Camperdown, NSW.
Background
Definition of chronic kidney
disease
CHRONIC kidney disease (CKD) is
defined as either kidney damage or
decreased kidney function that has persisted for three or more months. Cardinal markers of kidney damage include
proteinuria, haematuria, abnormalities
on kidney imaging and decreased
kidney function (glomerular filtration
rate [GRF] <60mL/min/1.72m 2
[adjusted for surface area]).1, 2
Prediction equations are a practical
way of estimating GFR. In 2005, following recommendations by Kidney
Health Australia, pathology laboratories throughout Australia initiated the
automatic reporting of estimated
glomerular filtration rate (eGFR) from
serum creatinine. Whenever eGFR is
<60mL/min, this is reported to the
clinician. As the prevalence of
eGFR<60mL/min is about 10%
among Australian adults, a rapid
increase in the awareness of CKD in
our community is anticipated.
Assessing severity of CKD based on
the above markers and eGFR allows
allocation of individuals into the five
stages of CKD according to the
Kidney Disease Outcomes Quality Initiative (K/DOQI) system (see Classification of chronic kidney disease, page
www.australiandoctor.com.au
20). Identifying severity and stage of
CKD, independent of the cause of
kidney damage, improves patient
management strategies.
Incidence, prevalence and
disease burden
Recent cross-sectional studies have
estimated the CKD prevalence in the
adult population of Australia straticont’d next page
2 February 2007 | Australian Doctor |
19
AD_HTT_019_026___FEB02_07 31/1/07 11:53 AM Page 20
How to treat – chronic kidney disease
from previous page
fied by K/DOQI stage. In Australian adults aged over 25, the
proportions with stage 1-5 CKD
were 0.9%, 2.0%, 10.9%, 0.3%
and 0.1%, respectively (table 1).1
These figures clearly delineate the
burden of CKD in Australia, with
more than 10% of the entire population having an eGFR <60mL/min.
The bulk of these patients have an
eGFR of 30-59mL/min — a population potentially at risk of further
deterioration in kidney function.
CKD is a significant burden in
terms of ongoing health provision
both in Australia and worldwide.
Managing CKD and providing
ongoing renal replacement therapy
in those who progress to end-stage
kidney disease (ESKD) is costly.
Population-based studies in Australia and the US have addressed
the prevalence and burden of disease. The AusDiab study1 suggests
that 14% of the population have
key manifestations of kidney
damage, although those with ESKD
considered in the AIHW report.
It is important to identify population groups at high risk of developing CKD, so that we can undertake targeted, primary care-based
opportunistic screening. This is
especially important given that
effective therapies are available to
delay progression of CKD and
because the ‘at risk’ population
continues to grow as a result of
population ageing and the rapid
increase in the prevalence of type 2
diabetes.
receiving renal replacement therapy account for significantly less
than 1%.
The Australian Institute of
Health and Welfare (AIHW) estimated that total health expenditure
on CKD in 2000-01 was $647 million, representing 1.3% of total
recurrent health expenditure.2
Furthermore, CKD is now recognised as an independent risk factor
for vascular disease, and the population and financial burden of vascular
disease associated with CKD was not
Because of the excess cardiovascular complications and other
comorbidities seen in people with
CKD, the health service burden
relating to providing care to people
with complex chronic disease will
also continue to grow.
Quality of life becomes a significant issue for patients approaching
ESKD, when decisions need to be
made about the use of renal
replacement therapies, and an education and preparation process
should begin.
Classification of chronic kidney disease
THERE are two distinct
methods for classifying
CKD: a classification system
based on cause of kidney
disease, and a system largely
based on the degree of
kidney damage independent
of the cause. The latter
system is simple, logical and
pragmatic and will be discussed first.
Table 1: K/DOQI classification of CKD3 (Prevalence from
AusDiab and ANZDATA [Stage 5])
K/DOQI classification
system according to
degree of kidney damage
A general lack of uniformity
in diagnosis, definition and
staging of CKD led to the
emergence of the K/DOQI
classification system in 2002
(table 1).3
The aim of this system is
to produce a consistent
framework on which diagnosis and management can
be based, both for nephrologists and GPs. As suggested,
K/DOQI is not a causal classification system; rather, it
classifies according to degree
of kidney damage, recognising the following key manifestations:
■ Reduced GFR.
■ Albuminuria/proteinuria.
■ Haematuria.
■ Abnormal kidney structure.
Early detection and uniform staging of CKD using
simple laboratory measurements should allow earlier
treatment and slowing of
progression.
Delineation of stage is primarily based on estimation
of GFR which can be
CKD stage
Definition
Prevalence in Australian adults
1
Kidney damage (albuminuria, haematuria or
abnormal kidney imaging), eGFR >90mL/min
0.9% (n = 112,000)
2
Kidney damage, eGFR 60-90mL/min
2.0% (n = 250,000)
3
Moderate kidney failure, GFR 30-59mL/min
10.9% (n = 1,400,000)
4
Severe kidney failure, GFR 15-29mL/min
0.3% (n = 40,000)
5
End-stage kidney failure requiring dialysis or
transplant, GFR <15mL/min
0.1% (n = 14,000)
CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; K/DOQI = Kidney Disease Outcomes
Quality Initiative
Table 2: Primary renal disease of new patients reaching ESKD,
4
01/01/2004-31/12/2004 (reproduced from ANZDATA Report, 2004 ).
Cause
assessed in a number of
ways; nuclear medicine scanning (cumbersome), 24-hour
urine for creatinine clearance
(inconvenient and inaccurate)
and, most recently, eGFR
derived from serum creatinine measurement using prediction equations.
In stage 1 and 2 CKD, in
which GFR is normal or
increased, kidney dysfunction is defined by the
presence of persistent albuminuria/proteinuria, haematuria (after exclusion of urological causes) or structural
abnormalities on kidney
imaging tests.
Classification according
to cause of kidney
disease
A more traditional way of
classifying CKD relates to
the actual pathological cause
of the kidney disease; however, not uncommonly, the
cause is difficult to determine.
