© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Clin Transplant 2014: 28: 616–622 DOI: 10.1111/ctr.12361
Clinical Transplantation
The incidence, management, and evolution of rapamycin-related side effects in kidney transplant recipients Verhave J, Boucher A, Dandavino R, Collette S, Senecal L, Hebert M-J, Girardin C, Cardinal H. The incidence, management, and evolution of rapamycin-related side effects in kidney transplant recipients. Abstract: Conversion from a calcineurin-inhibitor-based immunosuppression to a rapamycin-based immunosuppression may preserve kidney graft function. The side effects of rapamycin can limit its usefulness, but their management and evolution are rarely reported in clinical trials. We performed a retrospective cohort study in patients transplanted before December 31, 2008 and who received rapamycin to replace calcineurin inhibitors. In 219 patients studied, 98% presented ≥1 side effects after starting rapamycin. Side effects occurring in ≥10% of patients were dyslipidemia (52%, 95% confidence interval (CI): 45–59%), peripheral edema (37%, 95%CI: 31–43%), cytopenia (36%, 95% CI: 30– 42%), acne (29%, 95% CI: 23–35%), proteinuria (23%, 95% CI: 17– 29%), and oral ulcers 14% (95% CI: 10–18%). Proteinuria, ulcers, and edema were difficult to manage and were more likely to cause cessation of rapamycin. Rapamycin was discontinued in 46% of patients (95% CI: 40–52%). Age (odds ratio [OR] per 10-yr increase: 1.29, 95% CI: 1.05– 1.59) and obesity (OR: 2.57, 95% CI: 1.10–6.01) were independently associated with cessation of rapamycin. We conclude that successful control of dyslipidemia and cytopenia can be achieved without discontinuing rapamycin. Most other side effects are harder to manage. Leaner and younger patients are less likely to discontinue rapamycin due to side effects.
Over the last decade, rapamycin, an mTOR inhibitor (1), has been increasingly used for its immunosuppressive properties in the field of kidney transplantation. The use of rapamycin in place of calcineurin inhibitors (CNI) in de novo kidney transplant recipients (KTR) has fallen out of favor due to increased acute rejection rates, delayed graft function, and wound complications (2–5). However, recent clinical trials have focused on replacing CNI with rapamycin at a later time point in an effort to preserve kidney graft function. Better graft function in the first years after transplantation has been reported in subjects who were converted from CNI to rapamycin in the early post-transplant period (6, 7), but improvement in graft function at later time points is controversial (8, 9). Rapamycin has antiproliferative properties. Decreased nonmelanoma skin cancer (10) as well as overall malignancy rates (9) have been reported in
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Jacobien Verhavea, Anne Boucherb, Raymond Dandavinob, calb, Suzon Colletteb, Lynne Sene a e Hebert , Catherine Marie-Jose lo€ıse Cardinala Girardina and He Nephrology, Centre Hospitalier de l’Universite al and bNephrology, Hopital de Montre Maisonneuve Rosemont, Montreal, QC, Canada
a
Key words: kidney transplantation – rapamycine – side effects lo€ıse Cardinal, Corresponding author: He de Montre al, Centre Hospitalier de l’universite Notre-Dame, 1560, rue Sherbrooke Est, H2L al, QC, Canada 4M1 Montre Tel.: 514 890 8000; fax: 514 412 7831; e-mail: [email protected] Conflict of Interest: This study was supported by an unrestricted grant from Pfizer. Accepted for publication 10 March 2014
subjects who were converted to rapamycin when compared to those who continued CNIbased maintenance immunosuppression regimen. Hence, conversion of CNI to rapamycin is a therapeutic option after kidney transplantation, for decreasing the risk of post-transplant malignancies and avoiding CNI-based nephrotoxicity (11–13). Despite these potential benefits, the widespread use of rapamycin in KTR is overshadowed by its side effects. Clinical trials report 54–80% rapamycin-related side effects with rare mentioning of their management and evolution. In randomized trials that examined the outcomes of conversion to rapamycin, reported discontinuation rates were 12–36% after one yr and 23–61% after two yr (6, 12–15). However, discontinuation rates from randomized trials may not reflect those observed in general practice, given the strong incentive to persist with study drugs to avoid contamination
Rapamycin side effects in kidney transplantation between study groups. Furthermore, the reported rate of side effects may be underestimated due to the recruitment of a healthier set of patients (16, 17) and the implantation of run-in periods that ensure that only patients who tolerate the study drug are recruited (18). For clinicians who offer conversion from CNI to rapamycin, it is important to counsel patients on the expected rate of side effects and drug discontinuation and to know what to expect in terms of therapeutic success when these side effects occur. Current guidelines recommend that frequent and serious side effects be disclosed to patients when initiating a new therapy (19). Hence, we aimed to determine frequent and serious rapamycin side effects in a cohort of patients who were converted from CNIs to rapamycin. We also studied the management and evolution of rapamycin-related side effects and verified whether certain patient characteristics are associated with an increased rate of rapamycin cessation.
Methods Design and subjects
In this retrospective cohort study, we included KTR who received a single kidney graft at the Centre Hospitalier de l’Universite de Montreal and H^ opital Maisonneuve-Rosemont, and in whom conversion from a calcineurin inhibitor to rapamycin was attempted at least one month after transplantation. The earliest transplantation date from a patient converted to rapamycin was October 28, 1978, and we included patient transplanted up to December 31, 2008. Approval from the local ethics committee was obtained. Patients entered the cohort at the date of their renal transplantation and were followed up until graft loss, death, transfer to another center or December 31 2009, whichever occurred first.
