Q J Med 2002; 95: 41-49
© 2002 Association of Physicians
Diabetic nephropathy: how effective is treatment in clinical practice?
From the Renal Unit and 1 Diabetic Unit, Glasgow Royal Infirmary, Glasgow, UK
Received 7 August 2001 and in revised form 26 October 2001
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Summary |
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Background: Diabetic nephropathy is the most common cause of end-stage renal failure in patients starting dialysis in the developed world. In clinical trials, interventions, particularly blood pressure control, have achieved major reductions in the rate of decline in renal function.
Aim: To investigate whether results from clinical trials can be achieved in routine clinical practice.
Design: Observational study of 170 consecutive patients referred to a combined diabetic-renal clinic over a 10 year period.
Methods: We collected demographic and laboratory data from the electronic patient record.
Results: Median serum creatinine at referral was 170 µmol/l and was >350 µmol/l in 26% of patients. Mean blood pressure (BP) was 159/85. The publication of guidelines by the Scottish Intercollegiate Guidelines Network in 1997, recommending more active intervention and earlier referral, had no impact on referral BP and creatinine. In the 125 patients with at least 1 year follow-up, significant improvements in BP, albuminuria, HbA1c and serum cholesterol were seen. In the 63 patients followed up for 3 years (median creatinine 120 µmol/l), the median rate of decline in renal function slowed from 0.52 ml/min/month (first year) to 0.27 ml/min/month (third year) (p=0.003), nearly doubling the time to end-stage renal failure.
Discussion: Patients referred early to a combined diabetic-renal clinic benefited by slowing in the rate of decline of renal function. A challenging but achievable standard for audit would be to reduce the rate of progression to <0.25 ml/min/month in 70% of patients with diabetic nephropathy presenting with a serum creatinine <150 µmol/l.
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Introduction |
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Diabetic nephropathy has major health, social and economic consequences. It affects about one third of patients with type 1 and type 2 diabetes,1,2 and it is highly probable that the aetiology and response to treatment is the same in both types of diabetes. The number of patients with diabetes on renal replacement programmes is increasing. Patients with diabetes now account for 40% of patients starting dialysis in the USA and in parts of Germany;3,4 in Scotland the figure is nearer 18%.5 The onset of diabetic nephropathy is associated with the development of hypertension, an increase in vascular disease and, in the untreated state, a relentless decline in glomerular filtration rate (GFR), with a median decline of 1 ml/min/month.6,7 Factors which have been shown to correlate with the rate of decline in renal function include blood pressure, urinary albumin excretion, cholesterol, glycaemic control, dietary protein intake, smoking and certain genotypes. These have been recently reviewed comprehensively in patients with type 1 and type 2 diabetes.8,9 Clinical trials have clearly established that control of blood pressure reduces the rate of progression of diabetic nephropathy.10–12 Whether the results from these clinical trials can be achieved in routine clinical practice remains to be established. Guidelines have been published in an attempt to improve outcomes for these patients; in particular the Scottish Intercollegiate Guidelines Network (SIGN) published guidelines on the management of diabetic nephropathy in March 1997.13
Combined diabetic-renal clinics have been set up with the following aims: to identify non-diabetic renal disease; to slow the rate of progression of diabetic nephropathy; to improve the cardiovascular risk factor profile; to treat renal and diabetic complications; and to prepare patients for dialysis. Additionally, they improve communication between diabetologists and nephrologists. Our unit has run a combined diabetic-renal clinic since 1989. All patients referred to the clinic had previously been under regular review at one of six diabetic units. In an earlier study from our unit, data on 63 patients showed that end-stage renal failure was delayed by an average of 2 years,14 a relatively modest result compared to the benefits reported in trials. We have now performed a further retrospective study analysing: (i) the stage of renal disease at referral; (ii) the impact of the SIGN guidelines on patient status at referral; (iii) the effect of therapies on potential promoters of renal disease progression; (iv) the effect of management at the combined clinic on the rate of progression of renal disease; and (v) whether the results have improved with time.
