Side Effects of sirolimus: A Synthesis of Findings from 25 Studies

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Original Abstract of the Article

Major Research Findings

Sirolimus, an mTOR inhibitor, is used as an immunosuppressant after organ transplantation to prevent rejection and maintain organ function. Studies have shown that while sirolimus is effective, it can cause several side effects, ranging from metabolic changes to organ toxicity.

Studies have shown that sirolimus can lead to hyperlipidemia, anemia, proteinuria, joint pain, rash, and infections. It can also affect organs like kidneys, liver, lungs, and optic nerves. The severity and frequency of these side effects can vary depending on factors such as dosage, duration of treatment, patient age, and underlying conditions. Furthermore, the use of sirolimus in combination with other immunosuppressants can increase the risk of side effects. Regular monitoring and proper management are crucial to minimize the risk of side effects during sirolimus therapy.

Reasons for Side Effects

Sirolimus works by inhibiting the mTOR pathway, which plays a crucial role in cell growth and proliferation. While this action is beneficial in suppressing immune responses and preventing rejection, it can also affect normal cell growth and proliferation, leading to various side effects.

Common Side Effects

Hyperlipidemia

Sirolimus can increase cholesterol and triglyceride levels in the blood, possibly due to its inhibition of the mTOR pathway and its impact on lipid metabolism. 24 , 13

Anemia

Sirolimus can affect red blood cell production, potentially leading to anemia. 24 , 25

Proteinuria

Sirolimus can impair kidney function, leading to proteinuria. 24 , 22 , 12

Arthralgia

Sirolimus can cause joint pain. 24

Rash

Sirolimus can cause skin rash. 24 , 4

Infection

Sirolimus's immunosuppressive properties can increase the risk of infections. 24

Nephrotoxicity

Sirolimus can have adverse effects on kidney function, potentially leading to proteinuria, edema, and hypertension. 24 , 25 , 12

Hepatotoxicity

Sirolimus can negatively impact liver function, potentially causing jaundice, ascites, and cirrhosis. 23 , 10

Pulmonary Toxicity

Sirolimus can cause lung problems, potentially leading to shortness of breath, cough, and chest pain. 24

Optic Neuropathy

Sirolimus can damage the optic nerve, possibly leading to vision loss, visual disturbances, and even blindness. 14

Measures Against Side Effects

Hyperlipidemia

Managing hyperlipidemia related to sirolimus can involve lifestyle changes such as diet modification and exercise, as well as the use of cholesterol-lowering medications like statins.

Anemia

Addressing anemia caused by sirolimus may involve iron supplementation or the use of hematopoietic factors.

Proteinuria

Measures to manage proteinuria from sirolimus include blood pressure control and medications designed to protect kidney function.

Arthralgia

Treatment for joint pain caused by sirolimus may involve pain relievers and rehabilitation therapies.

Rash

Managing rash from sirolimus may involve antihistamines or steroid medications.

Infection

Preventing infections in patients taking sirolimus includes good hygiene practices such as handwashing and gargling, as well as vaccination.

Comparison Between Studies

Common Points of Studies

The studies included in this review consistently highlight the potential for sirolimus to cause a variety of side effects. These side effects can be influenced by factors such as sirolimus dosage, treatment duration, patient age, and pre-existing health conditions.

Differences Between Studies

The reviewed studies show variations in the incidence, severity, and types of side effects associated with sirolimus. These differences may be due to factors like study design, participant characteristics, sirolimus dosage, and treatment duration.

Points to Note Regarding Application to Real Life

Sirolimus is a valuable drug for immunosuppression after organ transplantation, but its potential for side effects needs to be acknowledged. It's important for individuals taking sirolimus to understand the risks and to follow their doctor's instructions carefully.

Limitations of Current Research

The understanding of sirolimus's side effects is still evolving. Research, especially on long-term side effects, is ongoing. The individual responses to sirolimus can also vary, necessitating further research to better characterize and manage these side effects.

Future Research Directions

To deepen our understanding of sirolimus's side effects, future research should focus on long-term side effects, the mechanisms behind these side effects, and the development of new treatments to minimize or mitigate these effects.

Conclusion

Sirolimus is a valuable drug in transplant medicine, but it comes with the risk of various side effects. Patients should be informed about these risks and work closely with their doctors. Continued research is needed to better understand and address the side effects of sirolimus, ultimately improving its safety and efficacy.

