Improved survival of type 2 diabetic patients on renal replacement therapy in Finland

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1 Nephrol Dial Transplant (2010) 25: doi: /ndt/gfp555 Advance Access publication 21 October 2009 Improved survival of type 2 diabetic patients on renal replacement therapy in Finland Marjo Kervinen 1, Seppo Lehto 1, Risto Ikäheimo 2, Pauli Karhapää 1, Carola Grönhagen-Riska 3,4 and Patrik Finne 3,5 1 Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland, 2 Department of Internal Medicine, Oulu University Hospital, Oulu, Finland, 3 Finnish Registry for Kidney Diseases, Helsinki, Finland, 4 Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland and 5 School of Public Health, University of Tampere, Tampere, Finland Correspondence and offprint requests to: Dr. Marjo Kervinen; marjo.kervinen@kuh.fi Abstract Background. Survival of type 2 diabetes mellitus patients on maintenance dialysis therapy is poor mainly due to cardiovascular events. The aim was to examine whether survival of type 2 diabetes patients on renal replacement therapy (RRT) in Finland has improved during Methods. Patients who entered RRT because of type 2 diabetes mellitus in (n = 314) and (n = 583) were identified within the Finnish Registry for Kidney Diseases. The two cohorts were followed up from start of RRT until death or end of follow-up on 31 December Survival probabilities and probabilities of receiving a kidney transplant were calculated using Kaplan Meier curves. Multivariate modelling was performed using Cox regression. Results. Patients who entered RRT in had lower risk of dying than those who entered in ; hazard ratio (HR) was 0.76 (95% CI ) and 0.74 (95% CI ) with adjustment for age and gender. The decreased risk of death was most obvious in age groups (HR 0.67, 95% CI ) and 65 74years (HR 0.69, 95% CI ). Adjustment for albumin in addition to age and gender only slightly weakened the effect of study periods (HR 0.83, 95% CI ). The patients in were more obese, had lower total and LDL cholesterol and higher HDL cholesterol and albumin concentration in serum than patients in Patients' probability to receive a kidney transplant was low in both groups. Conclusions. Survival of type 2 diabetes patients on RRT improved during the time period in Finland while the probability of receiving a kidney transplant remained low and unchanged. Keywords: diabetes mellitus; end-stage renal disease; survival Introduction Since the beginning of the 1990s, the incidence of renal replacement therapy (RRT) has increased more rapidly due to type 2 diabetes than due to any other diagnosis [1]. Similar trends were observed in data from 10 European national registries [2]. Diabetes is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) [3], and the prevalence of type 2 diabetes is increasing worldwide. Cardiovascular disease is the major cause of mortality both among patients with CKD and among diabetic patients [4]. Insulin resistance, lipid disturbances and hypertension predispose to premature atherosclerosis and cardiovascular derangements, which increase the risk of mortality [5]. In a study of Foley et al. [6], diabetic patients were more likely to have left ventricular hypertrophy (LVH), ischaemic heart disease, previous myocardial infarction and cardiac failure prior to start of dialysis therapy. Age, LVH, smoking, ischaemic heart disease, cardiac failure and hypoalbuminaemia were shown to associate independently with mortality. In addition to traditional risk factors for cardiovascular disease, other things such as prothrombotic agents, inflammatory markers and characteristics of chronic uremia may concern the dialysis patient [7,8]. Böger et al. [9] presented a genetic predictor of survival in type 2 diabetic patients on maintenance haemodialysis therapy. The survival of type 2 diabetic patients on maintenance dialysis is poor mainly due to cardiovascular events [6]. The median survival time for diabetic patients on dialysis has been <3years, i.e. much lower than in non-diabetic patients [1,6]. Kidney transplantation is known to improve the survival of diabetic patients on the kidney transplantation waiting list [10]. Today, risk factors for cardiovascular disease are probably better controlled than in the 1990s. This should lead to improved survival of type 2 diabetic patients on RRT. The aim of this study was to examine whether the survival of The Author Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 Survival of type 2 diabetes mellitus patients on renal replacement therapy 893 type 2 diabetic patients on RRT has improved during the time period Table 1. Characteristics of the study population P value Methods Study population Patients who entered RRT because of type 2 diabetes in and were identified within the