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Intensified treatment of patients with type 2 diabetes mellitus and overt nephropathy

N. Joss, C. Ferguson, C. Brown, C.J. Deighan, K.R. Paterson, J.M. Boulton-Jones
DOI: http://dx.doi.org/10.1093/qjmed/hch039 219-227 First published online: 17 March 2004

Abstract

Background: Diabetic nephropathy is the single most common cause of chronic renal failure requiring dialysis. Effective treatment exists, but no clinical audit or large trial has reduced the rate of loss of renal function as effectively as in small groups of intensively managed patients.

Aim: To determine the effect of intensive vs. standard medical management on the rate of progression of renal failure in patients with diabetic nephropathy.

Design: Prospective randomized controlled study.

Methods: Patients with type 2 diabetes and nephropathy were randomly allocated to an intensive group (n = 47) or control group (n = 43). Treatment targets were the same for both groups, but the intensive group were seen as often as required to meet the targets; controls were seen at their normal clinics. The primary end-point was the rate of progression of renal disease in the second year.

Results: The groups were well matched at baseline. During follow-up, the intensive group had lower mean SBP, DBP and cholesterol. Median rate of progression of renal failure in the intensive group fell from 0.44 ml/min/month in the first year to 0.14 ml/min/month in the second year, compared to 0.49 ml/min/month and 0.53 ml/min/month in the control group (p = 0.04 for second year). Patients in the intensive group spent significantly less time in hospital.

Discussion: Intensive treatment slowed progression of renal disease within 2 years in patients with established diabetic nephropathy. Mean creatinine clearance at the start of the trial was 55 ml/min, so assuming that the rates of progression achieved at the end of the second year persisted, onset of dialysis would be delayed by 20 years in the intensive group compared with the control group.

Introduction

Diabetic nephropathy is now the leading cause of chronic renal failure requiring dialysis in the Western world.1,,2 The onset is characterized by albuminuria > 300 mg/day, hypertension, accelerated atherosclerosis and, in the untreated state, a relentless decline in glomerular filtration rate of about 1 ml/min/month.3 Patients are easily identified, and effective treatment can slow the rate of progression and delay the need for renal replacement therapy (RRT).4 Various guidelines and targets have been published, but audits have shown that implementation is imperfect even in specialized clinics, probably because the size of the problem overwhelms available facilities.5,,6 To determine whether changes in the provision of care for patients with diabetic nephropathy would result in improved outcome, we set up a 2-year multi-centre, prospective randomized controlled study comparing intensive medical management with routine clinical practice in patients with established diabetic nephropathy.

Methods

Patients with type 2 diabetes and nephropathy were recruited from five centres in the West of Scotland. The diagnosis of diabetic nephropathy was made in patients with albuminuria > 300 mg/24 h, characteristic diabetic retinopathy and kidneys with near-normal morphology on ultrasound examination. The study design was an open prospective randomized controlled trial comparing intensive medical management with standard care. Patients were allocated to one of two groups by random number allocation. Randomization was performed by a telephone call to an individual at the Scottish Renal Registry, who then used a prepared set of random numbers. The intensive group was seen as often as necessary by a project team (doctor, nurse and dietician). The control patients were seen at their usual clinic. The treatment goals were identical for both groups, and agreed by local diabetologists and nephrologists: SBP < 140 mmHg, DBP < 80 mmHg, HbA1c < 8%, sodium intake < 120 mmol/day, protein intake 0.7–1 g/kg of ideal body weight per day and cholesterol < 4 mmol/l or cholesterol:HDL cholesterol ratio < 4. Exercise was encouraged, and advice given on smoking. The intensive treatment was introduced in steps starting with blood pressure and cholesterol management followed by dietary intervention after 3 months. In the first few months, the patients were seen every 2–3 weeks until blood pressure came under control.

The primary end-point was the rate of progression of renal disease in the second year of follow-up. We chose not to include the change in the first year, as previous studies have shown that intensive treatment can cause an initial rapid fall in renal function, which is then followed by a prolonged period of slower progression.7 Patients who started dialysis were given an arbitrary creatinine clearance of 10 ml/min for calculating the mean creatinine clearance of the group at subsequent time points. The primary end-point excluded patients who started dialysis or died during the two years; thus a further analysis was made including these patients by using the rate calculated from the last four available measurements of serum creatinine, excluding those of the last admission. The power calculation was based on previously published data.8

The project was approved by local and multi-centre ethics committees, and written informed consent was obtained from all participants.

