NDT Advance Access published online on November 24, 2006
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfl660
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Very early steroid withdrawal in simultaneous pancreas–kidney transplants
1Nephrology Unit Le Kremlin Bicetre, INSERM U542, IFRNT, 2Urology Unit Le Kremlin Bicetre and 3Surgical Intensive Care Le Kremlin Bicetre, Nephrology Unit Lille, France
Correspondence and offprint requests to: Correspondence and offprint requests to: Antoine Durrbach, Nephrology unit, Bicetre Hospital, Le Kremlin Bicetre, France. Email: antoine.durrbach{at}bct.aphp.fr
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Abstract |
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Background. Simultaneous pancreas–kidney (SPK) transplantation is an effective treatment for patients suffering from type 1 diabetes mellitus. Conventional immunosuppressive treatments include steroids that may induce insulin resistance and are responsible for many side effects. In de novo SPK, early withdrawal of corticosteroids may be an important issue.
Methods. A total of 24 consecutive patients with type 1 diabetes mellitus had been treated by SPK transplantation. All of them had a short induction therapy with anti-thymoglobulin (ATG) and steroids for only 4 days, association with CellCept and tacrolimus. The rate of acute rejection, graft and patient survival and side effects have been analysed.
Results. Patient and kidney survival was 100% and the pancreas survival was 95.6% at 1 year. The rate of acute rejection of kidney and pancreas was 4.2% and 8.3% at 6 months, respectively. The mean serum creatinine was 98.9±19.6 µmol/l and the mean HbA1c concentration was 5.1%±0.5% at 6 months. Only four patients developed a cytomegalovirus primo-infection, associated in one case with pneumonia, whereas 75% of patients developed a bacterial infection. Because of the occurrence of leucopenia and/or diarrhoea, CellCept has been dramatically decreased in 33% of cases and required the re-introduction of steroids.
Conclusion. A short induction with ATG and steroids associated with a chronic therapy with CellCept and tacrolimus is safe and efficient in preventing acute renal rejection in SPK.
Keywords: leucopoenia; pancreas transplantation; renal transplantation; steroids withdrawal
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Introduction |
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Simultaneous pancreas–kidney (SPK) transplantation has been developed for patients suffering from type 1 diabetes mellitus and end-stage renal disease. This treatment is the optimal solution for these patients, offering them a lifetime free of diabetes mellitus and renal failure. Patients are generally given conventional immunosuppressive treatment after transplantation, based on corticosteroids, calcineurin inhibitors and antagonists of purine metabolism [1,2]. However, steroids have many metabolic side effects, including peripheral insulin resistance, which reduces the benefit of pancreas transplantation and possibly leads to the re-introduction of exogenous insulin treatment. In addition, steroids are associated with a high risk of development of atherosclerosis that may increase the frequency of coronaropathy and arteritis, which are already very frequent in this population, or worsen stable cardio-vascular diseases.
In single renal transplantation, the occurrence of de novo diabetes mellitus, which could be favoured by calcineurin inhibitor (CNI) and/or steroid treatments following kidney transplantation, had led to envision new immunosuppressive regimens in which steroids are withdrawn within a week after kidney transplantation [3]. Transplantation teams in many centres have also been encouraged to attempt steroid withdrawal following pancreas transplantation, in an attempt to minimize insulin resistance [4,5]. However, late steroid withdrawal has been reported to be associated with a significant risk of acute rejection and/or adrenal function impairment [6–8], and then a significantly less favourable outcome [9]. However, although some groups proposed strategies in which the immunosuppressive regimen includes a sequential penta-therapy, including an induction with depleting antibodies [10], some attempted to withdraw steroids early in SPK transplantation, in the hope of reducing steroid- associated complications (i.e. de novo diabetes mellitus, atherosclerosis and infection) [11–16]. We report here our experience in SPK in which corticosteroids have been withdrawn during the 4 days following kidney transplantation.
