Ann Thorac Surg 2004;78:1940-1943
© 2004 The Society of Thoracic Surgeons
Original article: general thoracic
Recovery of Chronic Renal Impairment With Sirolimus After Lung Transplantation
Federico Venuta, MDa,*,
Tiziano De Giacomo, MDa,
Erino A. Rendina, MDa,
Serena Quattrucci, MDb,
Edoardo Mercadante, MDa,
Giuseppe Cimino, MDb,
Moshen Ibrahim, MDa,
Daniele Diso, MDa,
Alessandra Bachetoni, MDc,
Giorgio F. Coloni, MDa
a Department of Thoracic Surgery, Rome, Italy
b Cystic Fibrosis Unit, Rome, Italy
c Laboratory and RIA Unit, University of Rome "La Sapienza," Policlinico Umberto I, Rome, Italy
Accepted for publication March 8, 2004.
* Address reprint requests to Dr Venuta, Università di Roma "La Sapienza," Policlinico Umberto I, Cattedra di Chirurgia Toracica, V. le del Policlinico, Rome 00161, Italy
sofed{at}libero.it
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Abstract
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BACKGROUND: Standard immunosuppression after lung transplantation includes calcineurin inhibitors, azathioprine, and steroids. Calcineurin inhibitor administration is associated with an increased renal impairment. Sirolimus shows no renal toxicity and could be used in selected patients.
METHODS: We have prospectively administered sirolimus as an alternative to calcineurin inhibitors in 15 lung transplantation recipients with persistent drug nephrotoxicity. Eight patients had also bronchiolitis obliterans syndrome. The mean serum creatinine and azotemia were 2.7 ± 1.1 mg/dL and 111 ± 39 mg/dL. After starting sirolimus, azathioprine was reduced to 50%–25% of baseline, calcineurin inhibitors were gradually reduced and eventually stopped, and steroids were maintained stable. Patients started sirolimus with 2 to 5 mg/d orally; adjustments were made according to trough levels (4 to 12 ng/mL for combined sirolimus + calcineurin inhibitors; 12 to 20 ng/mL as monotherapy), toxicity, and perceived efficacy. Patients were monitored for renal and graft function and clinical status.
RESULTS: A significant creatinine decrease was observed after 6 months of treatment (p < 0.02); azotemia decreased after 1 month and remained stable (p < 0.01). Pulmonary function tests did not show any significant modification from before sirolimus baseline in patients without bronchiolitis obliterans syndrome. There were eight infectious complications and 10 episodes of toxicity (4 dermatitis, 2 epistaxis, 1 headache, 1 diarrhea, 1 nausea, 1 laryngeal cancer). Moderate leukocytopenia (n = 3) and hypertriglyceridemia (n = 6) responded to dose reduction. One patient was lost to follow-up. Three patients died of complications related to bronchiolitis obliterans. One patient underwent transplantation again.
CONCLUSIONS: Sirolimus administration allows amelioration of renal function with a relatively low morbidity and is useful for chronic renal impairment rescue after lung transplantation.
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Introduction
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Lung transplantation (LT) is now considered a viable therapeutic option for a selected group of patients with respiratory failure; however, a successful long-term outcome is still hindered by a number of problems such as infection, chronic rejection, and complications related to immunosuppression. Standard immunosuppression includes calcineurin inhibitors (CI), azathioprine, and steroids; other drugs can be used immediately after the transplant to induce immunosuppression, or azathioprine (mycophenolate mofetil) can be substituted. The immunosuppressive regimen after LT is usually extremely aggressive because the lung is considered a strongly immunogenic organ; this policy improves control of acute and chronic rejection, but favors the onset of complications. A common clinical problem is the development of acute or chronic renal failure [1, 2]; the Lung Transplantation Registry reports that more than 30% of the recipients show renal impairment at a certain point of the follow-up [3]. The direct effect of CI is certainly involved in the development of this complication, but there are also cofactors like diabetes, hypertension (both potentially related to CI therapy) [4], and administration of high-dose antibiotics and other nephrotoxic drugs. Until recently, there has been no alternative to the use of CI as a primary immunosuppressant in the LT population. Sirolimus (SRL) is a novel and powerful macrolide drug without renal toxicity; it has already been used after kidney transplantation to improve renal function [5]. This drug could also be used in selected patients undergoing LT [6, 7] to reduce toxicity and improve renal function.
We have prospectively administered SRL as an alternative to CI in a group of LT recipients showing serious renal impairment limiting CI dosing.