Patients were followed for 2 years and data were collected at 3 monthly intervals. Blood pressure was measured using an automatic digital blood pressure monitor after 5–10 min sitting at the clinic. HbA1c, urea and electrolytes and 24-h urine collections were obtained at 3-monthly intervals, and fasting cholesterol was measured at 0, 6, 12 and 24 months. Urinary albumin, urea and sodium excretion were measured using 24-h urine collections. The latter two were used to calculate the dietary protein and sodium intake, respectively. Urinary albumin:creatinine ratios (ACR) were also measured every three months. Information on smoking habits was obtained at interviews. New cardiovascular events and hospital admissions were recorded. Each patient was asked at their 3-monthly visit whether they had been in hospital, and hospital records were then analysed for exact dates. Inter-hospital analyses were not performed, because of the small number of patients from four of the five units (n = 4–6).

We calculated the rate of decline in renal function from linear regression of the slope of the plot of estimated creatinine clearance (ECC) vs. time, and expressed it as ml/min/month. The ECC was determined using the Cockcroft and Gault formula.9 We chose to use the ECC as opposed to the measured creatinine clearance as, although there are faults with the Cockcroft and Gault formula, it is an accurate measure of changes in renal function in an individual patient over time, because any distortion is consistent for that individual. Five measurements were obtained for each year (the creatinine at 12 months was included in both years).

Results of normally distributed data are shown as means and standard deviations (SD) and other data as medians and interquartile ranges (IQR). The rates of progression of the two study groups were expressed as medians and IQR, to reduce the effect of a small number of outliers in both groups. Intragroup comparisons were by Wilcoxon's paired signed-ranks tests. Intergroup comparisons were made by Student's t test for normally distributed variables and by Mann-Whitney U test for variables with a skewed distribution. χ2 tests were used to compare categorical variables. Comparisons between the number of days spent in hospital in the two groups were made by comparing the ratio of hospital days to total days expressed as a percentage. Analysis of data of the two groups was on an intention-to-treat basis. No patient was excluded because of unwillingness to adhere to the assigned treatments. All statistical analyses were done using SPSS for Windows, version 9.

Results

We identified 132 patients fulfilling the criteria of diabetic nephropathy, of whom 90 agreed to participate. The flow of patients in the study is shown in Figure 1. The mean (SD) age of the 90 patients was 63 (7) years, 57 (63%) were male and the median time from diagnosis of diabetes was 13 years (IQR 7–17). Mean (SD) ECC was 55 (17) ml/min, median 24-h albuminuria was 755 mg (IQR 392–2566) and ACR was 79 mg/mmol (IQR 38–243). Following randomization, the two groups were well matched at baseline (Table 1). There was no significant difference in gender between the two groups: 68% males in the intensive group vs. 58% in the control group. A clinical history of vascular disease was obtained in 66% of the intensive group and 72% of the control group. There were no differences in the number of smokers in the two groups (Table 2).

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Table 1

Comparison between intensive and control groups

ParameterBaseline24 monthsp for changeAbsolute changeMean over 24 months
Systolic BP (mmHg)
Intensive165 (25)143 (22)0.001−22 (27)147 (12)
Control165 (24)164 (27)*NS−1 (25)160 (18)*
Diastolic BP (mmHg)
Intensive88 (13)73 (9)0.001−15 (14)75 (6)
Control87 (11)82 (9)*0.004−5 (9)81 (9)*
HbA1c (%)
Intensive8.1 (1.7)8.1 (1.5)NS−0.05 (1.9)8.2 (1.4)
Control7.7 (1.5)7.9 (1.9)NS0.4 (1.7)8.1 (1.4)
Albumin:creatinine ratio (mg/mmol)
Intensive75 (44,154)69 (22,292)NS3 (−50, 46)67 (33,181)
Control83 (33,273)94 (37,285)NS22 (−45, 73)119 (44,220)**
Urinary sodium excretion (mmol/24 h)
Intensive188 (72)161 (62)0.02−27 (68)175 (53)
Control183 (75)178 (60)NS−4 (74)166 (53)
Estimated protein intake (g/kg ideal body weight/day)
Intensive1.24 (0.3)1.17 (0.4)NS−0.08 (0.3)1.2 (0.3)
Control1.14 (0.4)1.16 (0.3)NS−0.04 (0.2)1.1 (0.3)
Total cholesterol (mmol/l)
Intensive5.5 (1.1)4.2 (1.3)0.001−1.3 (1.0)4.4 (1.0)
Control5.6 (1.2)4.7 (1.0)**0.001−0.9 (1.0)5.1 (1.0)
Cholesterol:HDL ratio
Intensive5.4 (1.5)4.5 (1.7)0.001−0.9 (1.4)4.5 (1.2)
Control5.6 (2.0)5.0 (2.0)NS−0.4 (1.5)5.3 (1.6)**
BMI (kg/m2)
Intensive29.8 (5.2)31.2 (5.2)0.001
Control31.2 (4.8)31.9 (5.1)0.02
  • Data are means (SD), or medians (IQR). *p < 0.001 between intensive and control groups. **p < 0.05 between intensive and control groups. p < 0.01 between intensive and control groups.

