Epidemiology of end-stage renal disease in patients with diabetes mellitus: from the dark ages to the middle ages.

Nephrol Dial Transplant (1992) 7: 181-190 i 1992 European Dial>sis and Transplant Association-European Renal Association

Nephrology Dialysis Transplantation

Review Article Epidemiology of end-stage renal disease in patients with diabetes mellitus: from the dark ages to the middle ages C. Catalano 12 and Sally M. Marshall2 'Centro di Fisiologia Clinica del Consiglio Nazionale delle Ricerche e Divisione Nefrologica, Reggio Calabria, Italy and Department of Medicine, The Medical School, University of Newcastle upon Tyne, UK

2

Key words: classification of diabetes mellitus; diabetes mellitus; diabetic nephropathy; end-stage renal disease; epidemiology of diabetes mellitus

Introduction End-stage renal disease (ESRD) in patients with diabetes mellitus is commonly associated with other complications of diabetes, such as severe sight reduction due to retinopathy or cataract, and vasculopathy of the coronary, cerebral and peripheral arteries. For this reason, in the early years of renal replacement therapy (RRT), when facilities were very limited, diabetic patients were not usually treated. The first diabetic patient with ESRD started chronic dialysis in the Long Island College Hospital of New York in 1964 [1]. For many years after this pioneering start, diabetic patients were only occasionally treated by renal replacement therapy. As late as 1974, Ghavamian published a report entitled T h e Sad Truth About Hemodialysis in Diabetic Nephropathy' [2]. Of nine patients with renal failure resulting from diabetic nephropathy and treated by haemodialysis, only one survived longer than 3 years, and all patients had problems with clotting or infection of vascular access routes. In the following years as dialysis facilities Correspondence and oflprmt requests to: Dr Carlo Catalano, Department of Medicine, The Medical School. University of Newcastle upon T>ne. NE2 4HH. UK.

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became increasingly available both in the United States and in Europe, the number of diabetic patients who started RRT increased enormously. In the United States in 1978, diabetic subjects accounted for only 6% of the total population treated with dialysis or transplantation, while in 1986 they represented 20% of all end-stage renal disease patients [3]. According to the last available report, during 1988, 36 160 new end-stage renal disease cases were reported, and of these, 11 034 (30.5%) were attributable to diabetes [4]. In Europe, the situation was not very different. In 1972, only 0.5% of the treated ESRD patients had diabetes mellitus, while in 1985, this proportion had risen 21-fold to 10.5% [5-7]. With diabetic patients representing from 10 to 30% of the patients treated by dialysis or transplantation, it is obvious that this issue has attracted much attention from doctors and research workers in the last 10 years, as is demonstrated by a remarkable number of papers focusing on diabetes and ESRD. These reports have shown large differences in prevalence, incidence and characteristics of patients treated in different countries. Thus, in the United States at the end of 1987, the prevalence and the incidence of diabetes in patients treated by dialysis or transplantation were 100 and 39 per million respectively [8]. In the same period in the United Kingdom, the proportion was 17 and 4 per million respectively, while in Italy these numbers were respectively 28 and 9 per million [9]. On the other side of the world Japan presented the highest rate of patients treated by dialysis and transplantation (738 per million) with an acceptance rate for diabetic patients that approached

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that of the United States (30 versus 39 per million respectively) [10]. These differences are too large to be explained by referral bias alone. Moreover two recent reports have illustrated extremely interesting differences in the survival of all patients and in particular diabetic patients treated by RRT between Northern and Southern European countries [11] and between Europe, USA and Japan respectively [12]. EDTA data have shown a better three years survival for both CAPD and haemodialysis in nearly all age groups for Southern European diabetic patients compared to Northern European diabetic patients [11]. The relative risk for diabetic patients in RRT in the US compared with EDTA was 1.07, and 1.23 for the US compared with Japan [12]. There are even suggestions that the rate of the diabetic complications may be different in diabetic patients treated by RRT in different countries [9,11], even though there is little information available. A number of explanations have been suggested for these differences. These include: (i) differences in selection criteria for renal replacement therapy [13-20]; (ii) differences in the prevalence of diabetes and of the different types of diabetes [21-32]; (iii) differences in the definitions of insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) [33-60]; (iv) differences related to race and sex [6,8,14,20,61-71]; (v) differences in the incidence of ESRD in IDDM and NIDDM [9,13,20,39,42,43,53,72-74,78,79]; and, in some countries, (vi) a shortened life expectancy for non-insulin-dependent diabetes mellitus, because of high rates of cardiovascular disease [80,81]. In this review, after a short insight into the source of information and RRT registries, we will try to analyse these different possibilities in greater detail.

