Calcineurin Inhibitors and Other Immunosuppressive Drugs and the Kidney

AbstractOrgan transplant is often the treatment of choice as it extends and improves patient life. Immunosuppressive treatment, which prevents acute rejection of the organ, is used in transplant patients to prevent the loss of transplant. The aim of the study was to determine the impact of the CTLA4 (+49A>G, rs231775) and the TGF-β1 (−800G>A, rs1800468) polymorphisms on the therapeutic effect of immunosuppressive drugs (cyclosporine—CsA, tacrolimus—TAC) and the risk of acute rejection in renal transplant patients. The analysis of the CTLA4 +49A>G and the TGF-β1 −800G>A polymorphisms was carried out in 392 patients after kidney transplant using real-time PCR. The CTLA4 +49A>G polymorphism did not affect CsA or TAC dose, ratio of drug concentration to dose (C/D), and blood concentrations. As for the TGF-β1 -800G>A polymorphism, patients with the GA genotype required lower TAC doses compared to the GG genotype (TAC 12 h: 3.63 mg vs 5.3 mg, TAC 24 h: 2.38 mg vs 3.29 mg). Comparing the C/D ratio in both groups (TAC 12 h and TAC 24 h), higher C/D ratio was observed in patients with the GA genotype. These results indicate that patients with the A allele require slightly lower doses of TAC. The results suggest that the TGF-β1 −800 G>A polymorphism may influence the TAC dose, while the +49A>G polymorphism of the CTLA4 gene does not correlate with the dose of CsA or TAC. The analysis of the biochemical parameters of the renal profile showed no impact of the CTLA4 and the TGF-β1 polymorphisms on the risk of organ rejection.

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Comparison of treatment options in adults with frequently relapsing or steroid-dependent minimal change disease

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa133 ◽

2020 ◽

Author(s):

Cihan Heybeli ◽

Stephen B Erickson ◽

Fernando C Fervenza ◽

Marie C Hogan ◽

Ladan Zand ◽

...

Keyword(s):

Median Time ◽

Minimal Change Disease ◽

Treatment Options ◽

Calcineurin Inhibitors ◽

Immunosuppressive Drugs ◽

Minimal Change ◽

Line Treatment ◽

Second Line ◽

Steroid Dependent ◽

Time To Relapse

Abstract Background Studies comparing all treatment options for frequently-relapsing/steroid-dependent (FR/SD) minimal change disease (MCD) in adults are lacking. Methods Medical records of 76 adults with FR/SD MCD who were treated with corticosteroids as the first-line therapy were reviewed. Treatment options were compared for the time to relapse, change of therapy and progression (relapse on full-dose treatment). Results Second-line treatments included rituximab (RTX; n = 13), mycophenolate mofetil (MMF; n = 12), calcineurin inhibitors (CNI; n = 26) and cyclophosphamide (CTX; n = 16). During the second-line treatments, 48 (71.6%) patients relapsed at median 17 (range 2–100) months. The majority of relapses occurred during dose tapering or off drug. Twenty of 65 (30.8%) changed therapy after the first relapse. The median time to relapse after the second line was 66 versus 28 months in RTX versus non-RTX groups (P = 0.170). The median time to change of treatment was 66 and 44 months, respectively (P = 0.060). Last-line treatment options included RTX (n = 8), MMF (n = 4), CNI (n = 3) and CTX (n = 2). Seven (41.2%) patients had a relapse during the last-line treatment at median 39 (range 5–112) months. The median time to relapse was 48 versus 34 months in the RTX versus non-RTX groups (P = 0.727). One patient in the RTX group died presumably of heart failure. No major adverse event was observed. During the median follow-up of 81 (range 9–355) months, no patients developed end-stage renal disease. Conclusions Relapse is frequent in MCD in adults. Patients treated with RTX may be less likely to require a change of therapy and more likely to come off immunosuppressive drugs.

