Diabetes Mellitus in Tassin, France: Remarkable Transformation in Incidence and Outcome of ESRD in Diabetes

Diabetes Mellitus in Tassin, France: Remarkable Transformation in Incidence and Outcome of ESRD in Diabetes Bernard Charra, Cyrile VoVan, Daniele Marcelli, Martial Ruffet, Guillaume Jean, Jean-Marc Hurot, Jean-Claude Terrat, Thierry Vanel, and Charles Chazot The incidence and prevalence of diabetes mellitus (OM) in the dialysis population in Europe. and more especially in France. have been lagging behind the impressive United States and Japanese rates. For a decade. things have been changing. and the incidence of OM in hemodialysis (HO) reached almost 40% in Tassin. France in 1999. The prevalence has followed the same trend but increased more slowly. The increase in incidence and prevalence is almost totally accounted for by type 2 OM explosive outbreak and development. The morbidity on dialysis (hypotensive episodes. hospitalization number. and duration) was significantly worse in diabetic patients (without difference between type 1 and 2) than in nondiabetic patients. The mortality rate was higher in diabetic patients than in nondiabetic patients (mean half-life 3 and 13 years. respectively). even after adjustment for age and comorbidity. The mortality rate was higher in type 2 than in type 1 (mean half-life 2.7 and 5.2 years. respectively). a difference which disappears when adjusting for age and comorbidity. Specific causes of death were different in diabetic and nondiabetic HO patients; in diabetics there was a six-fold higher cardiovascular (CV) and three-fold higher infectious mortality. but there was the same mortality from cancer. A strong difference was observed between type 1 and type 2 OM: in type 1 there was no increased infectious mortality and a moderately increased CV mortality compared with nondiabetic patients. Type 2 diabetic patients had a four-fold increased infectious and an eight-fold increased CV mortality. Altogether. the eruption of OM in our unit over the last decade has drastically increased the crude mortality. but the standardized mortality ratio using the USROS mortality table remained unchanged. about 45% of expected mortality. © 2001 by the National Kidney Foundation, Inc. Index Words: Diabetes mellitus; epidemiology; end-stage renal failure; hemodialysis; morbidity; mortality.

T

he epidemiology of diabetes mellitus (OM) is increasing impressively all over the world. Type 1 diabetes incidence is reported as generally stable l or still increasing? whereas type 2 diabetes shows a universal rapid increase. ~iabetes has become a significant public health problem worldwide. 3 Its prevalence is predicted to double in the next decade, comprising grossly 10% type 1 and 90% type 2 OM.4 The rate of evolution of diabetic nephropathy to end-stage renal failure (ESRF) has alternatively been reported to be more rapid in type 15 or in type 26 OM, but the risk seems From the Centre de rein artificiel, Tassin, France; and Fresenius Medical Care, Bad-Homburg, Germany. Address correspondence to Bernard Charra, MO, Centre de rein artificiel, 42 Avenue du 8-Mai-1945, 69160 Tassin-lademi-lune, France; e-mail: [email protected]. © 2001 by the National Kidney Foundation, Inc. 1073-4449/01/0801-0005$35.00/0 doi: 10.1 053/jarr.2001.21708

42

equal in both types of OM?,8 The risk of nephropathy is reported to be stable or decreasing in type 19 but increasing in type 210,11 OM. Ten years ago, OM was already the most common cause of chronic renal failure (CRF) in the United States,l1 and this was viewed as a rather exceptional situation. In other countries, particularly in Europe, the incidence, although increasing, was still rather low.1° European nephrologists imagined that they would be speared by the American and Japanese "fatality." On the other hand, looking at the European situation from the United States, the low rate of admission of diabetics into dialysis programs was sometimes analyzed more negatively as a sign that most diabetic patients were refused access to maintenance dialysisP This conclusion has been the basis of some harsh polemics.1 3 - 15 Things have changed, and in Europe,16-18 in France,19,20 and in our part of the country, diabetes is an increasingly common cause of

Advances in Renal Replacement Therapy, Vol 8, No 1 (January), 2001: pp 42-56

Diabetes Mellitus in Tassin, France

CRF. This report describes the changes occured in the unit of Tassin, in the central part of France, and relates them to the situation found in other parts of France and elsewhere.

Patients and Methods We retrospectively analyzed our hemodialysis unit computer data. The oldest data (1968 through 1979) have not been entered online. They were collected from patient charts, dialysis log charts, and laboratory reports by the same observer (B.c.) over several years. Beginning in 1980, relevant data were regularly entered in special paperbooks and a systematic update (same data as before) was made at the end of each year. Finally, in 1991, a new computer system and organization were set up with direct online entry of dialysis, laboratory, and clinical data. Since the beginning, the same coding of data has been kept unchanged. The definition of DM varies slightly according to the source: it implies a fasting blood glucose level of 140 mg/dL for the World Health Organization and 126 mg/ dL for the American Diabetes Association (ADA). The 126-mg/ dL fasting level corresponds to a 200mg/ dL level at 2 hours after a glucose load, and according to the ADA, with a 126-mg/dL fasting level, diabetes can be defined by a 200-mg/ dL level 2 hours after a glucose load or by symptoms of diabetes or by a blood glucose level at any time of 200 mg/ dL or more. The distinction between type 1 and 2 is physiopathologic: type 1 is characterized by a lack of insulin secretion due to (3 cell destruction (usually autoimmune). Type 2 is characterized by resistance of peripheral cells to the effect of insulin. Type 1 DM was diagnosed when 2 or more of the following conditions were present: age at onset younger than 25 years, ketosis, need for insulin, body weight :5105% of ideal. Type 2 DM was diagnosed when 2 or more of the following criteria were met: age at onset older than 40 years, body mass index '2':.27 kg/m2 of body area, no ketosis, family story of DM. In Tassin, as in most places, for many years, reliance on the use of insulin to distinguish between insulin-dependent diabetes mellitus (IDDM) and non-insu-