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Methods |
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Study design
We carried out a prospective single-centre study of 24 consecutive kidney and pancreas transplantations performed in 24 patients with type 1 diabetes and steroid-free maintenance therapy between February 2000 and October 2004. The mean duration of follow-up was 30.8±14.6 months, with a minimum follow-up period of 12 months. No patient had reactive antibodies against leucocyte antigens before or at the time of transplantation.
Surgical procedure
All patients underwent simultaneous pancreas–kidney transplantation with two different abdominal incisions. After a coeliotomy, the whole pancreas was implanted in the right iliac fossa, with exocrine drainage between the donor duodenum and the recipient jejunum. Then, the kidney transplant was placed sub-peritoneally in the left iliac fossa, with ureter-bladder anastomosis and with a JJ bladder catheter that was removed on day 30 after transplantation. Perioperative broad-spectrum antibiotics (piperacillin and tazocillin) were administered for the first 24 h. Cytomegalovirus infection was prevented by oral ganciclovir or valacyclovir for 3 months. Oral ganciclovir was always used in the case of a cytomegalovirus (CMV)- positive donor and CMV-negative recipient. Trimethoprim-sulfamethoxazole treatment was used to prevent Pneumocystis jiroveci infections for 3 months. All patients were given prophylactic anti-coagulant therapy (sodium heparinate 100 units/kg/day) during their stay at hospital, replaced by aspirin 100 mg/day on discharge, to prevent pancreatic vascular thrombosis. In case of partial thrombosis of pancreatic veins, an efficient anti-coagulant treatment with sodium heparinate was used followed by anti-vitamin K anti-coagulant for at least 4 months.
Immunosuppression
Thymoglobulin (Merieux, France) infusion was initiated before surgery, with a mean dose of 75 mg/day, adjusted according to white blood cell count, for a total of 5 days (day 0–4). Intravenous methlyprednisolone was administered as follows: 500 mg on day 0, 250 mg on day 1, 125 mg on day 2, 60 mg on day 3, and then stopped. Oral tacrolimus was administered after transplantation, at a dose of 0.1 mg/kg twice daily. The daily dose was adjusted to achieve a target trough level of 10–15 ng/ml. Patients were treated with 1 g of mycophenolate mofetil (MMF) before transplantation and with 2 g/day of this drug, thereafter. After day 5, patients were treated with an immunosuppressive regimen consisting of a combination of MMF and tacrolimus (Table 1). For patients with leucopenia (<2000 leucocytes/ml), thymoglobulin dose was decreased to 50 or 25 mg/day. The dose of MMF was halved only if leucopenia persisted after thymoglobulin treatment had been stopped. The dose of MMF was also fractionated to give four administrations per day in patients who developed diarrhoea.
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Acute kidney rejection was suspected if serum creatinine concentration increased by more than 20% from its lowest value. Kidney biopsy was performed and interpreted according to the Banff 1997 criteria. Acute pancreas rejection was suspected if a sustained increase in fasting glucose concentration (>7 mmol/l) or an increase in plasma lipase concentration was observed in the absence of pancreatic thrombosis. No pancreas biopsy was performed. The first-line treatment for the prevention of rejection was high-dose steroids (500 mg/day for 3 days). In cases of corticosteroid resistance, patients were treated with horse anti-lymphocyte antibodies (Frezenius, Germany) or mouse anti-CD3 antibodies (Orthoclone, USA).
Follow-up
Blood tests were carried out twice weekly for the first month after discharge of the patient, weekly for the next 2 months and monthly thereafter. Total cholesterol and HbA1c concentrations were determined every 3 months. Target trough tacrolimus concentrations were maintained at 12–15 ng/ml for the first 3 months then lowered to 8–10 ng/ml. Profound leucopenia (white count cells below 3500/mm3) was managed by gradually lowering the dose of MMF and stopping this treatment altogether if it proved impossible to control white blood cell levels (white count cells below 2500/mm3). In some cases, persistent leucopenia or graft rejection required the re-introduction of steroid treatment.