Source of data and RRT registries In Table 1 we have reported data concerning the incidence and prevalence of RRT related to both the total population treated by RRT and to diabetic patients only: Japanese data comes from two separate registries for dialysis and transplantation (collected by the Japanese Society for Dialysis Therapy and by the Japanese Society for Transplantation respectively) [10,82,83]; Australian and New Zealand data come from the Australia and New Zealand dialysis and transplantation Registry (ANZDATA) [10,84,85]; Canada has the Canadian Renal Failure Registry [86]. Italian figures come from published and unpublished data of the Italian Survey of Diabetes and Renal Replacement Therapy [9,32]; European and UK reports come from published and unpublished data provided by the EDTA Registry [5.6.7]; Data


C Catalano and S. M. Marshall

from the United States comes from the US Renal Data System and from the US Department of Health and Human Services [8,69]. The development of the US Renal Data System is an important and recent achievement since the US has tried twice unsuccessfully before 1988 to start a comprehensive renal data system analogous to those previously mentioned [87,88]; Korean data comes from a report published in 1988 by the Korean Society of Nephrology [70]. Unless otherwise stated, prevalence and incidence data reported in this review refer to the years 19861988. We have concentrated on Europe, UK, Italy and the US because much more information (as publications and reports) is available.

Discussion Differences in Selection Criteria for Renal Replacement Therapy The exponential increase in the proportion of diabetic patients treated by dialysis and transplantation does not reflect a parallel increase in the incidence of diabetic patients with ESRD. Instead for the most part, it reflects the increased availability of dialysis and transplantation facilities. The existing differences between the different countries may be explained, at least in part, by different policies in treating ESRD patients with or without diabetes. Two types of selection bias are discernible. On one side, the dialysis units themselves may select the people that are referred for treatment of end-stage renal failure. On the other hand, general physicians often have some hesitation in referring a diabetic patient with severe ocular and vascular complications. It is likely that even in countries with very liberal policies, not all patients with ESRD receive treatment. For this reason, data coming from papers that define ESRD as treatment with dialysis or transplantation have serious limitations which need to be considered when interpreting the results. Thus the true proportion of diabetic people with end-stage renal disease is underestimated, and also the average characteristics of the patients do not take into account all those who were not treated and who probably are older or have more complications. Even if there is some way to analyse the renal unit selection bias, it is nearly impossible to analyse the referring physician's selection bias, even in carefully planned studies. The problem is even more complex if we consider that possibilities other than simple selection bias may exist. Thus patients may be referred with advanced renal failure from other parts of the country or of the region and in this case are usually re-referred, leaving all the decisions to another unit. Patients may

Epidemiology of ESRD in patients with diabetes mellitus

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Table 1. The prevalence and incidence (per million population) of all patients and diabetic patients treated by RRT in different countries in 1986 87. Numbers in parenthesis are the percentage of patients who have diabetes Prevalence all patients Japan Australia Canada Italy UK Europe USA Korea

738 153 186 467 267 221 524 62

Incidence diabetic patients

10 28 17 14

100

all patients

diabetic patients

137 44 71 75 51 41

30 (22) 4(9) 14 (20) 9(12) 4(8) 4(10) 39 (30) 3(13)

130 23

All the numbers have been rounded up to the nearest whole number. Dashes represent unavailable data.

