1
Report on Chronic Kidney Disease Project – Langimalie Clinic
Background
In New Zealand, more than half the patients with end stage renal failure taken onto
dialysis programs now have type 2 diabetes and proteinuric renal disease - a
proportion that has grown continuously over the past two decades. While dialysis in
these patients does extend life, the quality of life is often poor and life expectancy
remains lower than that for many cancers. Dialysis treatment is, moreover, very
costly at ~$70,000 per annum. Any measure that can prevent or delay the
progression of renal failure to the point where dialysis becomes necessary is therefore
likely to be cost effective.
It was established in the mid-1980s that good control of the hypertension that almost
invariably accompanies renal disease in diabetes can slow the progression of renal
failure. Landmark trials published in the 1990s showed that antihypertensive
regimens based on ACE inhibitor or ARB drugs were significantly more effective
than other types of antihypertensive agent. However, despite their widespread use,
the number of patients with type 2 diabetes going into renal failure has steadily risen.
In part this reflects the growing number of people with type 2 diabetes, but it also
suggests that current management is sub-optimal. It is known, for example, that many
patients do not reach target blood pressure levels and remain hypertensive.
Type 2 diabetes and proteinuric renal disease does not affect all sections of society
equally. The disorder is particularly prominent amongst poorer and migrant
populations, in particular Māori and Pasifika people, who are very over-represented in
the dialysis statistics. Deprivation and poverty are important factors in determining
whether patients with complex chronic medical problems are optimally managed.
We have undertaken this project aimed at trying to optimize treatment and its delivery
at the Langimalie Tongan Health Clinic in Onehunga. This is a general practice
where many of the staff speak Tongan and are well connected with the community, so
it is very popular and serves a large proportion of the Tongan community from all
parts of Auckland. This includes a large number of low income families. Over 850
patients with type 2 diabetes attend the clinic and proteinuric renal disease is common.
The Langimalie Renal Project
The Langimalie project was initiated in late 2010 as a Ministry of Health-funded pilot
aimed at improving outcomes in patients with chronic kidney disease (CKD).
The project has been led at Langimalie by Fifita McCready the Senior Nurse for the
Chronic Disease Management programme, with the help of Nurse Assistant Oketi
Tepueluelu and Dr Fiona Noovao. Dr Tim Cundy from the Auckland Diabetes Centre
visits fortnightly to consult, review results and advise on changes to treatment. The
protocols for intensification of antihypertensive treatment were devised by Dr John
Collins a senior nephrology specialist at Auckland City Hospital, and Dr Cundy.
The patients enrolled into the pilot study were those with heavy proteinuria
(macroalbuminuria) and type 2 diabetes. The degree of proteinuria is strongly linked
to the likelihood of progression of renal failure, and successful reduction of
1
2
proteinuria has been associated with improved prognosis. The aim of this intensive
community-based programme to optimise blood pressure control and reduce
proteinuria, with the ultimate aim of preserving renal function.
Inclusion criteria
Type 2 diabetes; age ≥18 years; life expectancy ≥2 years; current albumin/creatinine
ratio ≥40 (normal <3 g/mol); current glomerular filtration rate ≥40 ml/min/1.73m2.
Recruitment
The baseline characteristics are summarised in Table 1. The last patient was enrolled
in November 2011, so by November 2013 all patients will have completed 2 years in
the project.
Methods
Blood pressure measurements were made in duplicate in the sitting position, after a 10
minute rest period, using appropriately-sized blood pressure cuffs. Albuminuria was
assessed by the albumin/creatinine ratio (ACR) measured on random urine samples
(normal values are ≤ 3 g/mol; ‘macroalbuminuria’ is defined as ≥30 g/mol).
Glomerular filtration rate was calculated from the plasma creatinine according to the
Cockcroft-Gault equation, with adjustment to a body surface area of 1.73m2. This
was used in preference to the MDRD method reported by the local laboratories as the
latter does not take into account the patient’s size.
Antihypertensive treatment regimen
A stepwise protocol-driven intensification of antihypertensive therapy was the main
intervention, with the aim of achieving systolic blood pressure values < 130 mmHg.