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Table 2

Targets achieved and medication used at baseline and 24 months

Intensive groupControls
Baseline (n = 47)24 months (n = 39)Baseline (n = 43)24 months (n = 36)
Targets
SBP < 14013%41%14%23%
SBP < 15023%82%*33%34%
DBP < 8030%85%*30%46%
HbA1c < 8%60%56%63%57%
24-h sodium < 12021%26%28%15%
24-h sodium < 15032%53%47%40%
EPI (0.7–1 g/kg/day)30%26%26%31%
Chol or chol:HDL ratio < 421%68%**26%46%
Medications
ACE inhibitors or ARB79%95%77%83%
Lipid-lowering26%95%‡‡51%75%
Aspirin70%97%‡‡70%75%
Anti-hypertensive agents2 (0–5)3 (1–6)2 (0–5)3 (1–6)
Glucose-lowering methods
Diet alone8%8%7%11%
Oral hypoglycaemic agents43%36%35%33%
Insulin49%56%61%58%
Current smokers28%16%23%19%
  • Median (range). *p < 0.001 between intensive and control groups at 24 months. **p = 0.035 between intensive and control group at 24 months. p = 0.01 between intensive and control group at baseline. ‡‡p = 0.01 between intensive and control group at 24 months. SBP, systolic blood pressure; DBP, diastolic blood pressure; EPI, estimated protein intake; Chol, cholesterol; ARB, angiotensin II receptor antagonists.

Figure 1.

Trial profile. MI, myocardial infarction; CABG, coronary artery bypass grafting; PVD, peripheral vascular disease; CVA, cerebrovascular accident.

Outcomes

None of the 47 patients in the intensive group started dialysis, compared to three of the 43 controls, and four of the 42 who declined to join the study. Six patients in the intensive group and three in the control group died. The causes of death are shown in Figure 1. Four deaths in the intensive group and all deaths in the control group were caused by vascular disease. Five of the 42 who declined to take part in the study died, all as a consequence of vascular disease. Two patients withdrew from the intensive group and one from the control group.

Renal function

The mean ECC was 56 ml/min/month in the intensive group, and 54 ml/min/month in the controls at baseline. By 3 months, the mean ECC had fallen to 52 ml/min/month in the intensive group and was 53 ml/min/month in the controls. At 24 months, the ECC in the intensive group had fallen to 47 ml/min/month compared to 42 ml/min/month in the controls (Figure 2).

Figure 2.

Creatinine clearance at each visit. Data are means, whiskers show SEM. Figure includes patients until they died or withdrew from study. In the control group, the three patients who started dialysis were given an ECC of 10 ml/min from start of dialysis.

The primary end-point was the difference in rate of progression in year 2 between the two groups. The median rate of loss of renal function fell from 0.44 ml/min/month (0.92, −0.02) in the first year to 0.14 ml/min/month (0.55, −0.19) in the second year in the 39 patients who completed 2 years. The comparable results in the 36 controls were 0.49 ml/min/month (0.9, 0.12) in the first year and 0.53 ml/min/month (0.88, −0.05) in the second year. The difference in the rates of progression in the second year between the 2 groups was significant (p = 0.043).