In Australia in 2004, diabetes (primarily type 2) was
the most common cause of
ESKD, closely followed by
glomerulonephritis, then
hypertension, polycystic
kidney disease, reflux
nephropathy and analgesic
nephropathy (table 2).
Australia
New Zealand
Number
Per million
Number
Per million
Glomerulonephritis
479
24
107
26
Analgesic nephropathy
46
2
2
<1
Polycystic renal disease
126
6
24
6
Reflux nephropathy
55
3
12
3
Hypertension
256
13
72
18
Diabetes
576
29
177
44
Type 1, insulin dependent
63
13
Type 2, not requiring insulin
260
82
Type 2, requiring insulin
253
Miscellaneous
247
12
30
7
Uncertain
127
6
23
6
Total
1912
95
447
110
Glomerulonephritis can be
subclassified as to cause,
with IgA disease being the
most common form.
Some diagnoses of renal
disease will require specialist
nephrological guidance for
diagnosis and management
82
(see When to refer to a
nephrologist, page 21), especially given the wide array
of potential pathology.
However, the K/DOQI
stage classification, which
unifies diagnosis and global
management strategies, is a
more important focus for
primary care management.
This is further emphasised
by many aspects of treatment not being specific to
cause, such as blood pressure control and anti-proteinuric therapies.
Screening for chronic kidney disease
Who is at risk of CKD?
EVIDENCE does not support
screening the entire Australian population for CKD. However, certain
groups are known to have high risk
for developing CKD.
All people attending their primary care practitioner should be
assessed, as part of routine primary
health encounters, to determine
whether they are at increased risk
for developing CKD on the basis
of clinical and demographic factors
(table 3). Among high-risk individuals, a targeted opportunistic
screening program should be
adopted to identify those with
CKD.
The most significant risk factors
for CKD include age over 50, diabetes, hypertension, smoking and,
20
| Australian Doctor | 2 February 2007
to a lesser degree, obesity and raised
cholesterol and triglyceride levels.
There would also appear to be
genetic risks for kidney disease,
with evidence of familial clustering
of CKD and ESKD. Up to 20% of
new ESKD patients report a firstor second-degree relative with
ESKD, with a positive family history more common in patients with
diabetes or glomerulonephritis.
It may also be useful to ask
patients if there is personal or
family history of UTI, renal calculi
or analgesic use.
Certain ethnic groups within
Australia deserve a special mention
with regard to CKD risk. Indigenous Australians experience ESKD
at a rate about nine times higher
than the general population. How-
Table 3: CDK high-risk
groups*
Modifiable risk factors
■
Smoking
■
Diabetes
■
High blood pressure
Non-modifiable risk factors
■
Age >50
■
Family history of kidney disease
■
Aboriginal or Torres Strait
Islander heritage
*From Kidney Health Australia
www.australiandoctor.com.au
ever, this is thought to rise to up to
30 times the national incidence in
remote areas.
Reasons for this are complex,
with a much higher incidence of
proteinuria among remote Aboriginal populations — 50% of those
in their 20s have some degree of
proteinuria and 50% in their mid50s have heavy proteinuria.
General risk factors for both proteinuria and ESKD among Indigenous Australians include:
■ Rural or remote area of residence.
■ Low birth weight.
■ Recurrent skin infections.
■ Post-streptococcal glomerulonephritis.
■ Family history of ESKD.
■ Obesity.
Hypertension.
Uncontrolled blood sugar levels.
■ Poverty.
New Zealand Maori and Pacific
Islanders living in Australia are also
at increased risk for ESKD.
■
■
Targeted opportunistic
screening
In view of the burden of CKD in
Australia, people at high risk
should be identified to allow
opportunistic screening and intervention to prevent disease progression. This is particularly important
when the prevalence of diabetes
and hypertension, two cardinal
risk factors for CKD, is unlikely
to diminish.
Within primary health care, targeted opportunistic screening of
AD_HTT_019_026___FEB02_07 31/1/07 11:53 AM Page 21
people with clear risk factors
(table 3) should be carried
out, for example, at routine
health checks. Simple strategies involving blood pressure
checks, urine dipstick and
eGFR can be used for those
at risk.
Mass population screening
for CKD has not been
proven to be cost-effective.
However, given that advancing age is the strongest predictor of CKD, population
screening in the over-50 age
group is likely to be costeffective and also in people
with hypertension over age
30.
There is evidence that
screening of other high-risk
groups within the population is cost-effective. The
diabetic population is one
such group where anti-proteinuric therapies (see Antiproteinuric therapy, page
22), blood pressure control
and glycaemic control have
been shown to alter outcomes: screening for early
detection of modifiable risk
is worthwhile.
Screening concepts
Estimated glomerular filtration
rate
GFR is the best measure of
overall kidney function in
health and in disease.
Normal GFR varies with
age, sex and body size. The
normal value for GFR in
young adults is 120140mL/min and declines
from age 30 at an annual
rate of about 1mL/min.
It is clear that a significant
number of elderly Australians
will have an eGFR of 3060mL/min. This is an important finding, as it identifies a
group at increased long-term
risk of both cardiovascular
disease and ESKD. This population should be screened
for other markers of CKD,
such as proteinuria/haematuria, hypertension and diabetes.
There are several ways to
measure or estimate GFR.
However, prediction equations based on only one labbased measure (serum creatinine) allow automatic
estimation of GFR and rapid
classification of CKD stage
when GFR is reduced to
<60mL/min.
The Modification of Diet
in Renal Disease (MDRD)
5
Study prediction equation
has been in existence since
1999 and has many advantages. It is more accurate at
predicting GFRs <90mL/min,
is reasonably well validated
and does not require knowledge of patient weight or
height.
The eGFR now provided
automatically with every
serum creatinine measured
in Australia to help identify
CKD stage and at-risk populations (eGFR <60mL/min)
is calculated from the
MDRD equation.
