Spatiotemporal expression of RCAN1 and its isoform RCAN1-4 in the mouse hippocampus after pilocarpine-induced status epilepticus

Regulator of calcineurin 1 (RCAN1) can be induced by an intracellular calcium increase and oxidative stress, which are characteristic features of temporal lobe epilepsy. Thus, we investigated the spatiotemporal expression and cellular localization of RCAN1 protein and mRNA in the mouse hippocampus after pilocarpine-induced status epilepticus (SE). Male C57BL/6 mice were given pilocarpine hydrochloride (280 mg/kg, i.p.) and allowed to develop 2 h of SE. Then the animals were given diazepam (10 mg/kg, i.p.) to stop the seizures and sacrificed at 1, 3, 7, 14, or 28 day after SE. Cresyl violet staining showed that pilocarpine-induced SE resulted in cell death in the CA1 and CA3 subfields of the hippocampus from 3 day after SE. RCAN1 immunoreactivity showed that RCAN1 was mainly expressed in neurons in the shammanipulated hippocampi. At 1 day after SE, RCAN1 expression became detected in hippocampal neuropils. However, RCAN1 signals were markedly enhanced in cells with stellate morphology at 3 and 7 day after SE, which were confirmed to be reactive astrocytes, but not microglia by double immunofluorescence. In addition, real-time reverse transcriptase–polymerase chain reaction showed a significant upregulation of RCAN1 isoform 4 (RCAN1-4) mRNA in the SE-induced hippocampi. Finally, in situ hybridization with immunohistochemistry revealed astrocytic expression of RCAN1-4 after SE. These results demonstrate astrocytic upregulation of RCAN1 and RCAN1-4 in the mouse hippocampus in the acute and subacute phases of epileptogenesis, providing foundational information for the potential role of RCAN1 in reactive astrocytes during epileptogenesis.

Comparison of Transplant Outcomes for Low-level and Standard-level Tacrolimus at Different Time Points after Kidney Transplantation

BACKGROUND: Optimal tacrolimus (TAC) trough levels for different periods after kidney transplantation (KT) has not been definitely established. This study aimed to investigate transplant outcomes of low-level (LL) and standard-level (SL) TAC according to post-transplant period. METHODS: A total of 278 consecutive kidney transplant recipients (KTRs) receiving TAC-based immunosuppression were divided into LL and SL-TAC groups (4–7 and 7–12 ng/mL for 0–2 months, 3–6 and 6–10 ng/mL for 3–6 months, 2–5 and 5–8 ng/mL for 7–12 months, respectively) according to TAC trough level at each period. We compared estimated glomerular filtration rate (eGFR), biopsy-proven acute rejection (BPAR), de novo donor-specific antibody (dnDSA), calcineurin inhibitor (CNI) toxicity, opportunistic infection, and allograft survival. RESULTS: SL-TAC group showed significantly higher mean eGFR at 0–2 months than LL-TAC group (72.1 ± 20.3 vs. 64.2 ± 22.7 mL/min/1.73m2; P = 0.003). Incidence of BPAR at 7–12 months was significantly lower in SL-TAC group than in LL-TAC group (0.0% vs. 3.9%; P = 0.039). Patients with persistent SL-TAC lasting 12 months showed higher eGFR at 7–12 months than those with persistent LL-TAC (65.5 ± 13.0 vs. 57.9 ± 13.9 mL/min/1.73m2; P = 0.007). No significant differences in dnDSA, CNI toxicity, serious infections, or allograft survival were observed. CONCLUSIONS: Maintenance of proper TAC trough level after 6 months could reduce BPAR without adverse drug toxicities in KTRs. Moreover, persistent SL-TAC during the first year after KT might have a beneficial effect on a trend for a lower incidence of dnDSA and better renal allograft function.

Linear Lichen Planopilaris of the Face Successfully Treated with Topical Calcineurin Inhibitor / 대한피부과학회지

No abstract available.