Measurements
Trained research nurses collected information from the patient’s files on transplantation characteristics, laboratory values, dates of initiation and discontinuation of immunosuppressive agents, rapamycin-related side effects, management and evolution of these side effects. Side effects
Frequent side effects were defined as those occurring in ≥10% of patients (20), while serious side effects were defined as conditions that were life- or organ threatening (21). Dyslipidemia was defined as the initiation or increase in lipid-lowering drugs, or an increase of ≥50% in triglycerides or total cholesterol after rapamycin initiation with levels above the normal range (triglycerides >2 mM and total cholesterol >5.2 mM). Cytopenia was defined as a fall in hemoglobin, leukocytes, or thrombocytes to a value below the lower range of normal (hemoglobin < 120 g/L, leukocytes < 4000/lL, platelet count < 150 000/lL) and by more than 25% compared to pre-conversion values. Proteinuria was measured by a semi-quantitative dipstick method. Increased proteinuria was defined as dipstick levels ≥1 g/L if levels were 30 kg/ m2. Glomerular filtration rate (eGFR) was estimated by the four-variable MDRD formula at the time rapamycin was added and one yr later. We also collected information on the clinical motive invoked for conversion from CNI to rapamycin.
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Verhave et al. Statistical analyses
Continuous variables are reported as means and standard deviations or median and interquartile ranges, according to their distribution. Side effects are reported as proportions with an appropriate 95% confidence interval (CI). A side effect was considered frequent when the lower margin of its 95% CI was ≥10%. Multivariate logistic regression was used to identify the clinical factors associated with side effects that motivated discontinuation of rapamycin. (SPSS, IBM statistics 19, New York, NY, USA). The significance level was set at 0.05%.
Results Study population
We identified 219 KTR in whom conversion of a CNI-based immunosuppression regimen to a rapamycin-based regimen was attempted. The patients had a mean age of 45 yr (13) and were principally Caucasian with a male predominance of 61% (Table 1). Obesity was present in 12% of the patients. Sixty percent of patients used tacrolimus at the moment of rapamycin introduction, and 37% used cyclosporine in a triple-drug maintenance immunosuppression regimen based on CNI, mycophenolate mofetil, and prednisone. Rapamycin was started at a median of three yr after the transplantation; however, this ranged from one month to 26 yr. Rapamycin was added to the regimen with subsequent CNI weaning in 213 patients, whereas CNI discontinuation was complete before rapamycin introduction in six patients. In 44% of patients, rapamycin was started because of biopsy-proven CNI nephrotoxicity, in 15% because of other CNI-related side effects, and in 17% for empirical nephroprotection (i.e., in the absence of documented biopsy-proven CNI toxicity). Given its potential benefit on neoplasia (9) and BK replication (23), transfer to rapamycin followed a diagnosis of malignancy in 18% and of BK nephropathy in 6% of patients (Table 2). Despite the initial intention to completely discontinue CNI after adding rapamycin, 24 patients did not complete CNI withdrawal and used a combination of CNIs and rapamycin (in two-thirds, this was in addition to MMF). The mean eGFR at the start rapamycin was 42 mL/min/1.73 m2 (16), and 15 patients (6.8%) had significant proteinuria (≥1 g/L). Frequent rapamycin side effects: management and evolution
In our cohort, 98% of patients presented one or more side effects after the start of rapamycin. More
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Table 1. Demographic and transplant-related characteristics of patients Characteristics
n = 219
Mean age in years (SD) Male gender (%) Race (%) Caucasian Black Asiatic Other First transplantation (%) Deceased donor (%) Donor age in years (SD) Induction (%) Thymoglobulin Anti-CD25 Calcineurin inhibitor used at the time rapamycin was added (%) Tacrolimus Cyclosporine Other immunosuppressive agent used at the time rapamycin was added (%) Mycophenolate mofetil Azathioprine Prednisone dose at the time rapamycin was added in mg/day (SD) Median time between transplantation and addition of rapamycin in years (IQR) Mean eGFR (mL/min/1.73 m2) at the time rapamycin was added (SD) Median proteinuria by dipstick at the time rapamycin was added in g/L (IQR) Patients with dipstick proteinuria ≥1 g/L at the time rapamycin was added (%)
45 (13) 134 (61) 203 (93) 1 (0.5) 11 (5) 4 (2) 192 (88) 194 (89) 42 (16) 16 (7) 106 (48)
131 (60) 82 (37)
176 (80) 12 (5) 7.4 (5) 3.0 (0.9–8) 42 (16) 0 (0–0.0) 15 (7)
SD, standard deviation; IQR, interquartile range.