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Methods |
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All patients with a diagnosis of diabetic nephropathy were identified. The diagnosis of diabetic nephropathy was made according to previously published criteria.14 Electronic patient records15 were examined and demographic data at referral to a combined diabetic-renal clinic along with serum creatinine, HbA1c (reference range 3.4–5.2%), haemoglobin, parathyroid hormone (PTH, reference range 1.3–7.6 pmol/l), serum bicarbonate, cholesterol, urinary albumin:creatinine ratio (uAlb:Cr) and blood pressure were collected. Blood pressure was measured with an automatic digital blood pressure monitor after 5–10 min sitting at the clinic. Untreated secondary hyperparathyroidism was diagnosed if the concentration of PTH was >21 pmol/l. The estimated creatinine clearance (ECC) was calculated using the Cockcroft and Gault formula.16 The rate of progression of renal failure was calculated using linear regression from the slope of the plot of ECC vs. time and is expressed in ml/min/month (
ECC). At least four measurements over a minimum of 6 months were required. The rate of decline in renal failure was calculated separately for each of the first 3 years of follow-up. Medications at first visit and at last visit were noted, as were the end-points of death or dialysis. No patient was transplanted before dialysis. Four patients were lost to follow-up before reaching an end-point, data were collected on these four patients at their last clinic visit. Data on smoking habit were incomplete and were only analysed in the 63 patients followed-up for at least 3 years. Blood pressure, HbA1c and uAlb:Cr at the start of years 1, 2, 3 and the last recorded visit were documented. Cholesterol concentrations at referral, start of third year and last recorded visit were noted.
Results are shown as means and standard deviations or as medians and interquartile ranges. Intergroup comparisons were made by Student t test for normally distributed variables and by Mann–Whitney U test for variables with a skewed distribution. 
2 tests were used to compare categories. Linear regression analysis, initially univariate and then multivariate, was used to assess correlations between rate of progression and different parameters. All statistical analyses were carried out using SPSS for Windows version 9.
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Results |
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Renal disease at presentation
We identified 170 patients with diabetic nephropathy. Their characteristics at presentation are shown in Table 1
. Their median creatinine at referral was 170 µmol/l: 44.6% presented with a serum creatinine >200 µmol/l and 26.5% with >350 µmol/l. The median uAlb:Cr ratio was 272 mg/mmol, which is equivalent to a 24-h urinary albumin excretion of about 3 g. Mean blood pressure at referral was 159/85, and the median number of anti-hypertensive drugs used, including diuretics, was 1 (range 0–3). At referral, 46% of patients were on ACE inhibitors, 7% on ß-blockers, 36% on calcium-channel blockers and 36.5% on diuretics. Treatment of diabetes was by diet alone in 24%, oral medication in 19% and insulin in 57%. Aspirin was prescribed in 49% of patients and lipid-lowering agents in 15%, despite 68% of patients having a history of vascular disease.
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SIGN guidelines recommend that blood pressure should be maintained below 140/90, preferably with the use of an ACE inhibitor. Referral to a renal unit is suggested when the serum creatinine reaches 200 µmol/l. Figure 1
shows the percentage of patients who did not meet these targets, before and after publication of the SIGN guidelines.
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Effects of interventions targeting promoters of progression of renal disease
Factors thought to influence the rate of progression of renal failure were studied in the group of patients followed up at the clinic for more than 1 year. This excluded 45 patients followed up for <1 year who had advanced renal disease at presentation, (median serum creatinine 450 µmol/l) were more anaemic (mean haemoglobin at referral 9.8 g/dl) and had a higher incidence of untreated hyperparathyroidism (Table 1
). The median (95%CI) time to death or dialysis of this group was 5.06 months (1.77–8.35). Thirty-nine patients commenced dialysis, while six patients died before reaching end-stage renal failure. These 45 patients have not been analysed further.
The median follow-up of the remaining 125 patients was 36 months. Significant improvements were achieved in BP, HbA1c, cholesterol and albuminuria, with absolute reductions in SBP of 10 mmHg, DBP of 11 mmHg, HbA1c of 0.6%, cholesterol of 1.4 mmol/l and uAlb:Cr ratio of 66 mg/mmol (Table 2). At the last recorded visit, only 12.5% of patients did not meet the SIGN guideline target of a DBP <90 mmHg, but 67.5% did not meet the SBP target.
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The changes in medication required to achieve these improvements included an increase in the use of ACE inhibitors from 51% to 80%, with a further 6% commenced on an angiotensin II receptor antagonist. Only 3% discontinued ACE inhibitors because of hyperkalaemia. The use of other anti-hypertensive agents increased, from a median of 1 to 3 (range 0–6); ß-blockers were prescribed in 19%, calcium-channel blockers in 64%,
-blockers in 31% and diuretics in 84%. The use of statins increased from 15% to 50%, with a heavy bias towards patients treated in the later years. The majority of changes in the treatment of glycaemia involved dosage adjustment of existing medication.