Keywords

Benefit Keywords

Risk Keywords

Literature analysis of 25 papers

Positive Content

Neutral Content

Negative Content

Article Type

Randomized Controlled Trial3

Meta-Analysis0

Systematic Review0

Review3

Journal Article23

An open-label randomized trial of the safety and efficacy of sirolimus vs. azathioprine in living related renal allograft recipients receiving cyclosporine and prednisone combination.

Author: MachadoPaula G P, FelipeCláudia R, HanzawaNilva M, ParkSung I, GarciaRiberto, AlfieriFernando, FrancoMarcelo, SilvaHélio T, Medina-PestanaJosé O

Improved graft function

Reduced rejection

Hyperlipidemia

Sirolimus, in combination with reduced cyclosporine exposure, is effective in preventing acute rejection in renal transplant recipients. It also reduces the incidence of rejection compared to azathioprine with standard cyclosporine doses.

Language : English

Renal function, efficacy, and safety of sirolimus and mycophenolate mofetil after short-term calcineurin inhibitor-based quadruple therapy in de novo renal transplant patients: one-year analysis of a randomized multicenter trial.

Author: GubaMarkus, PratschkeJohann, HugoChristian, KrämerBernhard K, Nohr-WestphalConstanze, BrockmannJens, AndrassyJoachim, ReinkePetra, PressmarKatharina, HakenbergOliver, FischerederMichael, PascherAndreas, IllnerWolf-Dieter, BanasBernhard, JauchKarl-Walter,

Improved renal function

Reduced cytomegalovirus viremia

Acne

Aphtous

High rate of dropouts

Hyperlipidemia

Early conversion to a calcineurin inhibitor-free regimen with sirolimus (SRL) in combination with mycophenolate mofetil was associated with improved renal function in patients after renal transplantation. However, there was a significantly higher rate of drug discontinuation in the SRL group (36.2% vs. 19.7%) due to adverse events such as acne, aphtous ulcers, and temporary hyperlipidemia.

Language : English

Evaluation of off-label rapamycin use to promote healthspan in 333 adults.

Author: KaeberleinTammi L, GreenAlan S, HaddadGeorge, HudsonJohnny, IsmanAnar, NyquistAndy, RosenBradley S, SuhYousin, ZalzalaSajad, ZhangXingyu, BlagosklonnyMikhail V, AnJonathan Y, KaeberleinMatt

Healthspan extension

Lifespan extension

Safety data limited

Rapamycin is a medication that has been shown to extend lifespan in animals. This abstract describes a survey of 333 adults who have taken rapamycin off-label as a preventative therapy. The study found that rapamycin appears to be safe for adults with normal health.

Language : English

Sirolimus-Induced Rash in a Kidney Transplant Patient.

Author: BrussZachary, FarookShanza, ShahSana, Baker SheikhAbu

Maculopapular rash

Sirolimus is a medication used to suppress the immune system after a kidney transplant. While rare, maculopapular rash has been reported as a side effect. This case report describes a 78-year-old man who developed a rash after starting sirolimus. This highlights the importance of identifying this uncommon side effect quickly so that the drug can be stopped and the rash prevented from worsening.

Language : English

A comprehensive review of intravitreal immunosuppressants and biologicals used in ophthalmology.

Author: HasanNasiq, ChawlaRohan, ShaikhNawazish, KandasamySindhuja, AzadShorya Vardhan, SundarM Dheepak

Treat inflammatory diseases

Treat malignancies

This review summarizes the use of intravitreal immunosuppressants and biologics in the treatment of inflammatory eye diseases. While these drugs are effective, their safety profiles are not well-established, particularly in the eye. The review discusses the mechanisms of action, pharmacodynamics, pharmacokinetics, indications, efficacy, and side effects of these drugs. Most of the data comes from case reports and series, limiting the level of evidence.

Language : English

Pharmacological mTOR-inhibition facilitates clearance of AD-related tau aggregates in the mouse brain.

Author: MoraweMartina P, LiaoFan, AmbergWilli, van BergeijkJeroen, ChangRui, GulinoMary, HamiltonCaitlin, HoftCarolin, LumpkinCasey, MastisBryan, McGlameEmily, NuberJudith, PlaasChristian, RavikumarBrinda, RoyKaushambi, SchanzenbächerMarion, TiernoJoseph, LakicsViktor, DellovadeTammy, TownsendMatthew

Alzheimer's treatment

This study investigated the effect of long-term dosing with mTOR inhibitors on tau pathology in a transgenic mouse model of tauopathy. The study found that rapamycin treatment reduced tau pathology when applied to young mice, while PQR530 reduced tau pathology even when treatment started after the onset of pathology. The findings suggest that balanced therapeutic dosing of blood-brain-barrier permeable mTOR inhibitors could have a disease-modifying effect in Alzheimer's Disease.