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Results |
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Demographic data
The mean age of the recipients was 40.5±6.15 years; 29% of the patients were female and 71% male; 6% of the patients were African and the other 94% were Caucasian. All had type 1 diabetes mellitus with renal involvement and the mean duration of subcutaneous insulin treatment was 28.1±4.98 years. Before transplantation, dialysis had already been initiated in 71% of patients, but the transplant was pre-emptive in the other 29%. For dialysed patients, the mean time on dialysis before transplantation was 1.67±1.55 years. A severe ischaemic cardiac event requiring angioplasty had occurred in 6% of the patients. The mean age of donors was 33.4±10.3 years. All donors had died following traumatic accidents.
All the recipients underwent combined pancreas and kidney transplantation from the same donor. Organs were allocated on the basis of ABO blood group compatibility only, because human leucocyte antigen (HLA) phenotyping and cross-matching was not possible at the start of the recipient preparation process. However, none of the patients had lymphocytotoxic anti-HLA antibodies. Cross-matching was subsequently checked and found to be negative in all cases. The mean number of miss-matches was 4.7±1. There was no HLA compatibility between recipient and donor in 25% of cases, 30% had five mismatches and 45% had at least two histocompatibility allele matches.
The duration of cold ischaemia was 6.9±4.7 h for the pancreas and 9.8±5.4 h for the kidney. In all cases, recipients were given immunosuppressive treatment consisting of a combination of high-dose steroids initiated before surgery, with MMF and thymoglobulins. Prograft treatment was initiated on the day after surgery. The dose of steroids was rapidly decreased and steroid treatment was stopped in all patients, 4 days after transplantation (Figure 1).
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Patient and graft survival
All patients were followed for a minimum period of 6 months. The mean duration of follow-up was 30.8±14.6 months. All patients survived. No patient required post-transplant dialysis, and all patients displayed an immediate recovery of pancreatic function. At 6 months, the rates of kidney and pancreas survival were 100 and 95.8%, respectively (Table 1). One patient experienced pancreatic graft loss because of arterial and venous thrombosis on day 2. Five cases of partial pancreas venous thrombosis occurred and were localized in the upper cephalic part of the splenic vein. Evolution was favourable in all cases with an effective anti-coagulant treatment for 6 months consisting of sodium heparinate initially and then anti-vitamin K drugs.
Grafts function
At 6 months, mean serum creatinine concentration was 98.9±19.6 µmol/l. For all patients, fasting glucose concentration was <6 mmol/l and their mean HbA1c concentration was 5.1±0.5% 6 months after transplantation (Table 1). The mean trough level of tacrolimus was 9.73±1.29 ng/ml.
Rejection episodes
No kidney rejection was observed in the first 6 months. Only one case of biopsy-proven acute renal rejection occurred (grade Ia), 7 months after transplantation, giving an acute rejection rate at 1 year of 4.2%. This case was resistant to steroids, and was treated with anti-CD3 monoclonal antibody. Concomitant pancreas rejection was suspected, based on increases in plasma amylase and lipase levels. Two other cases of acute pancreas rejection were clinically suspected, 2 and 4 weeks after transplantation, based on increases in serum amylase and lipase levels. Concomitant kidney biopsy was normal, and no kidney rejection, according to the Banff classification, was observed. In these cases when a pancreas rejection was suspected, no partial thrombosis of the pancreatic vein was noted. Both cases responded to steroid pulses. The rate of clinically suspected acute pancreas rejection was 8.3% at 6 months and 12.5% at 1 year.
Re-introduction of corticosteroids
All three patients presenting acute rejection episodes were maintained on long-term steroid therapy. However, the major reason for re-introducing steroids was leucopenia, persisting even after the lowering of MMF dose and requiring the cessation of MMF treatment (Table 2). MMF was stopped in six patients for leucopenia. Three cases of leucopoenia were due to CMV infection. The cessation of MMF treatment was associated with the introduction of steroids to maintain a treatment with two immunosupprive drugs. At 6 months, steroids had been re-introduced in 33% of the patients. This re-introduction had occurred 3.9±3.5 months after transplantation in 41% of patients. No attempt has been made to withdraw steroids again in these patients.