than 10% of patients had up to 4 different side effects. The side effects reported with a frequency ≥10% were (in order of frequency) dyslipidemia, peripheral edema, cytopenia, acne, proteinuria, and oral ulcers. Blood levels of rapamycin were similar across side effects and within target (8.7– 10.7) at the time related symptoms supervened. New or worsened dyslipidemia occurred in 52% (95% CI: 45–59%) of patients. This was rarely severe as diet, reduction of rapamycin dose, or the Table 2. Motive for adding rapamycin to the maintenance immunosuppression regimen n = 219 Biopsy-documented calcineurin inhibitor nephrotoxicity (%) Empirical nephroprotection (normal or no biopsy prior to conversion) (%) Calcineurin inhibitor non-renal side effects (%) Cancer (%) BK-virus nephropathy (%)
96 (44) 37 (17) 34 (15) 40 (18) 12 (6)
Rapamycin side effects in kidney transplantation initiation/increase in lipid-lowering drugs led to successful control in the vast majority of patients: only 3% (95% CI: 0–6%) of patients who experienced dyslipidemia had to discontinue rapamycin for that motive. Peripheral edema was observed in 37% (95% CI: 31–43%) of patients. Although conservative maneuvers such as decreased rapamycin dose, salt and water restriction, diuretics, and withdrawal of calcium-channel blockers were undertaken, 20% (95% CI: 11–29%) of patients with peripheral edema had to discontinue rapamycin for unacceptable control of this side effect. Cytopenia occurred in 36% (95% CI: 30–42%) of patients. This was rarely severe enough to motivate rapamycin discontinuation, as only 10% (95% CI: 4–16%) of patients with cytopenia had to cease rapamycin for this side effect. The therapeutic maneuvers that successfully achieved control in cytopenic patients who persisted with rapamycin included decreased rapamycin dose, decreased mycophenolate mofetil dose, iron or erythropoietin supplementation in cases of anemia, and folic acid supplementation for leucopenia. Acne occurred or worsened in 29% (95% CI: 23–35%) of patients. This was of sufficient severity to cause rapamycin discontinuation in 13% (95% CI: 5–18%) of patients who experienced this side effect. Decreased rapamycin or prednisone dose, topical or oral antibiotic therapy resulted in acceptable control in other cases. New or worsened proteinuria was observed in 23% (95% CI: 17–29%) of patients. This was of sufficient severity to motivate rapamycin withdrawal in 33% (95% CI: 21–45%) of cases. In these patients, median proteinuria had increased from 0.31 g/24 h before the introduction of rapamycin to 3.1 g/24 h at the time of rapamycin discontinuation. Other patients showed acceptable control with decreased rapamycin dose, salt and water restriction, and use of/increase in renin-angiotensin inhibitors. Rapamycin-associated oral ulcers supervened in 14% (95% CI: 10–18%) of patients, but were severe enough to motivate discontinuation in 23% (95% CI: 9–37%) of subjects who presented with this side effect, while rapamycin dose reduction, steroid-based mouthwash, or antiviral agents led to successful control in other patients. Severe rapamycin side effects
We encountered few patients with severe side effects. In two patients, rapamycin was associated with an episode of thrombotic microangiopathy (TMA). These patients had no sign of decreased hemoglobin/thrombocytes or increased LDH before the start of rapamycin. One patient developed TMA four months after introducing rapamy-
cin for a Banff grade 1 acute rejection that was accompanied by an acute allograft glomerulitis. No C4d staining or donor-specific antibody (DSA) measurements were available at that time. The hemolytic parameters (thrombocytopenia, LDH) normalized with a decrease in rapamycin doses, but the patient lost the graft one month after the cessation of rapamycin. The second patient had hemolytic parameters during a hospitalization for diarrhea (40% increase in LDH, 33% decrease in thrombocytes, and undetectably low haptoglobin levels) without an increase in serum creatinine. Rapamycin was stopped in this patient for suspected TMA, in the absence of graft biopsy documenting the suspected diagnosis. Rapamycin was replaced by tacrolimus, and the hemolytic and diarrheal syndrome resolved. Three patients were diagnosed with rapamycin-associated pneumonitis. The patients presented with dyspnea, fever, and/or coughing. All cases underwent bronchoalveolar lavage to exclude infection. In two patients, bilateral interstitial infiltrates were observed on CT scans, and in one, on thoracic X-rays. There was no positive culture indicating an infectious origin. All patients stopped rapamycin, and pulmonary symptoms ameliorated in 2–4 months. One patient had severe acute rejection that seemed associated with conversion from CNI to rapamycin. The switch from CNI to rapamycin was undertaken for nephroprotection, and this patient had never experienced acute rejection. Pre-conversion biopsy was normal. Before transplantation, the patient had anti-HLA class I antibodies on pre-transplant flow cytometry assays that were not DSAs, and no anti-HLA class 2 antibodies. The patient developed Banff grade I cell-mediated rejection with glomerulitis and de novo HLA class II antidonor-specific antibodymediated rejection seven months after conversion. Despite treatment with methylprednisolone, intravenous immunoglobulins (IvIg), and resumption of CNIs, the graft was lost six months after the rejection episode. Withdrawal of rapamycin because of side effects. Overall, rapamycin was discontinued because of side effects (including less frequent side effects not discussed above) in 102 subjects (46%, 95% CI: 40–52%). This occurred most often (in ≥20% of patients with the side effect) when diarrhea, proteinuria, pulmonary symptoms, edema, and ulcers supervened. Among those who stopped rapamycin, this drug had been used for a median of six months (range one month to seven yr). Among patients who persisted for more than one yr after the introduction of rapamycin, mean
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eGFR increased by 1.2 mL/min/1.73 m2 after one yr of follow-up, whereas it decreased by 3.9 mL/min/1.73 m2 in those who had to discontinue rapamycin (difference in one-yr eGFR change between the 2 groups: 5 mL/min/ 1.73 m2, 95% CI: 8, 1). We then asked whether certain patient characteristics were associated with the withdrawal of rapamycin. In univariate analysis, age (OR per 10-yr increase: 1.29, 95% CI: 1.05, 1.59) and obesity (OR: 2.57, 95% CI: 1.10, 6.01) were associated with discontinuation of rapamycin. Other characteristics such as gender, race, smoking, type of donor, number of transplantations, diabetes, transplant center, eGFR or proteinuria at the time of rapamycin initiation, or the motive invoked to start rapamycin were not associated with rapamycin cessation. In a multivariate model, age (OR per 10-yr increase: 1.27, 95% CI: 1.03, 1.56) and obesity (OR: 2.39, 95% CI: 1.02, 5.64) were independently associated with cessation of rapamycin. Discussion