Language : English

Refractory immune thrombocytopenia successfully treated with bortezomib in a child with 22q11.2 deletion syndrome, complicated by Evans syndrome and hypogammaglobulinemia.

Author: ContiFrancesca, GottardiFrancesca, MorattiMattia, BelottiTamara, FerrariSimona, SelvaPaola, BassiMirna, ZamaDaniele, PessionAndrea

ES treatment

Infections

Toxicity

This case report describes the successful use of bortezomib in a child with multi-refractory Evans syndrome (ES) secondary to immune system impairment. The child was unresponsive to various treatments, including high-dose steroids, IVIG, mycophenolate mofetil, thrombopoietin receptor agonists, sirolimus, and rituximab. Bortezomib led to a good response at 6-month follow-up without side effects. This case suggests that bortezomib may be a promising therapeutic option for multi-resistant AICs in pediatric patients.

Language : English

The topical ocular delivery of rapamycin to posterior eye tissues and the suppression of retinal inflammatory disease.

Author: BadrMoutaz Y, HalwaniAbdulrahman A, OdunzeUchechukwu, EskandarpourMalihe, CalderVirginia L, SchätzleinAndreas G, UchegbuIjeoma F

Posterior eye disease treatment

Retinal inflammation reduction

This study evaluated the delivery of rapamycin (RAP) to the posterior eye tissues using nanoparticle-based eye drops in healthy rabbits and an experimental autoimmune uveitis (EAU) mouse model. The formulation delivered RAP to the choroid-retina and suppressed EAU in the mouse model, suggesting potential for a non-invasive treatment of posterior eye diseases.

Language : English

Management of Complex Pulmonary Vein Stenosis at Altitude Combining Comprehensive Percutaneous Interventional Treatment with Sirolimus, Pulmonary Hypertension Medications and Intraluminal Imaging with Optical Coherence Tomography.

Author: ShorofskyMichael J, MorganGareth J, MejiaErnesto, RodriguezSalvador A, GreeneMegan, SheaksPaige, IvyDunbar, ZablahJenny E

PVS treatment

This study evaluated the effects of sirolimus on re-intervention and vessel patency in patients with pulmonary vein stenosis (PVS) using Optical Coherence Tomography (OCT). Sirolimus has previously been shown to improve survival and slow down the progression of in-stent stenosis in patients with PVS.

Language : English

10.

Hepatocyte β-catenin loss is compensated by Insulin-mTORC1 activation to promote liver regeneration.

Author: HuShikai, CaoCatherine, PoddarMinakshi, DelgadoEvan, SinghSucha, Singh-VarmaAnya, StolzDonna Beer, BellAaron, MongaSatdarshan P

The Wnt-β-catenin pathway is crucial for liver regeneration, but its disruption can be compensated by other pathways. This study investigates the mechanism of liver regeneration in the absence of hepatocyte-β-catenin.

Language : English

11.

Activation of Rictor/mTORC2 signaling acts as a pivotal strategy to protect against sensorineural hearing loss.

Author: FuXiaolong, LiPeipei, ZhangLinqing, SongYuning, AnYachun, ZhangAizhen, LiuWenwen, YeChao, ZhangYuan, YueRongyu, SunXiaoyang, ChaiRenjie, WangHaibo, GaoJiangang

ARHL treatment

Cocaine-induced hearing loss prevention

Hearing loss

Sirolimus, an mTOR inhibitor, protected mice against cocaine-induced hearing loss, but high doses caused substantial hearing loss. Inactivation of mTORC2, a key regulator of AKT/PKB signaling pathway, was the major driver underlying hearing loss. Selective activation of mTORC2 could protect mice from acoustic trauma and cisplatin-induced ototoxicity.

Language : English

12.

Folate conjugated nanomedicines for selective inhibition of mTOR signaling in polycystic kidneys at clinically relevant doses.

Author: PalaRajasekharreddy, BaruiAyan K, MohieldinAshraf M, ZhouJing, NauliSurya M

Improved kidney function

Increased survival rate

Reduced side effects

Rapamycin is a drug that has been shown to be very effective in treating polycystic kidney disease (PKD) in rodents. However, it is not as effective in clinical trials because of its side effects. This study describes new nanoparticles that specifically target the kidneys. These nanoparticles are able to deliver rapamycin and an antioxidant directly to the kidneys, making the treatment more effective and reducing the side effects. This new approach has the potential to improve the treatment of PKD and other kidney diseases.

Language : English

13.