The Korean Organ Transplant Registry (KOTRY): Second Official Adult Heart Transplant Report

BACKGROUND AND OBJECTIVES: This second adult heart transplantation (HTx) report is based on Korean Organ Transplant Registry data submitted on 400 HTxs in recipients of all ages. METHODS: From March 2014 to December 2017, a total of 400 HTxs were performed at 4 major centers in Korea. We analyzed demographics and characteristics according to transplant years. Patterns of immunosuppression, allograft rejection, and survival after HTx were analyzed. Donor and recipient age were highlighted. RESULTS: Some distinct differences in HTx statistics were noted. Mean donor age increased significantly in the most recent years compared to 2014–2015, while mean recipient age did not change. The proportion of patients on pre-transplant extracorporeal membrane oxygenation (ECMO) increased over time. One-year and intermediate-term survival was significantly worse in patients on pre-transplant ECMO compared to those without mechanical support. Over the years, tacrolimus has increased to become the most frequently used calcineurin inhibitor over cyclosporine, while the number of patients using steroids both at discharge and 1-year follow-up has declined. Age did not affect 1-year survival, but significantly affected intermediate-term survival. CONCLUSIONS: From 2014 to 2017, centers were willing to accept older donors to address increasing organ shortages and more patients received transplant under ECMO care. Increasing age was a strong independent factor for intermediate-term survival, however, post-transplant comorbidities did not differ among age groups. Further studies with longer follow-up duration are needed to better understand age-related post-transplant prognosis.

Impact of calcineurin inhibitors on rat glioma cells viability / 영남의대학술지

BACKGROUND: Although kidney transplantation outcomes have improved dramatically after using calcineurin inhibitors (CNIs), CNI toxicity continues to be reported and the mechanism remains uncertain. Here, we investigated the neurotoxicity of CNIs by focusing on the viability of glioma cells.METHODS: Glioma cells were treated with several concentrations of CNIs for 24 hours at 37℃ and their cell viability was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.RESULTS: Exposure to 0, 0.25, 0.5, 2.5, 5.0, and 10.0 mM concentrations respectively showed 100%, 64.3%, 61.3%, 68.1%, 62.4%, and 68.6% cell viability for cyclosporine and 100%, 38.6%, 40.8%, 43.7%, 37.8%, and 43.0% for tacrolimus. The direct toxic effect of tacrolimus on glioma cell viability was stronger than that of cyclosporine at the same concentration.CONCLUSION: CNIs can cause neurological side effects by directly exerting cytotoxic effects on brain cells. Therefore, we should carefully monitor the neurologic symptoms and level of CNIs in kidney transplant patients.

Sarcoma de Kaposi intestinal en paciente trasplantado renal / Intestinal KaposiÆs Sarcoma in renal transplant patient

El sarcoma de Kaposi (SK) es una neoplasia vascular, en la cual podemos distinguir cuatro formas clínicas: la clásica o mediterránea, endémica o africana, asociada al VIH y la iatrogénica. Sus manifestaciones clínicas más frecuentes son las lesiones mucocutáneas y afectación de ganglios linfáticos si bien puede cursar con afectación a nivel visceral. Presentamos a continuación el caso de un paciente trasplantado renal que fue diagnosticado de un sarcoma de Kaposi intestinal, sin lesiones cutáneas asociadas

Kaposi's sarcoma (KS) is a vascular neoplasm, in which we can distinguish four clinical forms: the classic or Mediterranean, endemic or African, associated with HIV and iatrogenic. Its most frequent clinical manifestations are mucocutaneous lesions and lymph node involvement, although it may manifest with involvement at the visceral level. We present the case of a renal transplant patient who was diagnosed with an intestinal Kaposi's sarcoma, with no associated cutaneous lesions

Effects of hydrogen sulfide (HS) on cardiac hypertrophy and miRNA-133a-mediated Ca/calcineurin/NFATc4 signal pathway in rats / 中国应用生理学杂志