43

lin-dependent diabetes mellitus (NIDDM) has led to overestimation of the proportion of type 1 diabetics. For this study, the classification of type 1 or type 2 was therefore reviewed for each diabetic patient according to actual criteria. The relationship of CRF and diabetes covers different domains: CRF can be caused by DM (whatever its type), but all is not diabetic glomerulosclerosis. 21 CRF can have another cause in a diabetic patient. In type 2 DM, the role of HTA is essential, and it may difficult to differentiate nephrosclerosis from type 2 DM. The diagnosis of DM type may be relevant to clinical outcome. Diabetic patients with type 2 DM or nondiabetic nephropathy have been reported to have a better prognosis than those with diabetic glomerulosclerosis22 although this conclusion has been questioned. 23 On the other hand, DM can appear in 5% to 15% of patients who already are undergoing dialysis or have received transplants 24 and worsen the prognosis in these conditions. In this study, DM discovered more than 3 months after the beginning of dialysis start treatment was not considered (21 patients). The dialysis method used in Tassin has been widely described elsewhere. 25,26 Approximately 80% of patients are treated with long, slow dialysis for 8 hours 3 times weekly, and approximately 20% use a short schedule of 5-hour treatment 3 times weekly. The repartition of these 2 types of dialysis between diabetic and nondiabetic patients was unequal; 20.4% of nondiabetic patients were treated with the short schedule, compared with 11.3% of diabetic patients (P = .005). The dose of dialysis, estimated at quarterly intervals using the second-generation Daugirdas method,27 shows similar amounts of dialysis-as judged by urea Kt/V-was delivered to diabetic and nondiabetic patients (2.036 ± 0.446 v 1.982 ± 0.530 per session, respectively; P = NS). This is confirmed by the urea reduction ratio (URR) data (78.90 ± 5.78 and 78.10 ± 8.93, respectively; P = NS). Normalized protein catabolic rate (PCR) results in the two groups of patients also did not differ significantly (1.236 ± 0.276 v 1.205 ± 0.283, respectively; P = NS). The patients treated by dialysis in Tassin come from different origins. Patients referred directly by general practitioners (and usually

44

Charra et al

followed up in the clinics for several months or years) account for about 50% of the total. The remaining half of the population comes from the 2 big university hospitals or other dialysis units, and they are usually referred later, often after hemodialysis (HD) has already been started. These proportions have remained stable along calendar years. More thanol,lOO patients were accepted in the HD program between 1968 and 1999. A limited number of patients (less than 10 altogether) were not accepted for treatment exclusively for ethical reasons (terminal phase of cancer or hemopathy, dementia). In France, where social coverage is mandatory for the entire population, and dialysis treatment is free of charge to the patient, there has never been any pressure by health authorities to restrict or limit the access of diabetic patients to dialysis. A group of 49 diabetic patients were treated only with peritoneal dialysis (PD) between 1973 and 1992. Intermittent PD was used between 1973 and 1980, then continuous ambulatory PD (CAPD) exclusively. Since 1992, PD has not been used in Tassin. Of the 130 patients treated by PD in Tassin, diabetic patients represented an important part (38%). These diabetic patients were excluded from the study. Significant cardiovascular conditions present before dialysis treatment included coronary diseases (ie, angina and myocardial infarctions [MID, cerebrovascular diseases (ie, transient ischemic attacks [TIA] and cerebrovascular accident [CV AD, and peripheral vascular diseases. Other comorbid conditions such as cancer, chronic obstructive pulmonary disease, and liver or pancreatic disease were not considered as risk factors. Echocardiography measurements were available in approximately 35% of diabetic patients and 25% of nondiabetic patients. They were performed by the same operator between 2 sessions. Calculations were performed using the Penn convention, and results were expressed as left ventricular index (L VMI) in grams per square meter of body area. Among identified risk factors in diabetes, glycosylated hemoglobin, which gives a good estimation of mean glycemic control, and blood pressure (BP) data were collected. The

mean level of available glycosylated hemoglobin was compared in nondiabetic patients and patients with type 1 and 2 DM. Predialysis BP at the start of dialysis and duration of hypertension before dialysis were analyzed, as well as predialysis mean arterial pressure (MAP) during dialysis estimated from the average of all predialysis BP figures. Weight estimation included weight just before the start of the HD and postdialysis weight followed up for the first 5 years of HD. Body mass index (BMI) was evaluated for each patient for the entire dialysis treatment period using postdialysis weight and size. The number of hypertensive episodes during dialysis (systematically entered in the computer files) allowed calculation of incidence over the 2 previous years (approximately 55,000 sessions) and comparison between patient groups. Laboratory data included the mean of all predialysis values collected along maintenance dialysis period. Hematocrit and creatinine were checked every week, and total cholesterol, triglycerides, and apolipoprotein A and B were measured every 6 months.

