Diabetes and Transplant Centres, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
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Abstract |
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Methods. All first cadaveric renal transplants performed in type 2 diabetic patients from January 1, 1988 to December 31, 1998 in our centre were included. Non-diabetic controls were individually matched with diabetic patients with respect to year of transplantation, sex, age, selected immunological parameters, and graft cold ischaemia.
Results. We included 64 type 2 diabetic and 64 non-diabetic patients who were followed for a mean period of 37±27 and 41±31 months, respectively, after renal transplantation. Patient survival at 1 and 5 years post-transplant was 85 and 69 vs 84 and 74% (P=0.43, NS), while graft survival rates censored for patient death were 84 and 77 vs 82 and 77% for diabetic and non-diabetic subjects, respectively (P=0.52, NS). With graft survival results not censored for death with functioning graft, no significant change was seen (diabetic vs non-diabetic group: 77 and 54 vs 73 and 61%, P=0.19, NS). Age, but not the presence of diabetes, was the only factor significantly affecting patient survival when both patient groups were pooled. With regard to post-transplant complications requiring hospitalization, there was a significant difference only in the number of patients who had amputations (diabetic vs non-diabetic group: 8 vs 0, P=0.01).
Conclusions. Patient and graft survival after kidney transplantation was similar in type 2 diabetic and matched non-diabetic subjects, with more amputations occurring in the diabetic group. Thus, at a single-centre level renal transplantation results almost equivalent to those in non-diabetic patients may be achieved in type 2 diabetes mellitus.
Keywords: kidney transplantation; outcome; type 2 diabetes mellitus
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Introduction |
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Additionally, the designation of the type of diabetes in many patients with end-stage renal failure often remains uncertain. In the past, many type 2 diabetics treated with insulin were wrongly classified as insulin-dependent or, even more commonly, no distinction of the type of diabetes would be made.
Significantly worse transplantation results in type 2 diabetic patients in comparison with other patient groups have been reported in the few available studies. However, while this undoubtedly reflects the high-risk nature of this population, several variables important for an analysis of graft and patient survivalin particular related to immunological status and graft harvestingmay have not been controlled sufficiently. This may be of particular importance since, due to the presence of several risk factors, vascular morbidity and mortality is substantially increased in the end-stage renal disease population as a whole. Therefore, the current study was undertaken to evaluate the results of kidney transplantation in type 2 diabetic patients in comparison with carefully matched non-diabetic controls.
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Subjects and methods |
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Using the same transplant list which did not include information on transplantation results, non-diabetic controls who had had a first non-related cadaveric kidney graft in our centre were matched individually (first moving forward, then backward on the list) with the type 2 diabetic patients for the following criteria ranked in order of importance: year of transplantation (at most ±1 year), sex, age (±5 years), number of donor HLA A, B and Dr antigen mismatches (±2 max.), pre-transplant recipient's highest historic level of pre-sensitization to HLA antigens expressed as panel reactive antibody percentage (PRA) (020, 2179, 80100%), duration of graft cold ischaemia (±5 h), and duration of pre-transplant dialysis (±12 months).
Additional information, when available, was obtained from pre-transplant hospitalization records for the diabetic patients: date of diagnosis of diabetes, type of pre-transplant treatment (diet, oral anti-diabetic drugs, or insulin), level of metabolic control as assessed by HbA1c using ion exchange HPLC (BioRad Diamat Analyzer System, Bio-Rad Laboratories GmbH, Munich, Germany), and presence of background or proliferative diabetic retinopathy or blindness. Information on primary renal disease (whether biopsy-proven or not), time of initiation and the type of dialysis treatment, history of hospitalization for myocardial infarction or stroke, or of amputation was collected for all patients. Smoking status, results of extensive cardiovascular examinations (thallium-scintigraphy or coronary angiography), and the use of anti-hypertensive or hypolipidaemic treatments were also recorded for a comparison of cardiovascular risk in both groups. Pre-transplant clinical and laboratory data that were collected included: body mass index (BMI), blood pressure, haematocrit, albumin, cholesterol, and triglyceride levels.
Post-transplant information was obtained from standard transplantation follow-up protocols used in our institution and from all post-transplant hospitalization records until graft failure (initiation of dialysis) or death. This included: use of anti-T-cell induction therapy, the type of initial immunosuppressive regimen, creatinine, blood pressure, cholesterol and triglyceride levels at 1, 2, 3 and 5 years post-transplant, and the occurrence of complications requiring hospitalizationspecifically, hospitalization for graft complications necessitating operative intervention, myocardial infarction, stroke, heart failure, pulmonary thromboembolism, infection, malignancy, any amputations and complete loss of sight. Patients were followed until death or December 31, 1999, so that a minimal 1-year follow-up would be ensured in all living patients.