OBJECTIVE@#To investigate the effects of hydrogen sulfide (HS) on the negatively regulation of cardiomyocyte hypertrophy and the relationship between the effect of HS with miRNA-133a-mediated Ca/calcineurin/NFATc4 signal pathway.@*METHODS@#Cardiomyocyte hypertrophy was induced by isoproterenol (ISO). The cell surface area was measured by image analysis system (Leica). The expression of brain natriuretic peptide(BNP), β-myosin heavy chain(β-MHC), cystathionase (CSE), miRNA-133a, calcineurin (CaN) were detected by qRT-PCR. The protein expressions of CaN、nuclear factors of activated T cells (NFATc4) were detected by Western blot. The concentration of HS in the cardiomyocyte was detected by Elisa. The concentration of intracellular calcium was measured by calcium imaging using confocal microscope. The nuclear translocation of NFATc4 was checked by immuno-fluorescence cell staining technique.@*RESULTS@#①The level of system of CSE/HS and expression of miRNA-133a were significantly reduced in cardiomyocyte hypertrophy. Pretreatment with NaHS increased the concentration of HS and the expression of miRNA-133a mRNA in cardiomyocytes, and suppressed cardiomyocyte hypertrophy. ②The concentration of intracellular calcium, the expression of CaN and nulear protein NFATc4 were significantly increased, and the nuclear translocation of NFATc4 were obviously enhanced in cardiomyocyte hypertrophy. NaHS pretreatment markedly inhibited these effects of ISO induced cardiomyocyte hypertrophy. ③Application of antagomir-133a reversed the inhibitory effects of NaHS on cardiomyocyte hypertrophy, and increased the influx of intracellular calcium, and elevated the expression of CaN and nuclear protein NFATc4, and enhanced the nuclear translocation of NFATc4.@*CONCLUSIONS@#HS can negatively regulate cardiomyocyte hypertrophy. The effects might be associated with HS increasing expression of miRNA-133a and inhibiting inactivation of Ca/calcineurin/NFATc4 signal pathway.

Evodiamine Inhibits Angiotensin II-Induced Rat Cardiomyocyte Hypertrophy / 中国结合医学杂志

<p><b>OBJECTIVE</b>To investigate the effects of evodiamine (Evo), a component of Evodiaminedia rutaecarpa (Juss.) Benth, on cardiomyocyte hypertrophy induced by angiotensin II (Ang II) and further explore the potential mechanisms.</p><p><b>METHODS</b>Cardiomyocytes from neonatal Sprague Dawley rats were isolated and characterized, and then the cadiomyocyte cultures were randomly divided into control, model (Ang II 0.1 μmol/L), and Evo (0.03, 0.3, 3 μmol/L) groups. The cardiomyocyte surface area, protein level, intracellular free calcium ([Ca]) concentration, activity of nitric oxide synthase (NOS) and content of nitric oxide (NO) were measured, respectively. The mRNA expressions of atrial natriuretic factor (ANF), calcineurin (CaN), extracellular signal-regulated kinase-2 (ERK-2), and endothelial nitric oxide synthase (eNOS) of cardiomyocytes were analyzed by real-time reverse transcriptionpolymerase chain reaction. The protein expressions of calcineurin catalytic subunit (CnA) and mitogen-activated protein kinase phosphatase-1 (MKP-1) were detected by Western blot analysis.</p><p><b>RESULTS</b>Compared with the control group, Ang II induced cardiomyocytes hypertrophy, as evidenced by increased cardiomyocyte surface area, protein content, and ANF mRNA expression; increased intracellular free calcium ([Ca]) concentration and expressions of CaN mRNA, CnA protein, and ERK-2 mRNA, but decreased MKP-1 protein expression (P<0.05 or P<0.01). Compared with Ang II, Evo (0.3, 3 μmol/L) significantly attenuated Ang II-induced cardiomyocyte hypertrophy, decreased the [Ca] concentration and expressions of CaN mRNA, CnA protein, and ERK-2 mRNA, but increased MKP-1 protein expression (P<0.05 or P<0.01). Most interestingly, Evo increased the NOS activity and NO production, and upregulated the eNOS mRNA expression (P<0.05).</p><p><b>CONCLUSION</b>Evo signifificantly attenuated Ang II-induced cardiomyocyte hypertrophy, and this effect was partly due to promotion of NO production, reduction of [Ca]i concentration, and inhibition of CaN and ERK-2 signal transduction pathways.</p>

Síndrome doloroso por inhibidores de la calcineurina: reporte de 4 casos en pacientes con retrasplante renal / Calcineurin-inhibitor induced pain syndrome: a 4-case report on patients with kidney retransplantation