It is important to remember that MDRD-based eGFR
has not been validated in
Kidney disease in Australia:
the Titanic/iceberg model
Adults aged over 25
Stage 5 — kidney failure
14,000
Stage 4 — GFR <30mL/min
40,000
1.7 million
Stage 1-3
Hypertension
or diabetes
>4.5 million at risk
Derived from AusDiab data.
Table 4: Urinary albumin:creatinine ratio
■
<3mg/mmol
Normal
■
3-30mg/mmol
Microalbuminuria range
■
>30mg/mmol
Macroalbuminuria
It is rational
to screen for
proteinuria
among patients
at risk of CKD,
except for those
with diabetes,
who should be
screened for
microalbuminuria
instead.
certain population groups
within Australia (Aboriginal
and Torres Strait Islander
people, Asian populations
[including Japanese, Chinese
and Vietnamese], Maori and
Pacific Islander people).
In addition, MDRD has
not been proven for calculating drug dose reductions
in CKD (although it is likely
to be acceptable in this
regard). In these situations
other methods of evaluating
GFR may be necessary.
Screening for proteinuria
Proteinuria is a cardinal
marker of kidney damage.
Albumin, present in normal
urine in small amounts, contributes about 25% of the
total protein content of
urine. With the development
and progression of CKD, the
proportion of albumin to
total protein in urine
increases.
In early CKD, despite total
protein excretion remaining
within the normal range,
albumin content may
become abnormal. This is
usually termed microalbuminuria, while higher rates
of albumin excretion are
termed macroalbuminuria
(table 4). In such cases, tests
for (total) proteinuria will
usually be abnormal.
The AusDiab study
showed that 2.4% of the
Australian population had
proteinuria, most of which
was found among those with
hypertension and/or dia1
betes.
The AusDiab study also
suggests albuminuria (a term
that includes both microand macroalbuminuria) is
present in just over 6% of
Australian adults, much of
that being in the microalbuminuria range and in people
with diabetes.
Like proteinuria, microalbuminuria is a marker of
kidney damage, and testing
for proteinuria should form
the basis of any screening for
CKD.
In non-diabetic CKD,
anti-proteinuric therapies
have been shown to reduce
risk of disease progression.
However, in patients with
diabetes anti-proteinuric
treatment has only been
proven to be of benefit for
people with microalbuminuria.
Thus it is rational to
screen for proteinuria among
patients at risk of CKD,
except for those with diabetes, who should be
screened for microalbuminuria instead.
There are several ways to
detect proteinuria — standard dipstick, protein:creatinine ratio (spot urine) and
formal 24-hour urine for
protein excretion. In our
opinion dipstick testing for
proteinuria is a useful ‘first
round’ screening test for proteinuria in the non-diabetic
population, to be followed
by confirmatory testing with
a spot urine protein:creatinine ratio in those positive
on dipstick testing.
In the AusDiab survey,
dipstick testing at a threshold of 1+ or greater was
highly sensitive: dipstick testing was highly successful in
identifying people with significant proteinuria.
However, among those
who tested positive, secondround testing with spot urine
protein:creatinine ratio confirmed significant proteinuria in only half of the cases
(unpublished data, S. Chadban).
Dipstick testing had a negative predictive value of
more than 99%: those who
tested negative were
extremely unlikely to have
significant proteinuria.
Twenty four-hour urine collection for protein excretion
is not required as part of
screening for CKD.
Patients with diabetes
should be screened annually
for microalbuminuria by
spot urinary albumin:creatinine ratio (ACR), ideally
using a morning specimen.
If they test positive for
microalbuminuria, two further samples should be sent
www.australiandoctor.com.au
for ACR within two months,
given that only 63% of
patients persistently test positive.
Microalbuminuria, and
hence early-stage diabetic
nephropathy, can be diagnosed if at least two samples
are positive. Although an
early morning sample is
ideal, a spot urine for ACR
can be collected at any time,
which makes it a very versatile test and significantly
easier than a timed urine collection for albumin excretion
rate.
ACR is also achieving
widespread use in quantification of macroalbuminuria
for diagnosis, follow-up and
response to treatment. In our
opinion, and in accordance
with the position statement
of the Australian Diabetes
Society, screening for
microalbuminuria may be
performed on spot urine
specimens. Again, when
screening for kidney damage
in diabetes, timed urine collection is not required.
We suggest annual dipstick screening for proteinuria for those at risk of CKD
(table 3) and annual testing
for microalbuminuria by
spot urine ACR for all
patients with diabetes, in
addition to serum creatinine
(and so eGFR) and blood
pressure.
urgent referral to a nephrologist for investigation and
management.
Among people aged over
40 or at higher risk (eg,
smokers or people with a
history of compound analgesic use), further investigation is warranted to exclude
significant
urological
pathology, such as malignancy, prostatic disease or
stones.
Haematuria
When to refer to a
nephrologist
Microscopic haematuria is
common and was detected
in 4.6% of Australian adults
1
in the AusDiab study. A
standard urine dipstick is
highly sensitive for haematuria. In most people,
haematuria is related to
menstruation or UTI and is
transient and not a marker
of kidney disease. However,
persistent haematuria, or
haematuria found in conjunction with other markers
of kidney damage, necessitates follow-up.
Among people with persistent haematuria, key
issues for GPs include when
to consider referral to a
nephrologist and/or urologist. Accurate phase contrast
microscopy (on a fresh urine
sample) can identify
‘glomerular haematuria’ by
the red cell morphology;
however, this requires the
urine to be sent for pathology testing.
It is prudent to refer individuals with haematuria
found in conjunction with
reduced eGFR, proteinuria
or elevated blood pressure to
a nephrologist, as this may
signify treatable glomerular
disease.
Nephritic syndrome —
characterised by sudden
onset of haematuria (which
may be macroscopic and
thus reported by a patient as
abnormally dark-coloured
urine), elevated blood pressure and progressive reduction in urine output and
eGFR — is an uncommon
diagnosis that necessitates
Imaging
Classification of CKD stage
(especially 1 and 2) also relies
on knowledge of structural
kidney abnormalities. Baseline
renal imaging is not only of
use for classification purposes
but also constitutes an essential part of diagnostic workup
and should be done in patients
with cardinal signs of kidney
damage, such as proteinuria,
low eGFR or glomerular
haematuria.