Finnish Registry for Kidney Diseases. This registry is maintained by the Finnish Kidney and Liver Association and is supported by Finnish governmental grants. The registry covers ~97 99% of all dialysis and kidney transplantation patients in Finland [11]. The study was approved by the Ethics Committee of the University of Kuopio and the board of the Finnish Registry for Kidney Diseases. We also state our adherence to the Declaration of Helsinki. Data on patients' age, sex, kidney disease diagnosis, body mass index, glycated haemoglobin A1c (A1c), cholesterol, albumin, phosphate, blood pressure, haematocrit, date of first kidney transplantation and comorbidities (coronary heart disease, hypertension, peripheral vascular disease, cerebrovascular disease) at start of RRT are available in the registry. Age at start of RRT was analyzed in four categories: <55, 55 64, and 75years. Causes of mortality were classified into three groups: cardiovascular including all cardiac causes as well as other vascular causes, infection and other cause except kidney disease itself. Statistical methods Patients were followed up until 31 December Comparisons between groups were performed by Mann Whitney test for continuous variables and the chi-square test for categorical variables. Survival probability was calculated using the Kaplan Meier method. Death was the event and patients were censored at the end of follow-up time. Differences in survival probabilities between groups were assessed using the log rank test. The Kaplan Meier method was also employed to calculate the probability of receiving a kidney transplant. Patients' first transplantation was the event and censoring occurred at time of death or at the end of follow-up time. Multivariate modelling of survival probabilities was performed using Cox proportional hazards regression. Statistical analyses were performed using SPSS version Two-sided P values <0.05 were considered statistically significant. Results N Men 184 (59%) 371 (64%) Age when RRT started (years) 65.4 ± ± 9.4 NS Body mass index (kg/m 2 ) 28.0 ± ± 5.9 <0.001 A1c (%) 7.7 ± ± Total cholesterol (mmol/l) 4.75 ± ± 1.40 <0.001 LDL cholesterol (mmol/l) 2.82 ± ± 1.26 <0.001 HDL cholesterol (mmol/l) 0.98 ± ± Total triglycerides (mmol/l) 2.13 ± ± Systolic blood pressure (mmhg) 157 ± ± 24 NS Diastolic blood pressure (mmhg) 80 ± ± Albumin (g/l) ± ± 6.27 <0.001 Phosphate (mmol/l) 1.95 ± ± 0.59 NS Haematocrit (%) 31.4 ± ± HD (n) 257 (82%) 490 (84%) NS PD (n) 57 (18%) 93 (16%) NS Kidney transplant (%) Data are means ± SD. RRT = renal replacement therapy, HDL = high density lipoprotein, LDL = low density lipoprotein, HD = haemodialysis, PD = peritoneal dialysis, NS = not significant P value > A total of 897 patients were identified of whom 314 started RRT in (group 1) and 583 in (group 2). The clinical characteristics of the two patient groups are described in Table 1. The mean age of the patients was 65 66years in both groups (range 33 87years in group 1and31 88years in group 2). The patients in group 2 were more obese, had a lower total and LDL cholesterol concentration in serum and a higher level of HDL cholesterol. Patients who entered RRT in also had higher haematocrit values than those who entered in Glycated haemoglobin A1c and diastolic blood pressure were lower in group 2 than group 1, whereas no significant differences between the two groups were found regarding systolic blood pressure. Serum albumin values were higher in group 2 than in group 1. The proportional amounts of haemodialysis (82 84%) or peritoneal dialysis (18 16%) patients did not differ between the groups. Of the patients in group 2, 41% had coronary heart disease, 89% had hypertension, 28% had peripheral vascular disease and 14% had a history of cerebrovascular disease at start of dialysis therapy. The number of kidney transplant recipients remained low in both groups during the follow-up time: 7.6% in group 1 and 7.2% in group 2. It should be noted that, especially in group 2, some patients still waited for transplantation at the end of follow-up. During follow-up, 291 of 314 patients in group 1 and 341 of 583 patients in group 2 died. The distribution of death causes was similar in both groups: 45 49% of the patients died of cardiovascular diseases, 19 21% of infection and 21 24% of other causes. The cumulative survival probability was higher both in males and females in compared to (log rank P = 0.001). The median survival time was 2.23years in group 1 and 2.99years in group 2 (Figure 1). In multivariate analysis with adjustment for age and gender, patients who entered RRT in had lower risk of dying than those who entered in (hazard ratio [HR] 0.74, 95% CI ; P < 0.001). Gender was not significant in the multivariate model (P = 0.902). Adjustment for blood pressure