Conversion from CNI to rapamycin after renal transplantation is beneficial with regards to the reduction of non-melanoma cutaneous malignancy rates (12, 13). In addition, after five yr of follow-up, it preserved renal function compared to CNI-based immunosuppression in one trial (8). Because of the selection of healthier patient sets and procedures put in place to maximize adherence to protocol, side effects and drug discontinuation rates reported in randomized controlled trials may not be generalizable to everyday clinical practice. Physicians should disclose frequent and severe side effects to their patients when initiating new therapies. We undertook the present study to guide patient counseling for clinicians offering conversion to rapamycin to their KTR. In our clinical experience, 98% of patients presented at least one side effect. Ten percent of the patients had up to four different side effect attributed to rapamycin. Side effects occurring with a frequency ≥10% were dyslipidemia, edema, cytopenia, acne, proteinuria, and oral ulcers. Close to 50% of patients on rapamycin maintenance therapy discontinued the drug because of side effects. Patients who persisted with rapamycin had a favorable evolution in eGFR one yr after its introduction compared to patients who had to discontinue it. Few patients (3%) in our study had severe side effects. We observed two cases of rapamycin-associated TMA, three cases of pneumonitis, and one case of antibody-mediated rejection. Rapamycin
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may induce TMA by decreasing vascular endothelial growth factor expression (24) and enhancing platelet aggregation (25). TMA has been described when rapamycin is used in combination with CNI, as rapamycin may enhance the toxic effect of CNI on the endothelium (26). However, TMA is also observed in transplant patients on rapamycin without CNI (27). Rapamycin-associated pneumonitis is a well-described identity (28). In 85% of the cases, this phenomenon is reversible after cessation of the drug (29). This diagnosis is suspected in transplant patients using rapamycin who have pulmonary symptoms and infiltrates in the absence of pulmonary edema or of an infectious cause. In our cohort, all cases resolved after drug discontinuation. One patient who was at low immunological risk developed severe antibody-mediated rejection after switching to rapamycin for empirical nephroprotection and lost the graft despite aggressive antirejection therapy. We have since then observed another case of antibody-mediated rejection six wk after conversion to rapamycin for empirical nephroprotection in a patient with normal graft function who had been transplanted for one yr, had never experienced rejection episodes previously, and had no anti-HLA antibodies prior to transplantation. Again, this patient developed antiHLA class II antibodies and has now regained normal graft function after treatment with methylprednisolone, thymoglobulin, plasmapheresis, and IvIg. One major challenge is to assess the link of causality between rapamycin and its attributed side effects. The WHO-UMC system (30) is a generally accepted method in causality assessment in clinical practice. By fulfilling the assessment criteria, the causality between the drug and the side effect is graded from “certain” to “unclassifiable.” In both patients with TMA, the causality with rapamycin is “possible,” because we cannot exclude other potential causes for the clinical syndromes and because we did not rechallenge our patients with rapamycin. The patients with pneumonitis all had a probable causality with rapamycin, especially because extensive research eliminated other causes of pneumonitis. In the patient with antibodymediated rejection, causality assessment yielded a “possible” score. In contrast, reported non-severe side effects such as diarrhea and non-specific pulmonary symptoms may not have been causally linked to rapamycin. For instance, 28% of patients with diarrhea had a documented infectious cause, and all were also receiving other antirejection agents that could have caused diarrhea (tacrolimus, mycophenolate mofetil). Among those with non-specific pulmonary symptoms, 72% were
Rapamycin side effects in kidney transplantation diagnosed with pneumonia and 10% with heart failure. Given the high rate of rapamycin discontinuation observed among patients with diarrhea or non-specific pulmonary symptoms, one may question whether drug cessation was appropriate or whether the side effects could have resolved with time while continuing rapamycin. We showed that age and obesity are risk factors for cessation of rapamycin due to side effects. The adaptation of rapamycin dosage in elderly and obese patients is a concern, especially because of the narrow therapeutic index. The monography of rapamycin suggests that doses should be lowered in elderly patients because blood clearance decreases linearly with age (31). In general, elderly patients are prone to drug-related side effects (32), which may be explained by age-related changes in drug absorption, volume of distribution, and drug elimination (33). The effect of obesity on rapamycin pharmacokinetics is unclear (34). Rapamycin is a highly lipophilic molecule, which is likely to have a different volume of distribution in patients with increased fat mass per kg total body weight. At present time, there are no data on rapamycin-specific pharmacokinetic characteristics in elderly or obese patients, but our findings do suggest that these subgroups should be monitored more closely for the occurrence of side effects. Our study is limited by its retrospective nature. Although we used operational definitions in our research protocol when possible, the occurrence of certain side effects such as edema, oral ulcers, or diarrhea remains sensitive to practitioner’s subjectivity, and quantification of proteinuria through 24-h urine collection was not always available. Although this may reduce the accuracy of side effects reporting, it reflects everyday clinical care that was provided to patients. Conclusion
The present study illustrates our clinical experience with rapamycin-associated side effects. We showed that while the majority (98%) of patients who used rapamycin experienced at least one side effect, few patients had severe side effects. Side effects that should be discussed when counseling patients on the opportunity of a switch from CNI to rapamycin are those occurring in 10% of patients or more (dyslipidemia, peripheral edema, cytopenia, acne, proteinuria, oral ulcers) and those that are severe (TMA, pneumonitis, and rejection). Patients should also be aware that reconversion to CNI occurs in close to 50% of patients and is associated with a slight decrease in eGFR. We suggest close monitoring of the
elderly and overweight patients, because they are especially at risk of side effects necessitating cessation of rapamycin. Acknowledgments The authors would like to thank Mrs Suzanne Morrissette, Lucie Boutin, and Francine Trahan for their involvement in data collection. This study was made possible by an unrestricted grant from Pfizer.
