Outcome of cadaver kidney transplantation in 23 patients with type 2 diabetes mellitus

Ann Van Mieghem1, Catherine Fonck1, Willy Coosemans5, Bernard Vandeleene2, Yves Vanrenterghem4, Jean-Paul Squifflet3 and Yves Pirson1,

Departments of 1Nephrology, 2Endocrinology and 3Kidney transplantation, Cliniques Universitaires St-Luc, Université Catholique de Louvain (UCL), Bruxelles, and Departments of 4Nephrology and 5Abdominal Transplantation Surgery, Universitair Ziekenhuis Gasthuisberg, Katholieke Universiteit van Leuven (KUL), Leuven, Belgium



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Type 2 diabetes mellitus (DM) is a growing cause of end-stage renal failure worldwide. Yet, only a minority of type 2 diabetics are considered today for kidney transplantation (KT). The scarcity of data on the outcome of such patients after KT prompted us to review our experience.

Methods. Between 1 January 1983 and 30 June 1996, 23 patients with type 2 DM received a first cadaver KT at a mean age of 57±9 (41–73) years, after a dialysis period ranging from 5 to 72 (mean 25±18) months. Only nine patients had a history of coronary and/or peripheral vascular disease before KT. All were given cyclosporin- or tacrolimus-based immunosuppression. Post-KT follow-up ranged from 4 to 181 (mean 70±38) months. Outcome analysis focused on the impact of cardiovascular complications.

Results. Patient survival at 1, 5 and 8 years was 91, 83 and 76% respectively. Death was due to infection in three patients and to a cardiovascular event in two. The actuarial risk of coronary, cerebrovascular, peripheral vascular, and any cardiovascular event after KT was 14, 13, 9 and 30% at 1 year, 20, 13, 50 and 58% at 5 years, and 20, 46, 66 and 72% at 8 years respectively. Post-KT hospital readmissions averaged 10 days/patient-year and were mostly related to the management of peripheral vascular disease.

Conclusion. KT is an excellent therapeutic option for selected patients with type 2 DM. Peripheral vascular disease is the leading cause of morbidity following KT. KT should be considered in type 2 diabetics with a low/medium cardiovascular risk.

Keywords: coronary artery disease; kidney transplantation; type 2 diabetes mellitus; vascular complications



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Type 2 diabetes mellitus (DM) is a steadily growing cause of end-stage renal disease (ESRD) worldwide [13]. In Belgium, the proportion of type 2 diabetics among patients on renal replacement therapy (RRT) currently reaches 16% [3]. So far, only a minority of ESRD patients with type 2 DM are considered for kidney transplantation (KT). Thus in Belgium, patients with type 2 DM accounted for only 3% of the transplant candidates registered on the Eurotransplant waiting list during the year 1998 [4]. In the same way, other European national registers show that among type 2 diabetics on RRT during the years 1996–1997, only 1–8% were living with a functioning graft [3].

The substantial improvement in the survival rates obtained after KT in the past 15 years, both in type 1 diabetics and in older non-diabetic recipients [1,5,6] should lead to increasingly consider this option in type 2 diabetics. There is a surprising paucity of published information on the outcome of type 2 diabetics after KT. Only two reports addressing this issue are available [7,8]. In both, however, type 2 diabetes is loosely defined as ‘non-insulin-dependent’. Moreover, even though cardiovascular complications are the leading cause of morbidity and mortality in ESRD diabetics [9,10], their occurrence after KT is not detailed in these two reports [7,8]. This prompted us to review our experience of KT in type 2 diabetics defined with stringent criteria, focusing our analysis on the impact of cardiovascular complications.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Between 1 January 1983 and 30 June 1996, 23 patients with type 2 DM received a first cadaver kidney graft in our two centres (Université Catholique de Louvain, Bruxelles and Katholieke Universiteit van Leuven, Leuven). Charts were reviewed by December 1999, so that the potential follow-up exceeded 3.5 years in all living patients.

The diagnosis of type 2 DM relied on either a C-peptide level >=0.6 ng/ml [11] or, when C-peptide was unavailable, the presence of at least three of the following criteria: (i) onset of DM at an age >40 years; (ii) maximal body weight prior to KT exceeding by at least 15% the ideal body weight; (iii) absence of a history of polyuria, polydipsia, and weight loss at the time of DM diagnosis; (iv) interval of at least 2 years between the diagnosis of DM and the onset of insulin therapy; (v) evidence for diabetic nephropathy at the time of DM diagnosis or ESRD within 5 years after DM diagnosis [11,12] (Table 1Go).


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Table 1. Demographic features (n=23)

 
Patients with type 2 DM selected for KT met the general criteria adopted for a long period in our two centres for non-diabetic candidates, i.e. (i) an estimated life-expectancy of at least 5 years; (ii) absence of a major contraindication to immunosuppressive therapy; (iii) an estimated low perioperative risk.

Pre-transplant cardiovascular assessment is detailed in Table 1Go. None of the patients had evidence of heart failure. Two had a history of myocardial infarction (MI) treated by thrombolysis in one and angioplasty in the other and were placed on the waiting list following coronary angiography. Six had either a possible electrocardiographic sequela of MI (n=3) or symptoms suggestive of angina pectoris (n=3). They were placed on the waiting list after a negative stress test (n=3) or a coronary angiography (n=3) showing moderate lesions not requiring revascularization. The remaining 15 patients had no history or symptoms of coronary disease. They were put on the waiting list after a work-up including either electrocardiogram (n=7) or stress scintigraphy (n=8) which proved normal in 14 and doubtful in one; the last patient underwent a coronary angiography which revealed no abnormality.

Pre-transplant work-up included aorto-iliac angiography only in the presence of symptoms or signs of peripheral vascular disease (Table 1Go). This was the case in 12 patients. Four patients had undergone a revascularization procedure 6–24 months before KT (angioplasty in 3, after toe amputation in one of them, and bypass in one). Out of the eight other patients in whom arteriography was performed, five had no significant lesions and three had at least one >=75% stenosis not requiring immediate revascularization. Leg amputation was subsequently required in one of them.

Carotid endarterectomy had been performed in one patient. Another patient had a history of stroke.

We defined as significant post-KT cardiovascular event the following conditions: electrocardiographic sequelae compatible with MI; coronary artery stenosis of at least 75%; limb amputation; stroke; any myocardial or peripheral revascularization procedure.

Actuarial survival rates were calculated according to the Kaplan–Meier method. Survival curves were compared by the log-rank test. Mean values of blood pressure and lipid levels at different time intervals after KT were calculated.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Demographics
Patients' characteristics are depicted in Table 1Go. The cause of renal failure was regarded as diabetic nephropathy in 20 patients (histologically ascertained in seven of them), as nephrosclerosis in one and undetermined in the remaining two patients. Age at KT averaged 57 years. It was less than 50 years in six patients, between 50 and 60 years in nine, and more than 60 years in eight.

After KT, all patients were given an anti-calcineurin-based immunosuppressive regimen: cyclosporin–steroids in 21 and tacrolimus–steroids in two, plus a third immunosuppressant in 16 patients (azathioprine in 12, mycophenolate mofetil in three, and rapamycin in one). Acute rejection was treated with a 3–5 day course of i.v. methylprednisolone (125–500 mg/day). Steroid-resistant rejection episodes were treated with a 10-day course of polyclonal anti-lymphocyte antibodies.

Patient and graft survival (Figure 1Go)
Patient survival at 1, 5, 8 and 10 years after KT was 91, 83, 76 and 76% respectively. Five patients died, all with a functioning graft, 4–69 months after KT. The cause of death was infection in three cases (pneumonia in one, listeria meningitis in one, and unknown origin in one), stroke in one case, and sudden death probably due to a cardiovascular event in one case.



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Fig. 1. Post-KT outcome: patients and graft survival, cardiovascular complications. Current value of creatinine clearence (ml/min) calculated by the Gault–Cockroft formula is given in parentheses. C, cardiac event; P, first peripheral vascular event; S, stroke.

 
One graft was lost from thrombosis of the renal vein 107 months after KT. Interestingly, 14 patients remained free of acute rejection over the whole follow-up period. As seen in Figure 1Go, 17 patients have currently a functioning graft 49–181 (mean 80) months after KT. Creatinine clearance, calculated by the Gault–Cockroft formula, is >80 ml/min in four patients, 60–80 in one patient, 40–60 in six patients, and <40 in the remaining six patients. Steroid treatment was discontinued in four patients at a post-KT interval ranging from 4 to 15 years.

Cardiovascular complications (Figures 1Go–4Go)
The actuarial risk to suffer a cardiac complication after KT was 14, 20 and 20% at 1, 5 and 8 years respectively (Figure 2Go). Of four affected patients, three had a MI, occurring 1 day, 1 month, and 4 months after KT respectively and one experienced angina, requiring angioplasty 14 months after KT. None of them died from heart disease. Two of them had suffered a previous cardiac event before KT, whereas the other two had not (Figure 4Go).



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Fig. 4. Relationship between pre- and post-KT cardiovascular events (number of patients).

 


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Fig. 2. Actuarial risk of suffering a cardiovascular event after KT.

 
The actuarial risk of cerebrovascular event was 13, 13 and 46% at 1, 5 and 8 years respectively (Figure 2Go). Four patients experienced stroke 1, 4, 12 and 93 months after KT respectively, leading to death in one of them at 4 months. A carotid endarterectomy was performed in a fifth patient (90 months post-KT).

The actuarial risk of peripheral vascular event after KT was 9, 50 and 66% after 1, 5 and 8 years respectively (Figure 2Go). Of 12 affected patients, nine had a total of 19 amputations (one in four patients, two in three patients, four in one patient, and five in one patient) leading to the loss of one or multiple toes in five patients, one leg in two patients (associated with the loss of the contralateral foot in one), a toe and the contralateral foot in one, both legs and both forearms in the last patient. Four of the nine patients who had an amputation also had one or more revascularization procedures. Three patients had a revascularization procedure without amputation (Figure 3Go). As seen in Figure 4Go, four of the five patients who suffered a peripheral vascular event before KT had a recurrence after KT. Notably, eight of the 12 patients who experienced a peripheral vascular event after KT had no similar history before KT.



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Fig. 3. Peripheral vascular complications (n=12).

 
The actuarial risk to experience any cardiovascular event (cardiac, cerebrovascular, and peripheral events combined) was 30, 58 and 72% at 1, 5 and 8 years respectively.

Malignancies
Malignancy occurred in four patients (skin cancer in three, prostate cancer in one, renal-cell carcinoma in one). All of them are currently alive.

Hospitalization after KT
Overall, the mean number and duration of readmissions to the hospital following post-operative hospitalization was 0.76/patient-year and 10.1 days/patient-year. The most common reason for readmission was the management of peripheral vascular disease.

Current management of the 18 surviving patients
All but three patients are currently treated with insulin (once a day in one, twice a day in seven, thrice a day in two, and four times a day in five). HbA1c level averaged 7.5% (range 4.3–11.5); it was >8% in six and >10% in three patients.

Fifteen patients are currently on antihypertensive drugs (one drug in nine patients, two in four, >=three in two) including an ACE inhibitor or an angiotensin II receptor antagonist in eight of them. Mean blood pressure at 3, 6, 12, 36 and 60 months after KT ranged from 147/79 to 162/81 mmHg (Table 2Go).


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Table 2. Blood pressure control (mean±SD)

 
Eight patients are currently receiving lipid-lowering treatment (statin in six, fibrate in two). Total cholesterol, LDL and triglyceride levels at the time of KT and at regular intervals following KT are displayed in Table 3Go. Though mean cholesterol level was higher at 6 months than at baseline, it further decreased at a comparable value. A more favourable lipid profile was attained in the long term, as assessed by both decreased triglyceride and increased HDL levels.


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Table 3. Lipid levels (mean±SD)

 



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
We report the post-KT outcome of 23 patients with type 2 DM. The limitation of this retrospective study is its small size, while homogeneity regarding patients' selection and management is a definite strong point. Our main finding is that type 2 diabetics with no contraindication to KT have an excellent survival after KT. The 5-year survival rate of 83% observed in our series favourably compares with the 59 and 61% rates reported by Hirschl et al. [7] and Kronson et al. [8] respectively. This may be accounted for by differences in patient selection and management. The 18 patients transplanted by Hirschl et al. were slightly older than ours (mean age 61.4 vs 56.7) and some were transplanted before the cyclosporin era [7]. Among the 64 cadaver kidney recipients reported by the Minneapolis team, 14 received a simultaneous pancreas transplant [8]. Moreover, while the proportion of recipients with a history of coronary disease in those two reports is not known, only a minority of our patients had a pre-KT history of myocardial infarction or angina.

Did KT provide a higher survival for these patients than that expected if they had remained on dialysis? This issue was not addressed by our study. In an attempt to provide information on this point, Wolfe et al. [13] used data from the US Renal Data System. They compared the survival of 1091 diabetics who received a kidney transplant with that of 2312 diabetics who remained on the waiting list, with adjustment for age, race, sex, and time from first treatment for ESRD to placement on the waiting list. Transplantation substantially reduced the risk of death in all age categories, including the oldest one: thus, in 60–74-year-old recipients, presumably mostly with type 2 DM, the risk of death was reduced by 54% 18 months after KT, strongly suggesting that KT provides a better survival than dialysis to type 2 diabetics with no contraindication to transplantation.

Cardiovascular complications are the leading cause of morbidity and mortality in type 2 diabetics on renal replacement therapy [9,10]. Our study is the first one accurately assessing the risk of suffering a cardiovascular event following KT. The actuarial risk of suffering a cardiac event was only 18% at 8 years. This low rate is likely to be related to the low prevalence of coronary disease at the time of KT in this selected population. Interestingly, two of the four patients experiencing a cardiac event after KT had a similar history before KT. In the large Minneapolis series there was a trend, admittedly not statistically significant, for a lower patient survival among recipients with a history of cardiac disease compared with those with no such history [8]. Whether coronarography should be routinely performed in diabetic patients selected as candidates for KT remains controversial [14,15]. In patients with symptoms or signs of either coronary disease or severe atheromatosis in other territories, coronarography is mandatory. In the remaining patients, stress or dipyearidamole thallium scintigraphy as well as dobutamine stress echocardiography proved to be very useful though imperfect screening tests [16,17]. In patients with significant coronary disease, pre-transplant coronary revascularization reduces the risk for subsequent cardiac events [14].

The actuarial risk for a cerebrovascular event jumped from 13% at 5 years to 46% at 8 years. This was only due to the occurrence of stroke in a single patient at 93 months and the need for a carotid endarterectomy in another one at 90 months. A careful assessment of this issue would require an extended follow-up in a larger group of patients.

Peripheral vascular disease was responsible for a considerable morbidity in our patients, affecting more than half of them after 5 years follow-up and accounting for most readmissions to the hospital. Especially impressive is the course of some patients who underwent several revascularization procedures and amputations, as depicted in Figure 3Go. A 39% prevalence rate of amputation for a mean post-KT follow-up of 70 months is higher than the 19 and 22% rates reported in other series of younger transplanted diabetics (mostly type 1) with post-KT follow-up of 45 and 41 months respectively [9,18]. In the latter two series the risk of amputation following KT was predicted by the existence of coronary disease [9], abolishment of foot pulses, loss of vibratory sensation, smoking habit, and previous amputation [18]. Our data also strongly suggest that patients with a history of peripheral vascular event will have a recurrence of this complication following KT. Preventive measures have been reviewed elsewhere [18]. Recent progress in distal revascularization techniques should reduce the rate of primary major amputations [19].

Just as in the Minneapolis series, death with a functioning graft was the most frequent cause of graft loss and sepsis was the most common cause of death [8]. The low incidence of acute rejection observed in our patients may be related to their age: among non-diabetic recipients, kidney graft survival is indeed known to be better in older patients [20]. This suggests that the intensity of immunosuppressive regimens should be lowered in this category of recipients [8].

We conclude that KT is an excellent therapeutic option in selected type 2 diabetics. Both their selection for KT and post-KT prognosis essentially rely on their cardiovascular status. It is thus imperative to minimize as early as possible the common cardiovascular risk factors, including cessation of smoking, control of blood pressure, and normalization of blood lipids.



   Acknowledgments
 
To Jef Struyven for statistical analysis and Karin Voss for secretarial assistance.



   Notes
 
Correspondence and offprint requests to: Yves Pirson MD, Cliniques Universitaires St-Luc, Department of Nephrology, av. Hippocrate 10, B-1200 Bruxelles, Belgium. Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 3.10.00
Revision received 23. 3.01.