Antihypertensive agents selected from the following classes were prescribed:
Angiotensin converting enzyme inhibitors (ACEi), Angiotensin receptor blockers
(ARB), Calcium channel blockers, Thiazide diuretics, β-blockers, Loop diuretics,
Spironolactone, α-blockers.
ACEi were the initial treatment (ARB if intolerant), with thiazide diuretics as the
second line treatment and calcium channel blockers as third line. The protocol for
intensification was as follows:
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6
Step 7
Step 8
Step 9
Cilazapril 2.5mg
(Losartan 25mg in cases of intolerance)
↑Cilazapril 5mg
(Losartan 50mg)
Cilazapril/HCT 5/12.5mg
(Losaratan/HCT 50/12.5mg)
↑Cilazapril/HCT 5/12.5mg x2
(Losaratan/HCT 50/12.5mg x2)
Add Felodipine 5mg
(or Amlodipine 5mg)
↑Felodipine 10mg
(or Amlodipine 10mg)
↑Felodipine 20mg
(or Amlodipine 20mg)
Add 4th line agent from a different class
Add 5th line agent from a different class
- options include Frusemide, Spironolactone, Metoprolol or Doxazosin
We devised a scoring system to reflect the intensity of antihypertensive treatment
taking into account both the class of agents prescribed and the doses. For example,
Cilazapril 2.5mg scores 1; 5mg scores 2; 10mg scores 3. Hydrochlorthiazide 12.5mg
scores 1; 25mg scores 2. The scores for each agent can then be added.
2
3
Monitoring
Renal function, proteinuria and blood pressure are monitored closely, and are used to
guide the level of antihypertensive therapy. Glycaemic control and the management
of dyslipidaemia are also optimised.
Non-pharmacological intervention
The team has focussed particularly on ways of improving adherence to therapy. The
team works closely with the Pharmacy service at Langimalie (for example, by use of
blister packs) and makes frequent home visits (including evenings) to monitor blood
pressure, deliver prescriptions and check adherence. This has been necessary because
some patients have no means of transport, whilst others are working and unable to
attend. A number of important issues have been uncovered and, where possible,
addressed (see below Case A, for an example).
Results
Demographic features at baseline
Between November 2010 and November 2011 we recruited 47 subjects with type 2
diabetes (11 women and 36 men) aged from 29 to 65 years (mean 53). All but two
were of Tongan descent; there was one Niuean and one Cook Islander. The subjects
had migrated to New Zealand between 1959 and 1998 and lived here for a mean 23
years (SD 11).
The mean age at the diagnosis of diabetes was 44 years (SD 6.5). 17 subjects were
insulin-treated at the start of the project.
The mean BMI was 37.3 kg/m2 (range 27.8 to 50.9). 82% were non-smokers or exsmokers. 32% had no diabetic retinopathy (retinal photographic screening).
Hypertension was first diagnosed at a mean age of 46 (SD 9). Macroalbuminuria
was first detected at a mean age of 49 years – on average only 5 years after diabetes
was recognized.
Baseline assessments
The mean glycated haemoglobin (HbA1c) was 80 mmol/mol (range 49 to 140).
The mean systolic blood pressure was 140 (SD 20) and the mean diastolic pressure
was 85 (15) mmHg. The mean estimated GFR was 86 ml/min/1.73m2 (SD 27, range
41-149). The median ACR value was 84 g/mol (interquartile range 55-142).
Patient flow
At the time of writing 11 patients have left the programme: 2 patients migrated (1 to
Tonga, 1 to Australia); 1 moved away and was not contactable; 3 patients
discontinued their participation, 3 patients transferred to another general practice and
2 patients were referred to renal services for consideration for dialysis treatment.
3
4
Of the remaining 36 patients: 12 have completed 2 years follow up; 17 have >1.5
years follow up (i.e. ≤ 6 months to completion) and 7 have completed >1year but have
6-9 months to complete 2 years follow up).
Morbidity
In the course of the study two patients had hospital admissions with heart failure and
one was admitted with a non ST-elevation myocardial infarction. Two patients were
referred to renal services for consideration of dialysis treatmemt.