Morbidity Analysis The hospitalization rate in number of hospitalizations per year of HD treatment and in number of days of HD per year were compared in diabetic and nondiabetic patients and according to type of diabetes. Reasons for hospitalization were analyzed. The different reasons for hospitalization included surgery, blood access, infection, general medical causes, digestive problems, initial hospitalization at the start of dialysis, technical reasons (including hospitalization for diabetes equilibration and vascular and heart explorations), and mental causes. The unpaired t test was used to compare means, and the Jt test was used to analyze distribution. Mortality studies were performed in all patients, including the first 3 months of treatment. Kaplan-Meier survival analysis was used to compare nondiabetic with diabetic patients and to compare patients with type 1 and type 2 DM. The survival difference was assessed using the log rank test. As long as patients with type 1 and type 2 DM differed in demographic and comorbid fac-

~iabetes

45

Mellitus in Tassin, France

Table 1. DM Demographics and Mortality Patients (n) Female (% of total) Age at HD start (yr) Cardiovascular history (% of total) Total years at risk Deaths (n) Deaths/l,OOO patient-years

OM Type 1

OM Type 2

All OM

Non-OM

43 31 44.35 41.86 117.54

119 37 66.41 * 55.46 234.80 65 276.83

162 35.8 60.45 51.85 352.34 78 221.38

939 31.6 50.93t 47.71 6,366.94 390 61.25

13

110.60

'p < .001, type 1 v type 2 OM. tP < .001, OM v non-OM.

tors, a second-step mortality analysis used the Cox proportional hazard model. The analysis of cause-specific mortality included cardiovascular (including sudden death), infectious, cancer, and all other (including unidentified) causes. Mortality rates in number per 1,000 patient-years were compared using the 1" test. The limit of signification was set in all cases at a P value of <.05.

Results Population Data The overall Tassin experience over 32 years (1968 through 1999) included 1,101 patients (939 nondiabetic and 162 diabetic patients; Table 1.) The diabetic population includes a slightly greater number of female patients than the nondiabetic population. The mean age at the start of dialysis is about 10 years older in diabetic than in nondiabetic patients (60.5 ± 15.5 v 50.9 ± 16.9 years; P < .001). When diabetic patients were divided according to type of diabetes, type 1 DM represents 25.6% of the total, with a mean age at the start of dialysis of 42.9 ± 9.4 years, lower (P < .001) than for nondiabetic patients and patients with type 2 DM (mean, 66.1 :!:: 12.6 years). A history of cardiovascular significance was found before dialysis in a similar proportions of diabetic and nondiabetic patients and of patients with type 1 and type 2 OM (42% to 55%; P = NS). The overall experience as of December 31, 1999, represented 6,719 patientyears of HD. Diabetic patients accounted for only about 5% of this experience (352 out 6,366 patient-years).

Epidemiologic Data The prevalent population undergoing maintenance dialysis in Tassin has increased from 18 patients in 1968 to 124 on 1975, 223 in 1980, and 250 in 1985. Since then, it has remained stable at this level. The incident number of patients accepted for HD in the same time increased from 20 patients in 1969, to a mean of 40 per year in the mid-1980s, to about 50 per year since the mid-1990s. The incidence of new diabetic patients accepted for HD in Tassin, expressed as a proportion of total population admitted between 1968 and 1999, is shown on Figure 1. It remained stable, representing less than 5% of the population, until 1992. Thereafter, it increased steeply to reach almost 40% of the incident population in 1999. However, PD, 100% 80%

60% 40%

20% 0%

1968 1972 1976 1980 1984 1988 1992 1996

Figure 1. lncident diabetic HD population in Tassin, 1968 through 1999. D ,oth r ; . ,diabete mellitus.

46

Charra et al

100% 90% 80% 70%

60% 1 50% 40% 30%

20% 10% 0%

1968 1972

1976 1980 1984 1988

1992 1996

Figure 2. Incident diabetic population undergoing HD and PD in Tassin, 1968 through 1999. D , others; ., diabetes mellitus.

which is excluded from our study, was widely used in diabetic patients between 1979 and 1994. Taking into account the 36 diabetic patients admitted to the PD program during this period (Fig 2), the increase in diabetic patients in Tassin appears more progressive over calendar years than that shown in Figure 1. The proportion of diabetic patients admitted in the unit began to increase around 1980. The absolute number of patients with type 1 and type 2 DM who began undergoing dialysis is shown in Figure 3. The incidence of type 1 DM has remained rather stable and limited to 1 to 4 cases per year, whereas the incidence of type 2 DM has increased from 0 to 20 per year. This change has occurred mainly in the last decade.

According to data reported in the literature (Fig 4), in 1994 the number of patients started on dialysis per million population (PMP) varied widely by country and geographic region. From this point of view, the incidence in France was among the lowest, comparable to that in other southern European areas such, as Lombardy in Italy, and in Australia. On the other hand, the northeastern part of France (Alsace and Lorraine) showed an incidence rate of about 50 PMP, which is 3-fold higher than that in southern France and very near the German figure of 52 PMP. The incidence of ESRD in diabetic patients varies with ethnic factors.s In the United States, lout of 2 diabetic patients undergoing HD is black, whereas blacks represented only 12.5% of the total population. The same observation is made in overseas French territories, where the population of African or Indian origin is the majority.28 This is also true for Australian aborigines29 or New Zealand Maoris. 3D The 1994 figures have now changed, and the incidence of ESRF in diabetics over the world is increasing yearly (Fig 5). The increasing incidence and prevalence of ESRF in diabetic patients in Tassin over 30 years expressed as a percentage of the HD population is shown in Figure 6. The prevalence has been constantly lagging behind the incidence rate. This appears especially clear for the last decade. In this decade, ESRF prevalence in Tassin shows an increase but does not reach that of the highest-level countries (the United States and Japan; Fig 7). On the other hand, the 3 estimations performed for the popula-

25 20 Number of new patients

15 10

5

o

1968 1972 1976 1980 1984 1988 1992 1996

Figure 3. Incidence of OM types 1 and 2 in Tassin: calendar evolution. D , type 2 diabetes; . , type 1 diabetes.