Standard ultrasonography
of the renal tract is appropriate and can be used to
assess kidney size, cortical
thickness, presence of scarring, presence of cysts
(simple or otherwise) or
obstruction. For example,
bilateral decrease in kidney
size with cortical thinning is
likely to suggest a chronic
process with associated risk
of further disease progression.
Guidelines outlining what to
do with the results of clinical
and laboratory screening are
needed.
AusDiab data suggest that
14% of the Australian population have CKD, but that
most are elderly women with
isolated reduced eGFR in the
30-60mL/min range (stage 3
CKD). Referring all such
patients to a nephrologist is
impractical and unlikely to
be cost-effective.
Therefore the bulk of initial management and also
decision making about referral will fall to the GP.
Kidney Health Australia has
formulated the following
guidelines on when specialist
referral is indicated:
■ eGFR <30mL/min.
■ Rapidly declining kidney
function (>15% reduction
in eGFR over three
months, irrespective of
baseline level).
■ Proteinuria >1g/24 hours.
■ Glomerular haematuria
(especially when associated
with decreased eGFR,
proteinuria or hypertension).
■ Kidney disease and/or
hypertension that is difficult to control.
■ Diabetes
and eGFR
<60mL/min.
Following these guidelines
would require knowledge of
screening tests and CKD
clinical risk factors, and
implementing them would
establish primary care as the
appropriate arena for managing CKD.
2 February 2007 | Australian Doctor |
21
AD_HTT_019_026___FEB02_07 31/1/07 11:53 AM Page 22
How to treat – chronic kidney disease
Management of chronic kidney disease
THE aims of management are
to prevent disease progression
and deterioration of kidney
function to the level of ESKD
requiring renal replacement
therapy, and to manage the
elevated cardiovascular risk
associated with CKD.
This involves the following
strategies:
■ Anti-progression therapy —
blood pressure control, antiproteinuric therapy.
■ Specific therapy based on the
defined aetiology of CKD
(generally guided by a
nephrologist).
■ Preventing cardiovascular
disease.
■ Managing specific complications of CKD, including
preparation for renal
replacement therapy.
■ Appropriate drug dosing
(table 5).
50
20
Obesity is a risk factor for
CKD. Although people can
often lose weight, sustaining
the weight loss is particularly
difficult. If sustained, weight
loss is expected to be beneficial for CKD long term, but
also a generally effective secondary prevention goal.
10
Correction of renal
anaemia
Dialysis/Tx
40
N = 27,988 over 66 months
Event (%)
30
0
89-60
89-60 (prot)
30-59
GFR (mL/min)
29-15
Risk of dying from CVD events 20 times greater than requiring dialysis/transplant
Keith, et al. Archives of Internal Medicine 2004; 164:659-63.
Table 5: The eGFR action plan (Kidney Health Australia)
eGFR
(mL/min)
≥60
Maintaining tight blood
pressure control is a central
management goal in delaying
progression
of
CKD
(<130/85mmHg for proteinuria <1g/day; <125/75mmHg
for proteinuria >1g/day or
patients with diabetes).
In the patient with proteinuria, ACE inhibitors or
angiotensin-II-receptor antagonists should be considered as
first-line agents. Combination
therapy using both classes
may be the optimal strategy,
although multiple agents are
frequently required to achieve
targets. The choice of agent
should be tailored to the individual.
30-59
15-29
Anti-proteinuric therapy
22
Weight reduction
Death
Blood pressure control
Proteinuria is a strong marker
of the risk of progressive renal
injury in CKD. The extent of
decline in proteinuria that
occurs in response to therapy
is also a useful guide to the
likelihood that therapy will
delay progression.
Although most classes of
antihypertensive agents can
decrease proteinuria (by
decreasing systemic blood
pressure and hence intraglomerular pressures), ACE
inhibitors and angiotensin IIreceptor antagonists have consistently been shown to be the
most effective agents in
decreasing proteinuria and
delaying progression of proteinuric CKD.
This has recently been
shown to be true even in cases
of advanced disease (stage 4
CKD). Combination therapy
with these two classes of drug
may produce further benefits.
Detecting CKD early and
prescribing ACE inhibitors
might not only slow progression of kidney disease but also
reduce the high risk of cardiovascular disease.
The potential side effects of
these two classes of antihypertensive deserve mention:
■ Intractable dry cough.
■ Angioneurotic oedema/anaphylaxis.
■ Hypotension (elderly).
tigation in SHARP).
Outcomes in patients with CKD
<15
Description
Clinical action plan
No kidney damage
or
Stage 1 CKD (kidney
damage* with normal
kidney function) or
Stage 2 CKD (kidney
damage* with mild
kidney function)
Stage 3 CKD
(moderate kidney
function)
Further investigation for CKD may be
indicated in those at increased risk:
■ Assessment of proteinuria
■ Urinalysis
■ Blood pressure
Cardiovascular risk reduction (blood
pressure, lipids, blood glucose, smoking,
obesity, physical activity)
As above, plus:
■ Monitor eGFR three monthly
■ Avoid nephrotoxic drugs
■ Prescribe antiproteinuric drugs (angiotensin
converting enzyme inhibitors and/or
angiotensin-II-receptor blockers) if appropriate
■ Address anaemia, acidosis and hyperparathyroidism
■ Ensure drug dosages appropriate for level of
kidney function
Consider referral to nephrologist
As above plus referral to nephrologist is usually
indicated for preparation for dialysis (including
access surgery, education) or transplantation
As above plus referral to nephrologist
Stage 4 CKD
(severe kidney
function)
Stage 5 CKD
(end-stage kidney failure)
*Imaging or biopsy abnormalities or proteinuria/haematuria
Acute minor deterioration in
renal function (usually stabilises).
■ Acute continued deterioration in renal function (bilateral renal artery stenosis or
intra-renal small-vessel disease).
■ Hyperkalaemia.