The first was a 49 year old who had heavy proteinuria (ACR 645 g/mol) and impaired
renal function at entry into the programme; his GFR subsequently declined rapidly at
~2 ml/min/1.73m2/month. The other was a 50 year old woman also with heavy
proteinuria (ACR 743 g/mol) and impaired renal function at entry into the programme;
her GFR subsequently declined rapidly at ~4 ml/min/1.73m2/month, although it has
since stabilised at a low level, There were no deaths.
Blood pressure management
The patients were taking antihypertensive agents from a median of 3 classes at entry
to the programme (this included in all cases an ACE inhibitor or ARB). This was
increased significantly (p<0.001) and at the last follow up agents from a median of 4
classes were being prescribed (range 1 to 6).
The doses of antihypertensive agents were also increased so the composite score
(which factored in dose as well as number of agents) increased significantly from 5.1
to 7.9 (p<0.001, Figure 1).
Significant improvements in blood pressure were also obtained. Mean systolic blood
pressure decreased by 9 mmHg and diastolic blood pressure by 8 mmHg (p=0.007,
<0.001, respectively). Figure 2 illustrates the mean and range of blood pressures
obtained at intervals through the project. It is notable that despite the significant
reduction in mean blood pressure a substantial proportion of the subjects still record
pressures above the target of 130 mmHg.
Diabetes management
Glycaemic control as assessed by HbA1c also improved from a mean of 80 mmol/mol
to 71 mmol/mol (p=0.008, Figure 3). This was achieved by the intensification of
therapy including the introduction of insulin treatment in a further 2 subjects.
Albuminuria and renal function
Renal function fell with the mean serum creatinine rising by 23 umol/l. This reflects a
loss of GFR (averaged over time in the project) of 0.59 ml/min/1.73m2/month. If
untreated the GFR in diabetic kidney disease typically declines at ~ 1
ml/min/1.73m2/month.
The proportion of subjects with heavy albuminuria decreased significantly (p<0.001,
Figure 4). However, a marked heterogeneity in response was obvious. For example,
at one extreme some patients had near complete remission of proteinuria, while at the
other proteinuria fluctuated or increased despite good control of blood pressure.
Therefore summary data, looking at the average of the outcome measures, could
4
5
conceal significant information, and it is important to examine individual patient
responses.
The average rate of change of GFR was less in those whose ACR was persistently
suppressed <50 (n=17) as it was in those (n=22) whose ACR was not suppressed:
-0.24 vs -0.86 ml/min/1.73m2/month, although this was not statistically significant; p
= 0.11.
In the group whose ACR was suppressed it should be noted that some of the drop in
GFR may be a ‘one off’ effect resulting from of a fall in filtration pressure. Examples
of this can be seen in Figure 5. Intensification of treatment resulted in substantial
drops in blood pressure and albuminuria (ACR) but in all three cases there was an
increase in serum creatinine – equivalent to a fall in GFR of ~33% in each. However,
in two cases it appears to have stabilised, and if it can be maintained long term then
the expected progressive fall in GFR will be averted. In one patient it has not yet
stabilised, and it is notable that this patient had the lowest initial GFR.
We believe that there is much to gain from analysing individual patient-level data to
determine which factors influence responses to the intensive antihypertensive
treatment. These factors could include age, glycaemic control, smoking, GFR and
level of proteinuria at the entry into the project, retinopathy status, the presence of
non-diabetic renal disease, drug doses and drug combinations. When all the patients
reach the two year point we plan to undertake such an analysis, and hope to be able to
discover from this whether particular presentations indicate a good or poor prognosis
and whether tailored antihypertensive drug regimens might be developed.
Non-diabetic renal disease
It was notable that one third of the patients with macroalbuminuria in this cohort had
no evidence of retinopathy. In type 1 diabetes virtually all patients with established
nephropathy have retinopathy (usually moderate or severe), but in type 2 diabetes it is
commonly found that high proportion have no retinal disease. This raises the question
of whether some patients have renal pathology separate from or additional to diabetic
nephropathy. Because renal biopsies are rarely undertaken this possibility is not often
explored.
We identified one patient with an atypical presentation and a proven alternative
pathology. In a 50 year old man with type 2 diabetes had exceptionally heavy
proteinuria (ACR 546), and lymphopenia but good glycaemic control with no
retinopathy. He was found to have chyluria (lymphatic fluid in the urine). A
cystoscopy was arranged which showed that chyle was emerging from just one ureter.