INTRODUCCIÓN: El trasplante renal es el tratamiento de elección para pacientes con insuficiencia renal crónica. Los inmunosupresores como los inhibidores de la calcineurina pueden estar asociados a efectos adversos. El Síndrome Doloroso por Inhibidores de la Calcineurina (SDIC) se caracteriza por dolores óseos simétricos, agudos e incapacitantes de miembros inferiores, e imágenes características en la resonancia magnética. Se presentan 4 casos de SDIC con retrasplante renal, uso de tacrolimus como inmunosupresor y diagnóstico por resonancia magnética. MATERIAL Y MÉTODOS: Cuatro pacientes (3 mujeres y 1 varón) que se retrasplantaron con riñones cadavéricos, entre marzo de 2014 y septiembre de 2015, presentaron fuertes dolores en miembros inferiores. Tacrolimus fue el principal agente inmunosupresor. Se realizaron resonancias magnéticas de miembros inferiores, se indicó tratamiento y ajuste en la dosis de tacrolimus. RESULTADOS: El SDIC comenzó a los 2 meses del trasplante y 2 semanas de la detección de niveles tóxicos de tacrolimus. El cuadro doloroso permaneció aproximadamente 2 semanas y fue cediendo. La localización fue exclusiva de miembros inferiores (rodillas, tobillos y pies). El dolor fue referido por los pacientes como agudo, punzante, incapacitante y empeoraba de pie. La resonancia magnética confirmó el diagnóstico, revelando un patrón de edema de médula ósea en meseta tibial y astrágalos. Todos los casos fueron reversibles con el tratamiento indicado. CONCLUSIONES: Reportamos la aparición de SDIC en 4 pacientes con retrasplante renal, uso de tacrolimus y buena evolución. El diagnóstico se basó en sospecha clínica, forma de presentación e imágenes típicas en las resonancias magnéticas

INTRODUCTION: Kidney transplant is the first-line therapy for chronic kidney disease. Immunosuppressants such as calcineurin-inhibitors may be associated with side effects. Calcineurin-inhibitor induced pain syndrome (CIPS) is characterized by symmetrical, severe and disabling bone pain in the lower limbs and can be easily identified by magnetic resonance imaging due to its typical patterns. Four CIPS cases after kidney retransplantation are presented, confirmed by MRI and with immunosuppressive therapy consisting of tacrolimus. METHODS: Four patients (3 females and 1 male) with cadaveric kidney retransplantation, performed between March 2014 and September 2015 showed intense pains in their lower limbs. Tacrolimus was the main immunosuppressive agent. MRI scans of the lower limbs were performed; tacrolimus treatment and dosage adjustment were indicated. RESULTS: CIPS started 2 months after transplantation and 2 weeks after detection of tacrolimus toxic levels. Pain lasted around 2 weeks and it gradually became less severe. Symptoms were exclusively located in the lower limbs (knees, ankles and feet). Patients described the pain as sharp, throbbing, disabling, and becoming worse when standing. MRI confirmed the diagnosis, revealing a pattern of bone marrow edema in tibial plateau and tali. All cases were reversible with the indicated treatment. CONCLUSIONS: This study registers 4 cases of CIPS in patients who had undergone kidney retransplantation and had taken tacrolimus with good response. Diagnosis was reached by clinical suspicion, form and location of pain, and characteristic patterns in the MRI scans

Pimecrolimus increases the melanogenesis and migration of melanocytes in vitro

Vitiligo is an intriguing depigmentary disorder and is notoriously difficult to be treated. The ultimate goal of vitiligo treatment is to replenish the lost melanocytes by immigration from hair follicle and to restore the normal function of melanogenesis by residual melanocytes. There are two types of topical calcineurin inhibitors called tacrolimus and pimecrolimus, and are recommended as the first-line treatments in vitiligo. Although pimecrolimus is efficacious for the repigmentation of vitiligo, its intrinsic mechanisms have never been investigated in vitro. This research aimed to study the ability of pimecrolimus on stimulating melanogenesis, melanocyte migration and MITF (microphthalmia associated transcription factor) protein expression. Results showed that pimecrolimus at the dosages of 1, 10, 10² nM were neither mitogenic nor cytotoxic to melanocytes. The addition of pimecrolimus at 10, 10² and 10³ nM significantly increased intracellular tyrosinase activity, which was consistent with the elevated content of melanin content at the same concentrations. The peak effect was seen at 72 h in response to 10² nM pimecrolimus. Results of the wound scratch assay and Transwell assays indicate that pimecrolimus is effective in facilitating melanocyte migration on a collagen IV-coated surface. In addition, MITF protein yield reached the highest by pimecrolimus at 10² nM. In brief, pimecrolimus enhances melanin synthesis as well as promotes migration of melanocytes directly, possibly via their effects on MITF protein expression.