at start of RRT or body mass index did not affect the effect of study periods on prognosis. With adjustment for phosphate, the effect of study periods remained significant, but when adjusting for albumin in addition to age and gender, the effect of study periods appeared slightly weaker (HR 0.83, 95% CI ; P = 0.057). Low serum albumin is a known risk factor of mortality in diabetic end-stage renal disease patients. The proportion of patients >75years at start of dialysis was 2-fold in (Table 2). In this age group, survival did not improve over time (log rank P = 0.354; Figure 2). Median survival was 2.51years (95% CI ) in group 1 and 2.05years (95% CI ) in group 2. The difference in survival between the groups remained insignificant with adjustment for age and gender (P = 0.474), with median age at start of dialysis being 78.0years in group 2 and 76.7years in group 1. Almost half of the patients were 65 74years old at start of RRT. In this group, median sur-

3 894 M. Kervinen et al. Cumulative survival Cumulative survival Time of follow-up (years) Fig. 1. Kaplan Meier survival curves comparing type 2 diabetes mellitus patients who started renal replacement therapy (RRT) in (solid line) and (dashed line). P = Table 2. The percentages of different age groups (type 2 diabetes patients) at start of dialysis in and in Finland Age (years) % (n = 40) 12.3% (n = 72) % (n = 84) 31.0% (n = 181) % (n = 164) 40.5% (n = 236) % (n = 26) 16.1% (n = 94) All 100% (n = 314) 100% (n = 583) vival was only 1.72years (95% CI ) in group 1 and 2.64years (95% CI ) in group 2 (log rank P = 0.001). When adjusting for age and gender, HR for death was 0.69 (95% CI ) in compared to In year-olds, median survival in group 1 was 2.41 (95% CI ) and 3.76 (95% CI ) in group 2 (log rank P = 0.010). Age- and gender-adjusted HR for death was 0.67 (95% CI ) in compared to in this age group. In the youngest age group (0 54-year-olds), no significant difference in the survival probabilities was detected between group 1 and group 2 (log rank P = 0.732). Their median survival was 5.26 (95% CI ) in group 1 and 5.16 (95% CI ) in group 2. Age and gender adjustment did not alter the result (P = 0.748), with median age at start of dialysis being 51 years in both groups (Table 3). The probability to get the first kidney transplant after the start of RRT was not different (log rank P = 0.989) in the years compared to When the probability of kidney transplantation was adjusted for age and gender, there was no significant difference between the two time periods (P = 0.889). Discussion Time of follow-up (years) Fig. 2. Kaplan Meier survival curves comparing type 2 diabetes mellitus patients >75years old who started RRT in (solid line) and (dashed line). P = The cumulative survival of both male and female type 2 diabetic patients on RRT in Finland has improved during the past years. In general, the mortality of all dialysis patients in Finland has decreased in recent years [1]. In diabetic patients, this may be a result of improved diabetic care and successful preventive measures. Type 2 diabetic patients are increasingly treated with effective blood pressure drugs. Their glycaemic control has been more targeted to the best known goals with modern medication and methods. The use of statins and recombinant human erythropoietin medication for anaemia has become more ordinary in the treatment of this patient group. There are also more options to treat the disturbances of active vitamin D, hyperphosphataemia and secondary hyperparathyroidism. These developments may also prevent vascular calcification. The use of renin angiotensin aldosterone system blockers is beneficial both in renoprotection and for reducing the risk of cardiovascular events [12]. The use of statins in patients on dialysis has shown either beneficial effects or mixed results in some studies [13,14]. Type 2 diabetic patients on haemodialysis may benefit from statins irrespective of baseline LDL cholesterol level [15], which can be due to effects of statins on endothelial function or inflammation. Notably, type 2 diabetic patients with CKD often have advanced cardiovascular diseases when dialysis begins. According to the 4D study [16], statin therapy was not useful in type 2 diabetes mellitus patients on dialysis but should be implemented earlier during the course of progressive vascular damage. Erythropoietin treatment for anemia has become more common and is one of the risk reduction mechanisms in CKD patients [17]. However, aiming at a haemoglobin level