be discharged after a short admission and fail to come back to the clinic, may refuse renal replacement treatment, or may die immediately after the admission. It is probable that in all these cases the patients will be quickly forgotten unless a very organized records system is in operation (unusual), or all notes are reviewed. This is practically impossible if a centralized archive exists in the hospital or if the unit is very large and treats thousands of patients per year. The United Kingdom is the only country where selection bias has been analysed. In the early 1980s, it was claimed that in the United Kingdom, not all patients with diabetes and ESRD were treated [15]. For this reason in 1985-87, two surveys of diabetic renal failure were carried out by the Joint Working Party on diabetic renal failure of the British Diabetic Association, the Renal Association and the Research Unit of the Royal College of Physicians [16,17]. A survey of six selected health regions in 1985 identified 181 diabetic patients with advanced renal failure who had not been treated previously. Late in 1987, 176 of these 181 patients were traced: 164 had either died or received renal support treatment by the end of 1986. Two-thirds, 102, of the patients started renal support treatment, while 57 died. Of the latter, 15 deaths were judged to be unavoidable, mainly from acute myocardial infarction, but at least 28 patients died from untreated renal failure. A great deal of emphasis has been placed on this possible bias against diabetic patients with ESRD operating in the UK. However, it is interesting to note that the crude proportion of diabetic patients treated by renal replacement therapy in 1987 was similar in Italy and the United Kingdom (6.0% and 6.4% respectively), whilst the prevalence per million population of renal replacement therapy patients in Italy was double that of the United Kingdom, both for all patients and for diabetic patients (470 versus 267 and 28 versus 17 respectively). This suggests that if there was a selection bias in the United Kingdom, this was not influenced by the primary renal diagnosis


alone and this point has been well addressed by a recent paper [18]. Although the UK is the only country which has provided data showing its own selective biases, some amount of bias is probably operative everywhere but it is extremely difficult to assess. We believe that nearly all doctors hesitate when faced with a (very) old or severely ill patient. Two studies, coming from the United States, have suggested that ~ 30% of the patients with advanced renal failure receive no therapy [19,20].

Differences in prevalence of diabetes and of the different types of diabetes Diabetes arises through two aetiologically distinct pathways. Type 1 (insulin-dependent) diabetes is the result of immunologically mediated destruction of the pancreatic beta cell, and usually requires replacement therapy with insulin. Type 2 (non-insulin-dependent) diabetes results from a combination of decreased insulin sensitivity and impaired insulin secretion. It can be treated with dietary therapy or oral hypoglycaemic agents, but sometimes requires exogenous insulin. There are marked geographic differences in the incidence of both insulin-dependent and non-insulindependent diabetes mellitus. True insulin-dependent diabetes mellitus is, on average, much less common than the non-insulin-dependent type. The incidence and prevalence of patients with insulin-dependent diabetes mellitus vary greatly between countries: children living in Scandinavian countries or Scotland are over 20 times more likely to develop insulin-dependent diabetes mellitus than children in Japan or China. Even in Europe itself, the difference between Northern countries, such as Sweden, Finland and Scotland, and Southern countries such as Italy, is remarkable. In Finland the incidence of insulin-dependent diabetes mellitus among youngsters is >34 per 100 000 per

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year, while in the North of Italy, it is ~6-8 per 100 000 per year (21-27). Differences are present also in the incidence of non-insulin-dependent diabetes mellitus. The prevalence of non-insulin-dependent diabetes mellitus in Europe is 1-5% of the population, and tends to increase with age. However, there are populations in which the prevalence is much greater, such as in some Indian tribes in North America [22,28]. The difference in the prevalence and the incidence of the different types of diabetes will be reflected in the characteristics of the diabetic patients with renal failure. In Scandinavia (especially Finland) due to the very high incidence of IDDM in the general population, most of the diabetic patients treated by dialysis or transplantation are truly IDDM. Unfortunately we are not aware of any study specifically addressing this point. The EDTA Registry reported in 1985 that all of the diabetic patients treated in Finland were Type 1 [6] but unfortunately this information should be viewed with caution for reasons described below. Importantly however, the mean age of the Finnish diabetic patients in RRT was only 38 years (compared with 60 for Italy in the same report), thus suggesting that the majority of the Finnish patients were probably true IDDM patients. On the other hand, among the Pima Indians, it has been shown recently that a high proportion develop end-stage diabetic renal disease and virtually all are non-insulin-dependent [20]. However, even in countries where the majority of patients have one type of diabetes, there may be areas where the other type is predominant. Sardinia is a large Italian island located in the Mediterranean sea between the Italian peninsula and France. The peculiar position of this island has always isolated it from continental Europe [29]. Recently the EURODIAB study has reported an unexpectedly very high incidence of IDDM in Sardinia [30], and it has been suggested that this is related to genetic peculiarities [31]. Interestingly the Italian survey of diabetic patients in RRT has found a very high proportion of IDDM among RRT patients with diabetes compared to the rest of Italy (Sardinia 71%; rest of Italy 31%) with a mean age of 49 years compared to 59 for the rest of Italy [32].