CT scanning confirmed widespread lymphatic ectasia around that kidney and he is
currently awaiting laparascopic surgery which should cure his renal disease.
Social factors
A number of the subjects in the trial are living under conditions of real stress from
unemployment, overcrowding, ill health and financial hardship. This became evident
from home visits made by Fifita McCready and Okete Tapueluelu.
One example was that of a 46 year old man who had suffered a leg amputation
through severe necrotising fasciitis. He, his wife who had recently had a
5
6
pneumonectomy, his young son who had renal disease and was on dialysis, and his
young daughter were all living in a single room. Our patient was very depressed and
it was initially difficult to engage with him. We made strong representations through
the family’s various social workers to Housing NZ, and were able to get the family rehoused. Our patient’s mood was considerably lifted and we have been able to achieve
much better blood pressure control and a substantial reduction (66%) in ACR.
Summary









The community-based nurse-led intervention at Langimalie clinic was very
successful in improving blood pressure and glycaemic control in patients with
type 2 diabetes and proteinuric renal disease.
The improvement in blood pressure control was achieved primarily through
intensification of antihypertensive control – both through maximising doses
and introducing agents from additional classes.
The proportion of patients with heavy albuminuria decreased significantly, but
in two thirds the ACR remained >50 g/mol.
Two patients with heavy proteinuria and markedly impaired renal function at
entry to the programme were referred for dialysis treatment, suggesting that
intensive intervention late in the course of the disorder might be too late to
stabilise the disease.
The rate of loss of renal function appeared to be lower in those with good
suppression of albuminuria, but this did not reach statistical significance.
Longer follow up and individual patient-level analysis of results may help
clarify how renal function might be best preserved.
The absence of diabetic retinal disease in a third of patients suggests that renal
diseases other than diabetic nephropathy are likely to be important. It is
important to recognise such cases as alternative treatments might be required.
The support offered to the patients in this community-based intervention was
invaluable and we identified several instances where issues related to social
deprivation were impeding the effectiveness of treatment.
Similar socio-economic issues probably underlie the mobility of this
population and compound the difficulties of providing long-term care.
Acknowledgements
We would like to thank Nick Polaschek and Ailsa Jacobson and their colleagues at the
Sector Capability and Implementation section of the Ministry of Health for their
generous support of this programme, and also our colleagues at the Langimalie Clinic
for their enthusiastic collaboration.
Fiona Noovao was supported by a grant from the New Zealand Society for the Study
of Diabetes, sponsored by Eli Lilly.
Fifita McCready, Oketi Tepueluelu, Fiona Noovao, Tim Cundy
February 2013
6
7
Figure 1
Sequential changes in antihypertensive therapy intensity score in individual patients.
The x-axis is in months: the time of entry into the programme is indicated by time ‘0’.
7
8
Figure 2
The mean (solid line) and range (boxes) of systolic blood pressures obtained at
intervals (months) through the project. The x-axis is in months: the time of entry into
the programme is indicated by time ‘0’.
The target of 130 mmHg is indicated by the dashed line. A substantial proportion still
record pressures above the target although this is intermittent in some subjects.
8
9
Figure 3
The mean (solid line) and range (boxes) of glycated haemoglobin (HbA1c) obtained
at intervals (months) through the project. The x-axis is in months: the time of entry
into the programme is indicated by time ‘0’.
The reduction in HbA1c after entry to the programmed is statistically significant and
the proportion with very high HbA1c values (>90 mmol/l, dashed line) is lower.
9
10
Figure 4
The proportion of patients with ACR values within various ranges at the start of the
project and at the latest follow up. Two thirds of patients continued to have heavy
albuminuria (ACR >50 g/mol) but in just under one third the ACR had reduced to <30
g/mol (X2 test p = 0.0008). The two patients referred for dialysis were excluded from
this analysis.
10
11
Figure 5
Changes in blood pressure, albuminuria and renal function in three individuals.
Intensification of antihypertensive treatment resulted in substantial drops in blood
pressure and albuminuria (ACR) but in all three there was an increase in serum
creatinine – equivalent to a fall in GFR of ~30% in each case. In two cases (blue and
green lines) the GFR appears to have stabilised.
11