47

Diabetes Mellitus in Tassin, France

120 100 80 60 40 20

107

100

93 .8

----

66 25 .6 23.7 23.4 15.9

14

5.9

0

c

75

-----

o

~

"5

g.

50

0.

o i/.

Figure 4. Number of diabetic patients started on dialysis PMP in 1994 according to geographic area.

tion of France by the Uremidiab stud y I9,20,31,32 show that the increase in prevalence in Tassin follows the same trend as that in all of France. Clinical Data Significant cardiovascular histories before dialysis treatment are shown in Table 2. Cerebrovascular, coronary, and peripheral vascular diseases significantly preceded the start of dialysis more often in diabetic than in nondiabetic patients (P < .001). Cardiovascular history was more frequent in type 2 than in type 1 DM, but not significantly so (except for cerebrovascular disease; P = .05). Left ventricular hypertrophy was more often present during maintenance dialysis in diabetic than in nondiabetic patients. The mean left ventricular mass index was 165.4 ± 38.2 g/m2 body surface area in diabetic and 151.0 ± 51.8 g/m2 body surface area in nondiabetic patients (P < .0001). 120,00 100,00

6-

6-

6-

1973

1978

1983

1988

1993

1998

calendar years Figure 6. Incidence and prevalence of ESRF in diabetic patients according to calendar year in Tassin (1968 through 1999). -, incidence %; --, prevalence %.

Other morbidity at the start of HD included (Table 3) amputation, blindness, deafness, and peripheral neuropathy. All were significantly more frequent in diabetic patients, with the exception of mental problems, which were not more frequent than in nondiabetic patients. Mean glycosylated hemoglobin Al was much higher in diabetic than in nondiabetic patients undergoing HD (7.46% ± 1.77% v 4.98% ± 0.89%; P < .0001). Patients with type 1 DM had a significantly higher glycosylated hemoglobin than those with type 2 DM (7.98 ± 2.18 v 7.22 ± 1.67; P < .001) . BP at the start of the dialysis therapy was not different in diabetic and nondiabetic

6-

50,00

A

40,00

80,00 60,00

t

40,00 20,00 1 0,00

1990

<>

30,00 20,00

1992

1994

1996

Figure 5. Number of diabetic patients started on dialysis PMP according to geographic area and calendar year. - +- Lombardy; ---0 --- etherlans; - /:::,. - Finland; -- -X--· Badajoz; -~- Catalonia; --e - Denmark; -+- Sweden; - +- Germany; ___ Alsace; - 0 - Australia; ___ - New Zealand; - A - Japan; ~ USA.

10,00 0,00 1990

1992

1994

1996

Figure 7. Calendar evolution of prevalence rate of DM in Tassin compared with data in the literature. ---0 - Japan; - 0 - USA; X France; - A - Tassin.

48

Charra et al

Table 2. Cardiovascular History Before Dialysis Initiation

Non-DM All DM Type 1 DMt Type 2 DM

Cerebrovascular

Coronary

Peripheral

Total

12.00* 21.60 9.30 26.10

15.76* 39.51 27.50 43.44

18.00* 61.11 52.50 63.93

31.63* 75.93 65.00 79.51

*P < .001, non-DM v DM. +P < .05, type 1 v type 2 DM.

patients (115.29 ± 18.06 v 118.59 ± 21.46; P = NS). On the other hand, patients with type 2 OM had a higher initial BP than those with type 1 OM (119.20 ± 18.01 v 113.68 ± 18.06; P < .001). The mean length of hypertension (or antihypertensive treatment, excluding diuretics) was longer in diabetic than in nondiabetic patients (7.82 ± 7.06 v 4.86 ± 6.66 years; P < .001). The duration of hypertension before dialysis treatment was very different in patients with type 1 and in type 2 OM (4.32 ± 3.34 v 8.96 ± 7.61 years; P < .001). Maintenance dialysis BP values were slightly higher in diabetic than in nondiabetic patients (101.31 ± 11.63 v 97.78 ± 11.84; P < .05). Maintenance dialysis BP was significantly higher in patients with type 1 than type 2 OM (104.39 ± 11.61 v 98.71 ± 11.23; P < 0.01). BP control in patients with type 2 OM and nondiabetic patients undergoing dialysis was similar and significantly better than in patients with type 10M. The initial mean weight at the start of dialysis was similar in diabetic and nondiabetic patients (65.27 ± 14.58 v 64.86 ± 14.45 kg; P = NS) but differed according to the type of OM being much higher in patients with type 2 OM (67.39 ± 14.31 v 58.06 ± 11.59 kg; P = .005). Over the first 5 years of maintenance dialysis, the trend of weight evolution was opposite in the 2 types of diabetes. It decreased in type 2

(mean weight, 67 to 62 kg) but increased in type 1 (58 to 62 kg), so that after 5 years of HO, the mean weight was the same in both groups (62 kg). Hypotension occurred in 67.1 of 1,000 sessions. In diabetic patients, intradialytic hypotension episodes were more frequent (97.5/ 1,000 v 47.7/1,000 sessions) than in nondiabetic patients (P < .001). This occurrence of hypotension was 35% higher in 5-hour HO than in 8-hour HO in both diabetic and nondiabetic patients. The BMI (Table 4) was significantly higher in diabetic patients. This difference was attributable exclusively to patients with type 2 OM, whose BMI of 26.4 was higher than in those with type 1 and in nondiabetic patients. Nutritionallaboratory data mean values for diabetic and nondiabetic patients are shown in Table 5. Hematocrit levels were not significantly different in diabetic and nondiabetic patients. The mean serum creatinine level before dialysis was significantly higher in diabetic patients. Serum albumine and total cholesterol levels were higher in nondiabetic patients, and there was no difference in apolipoprotein B and triglyceride levels. Morbidity and Hospitalization The number of hospitalizations per year of HO was twice as high in diabetic as in nondiabetic patients (2.3 v 1.0 hospitalizations per

Table 3. Comorbid Conditions of Patients at Dialysis Start

Amputation Blindness Deafness Peripheral Neuropathy Mental Illness *P < .001.