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Clin Transplant 2014: 28: 616–622 DOI: 10.1111/ctr.12361
Clinical Transplantation
The incidence, management, and evolution of rapamycin-related side effects in kidney transplant recipients Verhave J, Boucher A, Dandavino R, Collette S, Senecal L, Hebert M-J, Girardin C, Cardinal H. The incidence, management, and evolution of rapamycin-related side effects in kidney transplant recipients. Abstract: Conversion from a calcineurin-inhibitor-based immunosuppression to a rapamycin-based immunosuppression may preserve kidney graft function. The side effects of rapamycin can limit its usefulness, but their management and evolution are rarely reported in clinical trials. We performed a retrospective cohort study in patients transplanted before December 31, 2008 and who received rapamycin to replace calcineurin inhibitors. In 219 patients studied, 98% presented ≥1 side effects after starting rapamycin. Side effects occurring in ≥10% of patients were dyslipidemia (52%, 95% confidence interval (CI): 45–59%), peripheral edema (37%, 95%CI: 31–43%), cytopenia (36%, 95% CI: 30– 42%), acne (29%, 95% CI: 23–35%), proteinuria (23%, 95% CI: 17– 29%), and oral ulcers 14% (95% CI: 10–18%). Proteinuria, ulcers, and edema were difficult to manage and were more likely to cause cessation of rapamycin. Rapamycin was discontinued in 46% of patients (95% CI: 40–52%). Age (odds ratio [OR] per 10-yr increase: 1.29, 95% CI: 1.05– 1.59) and obesity (OR: 2.57, 95% CI: 1.10–6.01) were independently associated with cessation of rapamycin. We conclude that successful control of dyslipidemia and cytopenia can be achieved without discontinuing rapamycin. Most other side effects are harder to manage. Leaner and younger patients are less likely to discontinue rapamycin due to side effects.
Over the last decade, rapamycin, an mTOR inhibitor (1), has been increasingly used for its immunosuppressive properties in the field of kidney transplantation. The use of rapamycin in place of calcineurin inhibitors (CNI) in de novo kidney transplant recipients (KTR) has fallen out of favor due to increased acute rejection rates, delayed graft function, and wound complications (2–5). However, recent clinical trials have focused on replacing CNI with rapamycin at a later time point in an effort to preserve kidney graft function. Better graft function in the first years after transplantation has been reported in subjects who were converted from CNI to rapamycin in the early post-transplant period (6, 7), but improvement in graft function at later time points is controversial (8, 9). Rapamycin has antiproliferative properties. Decreased nonmelanoma skin cancer (10) as well as overall malignancy rates (9) have been reported in
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Jacobien Verhavea, Anne Boucherb, Raymond Dandavinob, calb, Suzon Colletteb, Lynne Sene a e Hebert , Catherine Marie-Jose lo€ıse Cardinala Girardina and He Nephrology, Centre Hospitalier de l’Universite al and bNephrology, Hopital de Montre Maisonneuve Rosemont, Montreal, QC, Canada
a
Key words: kidney transplantation – rapamycine – side effects lo€ıse Cardinal, Corresponding author: He de Montre al, Centre Hospitalier de l’universite Notre-Dame, 1560, rue Sherbrooke Est, H2L al, QC, Canada 4M1 Montre Tel.: 514 890 8000; fax: 514 412 7831; e-mail: [email protected] Conflict of Interest: This study was supported by an unrestricted grant from Pfizer. Accepted for publication 10 March 2014
subjects who were converted to rapamycin when compared to those who continued CNIbased maintenance immunosuppression regimen. Hence, conversion of CNI to rapamycin is a therapeutic option after kidney transplantation, for decreasing the risk of post-transplant malignancies and avoiding CNI-based nephrotoxicity (11–13). Despite these potential benefits, the widespread use of rapamycin in KTR is overshadowed by its side effects. Clinical trials report 54–80% rapamycin-related side effects with rare mentioning of their management and evolution. In randomized trials that examined the outcomes of conversion to rapamycin, reported discontinuation rates were 12–36% after one yr and 23–61% after two yr (6, 12–15). However, discontinuation rates from randomized trials may not reflect those observed in general practice, given the strong incentive to persist with study drugs to avoid contamination
Rapamycin side effects in kidney transplantation between study groups. Furthermore, the reported rate of side effects may be underestimated due to the recruitment of a healthier set of patients (16, 17) and the implantation of run-in periods that ensure that only patients who tolerate the study drug are recruited (18). For clinicians who offer conversion from CNI to rapamycin, it is important to counsel patients on the expected rate of side effects and drug discontinuation and to know what to expect in terms of therapeutic success when these side effects occur. Current guidelines recommend that frequent and serious side effects be disclosed to patients when initiating a new therapy (19). Hence, we aimed to determine frequent and serious rapamycin side effects in a cohort of patients who were converted from CNIs to rapamycin. We also studied the management and evolution of rapamycin-related side effects and verified whether certain patient characteristics are associated with an increased rate of rapamycin cessation.
Methods Design and subjects
In this retrospective cohort study, we included KTR who received a single kidney graft at the Centre Hospitalier de l’Universite de Montreal and H^ opital Maisonneuve-Rosemont, and in whom conversion from a calcineurin inhibitor to rapamycin was attempted at least one month after transplantation. The earliest transplantation date from a patient converted to rapamycin was October 28, 1978, and we included patient transplanted up to December 31, 2008. Approval from the local ethics committee was obtained. Patients entered the cohort at the date of their renal transplantation and were followed up until graft loss, death, transfer to another center or December 31 2009, whichever occurred first.