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Real-Time PCR Determination of IMPDH1 and IMPDH2 Expression in Blood Cells

Clinical Chemistry ◽

10.1373/clinchem.2006.081968 ◽

2007 ◽

Vol 53 (6) ◽

pp. 1023-1029 ◽

Cited By ~ 12

Author(s):

Sara Bremer ◽

Helge Rootwelt ◽

Stein Bergan

Keyword(s):

Real Time ◽

Cultured Cells ◽

De Novo ◽

Geometric Mean ◽

Calcineurin Inhibitors ◽

Housekeeping Genes ◽

Immunosuppressive Drugs ◽

Inosine Monophosphate Dehydrogenase ◽

Gene Expressions ◽

Nucleotide Synthesis

Abstract Background: Inosine monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in de novo guanine nucleotide synthesis and is implicated in cell cycle control. Inhibition of this enzyme is associated with immunosuppressive, antiviral, and antitumor activity. IMPDH basal activity increases after initiation of immunosuppressive therapy. Methods: A real-time reverse-transcription PCR assay was developed and validated for mRNA quantification of the 2 human IMPDH isoforms. Target gene expressions were normalized to the geometric mean of 3 housekeeping genes. Assay utility was tested by analyzing patient samples and cultured cells exposed to immunosuppressive drugs such as the IMPDH inhibitor mycophenolic acid. Results: The assay was linear over 6 logs of cDNA input and demonstrated specific quantification of IMPDH1 and IMPDH2 expression in cultured cells and patient samples. Limits of detection and quantification were 10 and 103 copies of cDNA per reaction, respectively. Within-run and total between-day CVs were <15% for normalized expression. Changes in IMPDH1 and 2 expression were observed in patient samples after initiation of an immunosuppressive regimen that included calcineurin inhibitors, mycophenolate mofetil, and steroids. Conclusions: This assay can be used to study the regulation of IMPDH expression and the involvement of the enzymes in immunological and malignant proliferative conditions. This may contribute to the processes of drug development and to the establishment of monitoring strategies for treatment effect and disease activity.

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In Vitro Interactions between Antifungals and Immunosuppressive Drugs against Zygomycetes

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00184-09 ◽

2009 ◽

Vol 53 (8) ◽

pp. 3549-3551 ◽

Cited By ~ 37

Author(s):

Eric Dannaoui ◽

Patrick Schwarz ◽

Olivier Lortholary

Keyword(s):

Amphotericin B ◽

Calcineurin Inhibitors ◽

Immunosuppressive Drugs ◽

In Vitro Interaction ◽

Antagonistic Interactions ◽

In Vitro Interactions

ABSTRACT The in vitro interaction of antifungals with immunosuppressive drugs was evaluated against zygomycetes. The combination of amphotericin B with cyclosporine, rapamycin, or tacrolimus was synergistic for 90%, 70%, and 30% of the isolates, respectively. For posaconazole, itraconazole, and ravuconazole, synergy was more frequently observed with cyclosporine than with rapamycin or tacrolimus and antagonistic interactions were rarely noted. In summary, calcineurin inhibitors and rapamycin can be synergistic in vitro with amphotericin B and azoles against zygomycetes.

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Recent Topics on the Mechanisms of Immunosuppressive Therapy-Related Neurotoxicities

10.20944/preprints201905.0358.v1 ◽

2019 ◽

Author(s):

Wei Zhang ◽

Nobuaki Egashira ◽

Satohiro Masuda

Keyword(s):

Early Recognition ◽

Immunosuppressive Agents ◽

Calcineurin Inhibitors ◽

Mtor Inhibitors ◽

Immunosuppressive Drugs ◽

Individual Therapy ◽

Therapeutic Drug ◽

Neuroprotective Effects ◽

Neuropsychiatric Manifestation ◽

Neuropsychiatric Complications

Although transplantation procedures have been developed for patients with end-stagec hepatic insufficiency or other diseases, allograft rejection still threatens patient health and lifespan. Over the last few decades, the emergence of immunosuppressive agents, such as calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors, have strikingly increased graft survival. Unfortunately, immunosuppressive agent-related neurotoxicity is commonly occurred in clinical situations, with the majority of neurotoxicity cases caused by CNIs. The possible mechanisms whereby CNIs cause neurotoxicity include: increasing the permeability or injury of the blood-brain barrier, alterations of mitochondrial function, and alterations in electrophysiological state. Other immunosuppressants can also induce neuropsychiatric complications. For example, mTOR inhibitors induce seizures; mycophenolate mofetil induces depression and headache; methotrexate affects the central nervous system; mouse monoclonal immunoglobulin G2 antibody against cluster of differentiation 3 also induces headache; and patients using corticosteroids usually experience cognitive alteration. Therapeutic drug monitoring, individual therapy based on pharmacogenetics, and early recognition of symptoms have greatly reduced neurotoxic events. Once neurotoxicity occurs, a reduction in the drug dosage, switching to other immunosuppressants, using drugs to treat the neuropsychiatric manifestation, or blood purification therapy have proven to be effective against neurotoxicity. In this review, we summarize the recent topics on the mechanisms of neurotoxicity of immunosuppressive drugs. In addition, some information about neuroprotective effects of several immunosuppressants are also discussed.