Table 4. BMI Versus DM Status Non-DM (%)

DM (%)

0.32 1.06 0.74 3.51 4.25

12.27* 11.04* 2.45* 19.63* 5.52

Mean SD Mean SD

Non-DM

DM

P

22.84 4.17

25.21 6.27

<.0001

Type 1 DM

Type 2 DM

P

22.31 5.11

26.43 6.21

<.0001

49

Diabetes Mellitus in Tassin, France

Table 5. Laboratory Mean Values on Maintenance HD Non-DM

DM

Mean

SD

Mean

Mean

SD

Hematocrit (%) Creatinine (/Lmol/L) Serum albumine (giL) Total cholesterol (mmol/L) Apolipoprotein B (giL) Triglycerides (mmol/L)

28.31 655.69 40.69 5.14 1.25 2.45

5.45 91.79 4.65 1.60 0.35 1.74

29.30 858.22 37.28 4.62 1.21 2.70

4.41 136.42 4.80 1.58 0.35 2.23

dialysis year; P < .01), and the number of days of hospitalization was also double (23.9 v 10.4 hospitalization days per dialysis year; P < .01). The distribution of causes of hospitalization (in percentage of total) in diabetic and nondiabetic patients (Table 6) showed no difference (either in hospitalization stays or in number of days). On the other hand, the number of hospitalization stays and the number of days for each specific cause expressed in number per patient-year were quite different in diabetic and nondiabetic patients (Table 7). Hospitalization related to all causes, with the exception of those related to blood access, was dearly increased in DM: 2-fold for surgery, infection, general, and digestive medicine, 3-fold for initial and technical hospitalizations; 4-fold for mental causes; and 5-fold for cardiovascular causes. Mortality and Causes of Death Figure 8 shows the Kaplan-Meier survival curves for diabetic and nondiabetic patients. The median survival times were grossly 3 years for diabetic and 13 years for nondiabetic patients. The steep initial decrease in the survival curve of diabetic patients illustrates their

P

NS <.0001 <.001 <.01

NS NS

high early mortality. The log rank test shows the important survival difference between nondiabetic and diabetic patients . Dividing type 1 and type 2 diabetic populations allows for a separate Kaplan-Meier analysis; patients with type 1 DM had a significantly longer survival than those with type 2 (Fig 9). Their respective half-lives were 5.2 and 2.7 years. The Cox model analysis results are shown in Tables 8 and 9. In Table 8, monofactorial analysis (first line from the top) shows the difference in survival between diabetic and nondiabetic patients. A significant difference does persist (second line) when age and cardiovascular history prior to dialysis start are entered in the model. In Table 9, the difference in survival between patients with type 1 and type 2 DM observed in the Kaplan-Meier analysis is confirmed by Cox monofactorial analysis (first line from the top). This difference disappears (second line) when age and cardiovascular antecedents before dialysis are entered in the model. The heavy mortality in diabetic patients,

Table 6. Hospitalization and Days per Year of HD Non-DM

Surgery Vascular access Infection General medical Digestive Technical Cardiovascular Mental problems

DM

% of Stays

% Dayslyr

% of Stays

% Dayslyr

21.28 9.09 26.97 17.16 5.58 11.85 5.19 2.87

27.78 6.83 24.70 22.11 4.78 4.92 4.86 3.99

16.21 7.29 18.72 15.08 8.54 19.47 10.18 4.52

23.85 2.86 19.49 13.63 5.33 17.64 10.09 7.11

NOTE. Causes expressed as percent of total.

50

Charra et al

Table 7. Hospitalization Days per Year According to Cause and Diabetes Status

% Survival

Non-DM

DM

2.88 0.71 2.56 1.25 0.49 1.55 0.50 0.41 10.36

5.69 0.68 4.65 2.85 1.30 4.61 2.41 1.70 23.88

Surgery Vascular access Infection General medicine Digestive Initial and technical Cardiovascular Mental Total

together with the increasing diabetic population, explains the increasing gross mortality in the Tassin population over calendar years in spite of unchanged dialysis method. The median survival of the cohort of patients started on dialysis before 1975 was 17 years. It was 13 years for the 1980 through 1984 cohort and only 6.5 years for the 1990 through 1995 cohort. On the other hand, the standardized mortality ratio (SMR), which adjusts for age and cause of ESRF,33 did not change over the last decade (Table 10). Cardiovascular mortality in diabetic patients represents 51.8% of the total mortality, significantly more than in nondiabetic patients (35.6%; P < .005). Infection was the cause of death in 13% of diabetic and 18% of nondiabetic patients (P = NS). Cancer was the cause of death in 11% of nondiabetic and only 4% of diabetic patients (P = NS). Causes of death are better expressed in % Survival 100

80 60

P<.05

4

20

o

o

2

4

6

8

10

12 years

Figure 9. Kaplan-Meier survival curves of diabetic patients undergoing HD in Tassin: type 1 versus type 2 (1968 through 1999). Type 1 DM; ..... Type 2 DM.

number per 1,000 patient-years, as shown in Table 10. Cardiovascular mortality came first, with 122 cardiovascular deaths per 1,000 patient-years. In patients with type 10M, this number is double than in nondiabetic patients. In patients with type 2 OM, the cardiovascular mortality was 3-fold higher than in those with type 1. Infectious deaths were 3-fold more common in diabetic patients than in nondiabetic patients as a whole. In patients with type 10M, infectious deaths were not more common than in nondiabetic patients, but in those with type 2 they were 4-fold more common than in nondiabetic patients or in those with type 10M. There is no difference in cancer mortality. Other miscellaneous causes of death were 3- to 4-fold more frequent in diabetic than in nondiabetic patients.