Differences in the definitions of IDDM and NIDDM The classification of the major diabetic subclasses has changed many times in the last twenty years. IDDM has been called juvenile-type, JOD, Type 1 and NIDDM adult-onset, MOD. Type 2. Juvenile type (JOD) and maturity-onset (MOD) discriminate on


C. Catalano and S. M. Marshall

the grounds of the age at onset, Type 1 and Type 2 on the pathogenesis of the disease while IDDM and NIDDM reflect a clinical approach. The most recent guidelines are those suggested by the WHO in 1985 [33]: 'The basis of the distinction between the major subclasses of diabetes mellitus, is the patient's dependence for survival on insulin. Such dependence is judged to be present when the classical symptoms of diabetes (increased thirst, polyuria, wasting, and ultimately stupor and coma), are associated with greatly raised concentrations of glucose and ketone bodies in the blood and urine. All other patients meeting the glycaemic criteria for diabetes fall into the non-insulin-dependent class unless they have malnutntionrelated or gestational diabetes, or are among the small number who qualify for one of the other special categories.' These suggestions are based on common sense. Practical considerations, however, may give rise to different criteria, and when analysing a population of diabetic patients in RRT, every author has used different criteria or a combination of criteria. We have reviewed 22 papers considering purely the definition of IDDM: no criteria have been used in five [34-38], and very general criteria in two [39,40]. Eleven different sets of criteria were used in the remaining 15 papers [7,9,13,41-52] (Table 2) just by manipulating or combining the basic criteria listed in Table 3. Sometimes the differences between the criteria listed in Table 2 are tiny, but at the present moment we have no idea about the effect of using slightly different criteria on the main characteristics of the diabetic population in RRT. It is amazing to note that both the two major dialysis registries, Medicare and the EDTA [6,7,53] in their questionnaire-based surveys, give no formal Table 2. Different definitions used to make a clinical classification of IDDM Definition

Reference

Diabetes diagnosed before 25 plus insulin treatment within 3 months Current treatment for diabetes Treatment with insulin from diagnosis Treatment with insulin within I year from diagnosis Diabetes diagnosed ^ 3 5 years plus ketosis Ketosis and or insulin treatment within I >car from onset Judgement of the physician in charge Diabetes diagnosed ^ 3 0 years plus insulin treatment from diagnosis Diabetes diagnosed ^ 3 5 years plus insulin treatment from diagnosis Insulin treatment from onset plus ketonuna or ketoacidosis al the time of diagnosis Need for insulin plus evidence of ketosis plus relative weight < 1.2

43 16 9, 42. 50 46 43 48 7. 41 47 44. 45 51 52

Epidemiolog) of ESRD in patients with diabetes mcllitus Table 3. Clinical criteria used in epidemiological settings in order to discriminate between the major diabetic subclasses. Each criteria has beer, used a'onc or in combination with others 1. Treatment at onset of diabetes 2. Insulin treatment within the first >car 3. Age at onset of diabetes 4. Ketosis 5. Bod> weijiht (BMI. relative weight)

guidelines on how to classify a patient in the adult onset and juvenile type (Medicare) or Type 1 (insulindependent) and Type 2 (non-insulin-dependent) (EDTA Registry) categories respectively. As we have seen previously, this may give rise to a great deal of misunderstanding. We cannot exclude the possibility that this classification merely reflects the therapy currently taken by the patient rather than their true status (insulin-treated rather than truly insulindependent) and the EDTA registry itself seems now to be aware of this possibility [6,7]. This bias is increased by the fact that physicians tend not to prescribe oral hypoglycaemic agents to patients with advanced renal failure, a pattern based more on pharmacokinetic considerations than on the underlying disease being treated. We would like to add that there are particular situations which may need to be carefully explored and in which a clinical classification appears to be difficult. Diabetes diagnosed after the start of RRT is an uncommon, but not rare, situation. Gonzales et al. (1985) reported that 3/47 (6.4%) diabetic patients treated in the Avram Center for Kidney Diseases had diabetes diagnosed after dialysis was started [43]; Von Kiparsky in 1990 reported that 32/901 (3.6%) recipients of renal transplant [54] developed diabetes (defined as two consecutive blood glucose >6.7 mmol/1 or administration of insulin or oral hypoglycaemic drugs). We found that 7/60 (11.7%) diabetic patients treated in three Italian units between 1972 and 1987 developed diabetes after dialysis started (6 7) or transplantation was performed (1,7) [45,55]. Finally 43,1605 (3%) of the Italian diabetic patients treated by RRT at the end of 1987 had diabetes diagnosed after the start of RRT [9, unpublished data]. A simple clinical approach is open to criticism. On the other hand a biochemical approach to discriminate between the major diabetic subclasses is problematical. The assessment of islet cell autoantibodies is out of the question both for the costs involved and because the autoantibodies tend to disappear after the disease becomes apparent [56]. It has been shown that the incidence cf particular HLA-haplotvpes is particularly high in Type 1 diabetic patients [56-60]. We have compared the HLA profile of two matched groups of RRT patients treated in Newcastle upon


