The incidence of actively treated ESRD has increased continuously since the start of maintenance dialysis therapy in the sixties. This has been largely driven by a steady increase in take-on rates. There are two reasons for this. Firstly, economic growth and a steady reduction in the costs of dialysis, mean that health services have been able to afford treating more patients. Secondly, the results of treating patients of increasingly high age and morbidity, in particular DM, have improved, such that active treatment of marginal groups is justified. This pattern can be seen in this national survey. During the period, a linear increase in the age of the oldest patient in the registry was seen, and the age-adjusted morbidity increased. This increase, approximating 6 months per year, was far greater than the increase in expected life expectancy of the background population. During the nineties, increased incidence rates for 60-80-year-olds and diabetics [12] were seen. After 2000, in response to encouraging treatment results [13], the incidence of 80-year-olds rapidly increased, while the incidence of diabetics stabilized [12]. Thus, it is highly likely that the initial rise in incidence in elderly age groups is an expression of these secular trends. The increase in incidence rates for Type 2 diabetics over the age of 70 after 2001 is probably also part of this trend. One would therefore expect that incidence rates at some point would stabilize at a higher level.
The present study shows that ESRD incidence among patients <40 years has remained stable for 20 years. Since 2001 the ESRD incidence has fallen by 7% among 40–49 year olds, and 26% among 50-59-year-olds. These changes were not significant. Since 2001 the ESRD incidence among 60-70-year-olds has fallen by 42%, and 70-80-year-olds since 2002 by 33%. The Riskdiff analysis (Table4) shows that these changes are independent of population structure. A recent fall in incidence since 2007 of 39% among patients older than 80 years is too recent to be meaningful. It could be due to a real increase in incidence similar to the 60–80 year-olds, or a waning enthusiasm by primary health carers for referring these often frail patients for treatment. This is in contrast with other national results [14, 15] which have merely showed a stabilization in these age groups. We believe this to be one of the first cases of a national reduction in ESRD incidence in the absence of social or economic unrest. As a direct result the number of prevalent dialysis patients in Denmark has now fallen by 5% since 2008. Taiwan has also noted a fall in ESRD incidence from 432 to 384 ppm between 2005 and 2008; this has not however yet resulted in a fall in prevalence [15].
During the nineties, a number of possibly modifiable factors in the progression of uraemia were identified. Aggressive treatment of hypertension is probably important [1, 16]. RAS blockade by ACE-I and A2A were shown to have specific nephroprotective properties, in particular in patients with diabetes and proteinuria [4, 5, 9, 10, 17, 18]. A protective effect of protein restriction has been suggested [19], as has a nephrotoxic effect of tobacco [20]. Increased use of these prophylactic measures would be expected to reduce ESRD incidence. Figure2 shows that the prevalence of antihypertensive therapy, and in particular RAS blockade in the general population has indeed increased substantially, to a level of 0.27 DDDs/capita/year. The percentage of non-smokers (or irregular) has increased from 58 to 77% between 1995 and 2008 [7]. There is no evidence that the incidence of hypertension has increased in Denmark; thus the increased drug use is probably an expression of more intensive individual therapy. This study has only documented an increase in general antihypertensive therapy, in particular RAS blockade, and a reduction in ESRD incidence among the elderly. This being an observational study, any discussion about causality must be purely speculative, but it is possible that the observed decrease in ESRD incidence is an expected consequence of the intensified prophylaxis. If this is so, there appears to be a lag time of at least 5 years between a change in antihypertensive therapy and a decrease in incidence. This is not surprising: in order to delay ESRD significantly, treatment has to be initiated while the patient still has a significant renal function. During the period of observation, there were no governmental changes in the organization or financing of ESRD treatment. All patients are treated at hospital-based, publicly financed nephrology centers. There has been an increased awareness of the importance of predialysis nephrology care, and today all patients with a GFR below 30 ml/min are recommended specialist care. This may have contributed to the fall in ESRD rates, independently of concurrent antihypertensive therapy and RAS blockade. In common with international trends, there has probably been a tendency to start dialysis at a higher level of GFR since 2000; this would a priori increase the number of ESRD patients slightly.