Discussion There are wide geographical variations in OM CRF incidence and prevalence worldwide. A common point, though, is that ESRF in diabetic patients is increasing everywhere and that this increase is mainly related to type 2 OM.34,35 With some notable exceptions, such as Finland36 and Sardinia,! type 1 diabetes represents a minor proportion of cases leading to CRF. Besides, type 10M-related nephropathy seems to be decreasing9 or remaining stable. A

o 10

Log rank

60

P<.001

20

5

80

Log rank

40

o

10

15

20

25

30 35 years

Figure 8. Kaplan-Meier survival curves of diabetic and nondiabetic patients undergoing HD in Tassin (1968 through 1999). Non diabetic; ..... Diabetic.

51

Diabetes Mellitus in Tassin, France

Table 8. Cox Analysis for Diabetic and Nondiabetic Patients, Excluding (Line 1) or Including (Lines 2-4) Age at Dialysis Start and Cardiovascular Antecedents {3 Coefficient

SE

Relative Risk

95% Confidence Interval

P

Non-OM

-1.319

0.131

0.267

0.207-0.345

<.0001

Non-DM No cardiovascular antecedent Age at start

-0.879 -0.13 0.054

0.134 0.095 0.004

0.415 0.878 1.056

0.319-0.539 0.729-1.057 1.048-1.063

<.0001 .1691 <.0001

Abbreviation: SE, standard error.

tighter control of glycemia and BP should further improve this evolution. 37 Diabetes has changed considerably in the past 2 decades: from a stage at which almost exclusively type 1 DM was reported or even considered a potential cause of CRF, type 2 diabetes has become increasingly more preeminent in Europe,tO as in United States35 and in Japan. 38 In analyzing this change, one must consider that a large proportion of patients with type 2 DM who require insulin were initially misclassified (and sometimes still are).39 However, this does not explain the overall phenomenon. The incidence of type 2 DM is increasing in the overall population. There are logical explanations for this observation: population mean age increase, poor nutritional status, and lifestyle changes leading to overweight are important identified factors. s On the other hand, ESRF may also become more common in DM. Better DM treatment allows an increasing proportion of diabetic patients to avoid premature cardiovascular death and reach the stage of terminal renal failure. 40 The rapid and late increase in incidence and prevalence of DM in our unit reflects rapid increases in France and Europe. As shown in Figure 7, the trend in Tassin is

comparable to the French mean reported in the 3 successive steps of the Uremidiab analysiS. 19,20,31 Another interesting feature of DM epidemiology in Tassin, compared with the US situation, is the less rapid increase in prevalence, which seems to lag behind the steep incidence increase. In the United States in 1997,35 the incidence and prevalence were not very different and had almost achieved a plateau. Things appear very different in Tassin. In 1999, the incidence has almost reached the US level (38.3% v 41.8%), but the prevalence of 18.3% was much lower than in the United States, where it was 33.2%. Two explanations can be offered for this observation. The first is that we may observe a very high output rate of our patients from the dialysis program through high mortality and transplantation rates. The second is that the incidence of diabetic patients grows at a rate with which the dialysis treatment rate cannot catch up for some reason. The diabetic transplantation rate in Tassin has been rather low over the years (12 diabetic patients receiving transplants in Tassin, ie, 3.4% HD years, v 7.8% HD years in white patients in the United States35). The mortality rate of diabetic patients in Tassin is 221 deaths per 1,000 patient-years (Table 1), which com-

Table 9. Cox Analysis for Diabetes Type, Excluding (Line 1) or Including (Lines 2-4) Age at Dialysis Start and Cardiovascular Antecedent {3 Coefficient

SE

Relative Risk

95% Confidence Interval

P

DM type (type 1)

-0.659

0.287

0.518

0.380-1.564

.0219

DM type (type 1) No cardiovascular antecedent Age at start

-0.259 -0.714 0.016

0.361 0.236 0.011

0.771 0.49 1.016

0.293-0.909 0.309-0.777 0.994-1.038

.4719 .0024 .1478

Abbreviation: SE, standard error.