Statistical analysis
Group differences in discrete variables were compared with the 2 test, with Yates correction in case of expected values of less than 5. For continuous variables, Student's t-test or MannWhitney U test were used as appropriate. Patient and graft survival curves were calculated according to the KaplanMeier method. Patient deaths occurring 60 days or more after return to dialysis (in cases of graft failure) were censored, graft survival curves were calculated for death with functioning graft censored and without. The curves were compared using the log-rank test. Cox proportional hazards model was used to assess the effect of selected factors (presence of diabetes, sex, BMI, age, duration of dialysis, smoking status, and blood pressure pre-transplant) on patient and graft survival with the two patient groups pooled.
Means and standard deviations are presented unless otherwise stated. A P value <0.05 was considered statistically significant. We used BMDP 1990 software package for statistical calculations.
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Results |
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An identical number of controls with the same male to female ratio were selected. Pre-transplant clinical and laboratory data for both groups are shown in Table 1.
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No difference was found between the groups also with regard to immunological and transplantation-associated variables (Table 1). Induction anti-T-cell therapy had been used with equal frequency in both groups (diabetic patients vs controls: 14 (22%) vs 13 (20%) patients, P=0.83, NS) as had various types of initial immunosuppressive protocolswith an absolutely dominant combination comprising one of three available forms of cyclosporine A with azathioprine and prednisone (98% of patients in both groups).
Patient and graft survival
The mean duration of follow-up was 37±27 and 41±31 months in the diabetic and control groups, respectively. Patient survival in the diabetic group was 85, 84, 77, and 69% at 1, 2, 3, and 5 years post-transplant, respectively. The corresponding results for the control group were 84, 84, 82, and 74% and no statistical difference was found when survival curves of both groups were compared (Figure 1A).
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The results of comparison were unchanged even when deaths with functioning grafts were included and counted as cases of graft failure (graft survival of 77, 71, 62, and 54% vs 73, 73, 69, and 61% for the diabetic vs control group) (Figure 1C).
When adjusted for factorssex, BMI, age, duration of pre-transplant dialysis, smoking status, pre-transplant systolic, and diastolic blood pressurein the Cox proportional hazards model, no significant effect of diabetes on patient and graft survival was found with the two patient groups pooled (P=0.33, P=0.36, and P=0.35 for patient, patient death censored, and non-censored graft survivals, respectively, NS). Of all the other factors, only advanced age had a significant negative effect on patient survival (P=0.004).
Creatinine values increased similarly in both groups during the observation period, reaching 158±65 and 140±38 µmol/l (diabetic patients vs controls, P=0.71, NS) in 23 patients with a functioning graft at 5 years post-transplant (11 patients with type 2 diabetes and 12 non-diabetic controls).
There was no difference during the follow-up period between the groups in mean blood pressure (systolic blood pressure 147±14 vs 144±17 mmHg, P=0.31, NS, and diastolic blood pressure 84±8 vs 86±8 mmHg, P=0.17, NS, for the type 2 diabetic and non-diabetic groups, respectively) or lipid levels (cholesterol 6.1±1.6 vs 6.4±1.3 mmol/l, P=0.36, NS, and triglycerides 2.9±1.6 vs 2.4±0.9 mmol/l, P=0.15, NS, for the type 2 diabetic and non-diabetic groups, respectively). When comparing mean values at specific points of time, the only significant differences were higher systolic blood pressures at 5 years (153±15 vs 136±16 mmHg, P=0.01) and triglyceride levels at 3 years post-transplant (3.0±1.5 vs 2.2±0.8 mmol/l, P=0.01) in the diabetic patients.
Causes of patient death, graft failure, and post-transplant complications
During the follow-up period, 27 diabetic and 19 control patients died (P=0.158, NS), with 18 and 15 deaths in the respective groups occurring while the grafts functioned or within 60 days after return to dialysis (one patient in the control group was lost to follow-up after graft failure). In the type 2 diabetic group, deaths had occurred after a mean period of 34±32 months post-transplant and at a mean patient age of 58±8 years, the values being 25±29 months and 59±9 years for the control group. Vascular events (11 patients, 41%), malignancies (five patients, 18.5%), and infections (four patients, 15%) constituted the most frequent causes of death in the diabetic group. In the controls, patient death was most often due to vascular causes (eight patients, 42%) or infections (four patients, 21%).
Death with functioning graft represented the principal cause of graft function cessation in both groups (diabetic patients vs controls: 14 (47%) vs 10 (43%) patients, P=0.817, NS). The other single most important cause of graft failure was rejection (eight (27%) patients) in the diabetic group and primary non-function (four (17%) patients) in the control group (Table 2).
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Conclusions |
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The results add important evidence to previous information. In one of the first studies focusing on patients with type 2 diabetes, Hirschl et al. [6] reported in 1992 from Vienna that in patients without severe vascular complications, survival after kidney transplantation was better than on haemodialysis. However, Nyberg et al. [7] concluded that the high mortality and morbidity rates in their group of type 2 diabetic patients after kidney transplantation supported continued restriction of their acceptance for transplantation.