For these reasons patients
often require closer clinical
and laboratory monitoring on
starting these drugs, especially
elderly patients, those with
diabetes (hyperkalaemia) or
significantly impaired kidney
function.
Serum creatinine should be
checked at least once 3-5 days
after starting an ACE inhibitor
or angiotensin-II-receptor
antagonist. If any rise in creatinine level is seen, therapy is
safe to continue provided that
the rise is <30% of baseline,
and the creatinine test is
repeated within a month. If a
greater rise is observed, treatment should be suspended
and a search for renovascular
disease may be advisable.
While the choice of screening test depends on local
availability and expertise,
appropriate screening tests
include renal artery Doppler
■
| Australian Doctor | 2 February 2007
ultrasonography, CT angiography and MRI angiography.
(The gold standard test and
approach to confirm the diagnosis of renal arterial disease
remains referral to a nephrologist to arrange DSA renal
arteriography.)
Hyperkalaemia is frequent
among elderly people and
those with diabetes after starting an ACE inhibitor or
angiotensin-II-receptor antagonist. In the latter this may be
predisposed to by the presence
of hyperkalaemic-type renal
tubular acidosis (type 4).
Provided that hyperkalaemia is modest (potassium
level ≤6.0mmol/L) and stable
on repeat testing, therapy
should be continued because
of the beneficial effects of
ACE inhibitors in such populations. Advice on a low
potassium diet is often particularly useful.
Glycaemic control
Optimal glycaemic control
helps prevent CKD progression in patients with
nephropathy due to type 1 or
type 2 diabetes. HbA1c levels
<7.0% should be targeted by
use of diet, oral hypogly-
caemics and/or insulin, taking
care to avoid metformin and
sulfonylureas that are renally
excreted in patients with
eGFR<30mL/min.
Smoking cessation
Current smoking has been
shown to be a significant risk
factor for CKD in the general
population and increases the
risk of progression for those
with known kidney disease.
Smoking cessation is therefore
of paramount importance,
decreasing the risk of progression and also cardiovascular
events.
Lipid lowering
Raised serum cholesterol and
triglyceride levels may be an
independent risk factor for
CKD. The evidence that
lowering cholesterol with
statin therapy slows progression of CKD is lacking, but
is currently under investigation in the Study of Heart
and Renal Protection
(SHARP) study.
It seems likely that cholesterol lowering will also
decrease the risk of cardiovascular events for those with
CKD (this is also under inves-
www.australiandoctor.com.au
Renal anaemia is caused by
reduced erythropoietin production by loss of renal
parenchymal mass in progressive CKD. It can be corrected
by supplements of erythropoietin subcutaneously or intravenously, guided by a
nephrologist.
Two trials of erythropoietin
therapy in people with CKD,
published in November 2006
in the New England Journal
of Medicine (the CHOIR and
CREATE trials), showed no
benefit and possible harm in
correcting anaemia to a
normal
haemoglobin
(>130g/L).
Correcting anaemia has not
been convincingly shown to
slow CKD progression; however, improved quality of life
and reduced transfusion
requirements support therapy
for people with haemoglobin
levels <100g/L.
Control of
hyperphosphataemia
Phosphate retention is universal in CKD and is a strong
risk factor for cardiac death.
Correction of serum phosphate through the use of
binders such as calcium carbonate is likely to decrease the
risk of vascular events.
Protein restriction
A small amount of evidence
suggests protein restriction
will slow CKD progression.
However, this approach is
unlikely to be of benefit given
the significant risk of protein
energy malnutrition. Australian guidelines recommend
a normal dietary protein
intake.
Cardiovascular risk
CKD is an independent risk
factor for cardiovascular disease, with elevated risk arising
even at mild to moderate
stages of CKD. Large-scale
cohort studies have shown
that people with CKD have a
much higher risk of premature
death (largely due to cardiovascular disease) than of progressing to ESKD requiring
dialysis or a transplant.6
Among people who do
progress to ESKD, cardiovascular mortality rates are at
least 10 times higher than the
age- and sex-matched healthy
population. The reasons for
this increased risk are complex.
Cardiovascular risk factors
cluster in CKD; for example,
people with diabetes causing
significant kidney damage will
usually also have hypertension
and lipid abnormalities. In
addition, CKD alters calcium/phosphate regulation,
leading to increased coronary
artery calcification and
increased cardiovascular risk.
Altered salt and water
homeostasis and renal
anaemia lead to chronic cardiac overload, hypertension
and so left ventricular hypertrophy. Chronic overload
and/or cardiac ischaemia leads
to congestive cardiac failure.
Left ventricular hypertrophy
from chronic fluid overload is
a marker of risk for sudden
death in the ESKD population.
In view of this excess
burden of cardiovascular disease, primary care physicians
need to be aware of the potential for cardiac complications
in any person with CKD and
have a lower threshold for
investigation. Modifiable risk
factors for cardiovascular disease should be managed
aggressively.
Bone disease
Renal bone disease can be
split into two major groups:
disease associated with high
bone turnover stimulated by
high parathyroid hormone
(PTH) levels (osteitis fibrosa);
and low bone-turnover states
with low or normal serum
PTH levels (adynamic bone
disease or osteomalacia).
Secondary hyperparathyroidism is a common complication of CKD. With GFR
<60mL/min, phosphate retention, loss of activated vitamin
D and decreased serum calcium drive abnormal secretion
of PTH. Hyperparathyroidism
leads to abnormal bone
turnover, which in turn leads
to decreased bone strength
and fracture.
Laboratory tests typically
show raised serum phosphate,
low or low normal serum calcium, and raised PTH and
alkaline phosphatase levels.
Treatment primarily depends
on reducing serum phosphate
with phosphate binders such
as calcium carbonate taken
with meals.
Use of ‘activated’ 1,25 vitamin D in the form of calcitriol
(generally 0.25g/day) also
directly inhibits PTH secretion, but may cause hypercalcaemia and raised calcium/
phosphate product, potentially
increasing cardiac risk.