Analysis of serum lipid parameters predicting lipid metabolic disorders in TSC-AML patients with treatment of mTOR inhibitors.

Author: WangWenda, WangZhan, ZhaoYang, WangXu, LiHanzhong, ZhangYushi

TSC-AML treatment

This study examined the relationship between baseline serum lipid levels and the risk of hyperlipidemia in patients with tuberous sclerosis complex (TSC) associated renal angiomyolipomas (TSC-AML) treated with mammalian target of rapamycin (mTOR) inhibitors. It aimed to evaluate whether baseline lipid levels could predict the development of hyperlipidemia during mTOR inhibitor therapy in these patients.

Language : English

14.

Sirolimus Induced Toxic Optic Neuropathy.

Author: PakravanParastou, MiriShahnaz, LamByron L

Sirolimus risk

This case report describes a patient who experienced optic neuropathy after prolonged sirolimus therapy in the setting of cardiac transplantation. The patient's visual defects improved upon discontinuation of sirolimus and switching to cyclosporin.

Language : English

15.

Rapamycin maintains the primordial follicle pool and protects ovarian reserve against cyclophosphamide-induced damage.

Author: ChenXiuying, TangZhijing, GuanHaiyun, XiaHexia, GuChao, XuYan, LiBin, ZhangWei

Fertility preservation

Ovarian protection

Chemotherapy side effects

Ovarian reserve depletion

This study investigated the effects of rapamycin on ovarian follicle activation and development in a cyclophosphamide (CTX)-treated mouse model. Rapamycin was found to inhibit primordial follicle activation and reduce follicle loss and apoptosis, suggesting that it may have potential as an ovarian-protective agent for preserving fertility in young cancer patients undergoing chemotherapy.

Language : English

16.

RapaCaspase-9-based suicide gene applied to the safety of IL-1RAP CAR-T cells.

Author: BouquetLucie, Bôle-RichardElodie, WardaWalid, Neto Da RochaMathieu, TradRim, NicodClémentine, HaderbacheRafik, GeninDelphine, FerrandChristophe, DeschampsMarina

Cancer treatment

This abstract discusses the development of a new medical drug candidate, a chimeric antigen receptor (CAR) targeting interleukin-1 receptor accessory protein (IL-1RAP), and the use of inducible suicide genes to manage potential side effects.

Language : English

17.

Difficult Therapeutic Decisions in Gorham-Stout Disease-Case Report and Review of the Literature.

Author: Wojciechowska-DurczynskaKatarzyna, ZygmuntArkadiusz, MikulakMarta, LudwisiakMarta, LewinskiAndrzej

Gorham-Stout disease treatment

Treatment side effects

Gorham-Stout disease (GSD) is a rare and life-threatening condition characterized by the proliferation of lymphatic vessels and osteolysis. The combined treatment of sirolimus and zoledronic acid is a promising therapy for GSD, as it was effectively used in this case report.

Language : English

18.

Transcriptomic Analysis of the Effect of Torin-2 on the Central Nervous System of <i>Drosophila melanogaster</i>.

Author: VershininaYulia S, KrasnovGeorge S, GarbuzDavid G, ShaposhnikovMikhail V, FedorovaMaria S, PudovaElena A, KatuninaIrina V, KornevAlexey B, ZemskayaNadezhda V, KudryavtsevAlexander A, BulavkinaElizaveta V, MatveevaAnna A, UlyashevaNatalia S, GuvatovaZulfiya G, AnurovArtemiy A, MoskalevAlexey A, KudryavtsevaAnna V

Lifespan extension

Neuroprotection

This study investigates the effects of Torin-2, a TORC1/TORC2 inhibitor, on <i>D. melanogaster</i> heads, focusing on potential neuroprotective mechanisms. Torin-2 was found to affect various cellular pathways, including immune response, protein folding, histone modification, and neuronal signaling. The study suggests potential neuroprotective roles for Torin-2, particularly in relation to NMDA receptor activity and the MAPK cascade.

Language : English

19.

Center experience in liver transplantation (LTX): management of dermal side effects caused by sirolimus.

Author: SchaffellnerS, JakobyE, KniepeissD, StadlbauerV, DullerD, IbererF, TscheliessniggK H

Improved liver transplant maintenance therapy

Acne

Dermal side effects

Exfoliate forearm dermatitis

Leucocytoclastic vasculitis

Mouth ulcer

Perivascular lymphocytic eosinophilic dermatitis

Sirolimus is associated with dermal side effects that can limit patient compliance.

Language : English

20.