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Material and Methods
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Sirolimus was prospectively administered as an alternative to CI in 15 LT recipients with persistent renal impairment. Patients were enrolled into this study when serum creatinine was steadily 1.8 mg/dL or greater. Renal dysfunction was present despite attempted CI dose minimization to the lowest perceived efficacious level, alteration of immunosuppression strategies to use other nonrenal toxic therapies, and correction of any other predisposing reversible factor. The protocol was approved by the University of Rome "La Sapienza" Ethics and Research Committee, and written informed consent was obtained from each patient. The group enrolled in our study came from a total long-term survivors pool of 81 patients. There were 10 men (67%) and 5 women (33%); the mean age was 38.9 ± 13.6 years. The indication to LT was cystic fibrosis in 8 patients (53.3%), chronic obstructive pulmonary disease in 5 (33.3%), and pulmonary fibrosis in 2 (13.3%). Twelve patients underwent bilateral sequential LT and 3 received a single LT. The standard immunosuppressive regimen included cyclosporine (blood trough level > 400 ng/dL immediately after the transplant and 300 to 350 ng/dL after 6 months), azathioprine (2 mg/kg per day, to maintain white blood cell count > 4,000 cells/mL), and steroids (methylprednisolone 125 mg every 8 hours for 9 doses after the transplant and then prednisone 0.5 to 1 mg/kg progressively tapered to 10 to 15 mg/d); as an alternative to cyclosporine, FK506 was administered when toxicity or side effects appeared. At the time of conversion to SRL 8 patients (53%) were on cyclosporine and 7 (47%) were on FK506 (already switched from cyclosporine). Eight patients had bronchiolitis obliterans syndrome (BOS) at the time of enrolment. Conversion from CI to SRL was performed at a mean of 34.8 ± 19.7 months after transplantation. The mean serum creatinine and azotemia at the time of conversion were 2.7 ± 1.1 mg/dL and 11 ± 39 mg/dL, respectively. No patient was on dialysis. After starting SRL azathioprine was immediately reduced to 25%–50% of baseline, CI were gradually reduced and stopped within 3 months, and steroids were maintained stable. Patients started SRL with 2 to 5 mg/d orally; dose adjustments were made according to trough levels (4 to 12 ng/dL for combined SRL + CI and 12 to 20 ng/mL as monotherapy without CI), toxicity, and perceived efficacy. Patients were monitored for renal and lung graft function (pulmonary function tests, arterial blood gases) and clinical status after 1, 3, 6, and 12 months.
Data are presented as mean ± standard deviation. Paired two-tailed Student's t tests were used to analyze quantitative continuous variables comparing the means. Repeated measures analysis of variance was performed to compare the means of the variables that were measured on more than one occasion in each individual at the different times. A p value of less than 0.05 was considered to indicate statistical significance.
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Results
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Calcineurin inhibitors could be completely stopped in all patients within 3 months. A significant serum creatinine decrease was observed after 6 and 12 months of treatment (Fig 1); azotemia decreased after 1 month and remained stable for the rest of follow-up (Fig 2). The mean duration of follow-up was 19.7 ± 9.4 months.
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Fig 1. Serum creatinine after sirolimus conversion. In order from the inside to the outside, the box within the box, the box, and the bars represent, respectively, mean, standard error, and standard deviation. (T0 = baseline.)
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Fig 2. Azotemia after sirolimus conversion. In order from the inside to the outside, the box within the box, the box, and the bars represent, respectively, mean, standard error, and standard deviation. (T0 = baseline.)
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There were nine infectious complications in 6 patients (40%): two cytomegalovirus, two aspergillus, two Pseudomonas aeruginosa pneumonia, two pneumonia caused by Staphylococcus aureus, and one Staphylococcus enteritis; the mean time of onset of infections was 4.2 ± 2.5 months after conversion. There were nine episodes of potential SRL-related toxicity: four dermatitis, two epistaxis, one headache, one nausea, and one laryngeal cancer. Moderate leukocytopenia and hypertriglyceridemia were observed in 3 and 6 patients, respectively; they were related to the drug trough level and quickly responded to dose reduction or temporary cessation. One patient was referred for logistic reasons to another center: that center arbitrarily withdrew SRL and reintroduced cyclosporine; serum creatinine and azotemia immediately increased, and the patient required dialysis. One patient was lost to follow-up. One patient died of complications related to laryngeal carcinoma.
Pulmonary function tests did not show any significant modification from pre-SRL baseline in patients without BOS (Fig 3). The mean forced expiratory volume in 1 second of patients with BOS already diagnosed at the time of SRL conversion is reported in Figure 4. Three patients died of infectious complications related to BOS; they already had a significant functional impairment when starting SRL. One patient with BOS had bilateral pneumothorax requiring chest tube drainage; he underwent a second transplantation and died in the immediate postoperative period. Four patients with BOS at the time of enrolment had a decrease in BOS progression. One patient required reintroduction of low-dose cyclosporine and FK506 in association with SRL to control lung function deterioration.
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Fig 3. Forced expiratory volume in 1 second (% predicted) spirometric monitoring after sirolimus conversion in patients without bronchiolitis obliterans syndrome. In order from the inside to the outside, the box within the box, the box, and the bars represent, respectively, mean, standard error, and standard deviation. (ns = not significant; T0 = baseline.)