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Survival of Post-Transplant Lymphoproliferative Disorder after Kidney Transplantation in Patients under Rapamycin Treatment

International Journal of Hematology-Oncology and Stem Cell Research ◽

10.18502/ijhoscr.v15i4.7479 ◽

2021 ◽

Author(s):

Farzaneh Ashrafi ◽

Shahrzad Shahidi ◽

Valiollah Mehrzad ◽

Mojgan Mortazavi ◽

Sayyideh Forough Hosseini

Keyword(s):

Calcineurin Inhibitors ◽

B Cell Lymphoma ◽

Complete Response ◽

Immunosuppressive Drugs ◽

Lymphoproliferative Disease ◽

Mortality And Morbidity ◽

Post Transplant ◽

Causes Of Mortality ◽

The Mean ◽

Transplanted Kidneys

Background: One of the important causes of mortality and morbidity in kidney transplanted patients is Post Transplant Lymphoproliferative Disease (PTLD), which is due to immunosuppression therapy and viral activity. It seems that Rapamycin, with dual antineoplastic and immunosuppressive effects, may have a pivotal role in the treatment of PTLD patients and preserving transplanted kidneys. Methods and Materials: Twenty patients with PTLD were enrolled. Immunosuppressive therapy was reduced or ceased, and Rapamycin was initiated at the time of PTLD diagnosis. We evaluated the effects of switching immunosuppressive drugs to Rapamycin on graft status, the response of tumor, and 6, 12 months, and 5-year survival in patients. Results: PTLD remission was achieved in 14 patients, while six patients died; no relapse was detected in recovered patients. The median of PTLD free time was 25 months, and the mean overall survival in patients with PTLD treated by Rapamycin was 84.8 (95% CI=61.3-108.23).The five-year survival rate was 67%, 12 months survival was 73.8%, and six months' survival was 80%. The response rate to Rapamycin and immunosuppression reduction alone was 46.6%. Four out of 13 Diffuse Large B-Cell Lymphoma patients achieved a complete response just only after the reduction of immunosuppressive drugs and the consumption of Rapamycin. Conclusion: The present study demonstrated the effectiveness of conversion from immunosuppressive medication, particularly of Calcineurin inhibitors to Rapamycin in PTLD patients. However, more research is needed to confirm the Rapamycin effect on patients with PTLD.

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Use of Belatacept as Alternative Immunosuppression in Three Renal Transplant Patients withDe NovoDrug-Induced Thrombotic Microangiopathy

Case Reports in Medicine ◽

10.1155/2013/260254 ◽

2013 ◽

Vol 2013 ◽

pp. 1-4 ◽

Cited By ~ 11

Author(s):

Federico Cicora ◽

Marta Paz ◽

Fernando Mos ◽

Javier Roberti

Keyword(s):

Renal Transplant ◽

Thrombotic Microangiopathy ◽

De Novo ◽

Parvovirus B19 ◽

Calcineurin Inhibitors ◽

Immunosuppressive Drugs ◽

Drug Induced ◽

Transplant Patients ◽

Proliferation Signal Inhibitors ◽

Renal Transplant Patients

Thrombotic microangiopathy (TMA), a severe complication of renal transplantation, is a pathological process involving microvascular occlusion, thrombocytopenia, and microangiopathic hemolytic anemia. It generally appears within the first weeks after transplantation, when immunosuppressive drugs are used at high doses.De novoTMA may also be drug-induced when calcineurin inhibitors or proliferation signal inhibitors are used. We report three cases ofde novodrug-induced TMA in renal transplant patients who were managed by replacing calcineurin inhibitors or proliferation signal inhibitors with belatacept, a primary maintenance immunosuppressive drug, which blocks the CD28 costimulation pathway, preventing the activation of T lymphocytes. To identify the cause of TMA, we ruled out HUS, hepatitis C serology, HIV serology, parvovirus B19, cytomegalovirus, anti-HLA antibodies, and prolonged activated partial thromboplastin time. We suspect that the TMA was caused by the calcineurin inhibitors or proliferation signal inhibitors. Belatacept treatment was initiated at a dose of 10 mg/kg on days 1, 5, 14, 28, 60, and 90; maintenance treatment was 5 mg/kg once a month for 1 year. Belatacept, in combination with other agents, prevented graft rejection in three patients.