A Clinical and Etiological Analysis of Tinea Incognito Over 10 Years: A Single-Center Experience / 대한의진균학회지

BACKGROUND: Tinea incognito is the dermatophytoses of atypical clinical appearance that is induced by topical and systemic steroid treatment or topical calcineurin inhibitor. OBJECTIVE: The purpose of this study was to investigate the clinical and etiological aspects of tinea incognito. METHODS: In the 10-year-period 2007-2017, we reviewed fifty-one patients with tinea incognito with regards to the age, gender, duration, and associated diseases. The patients with tinea incognito were further evaluated concerning the clinical manifestations and culture of organisms. RESULTS: Age of the tinea incognito was most prevalent in the fifties (23.5%). The male-to-female ratio was 1:1.3. The most common type of infection was tinea corporis (52.9%), followed by tinea faciei (35.3%), tinea manus (5.9%), tinea barbae (3.5%), and tinea cruris (2.0%). The clinical features were to some extent diverse, ranging from eczema-like, seborrheic dermatitis-like, psoriasiform, folliculitis-like, rosacea-like, pyoderma-like, and purpura-like, and discoid lupus erythematosus-like. Trichophyton(T.) rubrum was the most common etiological agent (35.3%), followed by T. mentagrophytes (11.8%), Microsporum(M.) canis (7.8%), T. verrucosum (5.9%), T. erinacei, and M. gypseum (2.0%), respectively. CONCLUSION: Because of the increase in tinea incognito, there is a need for careful mycological examination in patients with tinea incognito.

Mechanisms of Alzheimer's Disease Pathogenesis and Prevention: The Brain, Neural Pathology, N-methyl-D-aspartate Receptors, Tau Protein and Other Risk Factors

The characteristic features of Alzheimer's disease (AD) are the appearance of extracellular amyloid-beta (Aβ) plaques and neurofibrillary tangles in the intracellular environment, neuronal death and the loss of synapses, all of which contribute to cognitive decline in a progressive manner. A number of hypotheses have been advanced to explain AD. Abnormal tau phosphorylation may contribute to the formation of abnormal neurofibrillary structures. Many different structures are susceptible to AD, including the reticular formation, the nuclei in the brain stem (e.g., raphe nucleus), thalamus, hypothalamus, locus ceruleus, amygdala, substantia nigra, striatum, and claustrum. Excitotoxicity results from continuous, low-level activation of N-methyl-D-aspartate (NMDA) receptors. Premature synaptotoxicity, changes in neurotransmitter expression, neurophils loss, accumulation of amyloid β-protein deposits (amyloid/senile plaques), and neuronal loss and brain atrophy are all associated with stages of AD progression. Several recent studies have examined the relationship between Aβ and NMDA receptors. Aβ-induced spine loss is associated with a decrease in glutamate receptors and is dependent upon the calcium-dependent phosphatase calcineurin, which has also been linked to long-term depression.

The effect of prenatal exposure to 1800 MHz electromagnetic field on calcineurin and bone development in rats

PURPOSE: To investigated the effects of exposure to an 1800 MHz electromagnetic field (EMF) on bone development during the prenatal period in rats. METHODS: Pregnant rats in the experimental group were exposed to radiation for six, 12, and 24 hours daily for 20 days. No radiation was given to the pregnant rats in the control group. We distributed the newborn rats into four groups according to prenatal EMF exposure as follows: Group 1 was not exposed to EMF; groups 2, 3, and 4 were exposed to EMF for six, 12, and 24 hours a day, respectively. The rats were evaluated at the end of the 60th day following birth. RESULTS: Increasing the duration of EMF exposure during the prenatal period resulted in a significant reduction of resting cartilage levels and a significant increase in the number of apoptotic chondrocytes and myocytes. There was also a reduction in calcineurin activities in both bone and muscle tissues. We observed that the development of the femur, tibia, and ulna were negatively affected, especially with a daily EMF exposure of 24 hours. CONCLUSION: Bone and muscle tissue development was negatively affected due to prenatal exposure to 1800 MHz radiofrequency electromagnetic field.