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Metabolic modifications and blood pressure
The reappearance of diabetes mellitus after pancreatic transplantation may occur very early after the transplantation and generally corresponded to a non-functioning pancreas due to vascular thrombosis. De novo diabetes mellitus may also occur later and can be due to acute or chronic pancreatic rejection or to peripheral insulin resistance due to the use of steroids or due to modification of food intake. Only two new cases of diabetes mellitus were noted. All of them occurred in patients treated with corticosteroids for suspected pancreatic acute rejection; both patients had normal or elevated plasma C peptide and insulin concentrations. Hypoglycaemic sulphamide treatment was effective in both cases. No new cases of diabetes mellitus or glucose intolerance occurred in patients remaining on a steroid-free regimen. Mean glycated haemoglobin (HbA1c) concentration at 6 months was 5.04±0.51% for those not treated with steroids and 5.13±0.58% for the others. Mean weight gain at 6 months was 1±2.7 kg for the group on steroids and 2.15±2.12 kg for group not treated with steroids. Plasma cholesterol concentration remained normal in all 24 patients, with a mean value at 6 months of 4±0.77 mmol/l. Blood pressure was 132.8 ± 16.2 mmHg (systolic) and 75.35±10.5 mmHg (diastolic) at month 6 (Table 1). The number of anti-hypertensive drugs taken by patients treated with re-introduced steroids was 1.5±1.2 before transplantation and 1±1.3 at 6 months after transplantation. For patients without steroid re-introduction, it varied from 1.5±1.1 before transplantation to 0.4±0.8 after transplantation (NS). The systolic blood pressure was not different in the group without re-introduction of steroids or in the group with steroids: without steroids 132±17 mmHg and with steroids 140±19 mmHg. Similarly, the diastolic blood pressure was not different in the two groups: without steroids 73±11.5 mmHg and with steroids 80±5.8 mmHg.
Infectious complications
At least one infectious episode corresponding to an elevated fever (>38°C) and an increase in C-reactive protein occurred within 1 month of transplantation in 18 patients (75%). In 5 of these 18 patients, no infectious aetiology could be identified and broad-spectrum antibiotics were effective. Six patients suffered from pyelonephritis, which was due to Candida infection in two cases or gram-negative bacilli for the other four cases. Four patients had peri-pancreatic fluid infections, and two patients had acute gangrenous cholecystitis requiring cholecystectomy. Four patients developed cytomegalovirus (CMV) infection, between day 15 and the 3rd month after transplantation. Only one patient developed CMV disease, resulting in pneumonia and requiring temporary respiratory assistance. All of the four patients tested negatively for CMV serology before renal-pancreatic transplantation, and they had received grafts from donors who had tested positive for CMV serology (IgG). This profile, with a CMV-positive donor and a CMV-negative recipient, was found in three other cases, but in these cases the recipients did not develop CMV infection. However, all patients received oral CMV prophylaxis, with gancyclovir or valacycovir. Finally, one case of BK virus infection was noted in the 7th month, in a patient presenting ureteral stenosis; BK virus infection resolved with the lowering of MMF dosage; even more, they had concomitantly leucopenia or diarrhoea.
Cardiac events
Two patients presented acute myocardial infarction after transplantation; in one case, infarction was secondary to haemorrhagic shock following vascular rupture of the splenic artery and a veinous thrombosis leading to loss of the pancreatic graft.
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Discussion |
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Steroids were the first drug used in transplantation. Their broad immunosuppressive action implies inhibition of several cytokine gene transduction, inhibition of T cell and macrophage activation and inhibition of monocyte migration [2]. However, steroids have many side effects and studies have, therefore, investigated the possibility of stopping steroid treatment late in the post-transplantation period. As shown in a recent meta-analysis of late steroid withdrawal in kidney transplantation, the risk of acute rejection was significantly higher in patients not treated with steroids than in patients with continuing steroid treatment [8]. However, the development of new immunosuppressive drugs in the last 10 years has made it possible to envision earlier steroid withdrawal even within 1 week of transplantation. With early steroid discontinuation, acute rejection rates for kidney grafts were similar to those observed with the continuous maintenance of corticosteroid treatment. Even a large single-centre study of 349 kidney transplant recipients with steroid-free maintenance regimens, reported an acute rejection rate at one year of 6% [17].