Measurements
Trained research nurses collected information from the patient’s files on transplantation characteristics, laboratory values, dates of initiation and discontinuation of immunosuppressive agents, rapamycin-related side effects, management and evolution of these side effects. Side effects
Frequent side effects were defined as those occurring in ≥10% of patients (20), while serious side effects were defined as conditions that were life- or organ threatening (21). Dyslipidemia was defined as the initiation or increase in lipid-lowering drugs, or an increase of ≥50% in triglycerides or total cholesterol after rapamycin initiation with levels above the normal range (triglycerides >2 mM and total cholesterol >5.2 mM). Cytopenia was defined as a fall in hemoglobin, leukocytes, or thrombocytes to a value below the lower range of normal (hemoglobin < 120 g/L, leukocytes < 4000/lL, platelet count < 150 000/lL) and by more than 25% compared to pre-conversion values. Proteinuria was measured by a semi-quantitative dipstick method. Increased proteinuria was defined as dipstick levels ≥1 g/L if levels were 30 kg/ m2. Glomerular filtration rate (eGFR) was estimated by the four-variable MDRD formula at the time rapamycin was added and one yr later. We also collected information on the clinical motive invoked for conversion from CNI to rapamycin.
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Verhave et al. Statistical analyses
Continuous variables are reported as means and standard deviations or median and interquartile ranges, according to their distribution. Side effects are reported as proportions with an appropriate 95% confidence interval (CI). A side effect was considered frequent when the lower margin of its 95% CI was ≥10%. Multivariate logistic regression was used to identify the clinical factors associated with side effects that motivated discontinuation of rapamycin. (SPSS, IBM statistics 19, New York, NY, USA). The significance level was set at 0.05%.
Results Study population
We identified 219 KTR in whom conversion of a CNI-based immunosuppression regimen to a rapamycin-based regimen was attempted. The patients had a mean age of 45 yr (13) and were principally Caucasian with a male predominance of 61% (Table 1). Obesity was present in 12% of the patients. Sixty percent of patients used tacrolimus at the moment of rapamycin introduction, and 37% used cyclosporine in a triple-drug maintenance immunosuppression regimen based on CNI, mycophenolate mofetil, and prednisone. Rapamycin was started at a median of three yr after the transplantation; however, this ranged from one month to 26 yr. Rapamycin was added to the regimen with subsequent CNI weaning in 213 patients, whereas CNI discontinuation was complete before rapamycin introduction in six patients. In 44% of patients, rapamycin was started because of biopsy-proven CNI nephrotoxicity, in 15% because of other CNI-related side effects, and in 17% for empirical nephroprotection (i.e., in the absence of documented biopsy-proven CNI toxicity). Given its potential benefit on neoplasia (9) and BK replication (23), transfer to rapamycin followed a diagnosis of malignancy in 18% and of BK nephropathy in 6% of patients (Table 2). Despite the initial intention to completely discontinue CNI after adding rapamycin, 24 patients did not complete CNI withdrawal and used a combination of CNIs and rapamycin (in two-thirds, this was in addition to MMF). The mean eGFR at the start rapamycin was 42 mL/min/1.73 m2 (16), and 15 patients (6.8%) had significant proteinuria (≥1 g/L). Frequent rapamycin side effects: management and evolution
In our cohort, 98% of patients presented one or more side effects after the start of rapamycin. More
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Table 1. Demographic and transplant-related characteristics of patients Characteristics
n = 219
Mean age in years (SD) Male gender (%) Race (%) Caucasian Black Asiatic Other First transplantation (%) Deceased donor (%) Donor age in years (SD) Induction (%) Thymoglobulin Anti-CD25 Calcineurin inhibitor used at the time rapamycin was added (%) Tacrolimus Cyclosporine Other immunosuppressive agent used at the time rapamycin was added (%) Mycophenolate mofetil Azathioprine Prednisone dose at the time rapamycin was added in mg/day (SD) Median time between transplantation and addition of rapamycin in years (IQR) Mean eGFR (mL/min/1.73 m2) at the time rapamycin was added (SD) Median proteinuria by dipstick at the time rapamycin was added in g/L (IQR) Patients with dipstick proteinuria ≥1 g/L at the time rapamycin was added (%)
45 (13) 134 (61) 203 (93) 1 (0.5) 11 (5) 4 (2) 192 (88) 194 (89) 42 (16) 16 (7) 106 (48)
131 (60) 82 (37)
176 (80) 12 (5) 7.4 (5) 3.0 (0.9–8) 42 (16) 0 (0–0.0) 15 (7)
SD, standard deviation; IQR, interquartile range.