Kronson et al. [8] found a 5-year survival of 61% for patients and 53% for grafts in their recent analysis of kidney transplantation in type 2 diabetics. This was still significantly worse than the results obtained in the generally younger patients with type 1 diabetes or non-diabetic patients over 50 years old. In our opinion, this may have been due toamong other reasons, which of course include the deleterious effect of the diabetes per seless rigorous matching of controls, e.g. in recipient age (the information about mean patient age in the non-diabetic control group is not available for the study by Kronson). In our study, age was the only factor having a significant negative effect on patient survival. Several other mainly immunologic and donor variables (e.g. pre-transplant PRA level or HLA matching) have also been shown consistently to influence the outcome of cadaveric kidney transplantation [9]. Additionally, as our study covered a slightly later period, the observed differences could reflect an improvement that may have occurred since.
On the other hand, very encouraging results of kidney transplantation in type 2 diabetic patients were reported recently from two transplant centres in Belgium [10]. Even though the small group (23 patients) and the lack of a control group are obvious limitations, an excellent patient survival (91 and 83% at 1 and 5 years post-transplant) and a relatively low complication rate are reported.
In our study, there was no significant difference in the proportion of patients experiencing post-transplant complications requiring hospitalization, apart from the number of amputations. This confirms information in other reports, that diabetic foot complications constitute one of the major problems of post-transplant care after kidney transplantation in diabetic patients [11]. Preventive podiatric care and regular post-transplant surveillance were in the past unavailable to many diabetic patients undergoing kidney transplantation at our institution. In accordance with reports that a reduction of gangrene and amputations in diabetic renal transplant patients can be achieved through attendance at a special foot clinic [12,13], such care is being provided currently at our centre to diabetic patients with end-stage renal disease.
When considering the results of our study, some reservations are inevitable. Undoubtedly, a prospective design would be more appropriate, to avoid possible sources of bias in the comparisons. Although the size of our group of type 2 diabetic patients after kidney transplantation was one of the two largest studied so far (alongside with the study by Kronson [8] which reported on an identical number of cadaveric transplant recipients), the slight tendencies towards worse patient and graft survival in the diabetic group (apparent in survival curve comparisons) could translate into significant differences if larger groups were analysed, in a multi-centre design, including several hundreds to thousands of subjects in each group.
A more restrictive selection process may have been applied in the case of our type 2 diabetic patients. They were referred after being selected by the staff of a number of external dialysis centres and a fixed set of examinations was not a prerequisite during the study period. The pre-transplant work-up included a standard ECG and echocardiography, with a more extensive cardiovascular examination performed in only a few cases in either group. However, due to substantial co-morbidities most type 2 diabetic patients probably were never considered for renal transplantation. The proportion of such patients on the transplant waiting list was much lower than their proportion among those treated by dialysis. According to the 1999 data of the Czech Nephrological Society, 33% of the dialysis population were diabetic patients, of whom at least half may be assumed to have had type 2 diabetes. However, only less than 3% of the transplant candidates on the Czech waiting list in December 1999 were classified as type 2 diabetic (information from the Czech transplant registry).
Several major risk factors directly linked to cardiovascular disease (hypertension, hyperlipidaemia, smoking, etc.) are present in the end-stage renal failure population as a whole. Thus, as a result of a more rigorous selection of type 2 diabetic patients a group with a more favourable risk profile could have been created. However, as the occurrence of pre-transplant vascular disease and the levels of major risk factors were comparable in both groups, this probably was not the case. Moreover, some of the follow-up data suggest that the control of some major risk factors in the post-transplant period was similar in both groups of transplant recipientse.g. no significant difference was found in overall mean blood pressure values, which in both groups were approaching levels currently considered as adequate.
Not all variables known to be associated with poorer long-term results (e.g. kidney donor status [14]) and increased mortality could be taken into account. The absence of conclusive biopsy information on the type of renal disease in most patients in the diabetic group probably is of little significance, for some data exists suggesting the primary importance of the diabetic state per se, and no effect of the primary renal disease, on the survival of diabetic patients with end-stage renal failure [15]. This may nevertheless be of certain importance in the non-diabetic group where an additional five cases of diabetes mellitus appeared in the post-transplant period. Post-transplant diabetes mellitus has been associated with worse patient survival [16], but perhaps it is confined to patients younger than 55 years [17]. There was also a significant difference between the groups in the duration of pre-transplant dialysis therapy with longer treatment in the non-diabetic patients. A long period on dialysis is an independent variable associated with poorer long-term results and increased mortality [18]. Although probably reflecting above all the higher age of our study subjects, our patient survival results in the non-diabetic group may have been influenced by some of these factors.
Still, this studylike some recent studies in patients with type 1 diabetes [19,20]in our opinion, provides important additional evidence of a substantial improvement in the results of kidney transplantation in type 2 diabetic patients with end-stage renal failure that has occurred in recent years. Several reasons including more rigorous pre-transplant screening, new types of immunosuppressive therapy, improved metabolic control and better care of complications, probably are responsible. Although the presence of diabetes undoubtedly constitutes a very important risk factor, the study results do not provide support for a restriction of the access to kidney transplantation of patients with type 2 diabetes mellitus.
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Acknowledgments |
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Notes |
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References |
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