This analysis excluded patients who either died or started dialysis. For these patients, the rates of change in renal function were calculated from the last four serum creatinines available, excluding those from the terminal illness. The median rate of progression of renal failure in the six patients who died in the intensive group was 0.07 ml/min/month (0.89, −0.16) vs. 0.97 ml/min/month (1.08, 0.60) in the six patients in the control group who either died (n = 3) or started dialysis (n = 3). When these patients were included, the median rate of progression of renal disease in the intensive group was unchanged at 0.14 ml/min/month, but increased to 0.65 ml/min/month in the control group (p = 0.02).

Changes in clinical data

Significant improvements were seen in SBP, DBP, cholesterol, cholesterol:HDL ratio and sodium intake in the intensive group over the 24 months of the study (Table 1). Significant improvements in BP were seen after 6 months of follow-up and were maintained for the rest of the study (Figure 3). In the control group, significant improvements occurred in DBP and cholesterol. The percentage change between baseline and 24 months was significantly greater in the intensive group for SBP (−12% vs. +0.6%, p = 0.001), DBP (−16% vs. −5%, p = 0.001) and cholesterol (−24% vs. −15%, p = 0.013). Although there was a significant reduction in sodium intake in the intensive group during the study, there was no significant difference between the two groups. The increase in ACR over the study was less in the intensive group but was not significant (Figure 4). No change was seen in glycaemic control, while body mass index increased in both groups during the 2-year study.

Figure 3.

Blood pressure at each visit. Data are means, whiskers show SEM. Figure includes patients until the start of dialysis or death.

Figure 4.

Albumin:creatinine ratio at each visit. Data are medians (whiskers show IQR). Dotted line, control group; solid line, intensive group. Figure includes patients until the start dialysis or death.

Medication

Table 2 highlights changes in medication. At baseline, significantly more patients in the control group were on lipid-lowering agents (p = 0.01), however, this was reversed at 24 months, when significantly more patients in the intensive group were treated with lipid-lowering agents (p = 0.01). The use of angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (ARB) and lipid-lowering agents increased in both groups, but more in the intensive group. By the last visit, only two patients in the intensive group were not on ACEI or ARB, both because of hyperkalaemia, compared to six in the control group. The median (range) number of anti-hypertensive agents used in both groups at the end of the study was 3 (1–6). However, full doses were used in a median of two anti-hypertensive drugs in the intensive group, compared to a median of only one in the control group. The use of aspirin at 24 months was significantly higher in the intensive group (p = 0.004). The median (range) number of drugs prescribed was 8 (4–14) in the intensive group and 7 (4–12) in the controls.

Targets

Table 2 highlights the percentage of patients achieving the predetermined targets. Significantly more patients in the intensive group met the DBP, the combined blood pressure of < 140/80 (p = 0.005) and cholesterol targets at 24 months. Six out of 12 smokers in the intensive group stopped smoking, compared to only one of the nine smokers in the control group. However, this was not statistically significant (p = 0.061). The other targets proved difficult to meet.

Number of visits and hospital admissions

The mean number of visits in the intensive group was eleven in year 1 and eight in year 2: the corresponding number of visits in the control group was the minimum required for the study: four in each year. Of the 87 patients who completed the study, 21 (47%) in the intensive group had 43 hospital admissions, while 26 patients (62%) in the control group had 69 hospital admissions (p = 0.05 for number of hospital admissions). The total number of days spent in hospital in the intensive group was 496, compared to 842 in the control group. In the control group, 2.75% of follow-up days were spent in hospital, compared with 1.51% for the intensive group. The relative risk for the intensive group was 0.55 (95%CI 0.49–0.61). Table 3 shows the number of new cardiovascular events during the two years. There were significantly fewer events in the intensive group compared to the control group (13 vs. 21, p = 0.038). More patients suffered an episode of congestive cardiac failure or underwent amputation in the control group, but numbers were small and the significance uncertain.

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Table 3

New cardiovascular events

Cardiovascular eventsIntensiveControl
Sudden death21
Fatal MI21
Fatal CVA01
Non-fatal MI13
CABG10
Non-fatal CVA34
Amputation or interventional vascular surgery25
Congestive cardiac failure26
No of events1321*
  • *p = 0.038. MI, myocardial infarction; CABG, coronary artery bypass grafting; CVA, cerebrovascular accident.