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Tyne (Table 4). The diabetic patients (77% of whom were clinically classifiable as IDDM) presented a \ery high rate of DR3, DR4 and a low rate of DR2 compared to the non-diabetic group. However, there is not a particular haplotvpe associated exclusively with Tvpe I diabetes (in the population we studied 8 non-diabetic patients were DR3 or DR4 positive) and for this reason the determination of the HLA profile cannot discriminate between the major diabetic subclasses. Recently attention has focused on the HLA-DQ beta chain and specifically on the amino acid at position 57, although its pre-eminent role is still debated [58-60]. In addition, HLA haplotypes associated with diabetes are racially constrained and thus may not be generally applicable. We cannot exclude that in the future a unique haplotype will be specifically linked to Type 1 diabetes but most probably the costs involved will always make it unsuitable for discrimination purposes. Type 1 diabetes is a progressive immunologicallymediated disruption of the beta cell and thus endogenous pancreatic secretion is exhausted within a few years of the onset of the diabetic disease. For this reason it has been suggested that assessment of C-peptide levels may discriminate between the two major diabetic subclasses. On the other hand, this approach may be criticized on the grounds that C-peptide is excreted by the kidney and for this reason its measurement has always been considered of little value in patients with renal failure. Moreover when analysing patients treated in many different hospitals it is objectively difficult to obtain C-peptide determinations, or even a reliable serum sample. Thus no single test can be used as an absolute marker for the different types of diabetes.

Differences related to race and sex Race. In 1977, Easterling provided the first careful racial analysis of a large group of uraemic patients in his study of renal failure in South-eastern Michigan. An unexpectedly high annual rate of 15 per million uraemic diabetic patients was found in blacks, compared with only 4.6 per million in whites [14]. This initial observation has been confirmed by other workers [61]. The 1990 annual USA report on endstage renal disease from the Division of Diabetes Translation shows an increased standardized incidence rate of end-stage renal disease due to diabetes, six times higher for blacks compared with whites [8], Blacks have a higher incidence of ESRD in both tvpe 1 diabetes (ODDS ratio 2.96) and type II diabetes (ODDS ratio 4.9) [62]. The higher rates of diabetesrelated ESRD seen among blacks are probably not all accounted for by the higher prevalence of diabetes

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C Catalano and S. M Marshal]

Table 4. Prevalence of DR2, DR3, DR4 in two matched populations of diabetic and non-diabetic patients treated by RRT in Newcastle upon Tyne [43, previously unpublished data) Diabetic patients IDDM* Number Patients in which the DR locus was tested DR3-positive DR4-positive DR3- or DR4-positive DR3- and DR4-positive DR2-positive

Non-diabetic patients

NIDDM'

30 17 12 11 15 8 0

Total 42 23 18 12 21 9 0

42 21 4 4 8 0 4

'Three diabetic patients could not be classified.

among blacks relative to whites. Differences in severity of diabetes and higher prevalence of hypertension are potential co-factors that might account for the higher rates seen in blacks [8]. Moreover Cowie showed that in black IDDM patients, ESRD develops at an earlier age, and after shorter duration of diabetes than in white IDDM patients [61]. In more recent years, some evidence has arisen to suggest that in other non-white, non-black populations, the incidence of end-stage renal disease due to diabetes is high. In 1988, Nelson reported a very high incidence of end-stage renal disease due to diabetes in Pima Indians [20]. A more recent report considering all the American/Indian population has shown that the age adjusted incidence of end stage renal disease for native Americans was 2.8 times that for whites [63]. Finally, Burden (1990) reported that among the Asian Indian population in Britain, the incidence of endstage renal failure due to diabetes was over twice that of the native population [64]. It is known that virtually all diabetic Pima Indians have non-insulin-dependent diabetes and that both Asian Indians, blacks and native Americans have a high prevalence of non-insulin-dependent diabetes mellitus, with a low prevalence of insulin-dependent diabetes. For this reason we should consider that in all these populations, non-insulin-dependent diabetes accounts for most of the cases. Sex. Among the general population IDDM is on average more common in males than in females [65] although not all reports confirm this [66,67]. The situation appears to be different for NIDDM. In the US population there is a higher prevalence and incidence of NIDDM in females than in males. In the UK it is now believed that there is a slight excess of male patients, whereas in some other countries, such as India, there is a considerable male excess [68]. This is probably accounted for by differences in the incidence and pre\alence of NIDDM in different ethnic groups.