Considerable changes have occurred in the background population between 1990 and 2011. The average longevity has increased from 72.2 to 77.8 years for males, and 77.3 to 81.6 for females [21]. While increased longevity will of course be expected to increase the absolute numbers of elderly patients, it will not in itself affect the incidence, expressed as a fraction of the population at risk. The Riskdiff analysis shows that the observed changes are real and independent of any change in population structure. It shows that the evolution of the population 60–80 years would have lead to a rise of incidence of 16% while the observed incidence was −21%. The underlying risk fell by 36%. Ischaemic heart disease as a cause of death fell from 25.6% of all deaths to 9.2%, and cerebrovascular disease from 9.1% to 6.9%. These changes could also partly be related to more intensive antihypertensive therapy. It is difficult to predict how these changes might affect ESRD incidence: on the one hand, since cardiac and renal disease are often related, with common etiologies such as diabetes, atherosclerosis and hypertension, a better cardiac survival might lead to more patients surviving to renal failure; on the other hand, the prophylactic treatments that reduce the incidence of heart disease might also reduce the incidence of renal disease.
Two findings were surprising. The fall in incidence was distributed between different renal diagnoses, without any clear distinction between proteinuric and non-proteinuric diseases. A change in coding practices during the period of observation cannot be excluded, but since the diagnoses were made by a small group of nephrologists, using standard ERA-EDTA definitions, we consider this unlikely. Also, the fall in incidence was mainly confined to patients over the age of 60. While ESRD incidence was lower for patients aged 30–59 was lower in 2011 than 2001, the difference was smaller and non-significant, partly because of the small number of patients in these age groups. There are several possible explanations for this apparent difference: some diagnoses, common among younger patients, such as polycystic renal disease and hereditary disorders, may be less amenable to prophylaxis; early diagnosis and prophylaxis may be rarer among younger patients; it is possible that long-term therapy is required to make a noticeable difference. Antihypertensive therapy has been shown in the ESCAPE study to also be effective in children [16]. This is a recent study, which cannot have affected previous therapy; no data is available concerning antihypertensive therapy among children in this population. A further disadvantage of this study is that data concerning antihypertensive use was only available after 1995, and only as DDDs, rather than number of patients being treated.
Not all health indicators have moved in the right direction. The number of obese adults (body mass index >30 kg/m2) has risen from 5.5% in 1987 to 7.6% in 1994 and to 13.4% in 2010. It is thus all the more remarkable that the expected epidemic in diabetic nephropathy has not occurred, and that the incidence of type 2 diabetic nephropathy is stabilised. Thus, the theory that intensive prophylactic intervention can reduce the incidence of diabetic nephropathy seems to have been justified in practice.
It is possible that unidentified factors could have contributed to the fall, e.g. a reduction in consumption of nephrotoxic drugs or an improvement in the urological treatment of patients with post-renal uremia. Improvements in immunosuppressive therapy may have contributed to the fall in vasculitis incidence. It is even possible that the initial increase in incidence seen among patients over 70 years is partly caused by a postponement of ESRD among patients 60–70 years to a later age, the real fall in incidence thereby being exaggerated.
If one assumes that there is a causal connection and that, without intervention, incidence among 60-70-year-olds would have remained at 400 ppm and among 70-80-year-olds at 592, a rough estimate of the possible economic benefits of prophylaxis can be made. Further assumptions are required for this calculation: the mean survival after ESRD is 4.3 and 2.5 years respectively (DNR average 2000–2010); the average cost is €50,000/year. It then follows that ESRD incidence has been reduced by 33.8 ppm/year, ESRD prevalence by 121 ppm and ESRD expenditure by approximately €6 per capita/year. Drug expenditure needs to be subtracted from this to calculate the net economic benefit. For commonly used ACE inhibitors this is however less than 10 cents/day.