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Charra et al

Table 10. SMR: Tassin, 1989-1999

Calendar Year

Observed/Expected Deaths

SMR

P

1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999

23/43.7 14/42.5 18/44.7 15/ 46.1 23/47.7 20/ 50.3 23 / 57 27/56.4 25 / 48.5 26/47.6 27/67.5

0.53 0.33 0.40 0.33 0 4. 8 0.40 0.40 0.51 0.52 0.55 0.41

<.005 <.001 <.001 < .001 < .001 < .001 <.001 <.001 <.001 <.005 <.001

Abbreviation: SMR, standardized mortality ratio.

pares favorably with the 316 deaths per 1,000 patient-years for white patients in 1997 reported by the US Renal Data System. 35 The first explanation does not. sound reasonable. The alternative explanation is that the incidence rate of ESRF in OM keeps increasing and that prevalence increases more slowly than incidence for other reasons. One could be the lacking or insufficient acceptance rate of diabetic patients, as suggested by Friedman,12 Several facts argue against this explanation. First, as already mentioned, no restriction has ever been made either by nephrologists or by the health authorities in the country to keep diabetic patients from being accepted in dialysis programs. Second, the increase in prevalence is not different in Tassin from that in other parts of the country 15,20 or other parts of the world. 41 -43 The factor that could prevent prevalence from catching up with incidence may be the good overall survival rate of nondiabetic patients in Tassin, especially compared with that of diabetic patients. As shown in Figure 8, the mean half-life of HD diabetic patients in Tassin is slightly over 3 years, whereas it is 13 years in nondiabetic patients. The mortality

rates for diabetic patients in Tassin and in the United States35 are not very different (221 v 280 deaths/l,OOO patient-years; P < .01), whereas the difference in mortality rates in nondiabetic patients is high and very significant (61 v 200 deaths/l,OOO patient-years; P < .0001). The effect of the increasing incidence of diabetic patients undergoing HD in Tassin on prevalence is therefore diluted by the long survival of the nondiabetic patients, who continue for many years to represent the larger proportion of HD patients. In contrast, in the United States, where mortality rates of diabetic and nondiabetic patients are not very different, the increasing incidence has a much more direct and rapid effect on prevalence. There is no reason to believe that the lower prevalence of diabetic patients in Tassin demonstrates a bias against accepting diabetic patients for uremia treatment. The differences in control of glycemia, as judged by hemoglobin AlC control, are small and may appear irrelevant to survival, but the UK Prospective Diabetes Study (UKPDS)44 shows that reducing hemoglobin Ale from 7.9% to 7% correlates with improvement of all diabetes-related endpoints by 12%, of microvascular endpoints by 25%, and of MI by 16% (all values statistically significant). The rapid increase in diabetic population in our unit has come as a surprise, and great effort will be needed to focus more on diabetic patients' specific care needs. A diabetologist was included in the Tassin team only 2 years ago. Another crucial aspect of care concerns BP control. Although in Tassin the focus has always been on BP control and strict dry weight policy, it appears that this may not apply strictly to diabetic patients. There was no difference in BP control between diabetic and nondiabetic patients at dialysis initiation, but thereafter BP was less well controlled in dia-

Table 11. Cause-Specific Deaths (per 1,000 Patient-Years)

Cardiovascular Infectious Cancer Other causes Total

Non-DM

All DM

Type 1 DM

Type 2 DM

21.36 10.52 6.60 21.52 60.00

121.81 31.16 8.50 73.65 235.13

50.85 8.47 8.47 59.32 127.12

157.45 42.55 8.51 80.85 289.36

Diabetes Mellitus in Tassin, France

betic patients. This is important because diabetic patients need tighter BP control than do nondiabetic patients. 45 The UKPOS also shows 46 that reducing the mean arterial pressure even by a limited 7 mm Hg correlates with an improvement of all diabetes-related endpoints by 24%, of microvascular endpoints by 37%, and of stroke by 40% (all values are highly statistically significant). There is a large benefit in tightly controlling glycemia and BP in diabetic patients, whether they are undergoing dialysis or not. Efforts should be made to improve BP control in the years preceding dialysis, especially in patients with type 2 OM. The evolution of weight and BP with HO in diabetic patients deserves some comment. Weight in diabetic patients followed a trend different from that in nondiabetic patients. Patients with type 2 OM were usually overweight, and their BMI was higher. The trend toward weight loss in the first few months of dialysis observed in nondiabetic patients26,47 was attenuated in diabetic patients. This might indicate impaired extracellular volume (ECV) control, leading to more hypertension. On the other hand, the common occurrence of hypotensive episodes during dialysis in diabetic patients may explain in part the difficulty of achieving dry weight and controlling BP. It is especially important to focus on volume and BP control in diabetic uremic patients because cardiovascular antecedents are common at the start of dialysis. As a consequence, cardiovascular morbidity is a much more common cause of hospitalization than in nondiabetic patients. Cardiovascular deaths are 5- to 6-fold more frequent (Table 10) in diabetic than in nondiabetic patients. In those with type 2 OM, the proportion reaches 7-fold. Although diabetic patients were treated proportionally more often with the long, slow dialysis schedule, they experienced significantly more events, especially hypotensive episodes, during dialysis sessions than nondiabetic patients. This confirms the sensitivity of diabetic patients to ultrafiltration.48 The malnutrition often reported in diabetic HD patients49 is not really confirmed in our study: BMI was higher in diabetic patients, and mean serum creatinine level before dial-