Low bone-turnover states
result in adynamic bone disease and osteomalacia, both
characterised by reduced
osteoclast and osteoblast
number and function. Adynamic bone disease may be
at least as common as hyperparathyroid bone disease
and probably relates to oversuppression of PTH. Bone
pain and increased fracture
risk are seen in low turnover
states.
AD_HTT_019_026___FEB02_07 31/1/07 11:53 AM Page 23
Other clinical problems
THERE are several other clinically
important effects of CKD, usually
seen with significantly reduced GFR.
16
Glucose metabolism
The kidneys play an important role
in the metabolism of insulin. Severe
CKD leads not only to increased
serum levels of both endogenous and
exogenous insulin, but also to
increased tissue resistance to insulin.
Note that renally excreted sulfonylureas should be avoided (especially in
the elderly) in CKD — gliclazide and
glimepiride are the best options. Metformin should be avoided in all
patients with diabetes and eGFR
<30mL/min, because of the risk of
lactic acidosis.
Fertility
Abnormal sex hormone levels and
cyclical changes are commonly seen
as CKD advances, leading to reduced
fertility with oligomenorrhoea or
amenorrhoea. Impotence and
decreased spermatogenesis is commonly seen in men.
Neurological effects
Central, peripheral and autonomic
Cumulative incidence of ESKD %
Urate retention is common in CKD
and often exacerbated by diuretic use.
NSAIDs are generally contraindicated,
leaving colchicines for use in acute
attacks and allopurinol for prevention
(dose reduction required in line with
decreased GFR).
CKD is a common
problem and frequently
goes undetected.
■ The K/DOQI classification
of CKD into five stages of
increasing severity,
independent of cause,
provides a practical
framework for diagnosis
and management
■ Within general practice,
clinical and sociodemographic risk factors
for CKD can identify an ‘at
risk’ population
appropriate for targeted
opportunistic screening.
■ The cardinal markers of
CKD are reduced eGFR,
proteinuria, haematuria
and kidney-imaging
abnormalities.
■ eGFR is now
automatically provided by
most labs when serum
creatinine is measured.
■ Guidelines are available
that indicate when referral
to a nephrologist is
appropriate.
■ Simple strategies can
prevent CKD progression:
blood pressure control,
anti-proteinuric therapies,
smoking cessation and
tight glycaemic control.
■ CKD is an independent
risk factor for
cardiovascular death.
■ Prescribing practices may
need to be altered for
patients with CKD.
■
Risk of ESKD related to baseline proteinuria
over 18-year period
Metabolic/endocrine effects
Gout
Summary
N = 106,000
14
12
10
8
Progression to ESKD
6
4
2
0
Proteinuria
Number of screened
Number of ESKD
NSAIDs, iodine contrast) unless
absolutely necessary. Many drugs
require dose adjustment in line with
progressive decline in GFR (eg,
digoxin, sotalol, allopurinol), generally when predominant clearance is
via renal excretion.
Very occasionally doses for drugs
which are dependent on GFR for
renal delivery (such as loop diruetics)
need to be increased.
86,253
185
±
10,000
38
+
4007
55
2+
1072
76
≥3+
357
55
Iseki, et al. Kidney International 2003; 63:1468-76.
neuropathy as well as abnormalities
in muscle composition and function
are complications in CKD.
protein restriction has been used to
delay the need for this therapy. However, this should not be at the risk of
protein energy malnutrition.
Gastrointestinal and nutritional
problems
Prescribing for patients with CKD
With advanced CKD, risk of gastritis
and peptic ulcer disease is increased.
In addition, diverticulosis and also
pancreatitis are more common, particularly in individuals with polycystic kidney disease.
Clinically patients suffer nausea,
vomiting, anorexia and hiccups late in
the course of their CKD. These symptoms should respond to introduction
of renal replacement therapy, although
A comprehensive discussion of renal
prescribing is beyond the scope of
this review (see also How to treat:
Kidney complications of commonly
used drugs part 1 and 2, 7 April and
14 April, 2006). It is always important to consider a person’s degree of
renal impairment when modifying
pharmacological treatment.
Consideration must be given to
avoiding renotoxic drugs (eg,
The aim of this review has been to
provide knowledge and improve
understanding of CKD to enable GPs
to identify CKD among their patients,
particularly through opportunistic targeted screening. The suggested classification, management and referral
strategy should help GPs to manage
this growing health problem.
This is important for two reasons:
best-practice CKD management will
reduce the risk of premature mortality
due to associated cardiovascular disease; and it will reduce the number
of people progressing to ESKD.
More than 15,000 Australians
with ESKD are receiving dialysis or
living with a functioning kidney
transplant. In addition, significant
numbers of patients are managed
conservatively and die as a consequence of their kidney disease.
CKD causes or contributes to
about 9% of all deaths in Australia.
Hopefully, early detection and
appropriate management in general
practice will help reduce this disease
burden.
Authors’ case study
Proteinuria with
hypertension and
significant CKD
A 73-YEAR-old Caucasian
woman attends her local GP
for a health checkup, admitting she has avoided doctors
over the years. There is very
little in her past history
beyond hypertension, and
she has refused medication
for blood pressure on three
previous visits. There is no
family history of kidney disease.
She smoked a packet of
cigarettes/day for 30 years
but “gave them away” 10
years ago because of cost.
She drinks no alcohol.
On close questioning she
informs her GP of a mild
ache in her chest when walking up hills, although she
still keeps pretty active.
There is little to find on clinical examination beyond
persistent hypertension of
160/90mmHg and obesity
(BMI 32).
In view of her age and
hypertension, urine dipstick is
performed, which shows 1+
protein and no blood. Serum
for routine blood count, fasting biochemistry and also
morning urine for ACR are
sent for testing. These tests
show haemoglobin 108g/L,
creatinine 178µmolL, urea
15.4mmol/L, fasting glucose
4.8mmol/L, cholesterol
6.8mmol/L and triglycerides
2.6mmol/L.
The urine ACR result is
45mg/mmol, consistent with
mild proteinuria. An automated eGFR of 28mL/min,
consistent with CKD stage
4, is provided with the creatinine result.