4 Survival of type 2 diabetes mellitus patients on renal replacement therapy 895 Table 3. Hazard ratio (HR) of death in type 2 diabetes patients by age groups in (group 2) and (group 1) in Finland adjusted for age and gender Age group Number of patients Variable HR (95% CI) a P value 0 54years 112 Group 2 vs group ( ) Age 1.02 ( ) Gender (female vs male) 1.52 ( ) years 265 Group 2 vs group ( ) Age 1.09 ( ) Gender (female vs male) 0.73 ( ) years 400 Group 2 vs group ( ) Age 1.03 ( ) Gender (female vs male) 1.15 ( ) years 120 Group 2 vs group ( ) Age 1.10 ( ) Gender (female vs male) 0.74 ( ) All Group 2 vs group ( ) <0.001 Age <0.001 Gender (female vs male) 0.99 ( ) a All hazard ratios (HR) are for the comparison between patients who entered RRT in (group 2) and those who entered in (group 1). >120g/l has been shown to increase risk for death and cardiovascular complications [18]. Technological or procedural development of dialysis therapy can help protect patients from cardiovascular events [19]. Dialysis therapy should be started early enough to improve the survival of the patients. Dialysis patients may be more effectively dialyzed today than in the 1990s. The burden of cardiovascular calcification in CKD patients can be reduced more efficiently with the dialysis treatment of today [20]. All the improvements in the care of ESRD patients are likely to reduce the overall mortality. The guidelines for the best dialysis treatment are part of this improved care. Diabetes is a vascular disease and cardiovascular risk factors should be efficiently controlled already at earlier stages of CKD. In this respect, improvements have probably occurred over the past years. This might be a reason why the incidence of RRT due to type 2 diabetes stopped increasing in the beginning of the 2000s. It can also be a reason for the decreased mortality of type 2 diabetic patients on RRT. Still, almost half of the patients in had coronary heart disease when dialysis began, and half of the deaths were caused by cardiovascular disease. In the first part of our study, the number of new RRT patients due to type 2 diabetes increased during the past decade, in the same way which the European data have shown [2]. However, in Finland, this increase has stopped since the year The fact that the patients were more obese in is in line with the general trend in the Western world. Not surprisingly, total, LDL and HDL cholesterol values were more favorable in with more frequent use of statins. Anaemia is better treated today, and the patients are probably not as volume loaded at start of dialysis as before. Today, more attention is most likely paid to low serum albumin values as a risk factor for mortality. In our results, the albumin values were higher in than in The A1c values were lower in , but according to other studies this may not affect survival of type 2 diabetic patients on dialysis [21,22]. It may be due to the fact that glycaemic control already is fairly good in most diabetic patients on dialysis or that other factors contribute more to the survival at this stage of CKD. Type 2 diabetic patients often have comorbidities at start of RRT. Somewhat surprisingly, the proportion of patients receiving a kidney transplant remained under 8% even in recent years. Because of many comorbidities, few type 2 diabetic patients ever reach the waiting list for transplantation. For type 2 diabetic patients who received a transplant, waiting time was similar as for other transplanted patients during the two periods. The probability of receiving a renal transplant did not get better over the decades, so this does not explain the improved survival. Sørensen et al. [23] found in Danish type 1 and type 2 diabetic patients a significantly improved survival rate observed among transplanted patients compared with dialysis patients on the waiting list for transplantation; however, even in their study, only few type 2 diabetic patients ever received transplantation (5%). It seems that type 2 diabetic patients often have worse possibilities to reach the transplantation than type 1 diabetic patients. In a study by Villar et al. [24], it was confirmed that survivals are different between ESRD patients with type 1 and type 2 diabetes; and also in their study, <10% of type 2 diabetic patients ever received renal transplantation but had significantly improved survival over the time period in Australia and New Zealand. The number of new RRT patients aged 75years has increased considerably. Murtagh et al. [25] found that patients >75years old entering dialysis had better survival than conservatively managed patients with advanced CKD. However, this was not true for patients with high comorbidity scores. Among type 2 diabetic patients >75 years old, the survival in RRT did not improve over time in Finland. However, when studying the whole cohort of type 2 diabetic patients on RRT, survival had improved which was observed even without adjusting for age. This calls attention to the considerable improvement in survival among year-old patients.