than 10% of patients had up to 4 different side effects. The side effects reported with a frequency ≥10% were (in order of frequency) dyslipidemia, peripheral edema, cytopenia, acne, proteinuria, and oral ulcers. Blood levels of rapamycin were similar across side effects and within target (8.7– 10.7) at the time related symptoms supervened. New or worsened dyslipidemia occurred in 52% (95% CI: 45–59%) of patients. This was rarely severe as diet, reduction of rapamycin dose, or the Table 2. Motive for adding rapamycin to the maintenance immunosuppression regimen n = 219 Biopsy-documented calcineurin inhibitor nephrotoxicity (%) Empirical nephroprotection (normal or no biopsy prior to conversion) (%) Calcineurin inhibitor non-renal side effects (%) Cancer (%) BK-virus nephropathy (%)
96 (44) 37 (17) 34 (15) 40 (18) 12 (6)
Rapamycin side effects in kidney transplantation initiation/increase in lipid-lowering drugs led to successful control in the vast majority of patients: only 3% (95% CI: 0–6%) of patients who experienced dyslipidemia had to discontinue rapamycin for that motive. Peripheral edema was observed in 37% (95% CI: 31–43%) of patients. Although conservative maneuvers such as decreased rapamycin dose, salt and water restriction, diuretics, and withdrawal of calcium-channel blockers were undertaken, 20% (95% CI: 11–29%) of patients with peripheral edema had to discontinue rapamycin for unacceptable control of this side effect. Cytopenia occurred in 36% (95% CI: 30–42%) of patients. This was rarely severe enough to motivate rapamycin discontinuation, as only 10% (95% CI: 4–16%) of patients with cytopenia had to cease rapamycin for this side effect. The therapeutic maneuvers that successfully achieved control in cytopenic patients who persisted with rapamycin included decreased rapamycin dose, decreased mycophenolate mofetil dose, iron or erythropoietin supplementation in cases of anemia, and folic acid supplementation for leucopenia. Acne occurred or worsened in 29% (95% CI: 23–35%) of patients. This was of sufficient severity to cause rapamycin discontinuation in 13% (95% CI: 5–18%) of patients who experienced this side effect. Decreased rapamycin or prednisone dose, topical or oral antibiotic therapy resulted in acceptable control in other cases. New or worsened proteinuria was observed in 23% (95% CI: 17–29%) of patients. This was of sufficient severity to motivate rapamycin withdrawal in 33% (95% CI: 21–45%) of cases. In these patients, median proteinuria had increased from 0.31 g/24 h before the introduction of rapamycin to 3.1 g/24 h at the time of rapamycin discontinuation. Other patients showed acceptable control with decreased rapamycin dose, salt and water restriction, and use of/increase in renin-angiotensin inhibitors. Rapamycin-associated oral ulcers supervened in 14% (95% CI: 10–18%) of patients, but were severe enough to motivate discontinuation in 23% (95% CI: 9–37%) of subjects who presented with this side effect, while rapamycin dose reduction, steroid-based mouthwash, or antiviral agents led to successful control in other patients. Severe rapamycin side effects
We encountered few patients with severe side effects. In two patients, rapamycin was associated with an episode of thrombotic microangiopathy (TMA). These patients had no sign of decreased hemoglobin/thrombocytes or increased LDH before the start of rapamycin. One patient developed TMA four months after introducing rapamy-
cin for a Banff grade 1 acute rejection that was accompanied by an acute allograft glomerulitis. No C4d staining or donor-specific antibody (DSA) measurements were available at that time. The hemolytic parameters (thrombocytopenia, LDH) normalized with a decrease in rapamycin doses, but the patient lost the graft one month after the cessation of rapamycin. The second patient had hemolytic parameters during a hospitalization for diarrhea (40% increase in LDH, 33% decrease in thrombocytes, and undetectably low haptoglobin levels) without an increase in serum creatinine. Rapamycin was stopped in this patient for suspected TMA, in the absence of graft biopsy documenting the suspected diagnosis. Rapamycin was replaced by tacrolimus, and the hemolytic and diarrheal syndrome resolved. Three patients were diagnosed with rapamycin-associated pneumonitis. The patients presented with dyspnea, fever, and/or coughing. All cases underwent bronchoalveolar lavage to exclude infection. In two patients, bilateral interstitial infiltrates were observed on CT scans, and in one, on thoracic X-rays. There was no positive culture indicating an infectious origin. All patients stopped rapamycin, and pulmonary symptoms ameliorated in 2–4 months. One patient had severe acute rejection that seemed associated with conversion from CNI to rapamycin. The switch from CNI to rapamycin was undertaken for nephroprotection, and this patient had never experienced acute rejection. Pre-conversion biopsy was normal. Before transplantation, the patient had anti-HLA class I antibodies on pre-transplant flow cytometry assays that were not DSAs, and no anti-HLA class 2 antibodies. The patient developed Banff grade I cell-mediated rejection with glomerulitis and de novo HLA class II antidonor-specific antibodymediated rejection seven months after conversion. Despite treatment with methylprednisolone, intravenous immunoglobulins (IvIg), and resumption of CNIs, the graft was lost six months after the rejection episode. Withdrawal of rapamycin because of side effects. Overall, rapamycin was discontinued because of side effects (including less frequent side effects not discussed above) in 102 subjects (46%, 95% CI: 40–52%). This occurred most often (in ≥20% of patients with the side effect) when diarrhea, proteinuria, pulmonary symptoms, edema, and ulcers supervened. Among those who stopped rapamycin, this drug had been used for a median of six months (range one month to seven yr). Among patients who persisted for more than one yr after the introduction of rapamycin, mean
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eGFR increased by 1.2 mL/min/1.73 m2 after one yr of follow-up, whereas it decreased by 3.9 mL/min/1.73 m2 in those who had to discontinue rapamycin (difference in one-yr eGFR change between the 2 groups: 5 mL/min/ 1.73 m2, 95% CI: 8, 1). We then asked whether certain patient characteristics were associated with the withdrawal of rapamycin. In univariate analysis, age (OR per 10-yr increase: 1.29, 95% CI: 1.05, 1.59) and obesity (OR: 2.57, 95% CI: 1.10, 6.01) were associated with discontinuation of rapamycin. Other characteristics such as gender, race, smoking, type of donor, number of transplantations, diabetes, transplant center, eGFR or proteinuria at the time of rapamycin initiation, or the motive invoked to start rapamycin were not associated with rapamycin cessation. In a multivariate model, age (OR per 10-yr increase: 1.27, 95% CI: 1.03, 1.56) and obesity (OR: 2.39, 95% CI: 1.02, 5.64) were independently associated with cessation of rapamycin. Discussion