Discussion

The purpose of this study was to measure the benefit of intensive treatment compared to that routinely available on the rate of progression of renal failure in patients with type 2 diabetes and diabetic nephropathy. It is important to stress that the therapeutic targets were the same in both groups. The results show that intensive supervision can indeed slow progression of renal disease within 2 years in patients with established diabetic nephropathy. This would lead to substantial delays in the need for dialysis. Assuming that the rates achieved at the end of the second year persisted (and there is good reason to think this might be so3), and given that the mean creatinine clearance of patients at the start of the trial was 55 ml/min, the average time to starting dialysis would be 27 years in the intensive group and 7 years in the control group. There was also a 45% reduction in number of days spent in hospital in the intensive group. These results would have considerable benefits for the patients and cost savings for the health service. Therefore, the main conclusion is that present services for the treatment of diabetic nephropathy are inadequate and need to be re-designed.

The reduction in the rates of progression of renal failure achieved in our intensive group is similar to that in other small intensively managed groups. We have expressed results as medians and interquartile ranges to reduce the effect of a small number of outliers. For comparison with other studies that calculated the mean rate, the mean rate of loss of function in the second year was 0.21 ml/min/month for the 45 patients in the intensive group and 0.57 ml/min/month in the 42 controls (p = 0.02). The first and most impressive results were reported in a small number of patients with type 1 diabetes, in whom the rate of progression was slowed from 1 ml/min/month to 0.1 ml/min/month, although this took some years to achieve with the use of diuretics, β-blockers and hydralazine.3 Small short-term trials comparing ACEI, diltiazem and atenolol in patients with type 2 diabetes and nephropathy reported a similar reduction in the rates of progression in the those patients treated with ACEI or diltiazem.10,,11 In contrast, the results reported in larger multi-centre trials have not been as good in either type 1 or type 2 diabetes, although the advantage of blockade of the renin-angiotensin pathway was demonstrated in both.10,,12 In two recent multicentre trials of ARB in patients with diabetic nephropathy and type 2 diabetes, the rate of progression of renal failure was reduced only to 0.37 and 0.46 ml/min/month in the ARB-treated groups.13,,14 In an audit of our clinical practice at a combined diabetic-renal clinic, the rate of progression of renal failure was reduced from 0.5 ml/min/month in the first year to 0.27 ml/min/month in the third year, but only in a small group of patients who were referred early.5 Therefore, it is comparatively easy to halve the rate of loss of renal function, but halving it again requires different organization of the service. The loss of renal function in the first few months of the study in the intensive group is likely to be the result of haemodynamic changes in the kidney associated with reduction in blood pressure. This has already been described in other studies including the large MDRD trial.7 Two years is a relatively short follow up time, but we have shown that intensive management lead to a slower rate of progression in the second year compared to routine care. It is hoped and expected that this benefit will persist with time. Others have shown that once the rate of progression has slowed, it is maintained over several years.15

Continuation of standard treatment offered by routine service, not surprisingly, made little impact on the rate of progression. Since the targets of treatment were identical in the two groups, the method of delivering care must have caused the difference. The obvious explanations for the difference in results between the intensive and control groups are intensity of supervision, frequency and number of corrections made to treatment and/or increased compliance. Targets were more likely to be met in the intensive group and the use of aspirin and lipid-lowering agents were significantly higher at 24 months in the intensive group. However, the median number of visits in the intensive group was 19, compared to eight in the control group. The number of visits in the control group exceeds routine clinical practice, as visits were required to collect our minimum data set.

Reductions in both systolic and diastolic blood pressure were greater in the intensive group. The final BP in the intensive group was similar to that reported in the two ARB trials, in which the BP of the treated groups fell to140/74 with losartan13 and 140/77 with irbesartan,14 compared to 143/73 in the intensive group in our trial. The specific benefit of ACEI and ARB has been appreciated, as almost 80% were on these drugs at randomization. At the end of the study, 95% of the intensive group and 83% of the control group were on ACEI or ARB. The median number of anti-hypertensive drugs at the final visit was the same in both groups, but the intensive group were more likely to be on maximal doses of drugs and may also have been more compliant. Compliance is a problem for patients receiving so many drugs (a median number of 8 in the intensive group and 7 in the control group): time spent at each visit in the intensive group reiterating the importance of each medication may have improved compliance. This is not an unique finding, as others have shown that more frequent clinic visits slow progression in other forms of renal failure.16 It is also possible that treatment was increased to an effective level more quickly in the intensive group, leading to an earlier response. A combination of these factors may explain the difference in response to treatment.