Patients who presented before 1995 (n=67) and those who presented from 1995 onwards (n=58) were compared (Table 3). There were no differences in age, sex, type of diabetes, presenting SBP, DBP, uAlb:Cr ratio, cholesterol or glycaemic control. Serum creatinine was significantly higher in the earlier period, with a median value of 170 µmol/l compared to 121 µmol/l in the later period. (Including late referrals, 85 patients presented before 1995, the median serum creatinine was 199 µmol/l compared to 150 µmol/l in the 85 patients referred from 1995 onwards, this difference was not significant.) There were reductions in BP, HbA1c and cholesterol in both periods, with a tendency for the reductions to be greater in the second period (1995–1999), but these were not significant. Similarly, the reduction in uAlb:Cr ratio was greater in the second period, with a mean absolute reduction of 101 mg/mmol compared to 33 mg/mmol, but again this did not reach significance.
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Progression of renal disease
We attempted to define which factors correlated best with rate of progression in the 125 patients with at least 1 year of follow-up. The factors analysed included: SBP, DBP, HbA1c, cholesterol, uAlb:Cr ratio at the start and end of follow-up, age, sex and type of diabetes. Univariate analysis identified a higher presenting uAlb:Cr ratio (p=0.001, r2=11%), age (p=0.01, r2=4%) and a higher final cholesterol (p=0.002, r2=8%) to be associated with faster progression of renal disease. Presenting cholesterol and type of diabetes did not correlate with rate of progression. The factors which were significant on univariate analysis were entered into a multivariate model, and this confirmed age (p=0.03, r2=5%), presenting uAlb:Cr ratio (p=0.001, r2=12.6%) and final cholesterol (p=0.04, r2=4%) to be independent predictors of a faster rate of progression of renal disease.
Of the 125 patients, 102 had sufficient data on albuminuria for a more detailed analysis. To determine the influence of a reduction in albuminuria on the rate of progression of renal disease the patients were divided into four groups (Table 4). The definition of a reduction was for the uAlb:Cr to be reduced for at least 6 months. The patients who had a >50% reduction in albuminuria for at least 6 months reduced their rate of decline in renal function from 0.64 ml/min/month to 0.17 ml/min/month.
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Of the 125 patients followed-up for more than 1 year, data from 63 patients were available for a period of at least 3 years. Of the remaining 62 patients for whom we have follow-up data for periods up to 3 years, 32 patients reached an endpoint (either death or dialysis), while 30 patients remained alive and independent of dialysis. The renal function at referral and rate of decline in renal function in the first year for each group are shown in Figure 2
. The patients who reached an endpoint had significantly more advanced renal disease but there was no significant difference in the rate of progression of renal disease in the first year between the three groups of patients.
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Of the 63 patients followed up for 3 years, data were available to calculate the decline in renal function annually in 55 patients. The median rate of progression decreased significantly between the first and third year (Table 5
). The rate of progression fell in 35 patients (slow progressors) while the rate remained unchanged or increased in 20 patients (fast progressors). There were no differences in age, sex or type of diabetes between the slow progressors and fast progressors. There were no statistically significant differences in presenting BP, HbA1c, cholesterol, albuminuria, creatinine and smoking habit between the two groups. The slow progressors had a tendency to have a greater reduction in SBP and uAlb:Cr ratio than the fast progressors, but it did not reach statistical significance (Table 6).
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The patients who presented from 1995 onwards had a more dramatic reduction in their rate of progression of renal disease from 0.68 ml/min/month (0.18–1.2) in the first year, to 0.18 ml/min/month (0.007–0.63) in the third year (Table 5
). Again no difference was seen in any baseline parameter, but the reduction in uAlb:Cr ratio was significantly greater in the second time period (Table 7).
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Discussion |
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In this observational study, 26% of patients were referred to our combined clinic with advanced renal disease. Publication of guidelines has not yet altered this referral practice. Patients followed up for more than 1 year had significant improvements in factors thought to affect progression of renal disease. The rate of progression of renal disease was slowed significantly in a sub-group of patients referred early to a routine service; this effect may take up to 3 years to develop. Finally, patients who were referred in the second half of the study period had a significantly greater reduction in the rate of progression of renal failure.
