Initiation Of Sirolimus Therapy Research Articles

Successful Treatment of Fibro-Adipose Vascular Anomaly with Sirolimus

BackgroundThe purpose of this study was to present our initial experience in using sirolimus therapy to treat fibro-adipose vascular anomaly (FAVA). MethodsWe retrospectively reviewed the medical records of eight patients with FAVA who were treated with sirolimus at our hospital between July 2017 and October 2020. ResultsSix girls (75%) and two boys (25%) were included in the cohort; the average age was 8 years (range, 1–13 years). Vascular tumors developed mainly on the extremities, including the forearm (n = 2; 25.0%), calf (n = 4; 50.0%), and thigh (n = 2; 25.0%). The predominant symptoms included swelling of the lesion (n = 8; 100%), pain (n = 7; 87.5%), contracture (n = 3; 37.5%), and phlebectasia (n = 3; 37.5%). Magnetic resonance imaging was the primary method used for FAVA diagnosis, and all patients underwent enhanced MRI. All lesions were heterogeneous with hyperintense T1 signals. The fat-suppressed T2-weighted images also revealed heterogeneous hyperintense masses, thus indicating fibrofatty infiltration. All eight patients received a sirolimus treatment regimen after FAVA diagnosis. One patient underwent tumor resection but experienced recurrence, whereas the other six patients underwent biopsy. Histological examination revealed that the lesions consisted of fibrofatty tissue with abnormal venous channels and anomalous lymphatic vascular components. Sirolimus softened the masses and caused tumor shrinkage within 5.25 ± 2.6 weeks (range, 2–10 weeks) after treatment initiation. The tumors also involuted rapidly and became stable within 7.75 ± 2.25 months after treatment initiation (range, 6–12 months). All seven patients experiencing pain reported relief within 3.8 ± 1.8 weeks (range, 2–7 weeks) after initiation of sirolimus therapy. Sirolimus alleviated but did not fully resolve the contracture in three patients. Remarkably, five patients exhibited a complete response, and three patients exhibited a partial response. At the time of the last follow-up, three patients had begun to gradually taper off sirolimus after 24 months of treatment and maintained a low blood sirolimus concentration. No serious adverse effects were observed during treatment. ConclusionFAVA is a complex vascular malformation that appears to respond well to sirolimus treatment. Thus, sirolimus may be an effective and safe treatment for FAVA. Level of evidenceLEVEL IV.

Severe adverse events during sirolimus “off‐label” therapy for vascular anomalies

Clinical studies have shown low toxicity and a favorable safety profile for sirolimus in vascular anomalies. Here, we describe severe adverse events (SAEs) observed during "off-label use" for vascular anomalies. We performed a retrospective, multicenter chart review for SAEs during "off-label" sirolimus therapy for vascular anomalies and analyzed these cases by a predesigned workflow. We identified 17 SAEs in 14 patients diagnosed with generalized lymphatic anomaly (n=4), Gorham-Stout disease (n=2), central conducting lymphatic anomaly (n=1), lymphatic malformation (n=4), tufted angioma (n=1), kaposiform hemangioendothelioma (n=1), and venous malformation in a patient with CLOVES syndrome (n=1). Three patients presented two SAEs each. The age at initiation of sirolimus therapy was under 2years (n=5), 2-6years (n=5), and older than 12years (n=4). SAEs occurred during the first 3months of sirolimus therapy (n=7), between 3 and 12months (n=7) and after 1year of therapy (n=3). The most frequent SAE was viral pneumonia (n=8) resulting in one death due to a metapneumovirus infection in a 3months old and a generalized adenovirus infection in a 28-month-old child. Sirolimus blood level at the time of SAEs ranged between 2.7 and 21ng/L. Five patients were on antibiotic prophylaxis. Most SAEs are observed in the first year of sirolimus therapy; however, SAEs can also occur after a longer treatment period. SAEs are potentially life threatening, especially in early infancy. Presence of other risk factors, that is, underlying vascular anomaly or immune status, may contribute to the risk of SAEs. Sirolimus is an important therapeutic option for vascular anomalies, but patients and physicians need to be aware that adequate monitoring is necessary, especially in patients with complex lymphatic anomalies that are overrepresented in our cohort of SAEs.

