Q J Med 1999; 92: 275-282
© 1999 Association of Physicians
Can intensive treatment alter the progress of established diabetic nephropathy to end-stage renal failure?
From The Richard Bright Renal Unit, Southmead Hospital, Bristol, UK
Received 18 December 1998 and in revised form 8 March 1999
Professor T.G. Feest, Richard Bright Renal Unit, Southmead Hospital, Southmead Road, Bristol BS10 5NB
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Summary |
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Diabetic nephropathy is now the leading cause of end-stage renal disease in the Western world, and is associated with a higher patient morbidity and mortality than other causes of renal failure, largely because of associated cardiovascular disease. Numerous studies have elucidated the factors which influence its onset and progression. The St Vincent Declaration in 1994 proposed standards for the appropriate management of patients with diabetic nephropathy. We assessed whether referral to a nephrology clinic attempting to apply these standards influenced the progression of diabetic nephropathy. The results show a significant improvement in blood pressure, glycosylated haemoglobin and serum cholesterol following referral. There was a significant reduction in the rate of decline of renal function following referral in 39% of patients. With the possible exception of diabetic control there were no significant differences in the management of those that did and did not show improvement. The results show that with intensive out-patient clinic monitoring it is possible to improve the quality of patient care, and that even in established diabetic nephropathy it is possible to slow the rate of progression to end-stage renal failure.
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Introduction |
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Diabetic nephropathy is now the leading cause of end-stage renal disease in patients entering renal replacement programmes in the Western world.1–4 One aim of the WHO St Vincent Declaration is to reduce the incidence of renal failure from diabetic nephropathy by 30%.5 To help achieve this aim, it proposed standards for the management of patients with established diabetic nephropathy, including vigorous treatment of hypertension (defined as >140/90 mmHg in patients aged <60 years, and >160/90 in patients aged >60 years), dietary protein restriction, use of angiotensin-converting enzyme (ACE) inhibitors unless contraindicated, and referral to a nephrologist when serum creatinine exceeds 200 µmol/l.
The development of clinical nephropathy has a significant impact on patient morbidity and mortality. In insulin-dependent diabetics with overt diabetic nephropathy, the excess mortality is 70–100 times that of an otherwise matched normal population.6,7 Much of this is due to an excess of cardiovascular mortality, which is 320 times higher in young diabetics on renal replacement therapy compared with a normal population.8 For patients on renal replacement therapy, hospitalization rates for diabetics are 2–3 times those of other patients,3 and 5-year survival figures are lower (28% vs. 37% for non-diabetics in America, and 28% vs. 61% for non-diabetics in Italy1,3.
This is a study of interventions intended to slow or halt the development of diabetic nephropathy. They inevitably also have the potential to increase the quality and duration of patient's lives, and to reduce health care costs. Primary prevention of diabetic nephropathy is the ultimate aim, and interventions that may help to achieve this have been reported.9,10 Once overt diabetic nephropathy is established, it is more difficult to slow the progression towards end-stage renal failure. Genetic factors may be important in the development and progression of diabetic nephropathy,11,12 and the degree of proteinuria and increasing age at diagnosis13,14 are associated with progression to end stage renal failure. Nevertheless, there is some evidence that the natural history of diabetic nephropathy can be altered by some therapeutic interventions. Those for which there is most evidence are: effective blood pressure control;15–18 use of angiotensin-converting enzyme (ACE) inhibitors;19 and non-dihydropyridine calcium channel blockers;20 dietary protein restriction;21–23 and treatment of dyslipidaemia.24,25 Smoking is associated with the development and progression of nephropathy.13,26 The role of good glycaemic control once nephropathy is established is less clear, but it is probably beneficial.9,10,27
This study was undertaken to determine whether referral to a nephrology clinic, where the proposed standards of the St Vincent Declaration and the interventions stated above were applied, slowed the progression of established diabetic nephropathy.
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Methods |
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The initial patient cohort comprised 152 consecutive referrals with diabetic nephropathy to a single nephrologist during a six-year period (1991–1997), from a catchment population of 1.5 million. Patients were excluded from this study if they required renal replacement therapy or died within 6 months of referral (26 patients), if they were referred within the six-month period prior to collation of the data (18 patients), or if there were insufficient data to determine the rate of decline of renal function prior to referral (32 patients). Therefore data were subsequently analysed from 76 patients.
The diagnosis of diabetic nephropathy was made on clinical grounds (significant albuminuria >300 mg/24 h, or a random urine albumin : creatinine ratio>20 mg/µmol, diabetic retinopathy, and a renal ultrasound scan showing near-equal-sized unscarred kidneys). In 22 patients where there had been doubt as to the diagnosis, diabetic nephropathy was confirmed by renal biopsy.
Patients were followed at varying time intervals according to their clinical need. Clinics were held in two hospitals. The end point of the study was defined as the initiation of renal replacement therapy, renal transplantation, or death, whichever was the soonest.