Among diabetic and non-diabetic white patients in RRT males appear to be prevalent over females worldwide [6,8,61,69,70]. However, within the diabetic population sex differences vary by race as has been shown by last USA reports [8,71]: in 1988 the ratio (relative risk) of diabetic ESRD for females compared with males was 1.2 in the black population, while it was 0.85 in whites, indicating that females are at higher risk than males in the black population and at lower risk than males in the white population for diabetic ESRD [71] and a pattern similar to this was reported for other ethnic minorities [8]. Overall in US diabetic patients in RRT, females outnumber males (incidence counts for 1986: (F) 14102 versus (M) 13706 [8] this being due to the high rates of ESRD in the non-white female population).

Difference in the incidence of ESRD in IDDM and NIDDM One of the issues raised first by doctors involved with patients treated by dialysis and transplantation was the characteristics of the diabetic population treated by RRT. Did they belong in equal measure to both major diabetic subclasses or did one of these subclasses account for the majority of diabetic patients in RRT? Was the relative risk of developing uraemia similar for IDDM and NIDDM or was one of those subclasses more at risk? For many years, the answer to both these questions has been that diabetic patients developing ESRD were predominantly young-onset, insulin-dependent diabetics with diabetes of long duration. The first paper addressing this issue was that published by Knowles in 1974 [72]. This author reported that in over 6800 deaths in diabetic patients, renal death accounted for 48% of the deaths in those who had developed diabetes before 20 years of age and only 6% in those who had developed diabetes at 20 or after, thus suggesting that renal death was


predominantly a feature of the patients who had developed diabetes in young age. Dr Knowles did not stress the point that even in his series, renal death was relatively more common in patients with diabetes diagnosed in their teens; on the other hand, the total number of older people with diabetes was so great in comparison, that the actual number of the old diabetic patients dying in ESRD out-numbered the young ones (386 versus 229). The point of view that end stage renal disease in diabetes was predominantly a feature of the young onset, insulin-dependent disease, was widely accepted for many years and this opinion has been reported as fact in major texts [73]. The EDTA Registry itself, for many years in all its reports, has always reported that most diabetic patients treated with dialysis and transplantation in Europe, were Type 1. However, as discussed above, this classification may be grossly misleading. It has become apparent that in most Western nations the majority of diabetic patients starting RRT are old and non-insulin dependent. Gonzales (1985) reported that 47 (87%) of the diabetic patients treated in The Avram Center for Kidney Diseases and at the Brooklyn Kidney Center of the Long Island College Hospital, had Type 2 diabetes, while only 6 (13%) had Type 1 diabetes [43]. Friedman (1986) claimed that > 80% of the patients treated in New York had non-insulin-dependent diabetes [13]. Of 4535 patients with diabetes who started renal replacement therapy in the United States in the period January to June 1988, 2577 (56.8%) were considered to have adultonset type diabetes [53]. Koch et al. in 1989 reported that of 215 patients starting dialysis in 14 German renal units, 73 (33.5%) suffered from Type 1 diabetes, 133 (61.9%) from Type 2 diabetes and 9 (4.1 %) from maturity-onset diabetes of the young [39]. Finally the Italian survey of diabetic patients in RRT has recently reported that at the end of 1987, 67% of the patients had NIDDM with a mean age of 59 years [9]. However, the higher proportion of NIDDM treated by RRT in comparison with IDDM does not necessarily mean that NIDDM has the same or even a higher incidence of ESRD compared to the IDDM patients. This is still a matter of speculation. Many authors have tried to establish the incidence of nephropathy in IDDM and NIDDM but not all of them have focused on the same endpoint. Most of the studies have been cross-sectional and some have considered the prevalence of microproteinuria, some the prevalence of persistent proteinuria, while others have considered raised creatinine levels, or the start of RRT, or death from chronic renal disease. In 1988 89 three papers reported a similar risk of developing renal failure for IDDM and NIDDM in different populations: Nelson and coworkers (1988) reported that in Pima Indians with Type 2 diabetes.