In SPK transplantation, corticosteroids also increase the risk of complications and of peripheral insulin resistance [18,19]. In 1991, Cantarovich et al. [7] attempted to stop steroid treatment as early as 2 months after transplantation, but found that this strategy was feasible in only 70% of their patients. Five studies of steroid avoidance or very early steroid withdrawal regimens have been reported since 2000 (Table 3) [11,12,14–16]. Rates of kidney and pancreas rejection after a mean of 6 months of follow-up varied between 0% and 7%, patient survival from 95% to 100%, kidney survival between 92.5% and 100% and pancreas survival between 80% and 100% (Table 3). Cantarovich et al. [15] compared the benefits of early and late (after 3 months) steroid withdrawal. Despite the small number of patients in the study, they found that the rate of acute rejection was similar in both groups but that serum creatinine concentration tended to be lower in the group with late steroid withdrawal. These results are similar to our study where kidney and patient survival rates of 100% were obtained. Pancreas survival was 95.8% and, at 6 months, the rate of acute pancreas rejection (clinically suspected) was 8%, with no concomitant kidney rejection, despite a poor HLA-matching. We did not perform pancreas biopsy to confirm acute rejection, but the clinical presentation of these two patients with high blood amylase and lipase levels and no clear cause of ischaemia or drug-associated pancreatitis, was highly suggestive of acute rejection. However, we cannot rule out the possibility that pancreatic enzyme levels increased due to other mechanisms, such as partial venous thrombosis or mechanical vascular twisting.
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Pancreas–kidney transplanted patients, in which corticosteroids were withdrawn, were placed on a two-drug (ciclosporin or tacrolimus with MMF) or three-drug (tacrolimus, sirolimus and MMF) maintenance regimen, with acute rejection rates of 2.5–10% in SPK transplants. In this SPK transplantation series, all patients received induction therapy consisting of thymoglobulin associated with a very short course of corticosteroids, as routinely used for our patients. The only study carried out to date in which steroids were completely eliminated from the induction therapy reported fever in 93% of the patients and two cases of acute serum disease [14,15]. In the modern area of induction therapy, basiliximab and daclizumab have been demonstrated to reduce significantly the rate of acute rejection in renal transplantation and to give good results in terms of survival and rate of acute rejection in cases of isolated kidney transplantation without steroids [3,20]. For SPK transplantation, it would also be a valid alternative to use a blocking anti-IL2 receptor instead of anti-thymoglobulins. Alemtuzumab was used in SPK without steroids and nor calcineurin inhibitors. Results were encouraging despite a higher rate of reversible acute rejection at 6 months as compared with a historical cohort [16] suggesting that more study would be required to substantiate their place in SPK transplantation.
One important reason to avoid steroids remains their many metabolic side effects, including osteoporosis, osteonecrosis, cataracts, hyperlipidaemia, glucose intolerance, weight gain and hypertension [1,2]. This is an important issue for type I diabetes mellitus patients, who may already have numerous cardiovascular atherosclerotic lesions and/or risk factors. Following transplantation, all of our patients had normal serum cholesterol concentrations, no excessive weight gain and less need for anti-hypertensive medication. Other studies have confirmed this improvement in metabolic profile following SPK. Pascual et al. [8] and Freise et al. [12] found that, without steroids, total cholesterol concentration was significantly lower, with no increase in the frequency of kidney graft failure. Opelz et al. [21] reported a series of kidney and heart transplants in which steroid-free patients showed improvements in cardiovascular risk factors and lower frequencies of osteoporosis and cataracts.