At referral, patient assessment included prescribed medication, smoking history, serum creatinine, blood pressure, serum cholesterol, and glycosylated haemoglobin. All data were entered into computerized case records. The initial blood pressure measurement recorded was that measured at the second visit to the renal clinic, in order to avoid the effects of anxiety associated with the initial visit.
Following referral all patients received specialist dietetic advice, and were assessed by a renal dietician at regular intervals. They received appropriate individualized advice in order to optimize their intake of protein (0.8–1.0 g/kg body weight/day) fat and minerals, to improve diabetic control, control biochemical variables (especially serum potassium and cholesterol), and to prevent malnutrition.
Serial measurements of blood pressure, serum creatinine, serum cholesterol, and glycosylated haemoglobin were recorded at each out-patient visit. These variables were then analysed at intervals of 6 months from referral, to determine whether any changes were evident. Any changes in drug therapy were also recorded. The rate of progression of renal failure was assessed by measuring the slope of the reciprocal of serum creatinine against time prior to, and following, referral to the nephrology clinic.
The serum HbA1c assays were performed in two separate laboratories. One laboratory used the customized HPLC system Biomen HAH140 assay throughout the study period. The second laboratory used an in-house HPLC system assay until March 1998, then changed to the Biomen HAH140 assay in line with the first laboratory. The in-house HPLC system assay recorded values of HbA1c at 20% lower than the Biomen HAH140 assay. The earlier values measured in the second laboratory were adjusted appropriately to enable comparison of the results.
Statistics
The results are presented as means±SEM. The paired Student's t-test and the Student's t-test were used for comparison of means where appropriate. The rates of deterioration of renal function were analysed by plotting the reciprocal of serum creatinine against time for each patient, and were analysed individually by applying the regression equation:
1/serum creatinine=a+ß1t1+ß2t2+e,
where t1=time of reading t, for t<0; t1=0 for t>/0, t2=time of reading of t for t>/0; t2=0 for t<0. a, ß1 and ß2 are estimated regression coefficients. a is the estimated reciprocal creatinine at time=0 (referral date), ß1 is the slope of readings before time=0 (prior to referral), and ß2 is the slope of readings after time=0 (post referral). e is the residual (the difference between observed reading and estimate from regression equation). The equation was fitted to test the hypothesis H0: ß1 does not equal ß2, which is equivalent to testing whether a regression equation with a common slope ß1=ß2=ß would be adequate.
The patients' data were analysed to determine whether there was evidence to suggest that ß1 did not equal ß2, and that a two-slope (breakpoint) model with a break at time 0 was a better fit than a single-slope model—indicating an improvement in the rate of deterioration of renal function following referral (time 0). p values of less than 0.05 were considered to indicate significance.
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Results |
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Referral data on the 76 patients is summarized in Table 1
. Twenty-eight patients had type I diabetes mellitus, 48 had type II. The mean age for the entire group was 58 years (range 29–80). The mean duration of diabetes for the group was 18.5 years (range 5–50). On assessing patients' smoking histories, 18 were current smokers, and 27 were ex-smokers. At referral, 39 patients (51%) were taking ACE inhibitors.
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The serial blood pressure measurements at referral, and 6 and 12 months following referral, are shown in Table 2
. Further analysis of measurements beyond 12 months following referral was not appropriate, due to the small numbers of patients remaining in the study. Table 3 shows the results of serial measurements of serum cholesterol and HbA1c in the patients at referral, and 6 and 12 months following referral.
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The mean duration of follow-up in these patients was 689 days (190–2277). ACE inhibitors were commenced in 20 patients. At the end of the study 54 patients (71%) were taking ACE inhibitors. Of the 76 patients, 27 (36%) reached end-stage renal failure during the study and started renal replacement therapy. Ten patients died during the study, five prior to commencing renal replacement therapy.
The rate of decline of renal function was assessed prior to, and following, referral for the 76 patients as a whole, and for each individual patient separately, by regression analysis of the plots of reciprocal serum creatinine against time (as a measure of the rate of decline of renal function). Analysis of the entire group showed that there was a significant slowing in the rate of decline of renal function, following referral to the nephrology clinic. The mean slope prior to referral was -2.6x10-6, which changed to -1.5x10-6 following referral (p=0.01). Figure 1 illustrates examples of the change in the rate of progression of renal function deterioration following referral.
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Analysis of the results of individual patients showed that in 30 patients (39%) there was a significant slowing in the rate of decline of renal function following referral. These 30 patients were further assessed individually to determine whether there had been specific changes in their management following referral that could be associated with the slowing in the rate of decline of renal function.
Of these 30 patients, 21 were hypertensive at referral. Following changes to their antihypertensive medication (including starting ACE inhibitors in nine), blood pressure improved in 20, and 14 patients became normotensive. At referral, nine patients had untreated hypercholesterolaemia (serum cholesterol >6.2 mmol/l), which normalized following commencement of statins. At referral four patients were being prescribed fibrates inappropriately in view of their degree of renal impairment (serum creatinine >300 µmol/l28), and these were subsequently discontinued, with dramatic improvements in their renal function. Following referral, seven patients managed to stop smoking, and seven patients had an improvement in their diabetic control as judged by HbA1c. These results are compared in Table 4 with those of the 46 patients in whom there was no improvement in the rate of decline in renal function.