Diabetic nephropathy is the commonest diagnosed cause of end-stage chronic renal failure, and in small trials of intensively studied patients, the rate of progression to end-stage renal failure has been slowed from 1 ml/min/month to 0.1 ml/min/month.10 Thus, an untreated patient may progress from a creatinine clearance of 50 ml/min to becoming dialysis-dependent in 4 years, whereas the best results so far reported could extend this period to 40 years. This means that end-stage renal failure is potentially preventable. There have been no reports of clinics achieving this degree of success in ordinary practice. In the first large trial in patients with type 1 diabetes,17 the rate of loss of renal function was described as ‘astonishingly bad’.18 In a large multicentre trial of patients with type 2 diabetes and nephropathy, the rate of progression of renal failure was 0.45 ml/min/month in the irbesartan-treated group, 0.57 ml/min/month in the amlodipine-treated group and 0.54 ml/min/month in the placebo group.19 There is thus a large gulf between clinical practice and large multicentre trials, and the results achieved in small intensively studied groups. In a previous study, we reported delaying dialysis by only 2 years.14 The Bristol group was able to slow the rate of progression in only 39% of their patients.20
In this report, we used change in ECC with time as a measure of renal deterioration. We accept that this is not the most accurate way of monitoring changes in renal function, but it is sufficient for retrospective audit of progress of individual patients. We selected a group of 55 patients who were referred relatively early, were followed up for at least 3 years and had sufficient data to make the calculations. Their median rate of loss of renal function of 0.52 ml/min/month in the first year was almost halved to 0.27 ml/min/month in the third year. The rate in the first year reflects treatment given before referral. Assuming the untreated decline in renal function was 1 ml/min/month, this would equate to an extension of renal survival, starting with a creatinine clearance of 50 ml/min/year, from 4 years (in the untreated state) to nearly 15 years. The extension achieved in our clinic was from 8 years to nearly 15 years.
All the patients had attended diabetic clinics before referral, but significant improvements were made in BP, glycaemic control, cholesterol and albuminuria during attendance at the combined diabetic-renal clinic. This was achieved by setting targets and performing regular audits. However, 20 of the 55 patients (36%) failed to show a response. Sawicki et al. showed that it was possible to improve or stabilize GFR in 62% of patients with type 1 diabetes with intensified treatment (blood pressure and glycaemic control) over a two-year period.21 This is the same ratio of success that we had in this selected group of patients with both types of diabetes. We were unable to find a measure that could explain the difference between the fast and slow progressors. There were similar reductions in BP, cholesterol and HbA1c in both groups, and although the absolute reduction in urinary albumin excretion was greater in the slow progressors, it was not significant. This experience has been reported previously.20 The most likely explanation is that genetic differences such as the ACE DD genotype affect the renoprotective effect of ACE inhibitors.22
The selection of patients followed up for 3 years or more introduces an obvious bias, because these patients may over-represent patients who respond to treatment. This is difficult to refute, and it is clear that the group of 55 represents those with less severe renal failure at referral. Forty-five patients were followed up for <1 year and they had advanced renal failure with a median creatinine of 490 µmol/l. Of the 125 patients followed up for >1 year, 32 reached an end-point within 3 years, and 30 others had been followed-up for between 1 and 3 years. The starting serum creatinines of these two groups were significantly higher, but the rate of loss of renal function in the first year was not different to that of the study group (Figure 2). We found that the rate of progression had not slowed in the second year and only occurred in the third year. Similarly, Parving et al. reported in a small group of patients with type 1 diabetes that the median rate of loss of GFR slowed from 0.94 ml/min/month to 0.29 ml/min/month in the first 3 years and to 0.10 ml/min/month in the second three years.10 Therefore, both the proportion of patients whose progression of renal disease slowed and the reduction in the rate of progression achieved at the end of 3 years in our patients are very similar to results described in small experimental groups of patients with type 1 diabetes.
The advantages of early referral were also apparent when we compared the results achieved in the 125 patients followed up for at least 1 year and divided them into those referred during the first half of the clinic's operation with those in the second half. All results were very similar (Table 3) except that the serum creatinine at referral was significantly lower in the later group and the reduction in the rate of progression was significantly greater.