Steroids are known to impair glucose metabolism, but other mechanisms must also be taken in account, including the mass of islets transplanted, islet rejection and calcineurin inhibitor toxicity [22]. In 57 renal transplant patients, Midtvedt et al. [23] found that lowering the daily dose of prednisolone to 5 mg/day had beneficial effects on insulin function, but the total withdrawal of this drug had no significant effect on insulin sensitivity. We recently showed that early steroid withdrawal in kidney transplant recipients was associated with a lower incidence of de novo diabetes mellitus [3]. In our series, the only two patients who developed diabetes mellitus with insulin resistance were maintained on steroids because of acute pancreas rejection. The other patients displayed well-controlled glucose regulation.
The steroid-free regimen was maintained in 60% of the patients. In the other 40% of patients, steroid re-introduction was required, for rejection in two cases (8.3%) and leucopenia in seven cases (29%), in order to maintain patients with a therapeutic association after a dramatic reduction or withdrawal of MMF. Indeed, MMF was suspected to be involved in the development of leucopenia in six of the seven cases, leading to large reductions of the dose given and the eventual withdrawal of this drug. In one case, leucopenia was due to CMV infection. This frequency of leucopenia associated with MMF was higher in our study than in studies carried out in kidney transplant patients, even when they were receiving thymoglobulin induction therapy, and may, therefore, indicate a particular susceptibility of this population to leucopenia. Alternatively, the absence of steroids may have favoured the marginalization of leucocytes favouring leucopenia. The careful determination of MMF concentrations will be required to clarify this point. The re-introduction of steroids has also been reported in other studies, after dose decreases or the complete withdrawal of MMF. Khwaja et al. [17] had to re-introduce steroids in 16% of kidney transplant patients. Cantarovich et al. [24] and Freise et al. [12] reported the re-introduction of steroids in 10% of SPK. Other strategies for dealing with leucopenia associated with MMF involve the transfer of patients onto sirolimus therapy, rather than the re-introduction of steroids [11]. However, this drug may have several different side effects, including hyperlipidaemia, wound disunion, anaemia, lymphoceles and interstitial pneumonia. Kaufman et al. [11] reported no side effects following the introduction of sirolimus, whereas Freise et al. [12] reported three cases of wound disunion with their sirolimus-containing protocol.
Finally, the incidence of CMV infection, in our series was of 7.1% and was very similar to the series of Axelrod et al. [25].
In conclusion, the early avoidance of steroids was associated with good evolution of SPK transplanted patients. However, steroids have to be re-introduced due to secondary effect of some immunosuppressors used, suggesting that a better monitoring of these drugs, and especially MMF, would be required to improve SPK transplantation.
Conflict of interest statement. None declared.
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References |
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- Stratta RJ. (1999) Review of immunosuppressive usage in pancreas transplantation. Clin Transplant 13:1–12.[Medline]
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[Abstract/Free Full Text] - Cantarovich D, Paineau J, Karam G, et al. (1991) Definitive corticosteroid withdrawal following simultaneous pancreas and kidney transplantation. Transplant Proc 23:1583–1584.[ISI][Medline]
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[Abstract/Free Full Text] - Vincenti F, Monaco A, Grinyo J, Kinkhabwala M, Roza A. (2003) Multicenter randomized prospective trial of steroid withdrawal in renal transplant recipients receiving basiliximab, cyclosporine microemulsion and mycophenolate mofetil. Am J Transplant 3:306–311.[CrossRef][ISI][Medline]
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- Cantarovich D, Karam G, Hourmant M, et al. (2005) Steroid avoidance versus steroid withdrawal after simultaneous pancreas-kidney transplantation. Am J Transplant 5:1332–1338.[CrossRef][ISI][Medline]
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[Abstract/Free Full Text] - Cantarovich D, Palneau J, Couderc JP, et al. (1991) Maintenance immunosuppression without corticosteroids following combined pancreas and kidney transplantation. Transplant Proc 23:2224–2225.[ISI][Medline]
- Axelrod D, Leventhal JR, Gallon LG, Parker MA, Kaufman DB. (2005) Reduction of CMV disease with steroid-free immunosuppresssion in simultaneous pancreas-kidney transplant recipients. Am J Transplant 5:1423–1429.[CrossRef][ISI][Medline]
Accepted in revised form: 12.10.06
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