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Many of the patients had more than one change in management that could have contributed to the subsequent improvement in the rate of decline of renal function. However in five patients, apart from attendance at regular out-patient reviews and the specialist dietary advice that they were given, there appeared to be no other active changes in management.
We further compared the management of the 30 patients whose rate of decline of renal function slowed following referral with that of the 46 patients whose renal decline did not improve (Tables 5 and 6). There was no significant difference in the degree to which blood pressure control or serum cholesterol improved following referral between the two groups, but the improvement in diabetic control was greater in the patients whose rate of decline in renal function slowed.
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On initial inspection, the variables measured (blood pressure, serum cholesterol, serum HbA1c) appeared to be worse at referral in the group of patients whose rate of decline in renal function improved following referral (`improvers'), compared with those in the other group of patients (`non-improvers'). Following referral the improvement in these variables appears greater in the first group than the second (Figure 2). However, statistical analysis does not show significant differences in the initial variable measurements at referral between the two groups.
Regression analysis showed no correlation between the change in slope of reciprocal serum creatinine and the change in mean arterial pressure, serum cholesterol, or serum HbA1c following referral.
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Discussion |
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In a previous analysis,29 we presented the results of an audit of the quality of care of these patients with diabetic nephropathy at the time of referral to our nephrology clinic. The results showed that care was suboptimal, and that referral was often late. During the course of the present study there was a significant lowering of blood pressure, and improvement in diabetic control and serum cholesterol. Assessment of renal function showed that following referral there was a slowing in the rate of decline in renal function for the 76 patients as a whole, and individual patient analysis showed a significant slowing of the rate of deterioration in 30 (39%) patients.
Assessment of the change in the rate of progression of renal failure was made by calculating the gradient of the slope of reciprocal serum creatinine plotted against time prior to, and following, referral. We accept that this method of determining the change in renal function is not ideal, and has been criticized by other authors, but we feel that it is a realistic method for auditing routine clinical practice.
Following referral, patients were assessed, and individual management plans invoked, including aggressive treatment of hypertension (St Vincent Declaration guidelines), and hypercholesterolaemia. Nephrotoxic drugs were discontinued, and all patients were regularly reviewed by a renal dietician. Of the 30 patients in whom the rate of deterioration slowed significantly, in four patients it was due to discontinuation of nephrotoxic drugs (fibrates).
On analysis of the patients by dividing them into two groups, those in whom the rate of decline in renal function slowed, and those in whom it did not, there were no significant changes between the groups in the improvements achieved in management of blood pressure, serum cholesterol, or diabetic control. Whilst on initial inspection of the results it appeared that the variables measured were more poorly controlled at referral in the group who `improved', and that this group therefore achieved a greater overall change in the variables, (which could relate to their improvement in rate of decline of renal function), statistical analysis found no significant difference between the values of variables at referral between the two groups.
The improvement in rate of renal decline is probably multifactorial. No single factor is identifiable in the majority of patients in this study. After referral, all patients were attending clinics more frequently than they had been before. This increased intensity of care, coupled with the fear instilled in the patients by having to face the reality of impending renal failure, may simply have encouraged them to attend more diligently to the finer points of their care. Bergstrom demonstrated that referral to a specialist renal clinic can slow the rate of progression of a variety of renal disorders,30,31 and concluded that the frequency and quality of clinical check-ups on patients may favourably influence the progression of chronic renal failure. Although this has often been attributed to improved blood pressure control, this is not proven. Parving et al., in a preliminary report on the treatment of Type II diabetics with microalbuminuria, found that the progression to renal failure was slowed, but were similarly unable to identify a single responsible intervention.32
At referral, by use of reciprocal creatinine plots, it was possible to predict the time of need for renal replacement therapy if no change in rate of progression of renal failure occurred. This was then compared with subsequent progress. Thus far the calculated length of time saved of renal replacement therapy is 30 years, although this will increase with time, as many patients who had been predicted to be needing renal replacement therapy by now have not yet reached that stage. Apart from the benefit to patients, at an annual cost of renal replacement therapy of £23 000,33 this has already achieved an estimated saving of £690 000.
One must accept that it is not possible to attain ideal standards of care in all patients, or even the minimum standards proposed in the St Vincent Declaration. However the timing of referral of many of these patients, and the standard of care of blood pressure and other factors was far from optimal at referral. This study shows that by intensive outpatient clinic monitoring it is possible to improve these indicators of the quality of care, and that even at a late stage of diabetic nephropathy it is possible to slow the rate of progression to end-stage renal failure. More investment in such intensive out-patient care of patients with diabetic nephropathy would not only increase patient well-being, but might prove cost effective by delaying the need for expensive renal replacement therapies.
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