Following these results her
GP arranges a baseline ultrasound scan of the renal tract,
which documents bilateral
reduced kidney size of 9.4cm
(normal 11-14cm), with mild
parenchymal thinning and a
simple cyst in the left kidney.
Although the patient is
clinically well, her GP is concerned about the degree of
renal impairment and risk of
progression and also cardiovascular disease risk, especially given her symptom of
mild exertional chest ache.
The main consideration is
to achieve blood pressure
control and, given the mild
proteinuria, first-line treatment with an ACE inhibitor
(perindopril 4mg daily) is
started.
With her degree of renal
dysfunction, creatinine and
potassium are checked five
days later as a safeguard
against bilateral renal artery
stenosis. The repeat creatinine is 191µmolL, which is
felt to be acceptable, and the
potassium is 5.0mmol/L.
A statin is added in view of
the cholesterol level, and
weight loss initiatives are diswww.australiandoctor.com.au
cussed with the patient. At the
same time, given the stage of
CKD and hypertension, the
GP refers her to a nephrologist, but also a cardiologist for
investigation and risk-factor
modulation for CVD.
On nephrologist review a
diagnosis of hypertensive
nephrosclerosis is made. Given
the symmetrical reduction in
kidney size and the stable creatinine level with ACE inhibition, investigation for renal
artery stenosis is not deemed
necessary at this stage.
Blood pressure is now
145/85mmHg and the
nephrologist increases the
perindopril dose to 8mg daily
with a view to adding atenolol
if required at a later date.
The patient is deemed
moderate to high risk for
CKD progression and the
nephrologist opts to see her
in three months, with
monthly creatinine, potassium and blood pressure
checks by her GP.
Repeat ACR at three
months has dropped to
30mg/mmol, blood pressure
is now 125/70mmHg and
renal function is stable. A
plan is made to see the
patient every 6-12 months to
monitor for CKD progression and further modulate
risk if possible. Coronary
angiography with prehydration and n-acetylcysteine
protection is booked.
References and
Further reading
Available on request from
julian.mcallan@
reedbusiness.com.au
Online resources
ANZDATA:
www.anzdata.org.au
■ Caring for Australasians
with Renal Impairment:
www.cari.org.au/
guideline.php
■ Australian Diabetes
Society:
www.racp.edu.au/ads/
posstate.htm
■ K/DOQI:
www.kidney.org/
professionals/KDOQI/
guidelines.cfm
■ Kidney Health Australia:
www.kidney.org.au
■
2 February 2007 | Australian Doctor |
23
AD_HTT_019_026___FEB02_07 31/1/07 11:53 AM Page 26
How to treat – chronic kidney disease
GP’s contribution
DR CAROLYN BLOCK
Double Bay, NSW
Case study
MRS D is 75 and surprisingly
spritely for her age. She looks
after herself and her many
grandchildren well.
She has no medical problems apart from a long history
of hypertension and hypercholesterolaemia, for which
she is being treated, nor any
significant family history. She
regularly sees an ophthalmologist and has had no microor macrovascular effects from
her conditions.
On her routine yearly blood
test her serum creatinine was
114µmol/L, eGFR 43mL/min,
cholesterol 5.0mol/L and LDLcholesterol 2.7mmol/L. Her
creatine kinase was 197U/L.
Her blood pressure was
140/80mmHg and her weight
was 57kg.
She had no symptoms of
the renal insufficiency on her
test results. Comprehensive
blood tests, including an
immunological screen and
urine analysis, including a
Bence-Jones protein were
normal.
Ultrasound of the renal
tract and renal artery
Dopplers was also normal.
The dosages of her antihypertensive (an angiotensin-IIreceptor antagonist) and lipidlowering agent were doubled
and on review she was tolerating the increases well.
Questions for the authors
If Mrs D had been unable to
tolerate these increases in
medication doses, what
options would there be for
treatment?
Although Mrs D is an
active 75-year-old, as an
elderly person with high blood
pressure, hypercholesterolaemia and chronic kidney disease, she has very high
absolute risk of cardiovascular
disease. In this setting, increasing her medication dosages
was appropriate.
If she had been unable to
tolerate a doubling of her
angiotensin-II-receptor antagonist, other options would
include: combination with a
low dose of another class of
antihypertensive
(ACE
inhibitor, diuretic, beta
blocker or calcium-channel
blocker), or investigating
changes to diet (particularly
to explore whether she has
high salt intake or low intake
of fruit and vegetables).
If she had been unable to
tolerate a doubling of her
lipid-lowering agent, other
options would be: combination with a low dose of
another class of lipid-lowering agent (for example, combining a statin with ezetimibe), provision of tailored
dietary advice with a possible
focus on the beneficial role of
plant-sterols and omega-3
fatty acids (fish oils).
What parameters should we
aim for when measuring her
LDL and total cholesterol and
blood pressure?
Emphasis is now being
placed on LDL levels rather
than total cholesterol. For Mrs
D, who has high absolute risk,
but has not had a previous
major CV event and does not
have proteinuria, appropriate
targets are an LDL-C level of
<2.5mmol/L and a blood pressure of <130/80mmHg.
Nevertheless, the key is to
provide effective therapy to
reduce her overall cardiovascular disease risk, which will
involve broader assessment
regarding appropriate dietary
and lifestyle change.
If I had used the CockcroftGault calculation instead of
the eGFR, the result would
have been 34 instead of 43.
Which is the more accurate
calculation and should it affect
my treatment?
There has been significant
debate regarding which calculation provides the most accurate estimate of eGFR. One
clear advantage of MDRD is
that the equation does not
require the persons’ weight;
eGFR can be calculated using
the serum creatinine, age and
sex.
Both the MDRD and
Cockcroft-Gault estimating
equations have been found to
be accurate when compared
with measured GFR in studies
How to Treat Quiz
INSTRUCTIONS
Chronic kidney disease
— 2 February 2007
FAX BACK
Photocopy form
and fax to
(02) 9422 2844
1. Which THREE findings are cardinal
markers of kidney damage or reduced
kidney function?