Survival Associated With Sirolimus Plus Tacrolimus Maintenance Without Induction Therapy Compared With Standard Immunosuppression After Lung Transplant

Median survival after lung transplant is less than 6 years. Standard maintenance therapy typically includes tacrolimus and an antimetabolite (mycophenolate mofetil or azathioprine). Replacing the antimetabolite with sirolimus after postoperative wound healing may improve long-term survival due to antifibrotic, antiproliferative, and antiaging effects of sirolimus. To compare survival between patients receiving sirolimus plus tacrolimus vs mycophenolate mofetil plus tacrolimus (the most common maintenance therapy) and to identify the combination of induction and maintenance therapy associated with the highest survival. This cohort study of US recipients of lung transplants from January 1, 2003, through August 31, 2016, analyzed United Network for Organ Sharing (UNOS) data from January 1 through September 13, 2018. Because initiation of sirolimus therapy is usually delayed 3 to 12 months after lung transplant, primary analyses were based on patients alive and free of chronic rejection and malignant disease at 1 year in all groups, whereas sensitivity analyses used appropriate methods to include all patients from transplant time. Regression models adjusted for available potential confounders, including transplant center performance. Cell cycle inhibitor maintenance therapies, including sirolimus (n = 219), mycophenolate mofetil (n = 5782), mycophenolate sodium (n = 408), azathioprine (n = 2556), and concurrent sirolimus plus mycophenolate mofetil (n = 54), were compared within a tacrolimus-based regimen. Combinations of each induction (basiliximab, daclizumab, antithymocyte globulin, alemtuzumab, or none) and maintenance (tacrolimus plus sirolimus, mycophenolate mofetil, or azathioprine) therapy were also compared. Survival was the primary outcome; chronic rejection incidence and subsequent mortality were secondary outcomes. Among this population of 9019 patients (median age, 57 years [interquartile range {IQR}, 46-63 years]; 5194 men [57.6%]), sirolimus plus tacrolimus was associated with better survival than mycophenolate mofetil plus tacrolimus (median, 8.9 years [IQR, 4.4-12.7 years] vs 7.1 years [IQR, 3.6-12.1 years]; adjusted hazard ratio [aHR], 0.71; 95% CI, 0.56-0.89; P = .003). Chronic rejection incidence (aHR, 0.75; 95% CI, 0.61-0.92) and mortality after chronic rejection (aHR, 0.52; 95% CI, 0.31-0.81) were lower with sirolimus plus tacrolimus. Compared with mycophenolate mofetil plus tacrolimus, survival differences for sirolimus plus mycophenolate mofetil plus tacrolimus (aHR, 1.14; 95% CI, 0.79-1.65), mycophenolate sodium plus tacrolimus (aHR, 0.95; 95% CI, 0.77-1.17), and azathioprine plus tacrolimus (aHR, 0.93; 95% CI, 0.84-1.02) were not significant. The induction-maintenance combination with the highest survival was sirolimus plus tacrolimus without induction therapy (median survival, 10.7 years [IQR, 7.3-12.7 years]; aHR, 0.48; 95% CI, 0.31-0.76; P = .002) compared with mycophenolate mofetil plus tacrolimus with induction therapy (median survival, 7.4 years [IQR, 3.9-12.6 years]). Sirolimus plus tacrolimus was associated with improved patient survival after lung transplant compared with mycophenolate mofetil plus tacrolimus; no antibody induction therapy with sirolimus plus tacrolimus was associated with maximal survival.

Long-term efficacy and safety of sirolimus therapy in patients with lymphangioleiomyomatosis

BackgroundSirolimus has been confirmed to be effective for lymphangioleiomyomatosis (LAM), a rare multisystem neoplastic disease in women. The long-term effects of sirolimus treatment for LAM, however, are largely unknown. We aimed to analyze the long-term efficacy and safety of sirolimus therapy for LAM with 4-year follow-up.MethodsIn total, 142 sporadic LAM patients who took sirolimus for 1–4 years were retrospectively enrolled for this analysis. The variables used for analysis included pulmonary function tests, arterial blood gas analysis, 6-min walking distance (6MWD), St. George’s Respiratory Questionnaires (SGRQ) and serum vascular endothelial growth factor-D (VEGF-D) levels before and after the initiation of sirolimus therapy. The rates of change (slope) in those variables were calculated, and adverse events were also analyzed.ResultsIn total, 122, 83, 60 and 32 patients out of 142 were followed for 1, 2, 3 and 4 years respectively. Sirolimus treatment improved the change rate in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) compared with the data before treatment (FEV1, − 10 ± 15 vs. − 178 ± 36 ml/y, P < 0.001 and FVC, 54 ± 22 vs.-72 ± 68 ml/y, P < 0.05). In comparison to the baseline measurements, significant improvements were observed in FEV1 at the first year; FVC at 1–2 years; arterial oxygen levels, 6MWD, and SGRQ at 1–3 years; and VEGF-D at 1–4 years. Overall, all variables stabilized or improved during the 4 years of observation. Adverse events related to sirolimus were mild.ConclusionSirolimus therapy is effective at improving or stabilizing pulmonary function, oxygen levels, exercise capacity, and quality of life in patients with LAM for up to 4 years. VEGF-D is maintained at a lower level for 4 years after treatment. Adverse events related to sirolimus were mild.