Long-lasting geroprotection from brief rapamycin treatment in early adulthood by persistently increased intestinal autophagy.

Author: JuricicPaula, LuYu-Xuan, LeechThomas, DrewsLisa F, PaulitzJonathan, LuJiongming, NespitalTobias, AzamiSina, ReganJennifer C, FunkEmilie, FröhlichJenny, GrönkeSebastian, PartridgeLinda

Geroprotection

Rapamycin side effects

This study investigated the effects of a brief pulse of rapamycin in early adulthood on lifespan and age-related decline in the intestine of female Drosophila and mice. A brief rapamycin treatment in early adulthood extended lifespan and attenuated age-related decline in the intestine in Drosophila to the same degree as lifelong dosing. The study also found that a 3-month early treatment in mice induced a memory effect, with similar maintenance as chronic treatment, of lysozyme distribution, Man2B1 level in intestinal crypts, Paneth cell architecture, and gut barrier function, even 6 months after rapamycin was withdrawn. These findings suggest that brief rapamycin treatments in early adulthood may offer geroprotective benefits without the need for lifelong dosing.

Language : English

21.

Acute Kidney Injury in Kidney Transplant Patients in Intensive Care Unit: From Pathogenesis to Clinical Management.

Author: FiorentinoMarco, BagagliFrancesca, DeleonardisAnnamaria, StasiAlessandra, FranzinRossana, ConservaFrancesca, InfanteBarbara, StalloneGiovanni, PontrelliPaola, GesualdoLoreto

Kidney transplantation

AKI in KTRs

Immunosuppression side effects

This review discusses the impact of acute kidney injury (AKI) on kidney transplant recipients (KTRs), particularly in the late post-transplant period. AKI is common in ICU-admitted KTRs, with a high mortality rate linked to illness severity and diagnosis. The review explores AKI epidemiology, pathophysiology, biomarkers, diagnosis, management, and immunosuppression modulation in this vulnerable population.

Language : English

22.

Frequency of CD39+, LAG3+, and CTLA4+ Regulatory T Cells in Two Different Immunosuppressive Protocols in Renal Allograft Recipients (Sirolimus vs Mycophenolate mofetil): A Cohort Report.

Author: Mollaei-KandelousYaghoub, AhmadpoorPedram, NafarMohsen, KhatamiMohammad Reza, Farashi BonabSamad, TajikNader, ShekarabiMahdi, AmirzargarAliakbar

Immune response

This study evaluated the influence of low-dose ATG induction therapy with two different protocols (Sirolimus versus Mycophenolate mofetil) on the expression of functional markers (LAG-3, CD39, and intracellular CTLA-4) on conventional Tregs in renal transplant recipients. Both treatment protocols resulted in an increase in the frequency of CD4+CD25+FOXP3+ Tregs, suggesting that both regimens may be clinically applicable in kidney transplant recipients.

Language : English

23.

De novo sirolimus-based immunosuppression after liver transplantation for hepatocellular carcinoma: long-term outcomes and side effects.

Author: TosoChristian, MeebergGlenda A, BigamDavid L, OberholzerJose, ShapiroA M James, GutfreundKlaus, MaMang M, MasonAndrew L, WongWinnie W S, BainVincent G, KnetemanNorman M

Acceptable side effect profile

Improved HCC survival

De novo sirolimus-based immunosuppression is associated with satisfactory outcomes after transplantation for hepatocellular carcinoma (HCC), even in selected patients beyond Milan criteria.

Language : English

24.

Side effects of sirolimus.

Author: MerkelS, MogilevskajaN, MengelM, HallerH, SchwarzA

Improved renal transplant function

Decreased hemoglobin

Glomerulopathy

Increased serum lipids

Proteinuria

Sirolimus, an mTOR inhibitor, improves renal transplant function but may be associated with adverse events including hyperlipidemia, anemia, and proteinuria. Careful monitoring is required, especially in patients with preexisting glomerular disease.

Language : English

25.

How often do we face side effects of sirolimus in pediatric renal transplantation?

Author: FidanK, KandurY, SozenH, GonulI I, DalgicA, SöylemezoğluO

Renal transplantation

Anemia

Hyperlipidemia

Hypokalemia

Interstitial pneumonia

Lower extremity edema

Nasal acneiform lesions

Proteinuria

This study examined the effects of sirolimus, an immunosuppressant drug, on pediatric kidney transplant patients. The study found that sirolimus was generally well-tolerated, with only a few patients experiencing side effects such as proteinuria, hyperlipidemia, and anemia. The study also found that sirolimus was effective in preventing acute rejection episodes.

Language : English

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