Safety and immunologic benefits of conversion to sirolimus in kidney transplant recipients with long-term exposure to calcineurin inhibitors

BACKGROUND/AIMS: Sirolimus (SRL) is a promising immunosuppressant replacingcalcineurin inhibitors (CNIs). This study was performed to evaluate the safetyand immunologic benefits of conversion to SRL in stable kidney transplant (KT)recipients exposed to CNIs for long periods. METHODS: Fourteen CNI-treated KT recipients with stable renal function for morethan 10 years were included. Either 2 or 3 mg per day of SRL was administeredwhile CNIs were reduced by half starting on day 1, and then stopped 2 weeks afterSRL introduction. The safety of SRL conversion was assessed considering thegraft function, acute rejection, and graft loss. Immunologic alterations were measuredvia serial changes of T cell and B cell subsets after SRL conversion. Adverseeffects of SRL conversion were also evaluated. RESULTS: Conversion to SRL was successful in nine patients (64.2%). Conversionto SRL preserved graft function as compared to the baseline value (p = 0.115). Noacute rejection or allograft loss was observed during the follow-up period. Immunemonitoring of T and B cells revealed a regulatory T cells increase after SRL conversion (p = 0.028). Most adverse events developed within 6 weeks after SRLconversion, and oral mucositis was the main cause of SRL withdrawal. CONCLUSIONS: Conversion to SRL can be safe and has immunologic benefits in KTrecipients with long-term CNI exposure. Close monitoring of mucocutaneous adverseevents is, however, required in the early period after SRL conversion.

A Comprehensive Review of the Treatment of Atopic Eczema

Atopic eczema (AE) is a chronic, inflammatory skin disorder which usually develops in early childhood. In spite of intensive investigations, the causes of AE remain unclear, but are likely to be multifactorial in nature. Environmental factors or genetic-environmental interactions seem to play a key role in disease progression. Among various measures of AE managment, cutaneous hydration, which improves barrier function and relieve itchiness, may be helpful to reduce the need for topical steroid use and therefore should be used as a basic treatment. Avoiding aggravating factors is also a basic treatment of AE. Standard medical treatment with a pharmacologic approach may be necessary if basic treatment fails to control symptoms satisfactorily. Recently, more attention is given to a proactive therapeutic by regular intermittent application of low potency steroids or topical calcineurin inhibitors to prevent new flares. Furthermore, various targeted biologics are being introduced for AE control and are proposed as promising therapies. This paper provides a summary of the recent literature on the manangement of AE and a treatment guideline.

Sirolimus Combination with Tacrolimus in Kidney Transplant Recipients at High Immunological Risk: Observational Results 3 Years after Transplantation / 대한이식학회지

BACKGROUND: The optimal immunosuppressive strategy for renal transplant recipients at high immunological risk requires clarification. We compared the 3 year outcomes of a sirolimus group (tacrolimus plus sirolimus) to those of a control group (tacrolimus plus mycophenolate mofetil). METHODS: This observational study was an extension of a prospective pilot study. We assessed acute rejection, glomerular filtration rate, adverse events, graft, and patient survival. RESULTS: Overall, 43% of the sirolimus group versus 78% of the control group were still on the initial immunosuppressive regimen at 3 years (P=0.005), and most discontinuations in each group were due to adverse events. No differences were observed between two groups with respect to acute rejection. The mean glomerular filtration rate at 36 months was greater in the sirolimus group than in the control group, but this was not statistically significant (64.0±6.8 mL/min/1.73 m² vs. 61.8±17.1 mL/min/1.73 m², P=0.576). Graft and patient survival were similar in both groups. Importantly, mean tacrolimus through levels were significantly lower in the sirolimus group than in the control group at each time point. No neoplasm was reported in the sirolimus group. In the control group, three cases of neoplasms developed during the study period. CONCLUSIONS: The sirolimus group had a greater number of discontinuations, particularly related to adverse events. Nevertheless, optimal concentration of sirolimus allowed reduced calcineurin inhibitor exposure in high immunologic risk patients, without increasing the risk of acute rejection and graft failure.

Calcineurin Inhibitor Induced Multiple Infarctions / 대한이식학회지

Tacrolimus is the most commonly used immunosuppressant after kidney transplantation. Here, we report a patient with multiple cerebral infarctions during tacrolimus treatment after kidney transplantation. A 54-year-old female was admitted due to sudden onset right leg weakness. Brain magnetic resonance imaging (MRI) showed multiple acute infarctions but normal vasculature. Evaluations of cardiac embolism were unremarkable. After 8 months, her weakness progressed and follow-up brain MRI showed additional multiple infarctions. We changed here medication from tacrolimus to mycophenolate mofetil, and her symptoms improved gradually.