MTOR inhibitor‐associated dermatologic and mucosal problems

Mammalian target of rapamycin inhibitor use is associated with numerous adverse events, including dermatologic and mucosal problems. Awareness of these complications, which clinically manifest across a severity spectrum from minor through severe and may occur at varied time points after initiation of sirolimus therapy, can be useful to clinicians in both managing these events and determining the appropriate intervention(s) for patients. This manuscript examines the dermatologic and mucosal problems associated with mammalian target of rapamycin inhibitor use, reviews the literature, and provides personal experiences regarding the management and treatment of these adverse events.

Mechanisms and Management of Proteinuria in Kidney Transplant Patients

Proteinuria is a common complication occurring after kidney transplantation. It is associated with an increased risk of renal failure and patient death. Treatment with ACE inhibitors or angiotensin receptor antagonists (blockers) has been shown to reduce proteinuria after kidney transplantation, as well as improve both graft and patient survival. An increase in proteinuria has been observed in some patients after initiation of sirolimus therapy. Although the mechanism of this remains unclear, high proteinuria at baseline and poor renal function at baseline have been identified as potential risk factors for the development of proteinuria after conversion to sirolimus. Initiation of sirolimus therapy is not recommended in patients with early histological indicators of glomerular damage; however, in patients with healthy grafts, sirolimus may prevent future glomerulosclerosis. Early treatment with an ACE inhibitor and sirolimus, prior to the appearance of glomerular changes, may result in better outcomes.

An Unusual Presentation of Sirolimus Associated Cough in a Renal Transplant Recipient

Sirolimus-associated pulmonary problems are rare but life threatening. Pulmonary problems due to sirolimus treatment are interstitial pneumonitis, bronchiolitis obliterans organizing pneumonia (BOOP), and alveolar hemorrhage. We present a case of sirolimus-related cough in the absence of any pulmonary radiological findings. A 55-year-old man with a history of 4 years of hemodialysis therapy because of end-stage renal disease of unknown etiology underwent cadaveric renal transplantation in June 2006. Three days following the initiation of sirolimus therapy he complained of dry cough and fever. There were no clinical or laboratory findings compatible with specific pulmonary disease. After switching sirolimus to tacrolimus, the cough improved within 1–2 days and resolved in 5 days. Sirolimus should be considered in the differential diagnosis of pulmonary problems in the early posttransplantation period even in the absence of radiological findings.

Proteinuria in Transplant Patients Associated With Sirolimus

Sirolimus (SRL) is a potent immunosuppressive drug used in organ transplantation for prophylaxis of acute allograft rejection. Conversion from calcineurin inhibitors to SRL has become an important alternative in patients with chronic allograft nephropathy. Recently, some reports have described the appearance of proteinuria after the use of SRL. The aim of the present study was to describe the incidence of proteinuria in transplant recipients receiving SRL in our transplant center. We studied 78 patients receiving SRL either de novo or after conversion. Eighteen transplant recipients (23.1%) developed proteinuria after SRL treatment. Proteinuria was diagnosed at 11.2 ± 2.1 months after the initiation of SRL; in eight patients (44.4%) it occurred in the first 6 months. The mean value of proteinuria was 2.6 ± 0.6 g/24 hours. In 5 patients (27.8%), proteinuria reached nephrotic levels, and in 13 patients (72.2%) was associated with edema. Renal allograft biopsies were performed before conversion to SRL, and a new biopsy, after the appearance of proteinuria. The light microscopy of biopsies performed after the onset of proteinuria showed no specific glomerular changes, except in 2 cases wherein the diagnosis was focal segmental glomerulosclerosis. Immunofluorescence was negative in all cases. In conclusion, in this study proteinuria was observed in 21.3% of patients receiving SRL therapy either as de novo protocol or after conversion to SRL. Proteinuria occurred early after the initiation of SRL therapy and in these cases, withdrawal of SRL was associated with reversion of proteinuria.