Attempts have been made to encourage early referral. The SIGN guidelines were published in 1997 and specifically recommended that patients should be referred to a nephrologist before the creatinine reached 200 µmol/l. This has not yet had an impact on our practice. Forty seven percent of patients reached end-stage renal failure, 13% within 6 months. These figures are similar to those found in Bristol, where 33% of patients were referred with a serum creatinine >350 µmol/l and 16% of patients started dialysis within 6 months.23 Therefore our results are likely to reflect British practice. Others have shown that late referral to a renal unit, whatever the cause of renal failure, is also detrimental because of increased early morbidity, prolonged hospital admissions and increased early mortality on dialysis.24
The rate of progression of renal failure has been found to correlate with blood pressure, urinary albumin excretion, cholesterol, smoking habits and glycaemic control.8,9 There is good evidence that control of blood pressure slows the rate of progression and that this is most effectively achieved with ACE inhibitors, which reduce proteinuria more than other anti-hypertensives for a given drop in blood pressure.17 Two recently published studies have shown angiotensin II receptor antagonists in patients with type 2 diabetes and nephropathy are effective to a similar degree.19,25 There is some inconclusive evidence that reduction of serum cholesterol may reduce proteinuria and even rate of progression.26–28 There is good evidence that reduction in proteinuria is the best guide to response to treatment in diabetic patients.29 The 125 patients followed for >1 year had significant improvements in all these measures (Table 2). The value of change in albuminuria was also confirmed. Patients with a >50% reduction in uAlb:Cr ratio maintained over 6 months reduced the rate of progression to 0.17 ml/min/month compared to 0.58 ml/min/month in those in whom the ratio increased (Table 4).
Blood pressure at referral was under-treated, with a mean BP of 159/85, and the median number of anti-hypertensives used was 1. The SIGN guidelines suggested a BP target of <140/90: unfortunately, this had no effect on the percentage of patients meeting the target, with over 80% presenting with a SBP >140 mmHg after publication (Figure 1). SBP proved to be a very exacting target which was achieved in only 32.5% of 125 patients followed up for >1 year. DBP both at referral and at the end of follow-up was better controlled. The median number of anti-hypertensive drugs used increased from 1 to 3, which is similar to the number of anti-hypertensive agents required in the UKPDS to achieve tight control of blood pressure in patients without major renal involvement.30 There are several reasons to explain poor control of SBP: firstly, blood pressure in a significant number of patients with diabetic nephropathy is sodium-sensitive, and perhaps we are not targeting this aspect of treatment.31 The diabetic-renal clinic ran for 2 h every month: we therefore have limits on the number of return visits in a year. Thirdly, patient compliance may be important. The median number of preparations patients were prescribed was eight, with a range of 3–15. Finally, diabetic patients have decreased vascular compliance, resulting in a tendency to systolic hypertension. This may represent an important failure, since the UKPDS showed that for each 10 mmHg reduction in SBP there was a 15% reduction in diabetes-related death.32
Glycaemic control improved modestly but significantly. The more dramatic improvement in cholesterol levels was a consequence of an increased use of statins. The extent of urinary albumin loss at referral was a valid guide to renal prognosis, and the only indicators of response at the end of treatment were the reduction in urinary albumin excretion and the serum cholesterol. The indicative value of the final serum cholesterol was independent of albuminuria. Age was also an independent predictor of a faster rate of progression, whereas type of diabetes was not.
The organization of a diabetic-renal clinic is clearly not essential for achieving targets. The main reason for the comparative success described is that the culture of renal and diabetic clinics is different. Diabetic clinics have a huge throughput, making it difficult to review patients more than twice a year, which makes it near-impossible to institute intensive management of these patients. Combined diabetic-renal clinics have a smaller number of patients who can be reviewed more frequently, and the patients are offered intensive therapy. In addition to the benefit for the patient in delaying dialysis, there are implications for resource allocation. The cost of hospital haemodialysis is more than £20 000 per patient per year. It is likely that delaying the need for dialysis by 5–10 years will generate considerable savings which could be used to staff clinics designed to protect renal function. However, the balance is difficult to calculate, because the effect of intensive treatment on macrovascular disease and patient survival is unknown. At present, 10% of the patients attending the clinic die each year but, even if this were reduced to 5% per year, significant long-term savings would be achieved. Therefore, these combined clinics should be cost-effective even if they require additional staff.
This study shows that results have improved with time, that early referral to a clinic concentrating on the preservation of renal function has advantages and that the earlier the referral, the greater the advantage because it may take some years to obtain the maximum effect of treatment. Even among those referred early, about a third showed no improvement despite equivalent control of BP, cholesterol and glycaemia. A challenging audit target would be to reduce rate of loss of renal function to <0.25 ml/min/month in 70% of patients with diabetic nephropathy and presenting with a serum creatinine of <150 µmol/l.
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Acknowledgments |
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We would like to thank the nursing, administrative, secretarial and laboratory staff for their contribution to the maintenance of our electronic patient record, without which this project would have been impossible.
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Notes |
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Address correspondence to Dr N. Joss, Renal Unit, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF. e-mail: njoss{at}compuserve.com
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References |
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