Successful Balloon Angioplasty with Low-pressure Balloon on Early Transplant Renal Artery Stenosis at Postoperative Day 7 / 대한이식학회지

Transplant renal artery stenosis (TRAS) is an important cause of hypertension, allograft dysfunction, and graft loss. Patient and allograft survival rates are lower in patients with TRAS. Causes of TRAS include acute rejection, cytomegalovirus infection, calcineurin inhibitor toxicity, atherosclerosis of recipient, and/or donor. Technical problems due to surgery are a common cause of early TRAS. A 62-year-old male in end stage renal disease received kidney transplant surgery. There was 5/6 mismatch of human leukocyte antigen and the panel reactive antibody of patient was class I 0% and class II 0%. End to side anastomosis was done between the graft's renal artery and the patient's common iliac artery. His serum creatinine was measured at 6.4 mg/dL before transplantation but his serum creatinine level did not fall below 2.6 mg/dL at 5 days postoperative. His blood pressures was 160/90~180/100 mmHg. There was a significant TRAS (about 80% luminal narrowing) at the arterial anastomosis site on the renal magnetic resonance angiography. We performed percutaneous transluminal angioplasty (PTA) for the stenotic lesion. The balloon angioplasty was done with a 5 mm balloon and low pressure (8 mmHg, nominal pressure was 10 mmHg) at the stenotic lesion. The arterial pressure gradient was 8 mmHg (recipient's common iliac arterial pressure, 147/73 mmHg; poststenotic segmental renal arterial pressure, 139/70 mmHg) just before the balloon angioplasty. After PTA, the arterial pressure gradient became 3 mmHg (recipient's common iliac arterial pressure, 157/66 mmHg; poststenotic segmental renal arterial pressure, 154/65 mmHg). The arterial size and blood flow recovered to within normal range and serum creatinine level was normal after PTA. PTA using low pressure and a small balloon was safe and effective modality in treating early TRAS.

Implications of Calcineurin/NFAT Inhibitors' Regulation of Dendritic Cells and Innate Immune Cells in Islet Xenotransplantation

Calcineurin inhibitors, such as cyclosporine and tacrolimus (FK506) are broadly used in organ transplantations as immune suppressants. As the calcineurin/NFAT signaling pathway has been identified as critical pathway in the interleukin-2 (IL-2) production of T cells, inhibition of T-cell derived IL-2 has been considered the major mechanism of calcineurin inhibitors. However, there is increasing evidence that NFAT transcription factor is involved in multiple functions of dendritic cells and innate immune cells as well. NFAT expression is not restricted to T cells, and IL-2 can be produced in dendritic cells and macrophages through the calcineurin/NFAT pathway. Furthermore, it has been discovered that NFAT regulates expressions of several inflammatory mediators, including TNF-α and cyclooxygenase-2 in innate immune cells. Therefore, calcineurin inhibitors may have much broader effects in the transplant recipients than previously being considered. In this review, we reviewed recently discovered roles of NFAT pathway in dendritic cells and innate immune cells, and discussed positive and negative implications of calcineurin inhibitors' broader effects with a focus on islet xenotransplantation.

Overcome of Drug Induced Thrombotic Microangiopathy after Kidney Transplantation by Using Belatacept for Maintenance Immunosuppression / 대한이식학회지

Thrombotic microangiopathy (TMA) is a serious complication of solid organ transplantation. Drug-induced TMA is typically caused by immunosuppressants, particularly calcineurin inhibitors. Withdrawing the causative drug can be one of the treatments for TMA. However, the more immunosuppressants are reduced, the more risk of rejection increases. Even if TMA is successfully resolved, the outcomes of patient and graft survival would be worse than expected. Therefore, it is necessary to maintain efficient and safe immunosuppression therapy. We report on a case of de novo TMA after kidney transplantation triggered by tacrolimus and reactivated by sirolimus. Belatacept, a novel CTLA4 Ig fusion protein, was administered for maintenance immunosuppressant with mycophenolate mofetil and prednisolon. The patient had excellent early graft outcome, and there have been no adverse events so far.