Conversion From Calcineurin Inhibitors to Sirolimus in Patients With Chronic Renal Allograft Dysfunction

Background Chronic renal transplant dysfunction in part may be due to the nephrotoxic effects of calcineurin inhibitors, which are still the mainstay of immunosuppressive therapy. Sirolimus, a new immunosuppressive compound devoid of significant nephrotoxicity, might therefore exhibit beneficial effects when used in renal transplant recipients with graft dysfunction. Methods Twelve renal transplant recipients included in this study had all been receiving calcineurin inhibitors for more than 12 months, and were free of rejection for more than 12 months. However, they demonstrated moderate renal dysfunction with serum creatinine values ranging from 1.8 to 4.0 mg/dL (164 to 351 μmol/L). After reaching a sirolimus level of 10 to 20 ng/mL, calcineurin inhibitor therapy was withheld. Results One month after initiation of sirolimus therapy, all patients were off calcineurin inhibitors. The average daily sirolimus dosage was 5.8 ± 3.4 mg. No acute rejection episode and no graft failure was observed. No patient required hemodialysis or admission to the hospital. Calculated creatinine clearance increased from 63.4 ± 9.9 to 69.2 ± 9.7 mL/min ( P = .0368) and serum bicarbonate increased from 20.8 ± 3.17 to 22.5 ± 3.7 meq/L ( P = .001). Serum cholesterol increased from 180 ± 26.5 to 239 ± 28.8 mg/dL (4.65 ± 0.69 to 6.18 ± 0.74 mmol/L, P < .001), triglycerides increased from 155 ± 53 to 289 ± 123 mg/dL (1.75 ± 0.6 to 3.26 ± 1.39 mmol/L) and low-density lipoprotein cholesterol increased from 99 ± 32 to 131 ± 25.1 mg/dL (2.56 ± 0.83 to 3.39 ± 0.65 mmol/L, P = .01). Arterial blood pressure remained well controlled (126 ± 15.6/74 ± 8.9 vs 134 ± 16.8/83 ± 9.7). Conclusion Conversion from calcineurin inhibitor therapy to sirolimus in patients more than 1 year after transplantation with impaired organ function is feasible, safe, and associated with a trend toward improved renal function.

Renal function improves in liver transplant recipients when switched from a calcineurin inhibitor to sirolimus

Sirolimus (Rapamune; Wyeth-Ayerst, Philadelphia, PA) is a newer immunosuppressive drug with no known acute or chronic nephrotoxic effects; however, limited data are available in liver transplant recipients. We prospectively evaluated changes in renal function in liver transplant recipients after conversion from a calcineurin inhibitor to sirolimus monotherapy. We measured serial serum creatinine levels in liver transplant recipients with chronic nephrotoxicity caused by calcineurin inhibitors before and after conversion to sirolimus therapy. Estimated glomerular filtration rate (eGFR) was calculated from the Modification of Diet in Renal Disease formula. Change in eGFR over time, incidence of acute hepatocellular rejection, and adverse events while being administered sirolimus monotherapy were recorded. Mean interval between liver transplantation and initiation of sirolimus therapy was 310 weeks (range, 9 to 780 weeks). Of 21 patients included in our study, 18 patients were converted to sirolimus monotherapy and 3 patients were switched to sirolimus and low-dose steroid therapy. Patients were followed up for a mean of 66.8 ± 38.9 (SD) weeks after conversion. Renal function improved in 71% of patients (15 of 21 patients). Median eGFR improved significantly from 34 mL/min/1.73 m2 at the time of conversion to 43 mL/min/1.73 m2 at the last follow-up (27% increase in eGFR; P = 001). Median monthly change in eGFR was from −0.25 mL/min/1.73 m2 pre-sirolimus therapy to +1.28 mL/min/1.73 m2 post-sirolimus therapy (P = .09). Adverse events were mostly mild and self-limited. Only 1 patient developed biopsy-proven acute cellular rejection, which was treated with sirolimus and mycophenolate mofetil. Two patients discontinued sirolimus therapy because of toxicity (oral ulceration, 1 patient; interstitial pneumonitis, 1 patient). Renal function improved significantly in the majority of liver transplant recipients with renal insufficiency caused by calcineurin inhibitors when converted to sirolimus therapy. Sirolimus monotherapy provided adequate immunosuppression with a low incidence of acute cellular rejection and minimal adverse events. (Liver Transpl 2003;9:1079-1085.)