5 896 M. Kervinen et al. Approximately half of the patients on dialysis die of cardiovascular diseases. Therefore, the reduction of risk factors for cardiovascular disease is essential when striving to improve survival. Infection causes one-fifth of deaths, and preventing infection remains important for dialysis patients. A closer study of individual risk factors for mortality would be important to identify the factors affecting mortality the most. This could help improve survival of type 2 diabetic patients on RRT in the future. The overall risk reduction in type 2 diabetic patients can decrease the risk of ESRD, which in fact already has been seen during the past 5years in Finland [1]. In conclusion, the survival of type 2 diabetic patients on RRT has improved since 1995 in Finland. Conflict of interest statement. None declared. References 1. Finnish Registry for Kidney Diseases. Annual report 2005: Finland- Helsinki. Finnish Registry for Kidney Diseases, available from (2006). 2. Van Dijk PC, Jager KJ, Stengel B et al. Renal replacement therapy for diabetic end-stage renal disease: data from 10 registries in Europe ( ). Kidney Int 2005; 67: McFarlane SI, Salifu MO, Makaryus J et al. Anemia and cardiovascular disease in diabetic nephropathy. Curr Diab Rep 2006; 6: McFarlane SI, Banerji M, Sowers JR. Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 2001; 86: El-Atat FA, Stas SN, McFarlane SI et al. The relationship between hyperinsulinemia, hypertension and progressive renal disease. JAm Soc Nephrol 2004; 15: Foley RN, Culleton BF, Parfrey PS et al. Cardiac disease in diabetic end-stage renal disease. Diabetologia 1997; 40: Parfrey PS, Foley RN. The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol 1999; 10: Vlagopoulos PT, Sarnak MJ. Traditional and nontraditional cardiovascular risk factors in chronic kidney disease. Med Clin North Am 2005; 89: Böger CA, Fischereder M, Deinzer M et al. RANTES gene polymorphisms predict all-cause and cardiac mortality in type 2 diabetes mellitus hemodialysis patients. Atherosclerosis 2005; 183: Rabbat CG, Thorpe KE, Russell JD et al. Comparison of mortality risk for dialysis patients and cadaveric first renal transplant recipients in Ontario, Canada. J Am Soc Nephrol 2000; 11: Finne P, Reunanen A, Stenman S et al. Incidence of end-stage renal disease in patients with type 1 diabetes. JAMA 2005; 294: Burnier M, Zanchi A. Blockade of the renin angiotensin aldosterone system: a key therapeutic strategy to reduce renal and cardiovascular events in patients with diabetes. J Hypertens 2006; 24: Baber U, Toto RD, de Lemos JA. Statins and cardiovascular risk reduction in patients with chronic kidney disease and end-stage renal failure. Am Heart J 2007; 153: Molitch ME. Management of dyslipidemias in patients with diabetes and chronic kidney disease. Clin J Am Soc Nephrol 2006; 1: Gotz AK, Böger CA, Hirschmann C et al. Effect of HMG-CoAreductase inhibitors on survival in type 2 diabetes patients with end stage diabetic nephropathy. Eur J Med Res 2005; 10: Wanner C, Krane V. Lessons learnt from the 4D trial. Nephrol Ther 2006; 2: Spiegel DM. Anemia management in chronic kidney disease: what have we learned after 17years? Semin Dial 2006; 19: Singh AK, Fishbane S. The optimal hemoglobin in dialysis patients a critical review. Semin Dial 2008; 21: Ronco C, Bowry S, Tetta C. Dialysis patients and cardiovascular problems: can technology help solve the complex equation? Blood Purif 2006; 24: Qunibi WY. Reducing the burden of cardiovascular calcification in patients with chronic kidney disease. J Am Soc Nephrol 2005; 16 (Suppl 2): S95 S Okada T, Nakao T, Matsumoto H et al. Association between markers of glycemic control, cardiovascular complications and survival in type 2 diabetic patients with end-stage renal disease. Intern Med 2007; 46: Williams ME, Lacson E Jr, Teng M et al. Hemodialyzed type I and type II diabetic patients in the US: characteristics, glycemic control, and survival. Kidney Int 2006; 70: Sørensen VR, Mathiesen ER, Heaf J et al. Improved survival rate in patients with diabetes and end-stage renal disease in Denmark. Diabetologia 2007; 50: Villar E, Chang SH, McDonald SP. Incidences, treatments, outcomes, and sex effect on survival in patients with end-stage renal disease by diabetes status in Australia and New Zealand ( ). Diabetes Care 2007; 30: Murtagh FE, Marsh JE, Donohoe P et al. Dialysis or not? A comparative survival study of patients over 75years with chronic kidney disease stage 5. Nephrol Dial Transplant 2007; 22: Received for publication: ; Accepted in revised form: Received for publication: ; Accepted in revised form: