Long-term renal allograft outcome after simultaneous kidney and pancreas transplantation

Jean Philippe Rerolle1, Eric Thervet1,, Dany Anglicheau1, François Desgrandchamps2, Dominique Nochy3, Anne Janin4, Sophie Fornairon1, Philippe Passa5, Janine Bedrossian1 and Christophe Legendre1

1 Service de Néphrologie, 2 Service d'Urologie, 4 Service d'Anatomopathologie and 5 Service d'Endocrinologie, Hôpital Saint Louis, Paris and 3 Service d'Anatomopathologie, Hôpital Européen Georges Pompidou, Paris, France



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. In selected young patients with type 1 diabetes mellitus and end-stage renal failure, simultaneous pancreas and kidney (SPK) transplantation is the treatment of choice. We conducted a retrospective, case-controlled study to compare the function, survival and pathology of renal allografts after SPK and kidney-alone (KA) transplantations.

Methods. We studied 26 consecutive SPK patients and 67 KA controls matched for time of transplantation. Renal function was assessed by routine evaluation of serum creatinine and its course by the 1/serum creatinine vs time curve. Histologic evaluation of early biopsies (0–3 months post-transplantation, n=63), intermediate biopsies (3 months–1 year, n=75) and late biopsies (after 1 year, n=35) were performed by two independent reviewers.

Results. SPK and KA recipients differed significantly with regard to donor and recipient age, time on the waiting list, HLA sensitization, renal cold ischaemia time (CIT) and the incidence of delayed graft function. Acute rejection was more frequent after SPK than KA (54 vs 27%; P=0.01), despite higher trough levels of calcineurin inhibitors. After SPK and KA, actuarial patient and renal allograft survival and renal function were comparable at 1 and 4 years. Severe chronic lesions, especially vascular lesions, and calcineurin-inhibitor nephrotoxicity were more frequent in intermediate and late biopsies in the SPK group.

Conclusions. We confirmed that patient and graft survival is comparable between SPK and KA recipients. Despite the use of optimal organs and shorter CIT in SPK, renal graft function was not different in the two groups. Histologic chronic lesions were more severe in SPK than in KA recipients. This might be caused by acute rejection episodes or be due to more severe nephrotoxicity after SPK, because of higher doses of calcineurin inhibitors, or higher sensitivity to calcineurin-inhibitor nephrotoxicity.

Keywords: chronic graft dysfunction; cyclosporin; nephrotoxicity; pancreas transplantation; renal transplantation



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Diabetic nephropathy has become the leading cause of end-stage renal disease in many countries [1,2]. Diabetic patients make up nearly 25% of the population receiving a kidney transplant for end-stage renal failure [5]. In this population, kidney transplantation allows better patient survival than dialysis [3,4]. In selected young patients with type 1 diabetes and chronic or end-stage renal failure, simultaneous pancreas and kidney (SPK) transplantation is considered the treatment of choice [6,7], providing a functioning pancreatic allograft and at the same time addressing secondary complications of diabetes [810]. Beginning in 1994, the addition of new immunosuppressive agents such as a new formulation of cyclosporin, tacrolimus and mycophenolate mofetil has improved graft and patient survival. According to a recent review [11], the use of mycophenolate mofetil and tacrolimus in a primary maintenance immunosuppressive regimen resulted in 2-year actuarial patient, kidney and pancreas survivals of 97.7, 93.3 and 90.0%, respectively. This improvement in survival raises the question of the effects on renal allograft outcome of SPK transplantations compared with KA transplantations.

A major consideration when assessing renal function is the quality of the organ grafted. The organs used for SPK grafting are optimal because of the reduction of the well-established harmful effects of age, hypotension and cold ischaemia time (CIT) on pancreas allograft. There is only one previous study in which SPK recipients were compared with KA recipients of the controlateral kidney of the same donor [12]. Evaluation of the impact of SPK vs KA on renal allograft outcome must take into account the intrinsic quality of the organ used and must include histologic assessment. We therefore decided to match SPK and KA recipients in a retrospective case-controlled study for the time of transplantation, and to include allograft pathology in the assessment.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patient selection
We included 26 consecutive patients who had received a kidney and, simultaneously, a segmental pancreas (n=2), a bladder-drained pancreas (n=20) or an enteric-drained pancreas (n=4) graft in our institution between 1992 and 1998 from cadaveric donors with beating hearts. The control group comprised 67 KA recipients. We matched KA controls with SPK recipients for the date of transplantation, with a difference of <1 week.

Immunosuppressive treatment
All patients had received induction therapy using polyclonal antibodies (Thymoglobuline®; Merieux Institute, Lyon, France) at an initial dose of 75 mg/day, subsequently adjusted to maintain a level of <200 lymphocytes/ml. The initial immunosuppressive regimen combined steroids (initial dose of 1 mg/kg/day, tapered to 10 mg at 3 months) and azathioprine (2 mg/kg/day). A calcineurin inhibitor, either cyclosporin A (CsA) or tacrolimus, was given in order to maintain a whole blood trough level of 150–250 ng/ml for CsA and 12–15 ng/ml for tacrolimus during the 3 months following transplantation. After that time, whole blood trough level targets were 100–150 ng/ml for CsA and 8–10 ng/ml for tacrolimus.

Biopsy-proven rejection episodes were treated with high doses of steroids, with polyclonal antibodies or OKT3 depending on the severity of rejection. Six patients in the SPK group and 10 in the KA group received mycophenolate mofetil during follow up.

Renal allograft evaluation
Renal function was assessed by routine measurements of serum creatinine. The course of renal function was evaluated using the 1/serum creatinine vs time curve. We documented the incidence of biopsy-proven or clinically presumed acute rejection. Proteinuria and blood pressure also were routinely measured.

Pathological examinations of 173 renal biopsies were performed by two independent reviewers who examined biopsies without prior knowledge either of the transplant group or of the time since transplantation. Biopsies performed between 0 and 3 months after transplantation were classified as ‘early’ (n=63), those perfomed between 3 months and 1 year as ‘intermediate’ (n=75), and those performed after 1 year as ‘late’ (n=35). Early biopsies consisted of pre-transplant routine biopsies (n=10) or were performed for clinical indications, mainly suspected acute rejection (n=53). All intermediate and late biopsies were part of a periodic routine examination for pathological changes in renal allografts. We evaluated chronic lesions semi-quantitatively using the 1997 revised BANFF classification [13]. Interstitial fibrosis was graded from 0 to 3 according to the surface area of fibrous tissue in the biopsy. Transplant vascular sclerosis was defined by the presence of fibrointimal hyperplasia in muscular arteries. Its severity was scored from grade 0 to grade 3 according to the percentage of the original vascular lumen occupied by the expanded intima. Calcineurin-inhibitor nephrotoxicity was defined as changes in hyaline arteriolar deposit with or without isometric vacuolization of the tubules.

Statistical analysis
After confirmation of the normal distribution of the parameters studied, values were expressed as means±SEM (standard error of the mean), and both student's t-test and analysis of variance were used for comparison between groups. Within-group correlations were expressed by the Spearman rank correlation coefficient. The chi-squared test and contingency table were used to compare subgroups of patients. Differences in actuarial graft and patient survival were tested by the log-rank method. Probability values of <0.05 were considered significant.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Donor and recipient characteristics (Table 1Go)
SPK donors were comparable for sex but significantly younger than KA donors (34.3±8.6 vs 40.8±14.1 years; P<0.005). SPK recipients were significantly younger than KA recipients (39.9±7.1 vs 43.1±11.3 years; P=0.006). The mean waiting time and duration of dialysis were significantly shorter in the SPK than the KA group. Panel-reactive antibodies were present in 3.8% of the patients in the SPK group and 13.4% of those in the KA group (P<0.0001). The mean number of total HLA matches was lower in SPK group compared with the KA group (2.9±0.3 vs 3.4±0.1; P<0.0001).


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Table 1. Demographic and post-transplant characteristics of simultaneous kidney–pancreas (n=26) and kidney-alone (n=67) transplantation recipients

 

Post-transplant course (Table 1Go)
The follow-up period after transplantation was not different for the two groups (42.7±19.7 vs 38.8±19.8 months). Renal CIT was significantly shorter in the SPK than the KA group (7.2±2.2 vs 23.2±8.6 h; P<0.0001); consequently, delayed graft function was less frequent in the SPK than the KA group (0 vs 49%; P<0.0001). The prevalence of an acute rejection episode was significantly higher in the SPK than the KA group (54 vs 27%; P=0.01), despite higher cumulative doses of calcineurin inhibitors. For patients treated with CsA, trough blood levels at 6 months post-transplant were 225±59 ng/ml in the SPK group vs 163±45 ng/ml in the KA group (P=0.0003). This difference was still present at 2 years but was not significant (143±36 vs 125±34 ng/ml; P=0.14). For patients treated with tacrolimus, trough blood levels at 6 months were significantly higher in the SPK than the KA group (12.5±2.2 vs 8.3±2.7 ng/ml; P=0.0009). This difference was still present at 2 years but was not significant (10.4±3.3 vs 8.1±1.8 ng/ml; P=0.08).

Systolic and diastolic blood pressures were not significantly different in the two groups at 6 months and 2 years after transplantation. There was no difference in the use of angiotensin-converting enzyme inhibitors by the two groups.

Patient and allograft survival
Actuarial patient survival was comparable in the SPK and KA group at 1 and 4 years (100 vs 97.1% and 100 vs 94.1%, respectively; P=not significant (NS)).

For SPK recipients, kidney allograft survival was 96.2 and 96.2% at 1 and 4 years after transplantation. For KA recipients the corresponding survival rates were 93.6 and 86.6%. When adjusted for patient death, five KA recipients (7.5%) and one SPK recipient (3.8%) had lost their renal allograft (P=NS). The causes of renal graft loss after KA transplantation were chronic rejection (n=2), acute rejection (n=1), thrombotic microangiopathy (n=1) and cortical necrosis (n=1), and after SPK transplantation rejection followed the withdrawal of immunosuppression because of the development of lymphoma (n=1). Pancreas allograft survivals after SPK were 88.5 and 80.2% at 1 and 4 years, respectively. Overall, five patients lost their pancreas because of thrombosis (n=3), acute rejection (n=1) and allograft lymphoma (n=1).

Renal function
Serum creatinine was not different in the SPK and KA groups at 1 year after transplantation (147±41 vs 149±70 µmoles/l), at 2 years (165±76 vs 141±47 µmoles/l) and at 4 years (132±19 vs 136±47 µmoles/l). The course of renal function, as evaluated by the slope of 1/creatinine vs time, was stable during follow-up (Figure 1Go).



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Fig. 1.  1/serum creatinine vs time during the 40 months after simultaneous kidney and pancreas (SPK) or kidney-alone (KA) transplantation.

 

Pathological examination of renal allografts (Figure 2Go)
Early biopsies were performed later in SPK than in KA recipients (30.3±6.6 vs 17±1.8 days; P<0.0002). The delay between transplantation and renal biopsy did not differ between the two groups, either for intermediate biopsies (165.1±12.2 vs 168±45.8 days) or for late biopsies (748±163 vs 624±109 days).



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Fig. 2.  Incidence of grade 2 or 3 chronic rejection lesions (a) and chronic vascular lesions (b) in early, intermediate and late biopsies after simultaneous pancreas and kidney (SPK) and kidney-alone (KA) transplantation.

 
As expected, the prevalence of lesions of chronic rejection increased in both groups with time after transplantation. We compared the incidence and severity of chronic lesions in the SPK and KA groups in their early, intermediate and late biopsies. The incidence of grade 2 or 3 chronic lesions in intermediate biopsies was 32% in the SPK group and 19% in the KA group (P<0.01). In the late biopsies, these incidences were 54 and 24%, respectively (P<0.01). For chronic vascular lesions, the incidence in intermediate biopsies was 45% in the SPK group and 28% in the KA group (P=0.003). The incidence of grade 2 and 3 chronic lesions were 64 and 24%, respectively, in late biopsies (P=0.002). In intermediate biopsies, more of those in the SPK than the KA group exhibited evidence of calcineurin-inhibitor nephrotoxicity (32 vs 8%; P=0.003).



   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Increasing experience with the pre-transplantion management of diabetic patients, organ retrieval technology, surgical techniques, antimicrobial prophylaxis and immunosuppressive treatments has resulted in a progressive continuous improvement in SPK outcomes [14] and an increase in the number of patients treated. As early graft survival rates have improved, the long-term consequences of SPK for kidney graft function have become more important, because the benefits must be balanced with the costs and risks of the procedure and the effects of immunosuppressive treatments.

In this study, we confirmed that patient survival is identical among SPK and KA recipients in a selected diabetic population [4,12]. It was recently shown that kidney transplantation in diabetic patients prolonged their life span by 11 years more than dialysis [3].

The survival rate reported here after combined pancreas and kidney transplantation is identical to that reported previously by other centres [12,15], and there was no difference between kidney graft function in the two groups at the end of follow-up. However, the chronic lesions observed in renal allograft biopsies from SPK recipients were more severe than those found in biopsies from KA recipients. Although the clinical relevance of the histological modifications found on protocol biopsies is still controversial, evidence has recently emerged that both the acute and chronic lesions noted were clinically relevant, even in patients with stable graft function. The results of various studies have shown a relationship between chronic lesions in allograft biopsies, and graft function. Isoniemi et al. [16] reported that the presence of interstitial inflammation and fibrosis, glomerulosclerosis, mesangial matrix increase and tubular atrophy correlated with deteriorating graft function. We demonstrated that, if histologic chronic allograft nephropathy was found in 25% of the protocol biopsies performed 3 months after transplantation in patients with normal renal function, such lesions were present in 50% of the same patients at 2 years [17]. In SPK recipients, two recent clinical studies [18,19] showed better graft function in KA than SPK recipients 3 years after transplantation. Our results are even more striking because the organs used were retrieved from optimal donors. Because pancreas is more sensitive to aging and ischaemic lesions than kidney, SPK recipients received organs from younger donors and after a shorter CIT than KA recipients, as already reported [12,18]. As a result, no patients experienced delayed graft function. After KA, the incidence of delayed graft function is in accordance with the one observed in our centre. Our patients, like those in the studies of others, experienced frequent acute rejection episodes [20]. Hricik et al. [18] demonstrated that the occurrence of episodes of acute renal allograft rejection is a powerful independent predictor of long-term renal function and of chronic allograft nephropathy in type 1 diabetics receiving combined SPK grafts. This higher risk of acute rejection, even when induction therapy is used [21,22], may be avoided with a shorter CIT, which would result in fewer HLA matches between donor and recipient.

Calcineurin-inhibitor toxicity was also more frequently observed among the intermediate biopsies in the SPK than in the KA group. This was attributed to higher CsA and tacrolimus trough levels in the SPK group. These higher trough levels have already been reported and are correlated with the expected higher risk of acute rejection [18]. Despite its diabetogenic effect, we used tacrolimus more often than cyclosporin after SPK because of recent data showing better initial results [23]. The more frequently used tacrolimus could also be involved in the pathological changes of renal grafts after SPK. However, it has been reported that, based on biopsies performed 2 years after transplantation, patients receiving tacrolimus have the same incidence and severity of chronic rejection lesions as patients receiving CsA [24]. In SPK recipients, the higher risk of developing calcineurin-inhibitor toxicity may also be related to the urinary loss of sodium bicarbonate. In rodents, salt depletion has been shown to increase susceptibility to the effects of CsA, thus facilitating the production of an interstitial fibrosis that mimics the striped interstitial fibrosis found in humans [25]. Dehydration by such depletion was necessary for the development of specific arteriolopathy [26].

In summary, we show here that SPK transplantation is a safe procedure for selected diabetic patients. The use of new immunosuppressive treatments has been associated with better short-term results. Patients nevertheless exhibit more frequent and severe chronic lesions, even though the organs used are optimal. Attention must be paid therefore to the long-term results of renal allograft function after SPK transplantation. Non-nephrotoxic immunosuppressive regimens are needed in order to obtain long-term functionality after such transplantation.



   Notes
 
Correspondence and offprint requests to: E. Thervet, Service de Néphrologie, Hôpital Saint Louis, 1, Avenue C. Vellefaux, F-75010 Paris, France. Email: eric.thervet{at}sls.ap\|[hyphen]\|hop\|[hyphen]\|paris.fr Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 15. 5.01
Accepted in revised form: 20.10.01





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