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the incidence of end-stage renal disease (defined as death from chronic renal failure or starting dialysis) was similar to that in subjects with Type 1 diabetes who were followed at the Joslin Clinic (Boston, Massachusetts) when those with similar duration of diabetes were compared [20]. In the same year Humphrey and coworkers reported the results of a population-based survey in Rochester, Minnesota. The cumulative incidence of chronic renal failure (defined as creatinine greater than 4 mg/dl [354umoM] or RRT) in a predominantly non-hispanic, white population was similar for both IDDM and NIDDM [19]. Finally in 1989 Hasslacher and coworkers reported that in a German population the cumulative risk of proteinuria after 20 years of diabetes mellitus was 27% in Type 2 and 28% in Type 1 diabetes and that in the same population the cumulative risk of renal failure (serum creatinine > 1.4 mg/dl [125 umol/1] after 5 years of proteinuria were 63% and 59% respectively [74]. There are at least three important confounding factors. First the prevalence of raised albumin excretion increases with age regardless of the presence or absence of diabetes [75-77]; second, especially in NIDDM patients, a significant proportion with renal failure have non-diabetic renal disease [9,39,42]. Thirdly, proteinuria is associated both in diabetic and in non-diabetic patients with increased morbidity and mortality from cardiovascular disease but possibly there are racial and geographic differences [78,79].

Shortened life expectancy for NIDDM patients Jarrett has pointed out that the chief cause of the relatively low proportion of uraemic deaths in noninsulin-dependent diabetes in Europe and North America is the competing risk of ischaemic heart disease [80]. In Japan deaths from ischaemic heart disease are still relatively uncommon, even in diabetic patients. However, in Japanese migrants to Hawaii with diabetes, cardiovascular disease assumes the prominence seen in European populations and renal disease accounts for a much smaller proportion of causes of death in non-insulin-dependent diabetes [81]. The competing risk probably has a different impact according to the population considered. In Indian people who are living in the United Kingdom, and in American Indians, the impact of uraemic deaths is probably not so strong since these populations have a high rate of cardiovascular disease, but there are few data available.

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Conclusions The number of diabetic patienis treated by RRT is increasing in all countries in which dialysis and transplantation facilities are available, probably because of an increasing acceptance rate of older patients with more complications. Many factors can affect the incidence, prevalence and main characteristics of these patients and since all that is known nowadays about diabetic patients in RRT comes from a few Western countries, we cannot report general characteristics of diabetic patients in RRT even by analysing a large cohort of patients. Careful national surveys are necessary to assess the characteristics and needs of uraemic diabetic patients treated in different countries. There is moreover, lack of agreement over the classification of diabetic patients in RRT and we cannot exclude that this may account at least in part for different findings in different studies. Differences in incidence, prevalence and main characteristics of diabetic patients on RRT may be at least partly accounted for by different incidences of diabetes, problems of classification and selection biases. In view of the enormous growth of literature on this topic we would like to make some recommendations to lessen confusion. 1. When reporting data an attempt should be made to identify selection bias on the part of the referring diabetologist and nephrologist: number of patients not referred, referred but refused, as well as those accepted. 2. When reporting on the prevalence of IDDM/NIDDM, or characteristics or complications, among RRT patients a description of the general population treated in the same region or country should be given. Possibly data from diabetic patients should come after data from the general population. 3. The definition of type of diabetes should always be given. Ideally, a consensus definition should be reached, perhaps on the basis of that suggested by WHO [33]. When reviewing reports, comparisons between studies that have used similar criteria should be made or it should be stressed that different definitions have been used. 4. The racial composition of the general population in the area and the racial composition of the study population should be analysed. 5. When analysing survival or cause of death reference to a matched control group and, possibly, to mortality tables should be made. Acknowledgements We are grateful to Dr F Brunner and Mrs S Dvkes from the EDTA for ha\ing provided us with data for Europe and UK, to Dr J M N e u x a n from the Department of Health and Human Services. USA for having provided us with


C. Calalano and S. M Marshall data for the US, to Professor KGMM Albert! for reviewing this paper and to Miss Pauline Jackson for typing the manuscript.

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