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Developments in the Immunotherapy of Glomerular Disease

Journal of Pharmacy Practice ◽

10.1177/089719002237666 ◽

2002 ◽

Vol 15 (6) ◽

pp. 472-489

Author(s):

Patrick H. Nachman ◽

Jeffrey Martin

Keyword(s):

Alkylating Agents ◽

Clinical Manifestations ◽

Calcineurin Inhibitors ◽

Immunosuppressive Drugs ◽

Glomerular Disease ◽

Drug Induced ◽

Glomerular Diseases ◽

Care Givers ◽

Clinical Syndromes ◽

History Of

Glomerular diseases span a broad spectrum of clinical syndromes, with varied clinical manifestations, underlying etiologies, and pathogenic mechanisms. They can be secondary to underlying infectious, toxic, environmental, or drug exposures, or present as “primary entities.” In the latter case, most glomerular diseases are thought to be due to autoimmune dysregulation, and their treatment is primarily immunosuppressive. The armamentarium for immunomodulation includes corticosteroids, alkylating agents, anti-metabolites, calcineurin inhibitors, and new biological agents designed to block specific inflammatory pathways. The choice of therapy for an individual patient must be based on the specific character of the glomerular disease and its acuity and severity, as well as the patient’s comorbidities, history of prior exposure to immunosuppressive drugs, and risk factors for developing complications of the disease or its treatment. The complexities of such therapy can best be addressed by an experienced team of care givers in which the clinical pharmacist can help minimize, if not eliminate, potential sources of drug induced toxicities and adverse effects. This article will describe the major agents and modalities used in the management of the most common glomerular diseases.

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Role of Kaletra (combination of lopinavir and ritonavir) in the treatment of COVID-19 virus infection; an issue related to kidney transplant patients – A review study on current knowledge

Journal of Preventive Epidemiology ◽

10.34172/jpe.2020.28 ◽

2020 ◽

Vol 5 (2) ◽

pp. e28-e28

Author(s):

Seyed Seifollah Beladi Mousavi ◽

Fatemeh Hayati ◽

Ehsan Valavi ◽

Isa Rezaee ◽

Shokouh Shayanpour ◽

...

Keyword(s):

Kidney Transplant ◽

English Language ◽

Current Knowledge ◽

Calcineurin Inhibitors ◽

Mtor Inhibitors ◽

Immunosuppressive Drugs ◽

Current Data ◽

Blood Concentrations ◽

Transplant Patients ◽

Frequent Monitoring

A number of therapies are prescribed for the treatment of COVID-19, but none of them have proven efficacy. In this review article, we summarized the pharmacodynamic and pharmacokinetic properties, effect and potential toxicity of Kaletra (combination of lopinavir and ritonavir) among kidney transplant (KTP) patients who have COVID-19. We used a variety of sources by searching through PubMed, Scopus, Embase and Current Content to collect current data about our issue. Articles published in the English language, as full-text manuscripts, and or as abstract form were included in the study. Lopinavir and ritonavir are two structurally related novel protease inhibitors which have antiretroviral properties. They have primarily been used as part of combination therapy for the treatment of HIV, SARS-CoV and MERS-CoV viruses. However, it seems that use of Kaletra is not associated with clinical improvement, or reduces mortality among patients including KTP recipients who have laboratory-confirmed COVID-19. On the other hand, co-administration of Kaletra with medications that are commonly used among KTP recipients including calcineurin inhibitors and mTOR inhibitors has profound drug-drug interactions. Co-administration of Kaletra with these medications could lead to significant and unexpected increase of blood concentrations of both calcineurin and mTOR inhibitors and therefore frequent monitoring of the immunosuppressive drugs concentrations are necessary to optimize immunosuppressive therapy and prevention of toxicity. It is important to note that frequent monitoring of the immunosuppressive drugs concentration is expensive and also not easily available in many countries including our country. According to the above important points, we recommend that use of Kaletra among KTP patients who have laboratory-confirmed COVID-19 should be avoided especially among patients who are still on calcineurin and mTOR inhibitors.

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