2
❏ a) GFR of >60mL/min/1.72m
❏ b) Haematuria
❏ c) Abnormalities on kidney imaging
❏ d) Proteinuria
2. Jim, 63, is a new patient. He has
an Anglo-Saxon background, is obese
and has had type 2 diabetes and hypertension for 10 years. He rarely attends
the doctor. He requests a script for
metformin and perindopril. Which
THREE aspects of Jim’s history indicate
he is at particular risk of renal impairment?
❏ a) Diabetes
❏ b) Treatment with perindopril
❏ c) Age over 50
❏ d) Hypertension
3. Which THREE findings on examination
and office testing are consistent with Jim
having chronic kidney disease (CKD)?
❏ a) Pallor
❏ b) Blood pressure of 180/105mmHg
❏ c) +2 protein on dipstick testing
❏ d) Spider naevi
4. If Jim has evidence of CKD, appropriate
investigations would include which THREE
tests?
❏ a) Serum creatinine and eGFR
❏ b) Plasma aldosterone
❏ c) Spot urine albumin:creatinine ratio
(ACR)
❏ d) Renal ultrasound
5. Jim is found to have reduced renal
function and a urinary ACR of 20mg/mmol.
Which THREE strategies are important in
preventing progression of his kidney
disease?
❏ a) Blood pressure control with a target of
<130/85mmHg
❏ b) Decrease proteinuria with an ACE
inhibitor or angiotensin-II-receptor
antagonist
❏ c) Weight reduction
❏ d) Optimal glycaemic control
6. Despite working with Jim to put a
number of kidney protective strategies
in place, his renal function slowly
deteriorates. Which THREE other
among people with CKD.
MDRD appears to be more
accurate among elderly and
obese people.
In general, biological and
measurement variability of
GFR is greater at higher GFR
levels and, for this patient, the
MDRD eGFR would provide
a reliable estimate of kidney
function.
General questions for the
authors
eGFR is now routinely
reported. If it is low but the
patient is optimally managed,
is a diagnosis of chronic renal
failure required?
Mrs D would be classified
as having stage 3 CKD. Even
if optimally managed, a diagnosis of CKD is potentially
beneficial in her management
for the following reasons:
■ CKD is associated with
increased CV risk.
■ Concomitant
metabolic
abnormalities need to be considered, including anaemia,
bone disease and acidosis.
■ Priority should be given to
avoiding agents with potential kidney toxicity.
■ Progression
of disease
should be monitored so that
if Mrs D’s kidney function
deteriorated further she
would have adequate time
to explore ESKD treatment
options with her family, GP
and nephrology team.
What are the implications of
these abnormal eGFRs in the
light of insurance medicals?
Will they result in excessive
unnecessary investigations?
Reporting of abnormal
eGFRs is unlikely to constitute a major problem in terms
of unnecessary investigations
relating to insurance medicals.
In population terms, advanced
age is the strongest predictor
of reduced kidney function.
For elderly people, insurance
medicals are not normally a
concern.
Young and middle-aged
adults might have an unexpected finding of reduced
eGFR reported as a result of
an insurance medical. For
these people, a finding of an
eGFR of <60mL/min necessitates further investigation starting with screening for elevated
blood pressure, diabetes, protein and blood in the urine.
Decisions regarding further
investigation can be shaped by
these simple tests; however, a
finding of significantly reduced
kidney function in a younger
adult cannot be ignored.
Complete this quiz to earn 2 CPD points and/or 1 PDP point by marking the correct answer(s)
with an X on this form. Fill in your contact details and return to us by fax or free post.
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How to Treat quiz
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Chatswood DC NSW 2067
health problems is he most likely to
encounter?
❏ a) Osteoporosis
❏ b) Peptic ulcer
❏ c) Peripheral neuropathy
❏ d) Congestive cardiac failure
7. In which TWO situations would Jim
benefit from referral to a nephrologist?
❏ a) An eGFR of 50mL/min
❏ b) eGFR that has declined 12% over a
12-month period
❏ c) Proteinuria 0.5g/24 hours
❏ d) Kidney disease and/or hypertension that
proves difficult to control
8. ACE inhibitors and angiotensin-II-receptor
antagonists have been associated with
which TWO effects?
❏ a) An immediate reduction in serum
creatinine
❏ b) Angioneurotic oedema and anaphylaxis
❏ c) Polycythaemia
❏ d) Hypotension
9. When screening for proteinuria, which
TWO statements are correct?
❏ a) It is appropriate to screen all Australian
ONLINE
www.australiandoctor.com.au/cpd/
for immediate feedback
adults aged 25 years for proteinuria using
dipstick testing
❏ b) People with diabetes should be
screened annually for microalbuminuria by
spot urinary ACR, ideally using a morning
specimen
❏ c) A urinary ACR of 50mg/mmol is
classified as microalbuminuria
❏ d) If a spot urinary ACR in a patient
with diabetes is elevated, two further
specimens should be sent within the
next two months to confirm persistent
microalbuminuria
10. Which TWO statements about CKD in
Australia are true?
❏ a) More than 15,000 Australians with
end-stage kidney disease are receiving
dialysis or living with a functioning kidney
transplant
❏ b) Indigenous Australians living in
remote areas are at lower risk of
end-stage kidney disease than those
in urban areas
❏ c) CKD causes or contributes to
about 9% of all deaths in Australia
❏ d) The ‘at risk’ population for CKD is
reducing
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HOW TO TREAT Editor: Dr Martine Walker
Co-ordinator: Julian McAllan
Quiz: Dr Martine Walker
The mark required to obtain points is 80%. Please note that some questions have more than one correct answer. Your CPD activity will be updated on your RACGP records every January, April, July and October.
NEXT WEEK The next How to Treat on pharmacogenetics explores the role of inheritance (or genetics) in the inter-individual variability in drug response. The author is Professor John O Miners, professor
and head, department of clinical pharmacology, Flinders Medical Centre and Flinders University school of medicine, Bedford Park, SA
26
| Australian Doctor | 2 February 2007
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