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Fig 4. Forced expiratory volume in 1 second (% predicted) spirometric monitoring after sirolimus conversion in patients with bronchiolitis obliterans syndrome. In order from the inside to the outside, the box within the box, the box, and the bars represent, respectively, mean, standard error, and standard deviation. (ns = not significant; T0 = baseline.)
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Comment
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The introduction of cyclosporine in the late 1970s allowed a dramatic improvement in the outcome of solid organ transplantation; at that point LT entered a new era, becoming a real therapeutic option for a selected group of patients with end-stage respiratory failure [3, 8]. Since then other immunosuppressant have been introduced including the CI FK506 and others. The development of new therapeutic regimens has contributed to maximize the efficacy of immunosuppression with a decrease of rejection rates and overall survival improvement. However, the long-term benefit of these agents is often limited by major side effects such as chronic nephrotoxicity.
Sirolimus is a novel immunosuppressive drug structurally similar to FK506 but with a different mechanism of action. Whereas cyclosporine and FK506 achieve their effects principally by blocking calcineurin and thereby inhibiting interleukin 2 production, SRL has no effect on calcineurin. A key action of SRL is to interrupt T-cell cycle transition from the G1 to the S phase by inhibiting interleukin 2 signal transduction pathways. Binding SRL to mTOR (mammalian target of rapamycin) inhibits T-cell proliferation by selectively blocking the activation of the process within the cell that is necessary for G1 to S phase transition. As the significant nephrotoxicity, neurotoxicity, and hypertension associated with CI can be attributed in part to calcineurin blockade [9, 10], SRL would be expected to have a different toxicity profile.
Recent studies in the kidney transplant population have demonstrated that SRL therapy results in better preservation of renal reserve [11, 12] and a decrease of acute rejection rates from 40% to less than 10% when compared with cyclosporine [13]. Most patients with renal dysfunction during CI administration show the coexistence of chronic damage, which is usually irreversible, and acute damage, which is reversible after CI withdrawal. It is well known that when renal dysfunction appears, progression is usually irreversible if CI are not withdrawn; however, this is almost impossible in the LT population if we want to ensure adequate immunosuppression. For this reason early conversion to SRL is recommended, before chronic damage and irreversible decline in renal function occurs. None of our patients was on dialysis and probably we were within the appropriate time for conversion. The timely administration of SRL allowed us to completely withdraw CI in all patients, normalizing serum creatinine and azotemia as soon as CI were interrupted. The improvement obtained was stable during follow-up. Our report confirms the experience of Snell and colleagues [6]; they clearly showed that SRL can be considered a useful alternative immunosuppressant after LT. The introduction of SRL allowed significant CI withdrawal in transplant recipients with renal impairment. The group from Melbourne underlined that long-term improvement in creatinine probably depends only on the balance between the extent of acute and chronic renal damage.
It has been questioned whether SRL alone (or in combination with low-dose azathioprine and steroids, as in our group of patients) is a sufficient immunosuppression. Randomized controlled studies in patients undergoing kidney transplantation compared a cyclosporine-based regimen with one based on SRL to determine whether the latter is a viable alternative [11–13]: in those studies, graft survival rates at 1 year were equal in the two arms, with a lower rate of acute rejection episodes and an improved preservation of renal reserve in the SRL group. We did not observe any episode of acute rejection during SRL administration.
The most dreadful complication during long-term follow-up after LT is BOS. The mechanisms of onset are not well known, but it is now clear that it should be interpreted as chronic rejection. The natural history of BOS usually shows a progressive decline in lung function, even if a short-term improvement or stabilization may be observed with augmented immunosuppression in selected cases [14, 15]. Sirolimus shows an important antiproliferative effect on adult lung fibroblasts [16] that could play an important role in preventing the onset of this complication or in slowing down its clinical course once it appears. It has been reported [17] that among individuals with rapidly declining pulmonary mechanics, SRL resulted in stabilization or improvement of pulmonary function. In our group there were no new episodes of BOS in patients with stable pulmonary function tests and BOS grade 0 at the time of enrolment; patients already exhibiting BOS had a reduction of the deterioration rate in four cases (50%). Three patients died of infectious complications related to BOS; however, they already had a significant functional deterioration when SRL was introduced. Certainly a larger group of patients and prospective randomized studies will be required to confirm this trend. It should be noted that SRL cannot be administered early in the postoperative period after LT because it has a detrimental effect on airway healing [18, 19].
In conclusion, SRL allowed amelioration of renal function with a return of serum creatinine and azotemia within the normal range; the administration of this drug shows a reasonable rate of complications that are not uncommon with other immunosuppressive regimens. Side effects were related to the drug trough level and responded to dose reduction. Early conversion to SRL from CI is advised when renal dysfunction appears to prevent the onset of chronic irreversible renal damage leading to dialysis.
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References
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Abstract
Introduction