Conversion from CNI to rapamycin after renal transplantation is beneficial with regards to the reduction of non-melanoma cutaneous malignancy rates (12, 13). In addition, after five yr of follow-up, it preserved renal function compared to CNI-based immunosuppression in one trial (8). Because of the selection of healthier patient sets and procedures put in place to maximize adherence to protocol, side effects and drug discontinuation rates reported in randomized controlled trials may not be generalizable to everyday clinical practice. Physicians should disclose frequent and severe side effects to their patients when initiating new therapies. We undertook the present study to guide patient counseling for clinicians offering conversion to rapamycin to their KTR. In our clinical experience, 98% of patients presented at least one side effect. Ten percent of the patients had up to four different side effect attributed to rapamycin. Side effects occurring with a frequency ≥10% were dyslipidemia, edema, cytopenia, acne, proteinuria, and oral ulcers. Close to 50% of patients on rapamycin maintenance therapy discontinued the drug because of side effects. Patients who persisted with rapamycin had a favorable evolution in eGFR one yr after its introduction compared to patients who had to discontinue it. Few patients (3%) in our study had severe side effects. We observed two cases of rapamycin-associated TMA, three cases of pneumonitis, and one case of antibody-mediated rejection. Rapamycin
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may induce TMA by decreasing vascular endothelial growth factor expression (24) and enhancing platelet aggregation (25). TMA has been described when rapamycin is used in combination with CNI, as rapamycin may enhance the toxic effect of CNI on the endothelium (26). However, TMA is also observed in transplant patients on rapamycin without CNI (27). Rapamycin-associated pneumonitis is a well-described identity (28). In 85% of the cases, this phenomenon is reversible after cessation of the drug (29). This diagnosis is suspected in transplant patients using rapamycin who have pulmonary symptoms and infiltrates in the absence of pulmonary edema or of an infectious cause. In our cohort, all cases resolved after drug discontinuation. One patient who was at low immunological risk developed severe antibody-mediated rejection after switching to rapamycin for empirical nephroprotection and lost the graft despite aggressive antirejection therapy. We have since then observed another case of antibody-mediated rejection six wk after conversion to rapamycin for empirical nephroprotection in a patient with normal graft function who had been transplanted for one yr, had never experienced rejection episodes previously, and had no anti-HLA antibodies prior to transplantation. Again, this patient developed antiHLA class II antibodies and has now regained normal graft function after treatment with methylprednisolone, thymoglobulin, plasmapheresis, and IvIg. One major challenge is to assess the link of causality between rapamycin and its attributed side effects. The WHO-UMC system (30) is a generally accepted method in causality assessment in clinical practice. By fulfilling the assessment criteria, the causality between the drug and the side effect is graded from “certain” to “unclassifiable.” In both patients with TMA, the causality with rapamycin is “possible,” because we cannot exclude other potential causes for the clinical syndromes and because we did not rechallenge our patients with rapamycin. The patients with pneumonitis all had a probable causality with rapamycin, especially because extensive research eliminated other causes of pneumonitis. In the patient with antibodymediated rejection, causality assessment yielded a “possible” score. In contrast, reported non-severe side effects such as diarrhea and non-specific pulmonary symptoms may not have been causally linked to rapamycin. For instance, 28% of patients with diarrhea had a documented infectious cause, and all were also receiving other antirejection agents that could have caused diarrhea (tacrolimus, mycophenolate mofetil). Among those with non-specific pulmonary symptoms, 72% were
Rapamycin side effects in kidney transplantation diagnosed with pneumonia and 10% with heart failure. Given the high rate of rapamycin discontinuation observed among patients with diarrhea or non-specific pulmonary symptoms, one may question whether drug cessation was appropriate or whether the side effects could have resolved with time while continuing rapamycin. We showed that age and obesity are risk factors for cessation of rapamycin due to side effects. The adaptation of rapamycin dosage in elderly and obese patients is a concern, especially because of the narrow therapeutic index. The monography of rapamycin suggests that doses should be lowered in elderly patients because blood clearance decreases linearly with age (31). In general, elderly patients are prone to drug-related side effects (32), which may be explained by age-related changes in drug absorption, volume of distribution, and drug elimination (33). The effect of obesity on rapamycin pharmacokinetics is unclear (34). Rapamycin is a highly lipophilic molecule, which is likely to have a different volume of distribution in patients with increased fat mass per kg total body weight. At present time, there are no data on rapamycin-specific pharmacokinetic characteristics in elderly or obese patients, but our findings do suggest that these subgroups should be monitored more closely for the occurrence of side effects. Our study is limited by its retrospective nature. Although we used operational definitions in our research protocol when possible, the occurrence of certain side effects such as edema, oral ulcers, or diarrhea remains sensitive to practitioner’s subjectivity, and quantification of proteinuria through 24-h urine collection was not always available. Although this may reduce the accuracy of side effects reporting, it reflects everyday clinical care that was provided to patients. Conclusion
The present study illustrates our clinical experience with rapamycin-associated side effects. We showed that while the majority (98%) of patients who used rapamycin experienced at least one side effect, few patients had severe side effects. Side effects that should be discussed when counseling patients on the opportunity of a switch from CNI to rapamycin are those occurring in 10% of patients or more (dyslipidemia, peripheral edema, cytopenia, acne, proteinuria, oral ulcers) and those that are severe (TMA, pneumonitis, and rejection). Patients should also be aware that reconversion to CNI occurs in close to 50% of patients and is associated with a slight decrease in eGFR. We suggest close monitoring of the
elderly and overweight patients, because they are especially at risk of side effects necessitating cessation of rapamycin. Acknowledgments The authors would like to thank Mrs Suzanne Morrissette, Lucie Boutin, and Francine Trahan for their involvement in data collection. This study was made possible by an unrestricted grant from Pfizer.
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