53

ysis was also higher. On the other hand, serum albumin and total cholesterol were slightly lower than in nondiabetic patients. The higher number of hospitalizations per year of HO and the longer hospitalization stays than in nondiabetic patients are related to all causes, with the exception of those related to blood access. This is an interesting and unusual point that may be related to the high use of native arteriovenous fistulas. The highest increment of risk was attributable to cardiovascular morbidity. The median survival of 3 years for diabetic patients (including the first 3 months of treatment) contrasts with 13 years for nondiabetic patients. This difference is not surprising: even adequate treatment of ESRF does not protect the patient from the ill effects of poor control of glycemia and hypertension over years. It also does not protect the patient from the effects of age and comorbidity. Although a large dose of dialysis improves survival of diabetic patients undergoing HO,50 diabetic patients did not survive significantly longer in Tassin than in Nottingham, in spite of a higher dose of HO and better BP contropl The explanation probably lies in part in the limited number of patients at risk in this study, but the effect of dialysis treatment per se is also most obvious in low-risk subgroups of patients. 52 The longer survival of patients with type 1 than of those with type 2 OM was observed long ago by others.53,54 In this analysis, it disappears when age and cardiovascular antecedents before dialysis are considered. In other words, the survival difference observed between types 1 and 2 is explained by the difference in the patients' case mix, especially by the difference in cardiovascular history before dialysis. The long survival achieved in Tassin is mainly related to a low cardiovascular mortality compared with other reported HO series. 55 Cardiovascular events are by far the first cause of mortality in HO. In proportion to other causes of mortality, they are not much more frequent than in nondiabetic patients, but things appear quite different in terms of absolute risk. Cardiovascular deaths are about 3-fold more frequent than in the age-adjusted nondialysis French population (Table 11). In

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Charra et al

the overall diabetic HD population, although BP control is as good as in nondiabetic patients, cardiovascular mortality reaches 121 cardiovascular deaths per 1,000 patient-years, 6 times higher than in nondiabetic HD patients and 18 times higher than in age-adjusted nonuremic subjects. Again, an important difference is observed between type 1 and type 2 DM. In patients with type 1 DM, cardiovascular mortality is "only" 2-fold higher than in nondiabetic HD patients, whereas in those with type 2 DM it is 8-fold higher (24fold higher than in the age-adjusted standard population). The cost of poor BP control before dialysis is obviously very high in terms of mortality. Deaths of infectious causes are 3-times more common in diabetic than in nondiabetic patients as a whole (Table 11). In those with type 1 DM, infectious deaths are not more common than in nondiabetic patients, but in those with type 2 DM, infectious deaths are 4 times more common. There is no difference in cancer mortality. Other causes of death are also 3 to 4 times more frequent in diabetic than in nondiabetic patients (Table 11). We have tried to summarize the changes in a single unit (using the same unchanged HD method over 30 years) related to the impressive increase in DM. We had hoped that the increase in incidence and prevalence of diabetes long announced and reported by others 17,49,54,56 would spare our population as a kind of second French paradox, but it did not. Although the gravity of the situation has not reached the catastrophic proportions reported elsewhere,57,58 the increase in diabetes in the last decade has deeply affected this aspect of HD treatment in our unit. The crude mortality has increased drastically, although the SMR has not changed. Diabetic patients received a comparable dose of dialysis and had comparable control of hypertension and a grossly similar nutritional state as nondiabetic patients, yet the cardiovascular mortality and morbidity were impressively higher in diabetic patients. This is particularly true for those with type 2 DM. This finding suggests a strong need for better predialysis treatment and prevention of cardiovascular disease. This retrospective inquiry has also been an opportunity for us to realize that there was a strong

need for improvement in the care of diabetic patients' specific problems. Tighter control of glycemia, systematic detection of silent coronary disease, and regular eye and foot examinations are needed and should improve the overall results of treatment of diabetic patients with HD.

References 1. EURODIAB ACE Study Group: Variation and trends in incidence of childhood diabetes in Europe. Lancet 355:873-876, 2000 2. Onkamo P, Vaananen S, Karvonen M, et al: Worldwide increase in incidence of type 1 diabetes-The analysis of the data on published incidence trends. Diabetologia 42:1395-1403,1999 3. White F, Nanan D: Status of national diabetes programmes on the Americas. Bull World Health Organ 77:981-987, 1999 4. Heine RJ: Diabetes in the next century: Challenges and opportunities. Neth J Med 55:265-270, 1999 5. Cowie CC, Port FK, Wolfe RA, et al: Disparities in incidence of diabetic end-stage renal disease according to race and type of diabetes. N Engl J Med 321:1074-1079,1989 6. Bruce R, Williams L, Cundy T: Rates of progression to end stage renal failure in nephropathy secondary to type 1 and type 2 diabetes mellitus. Aust N Z J Med 24:390-395, 1994 7. Hasslacher Co Ritz E, Wahl P, et al: Similar risks of nephropathy in patients with type I or type II diabetes mellitus. Nephrol Dial Transplant 4:859-863, 1989 8. Ritz E, Orth SR: Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med 341:1127-1133, 1999 9. Bojestig M, Amqvist HI. Hermansson G, et al: Declining incidence of nephropathy in insulin-dependent diabetes mellitus. N Engl J Med 330:15-18, 1994 10. Raine AEG: Epidemiology, development and treatment of end-stage renal failure in type 2 (non-insulindependent) diabetic patients in Europe. Diabetologia 36:1099-1104,1993 11. United States Renal Data System: USRDS 1993 Annual Data Report, Bethesda, MD: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 1993 12. Friedman EA: Haemodialysis for French diabetic patients. Nephrol Dial Transplant 14:30-31, 1999 13. Laurent G, Calemard E, Charra B: Haemodialysis for French diabetic patients. Nephrol Dial Transplant 14: 2044-2045, 1999 (letter) 14. Cordonnier D, Halimi S, Zaoui P: Health policies and epidemiology of diabetes among dialysed patients in France. Nephrol Dial Transplant 14:2519, 1999 (letter) 15. Guiserix J: Survival comparisons in haemodialysis between France and USA. Nephrol Dial Transplant 14:2519, 1999 (letter) 16. Locatelli F, Marcelli D, Conte F, et al: 1983 to 1992: Report on regular dialysis and transplantation in Lombardy. Am J Kidney Dis 25:196-205, 1995

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