Dietary and lifestyle targets were difficult to meet. A significant reduction in the sodium intake of the intensive group occurred over the 24 months of the study, but it was modest, and there was no difference between the two groups either at the beginning or at the end of the study. The use of diuretics may be an easier option.17 Body mass index increased significantly in both groups. More smokers gave up in the intensive group, but we were unable to demonstrate an effect of smoking on rates of progression as others have done.18 Cholesterol was reduced significantly in both groups, but the reduction was greater in the intensive group, and more patients in the intensive group met the target. Cholesterol and protein intake have been identified as factors affecting the rate of progression of renal failure in both diabetic and non-diabetic patients.19–,21 There was little impact on glycaemic control in either group with the HbA1c being relatively stable throughout the 2 years. Attempts to improve control by the introduction of insulin made little difference to the HbA1c, but led to marked increases in weight. The UKPDS clearly showed a progressive increase in HbA1c with time, and our results were similar to those achieved in the UKPDS after 10 years of follow-up.22

There are now a multitude of guidelines for the management of diabetic nephropathy, with a wide variation in their recommendations from a BP < 140/90 by the Scottish Intercollegiate Guidelines Network23 (later reduced to 140/8024) and 125/75 mmHg in patients with more than 1 g/day of proteinuria by the Joint National Committee (JNC VI).25 Clinical experience suggests that the diastolic pressure is relatively easy to reduce, but that the systolic target is difficult. At the end of the study, only 5/36 patients in the control group met the BP target < 140/80, compared to 17/39 patients in the intensive group. A target of 125/75 may be impossible to achieve, because the treatment required may induce postural hypotension in elderly patients, causing loss of mobility and confidence, which they find unacceptable even after full explanations have been given. Our results imply that these lower targets may be unnecessarily low.

Diabetic nephropathy is associated with accelerated vascular disease. This study was not powered to detect differences in mortality or cardiovascular events, but the number of cardiovascular deaths was similar in both groups (four in the intensive group, three in the controls). More encouragingly, the patients in the intensive group had fewer cardiovascular events and spent significantly fewer days in hospital. Intensive management in the Steno-2 study of patients with type 2 diabetes and microalbuminuria showed an absolute reduction of 20% in cardiovascular events after a mean follow up of 7.8 years.26 However, the study also failed to show a difference in deaths resulting from cardiovascular disease: 15/80 in the conventional group and 12/80 in the intensive group, died with seven deaths in each group related to cardiovascular disease. In a retrospective observational study of patients attending a combined diabetic-renal clinic in our unit, the annual mortality rate in patients with type 2 diabetes and established nephropathy was 10% per year.27 In our prospective study, 10% of our patients died within two years. This mortality rate is similar to that seen in the RENAAL and IDNT studies.

In conclusion, this study has shown that intensive medical management can slow the rate of progression of renal disease in established diabetic nephropathy within 2 years, and is associated with fewer days spent in hospital. The delay in onset of renal replacement therapy and fewer admissions will have cost savings for the National Health Service. We believe that the benefit achieved in this study was by more frequent reviews, which led to a quicker deployment of appropriate treatment and increased compliance by the patient. The present system relies on a doctor-led service with some input from a dietician. Appointments are typically 3 or more months apart. There are simply not enough doctors to provide the required level of care in ordinary practice, given the large number of patients with diabetic nephropathy. The proposed transfer of diabetic patients to primary care institutions is unlikely to help, because each practice is unlikely to have a sufficient number of patients to develop the necessary infrastructure. A better solution may be to have a hospital-based nurse-led service in which the patients are seen as often as necessary to achieve the targets as quickly as possible, using protocols developed for the purpose and nurses trained in their implementation.

Acknowledgments

We wish to thank Drs N. Peden, J. Doig, R. O’Brien, A. Gallagher, D. Rooney, C. Kesson, H. McLaren and D. Gordon, and research nurse Lucy Cumming, for their help with this study. We also wish to thank the Glasgow Royal Infirmary Renal and Diabetic Units’ funds and Glasgow Royal Infirmary endowment fund.

References

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