CsA Group Research Articles

Topical cyclosporine-A versus prednisolone for herpetic stromal keratitis: a randomized controlled trial.

To compare topical cyclosporine-A 2% eye drop (Cs-A) with prednisolone acetate 1% eye drop for treatment of herpetic stromal keratitis (HSK). In this randomized clinical trial, 38 eyes of 33 patients with HSK were randomly assigned to receive either 2% Cs-A or 1% prednisolone acetate eye drops. All subjects received oral acyclovir 400mg twice a day. Slit-lamp examination, Scheimpflug tomography corneal optical densitometry (Pentacam®, Oculus Inc., Wetzlar, Germany), best-corrected visual acuity (BCVA), and intra-ocular pressure (IOP) were evaluated at the first visit, and 14 and 30days after the treatment. Within-group analysis revealed significant improvement of total cornea optical density after 30days of treatment in both groups (30.3±10.5 to 28.3±9.8, p<0.001 for prednisolone group, and 30.5±8.8 to 28.8±8.3 p<0.001 for Cs-A group, mean±SD). We were not able to disclose any significant difference between the two groups regarding the improvement of cornea optical density (p=0.66). Best-corrected visual acuity (BCVA) logMAR significantly improved in both groups after 30days of treatment (0.20±0.52, p=0.002 in prednisolone group, and 0.24±0.31, p<0.001 in Cs-A group, mean±SD). Analysis between groups did not show a significant difference of BCVA improvement (p=0.45). We did not observe any severe side effect attributable to drugs. Cs-A 2% and prednisolone acetate 1% topical eye drops are effective for treatment of HSK.

Metastases-yield and Prostate-specific Antigen Kinetics Following Salvage Lymph Node Dissection for Prostate Cancer: A Comparison Between Conventional Surgical Approach and Prostate-specific Membrane Antigen-radioguided Surgery

The first results on 99mTechnetium prostate-specific membrane antigen-radioguided surgery (99mTc-PSMA- RGS) showed promising outcome. Here, we sought to evaluate if this targeted molecular surgical approach might be more effective than conventional salvage lymph node dissection (sLND). We prospectively analysed 42 consecutive patients who underwent sLND based on preoperative 68Gallium (68Ga)-PSMA-positron emission tomography (PET) imaging between 2015 and 2018. In 29 patients, the dissection field was based solely 68Ga-PSMA-PET imaging (conventional surgical approach [CSA]), whereas 13 patients underwent 99mTc-PSMA-RGS. Preoperative characteristics of both groups were similar. Final pathology revealed no metastases in nine CSA patients (31%), whereas all visible lesions on preoperative 68Ga-PSMA-PET were removed in patients who underwent RGS. A PSA decline in general, >50% and >90% within 6 wk was seen in 50%, 29%, and 7% versus 100%, 92%, and 53% in CSA versus RGS groups, respectively (all p<0.01). This is the first comparison of conventional and PSMA-radioguided approach with regards to short-term efficacy of sLND. Although long-term outcome needs to be awaited, RGS offers promising results. Patient summaryWe compared two surgical approaches for lymph node dissection in lymph node only recurrent prostate cancer patients. The radioguided approach was superior in removing the affected lymph nodes, resulting in a more pronounced prostate-specific antigen decline.

Long-term cardiovascular outcome of renal transplant recipients after early conversion to everolimus compared to calcineurin inhibition: results from the randomized controlled MECANO trial.

Long-term data on cardiovascular (CV) outcome of renal transplant recipients (RTR) on mTOR-i (mammalian Target Of Rapamycin-inhibitors) are scarce. In a sub-study of the MECANO trial we investigated changes in intima media thickness (IMT), CV risk profile, Major Adverse CV Events (MACE) and survival in RTR on a mTORi versus CNI based regimen. Patients (enrolled 361) were treated with (basiliximab) and triple IS (CsA-Cyclosporine A-(C), MPS (M), prednisolone (P)). At M6 patients were randomized (n = 224) to the CsA group (C, P, N = 89), MPS group (M, P, N = 39) EVL group (Everolimus, P, N = 96). At week 2, M6 and M 24, IMT measurements of the Common Carotid Artery were performed. Cardiovascular risk factors were assessed at baseline, 6 and 24 months of follow-up. Seven years survival and MACE-free survival probability were calculated by the Cardiovascular Risk Calculator for RTR. After 7 years of follow-up, incidence of cardiovascular events and patient survival were assessed. Mean IMT at baseline (N = 192), was 0.64 ± 0.14 mm. At M6 (N = 158), 0.66 ± 0.15, M24 IMT was 0.68 ± 0.15 (N = 95). No significant differences between groups concerning IMT, true CV events and mortality, CV risk profile, predicted MACE/Mortality were found between mTORi and CNI-based regimen after 7 years of follow-up.

Histological findings to five years after early conversion of kidney transplant patients from cyclosporine to everolimus: an analysis from the randomized ZEUS study

BackgroundConversion from calcineurin inhibitor (CNI) therapy to everolimus within 6 months after kidney transplantation improves long-term graft function but can increase the risk of mild biopsy-proven acute cellular rejection (BPAR). We performed a post-hoc analysis of histological data from a randomized trial in order to further analyze histologic information obtained from indication and protocol biopsies up to 5 years after transplantation.MethodsBiopsy samples obtained up to 5 years post-transplant were analyzed from the randomized ZEUS study, in which kidney transplant patients were randomized at month 4.5 to switch to everolimus (n = 154) or remain on cyclosporine (CsA)-based immunosuppression (n = 146). All patients received mycophenolate and steroids.ResultsAt least one investigator-initiated biopsy was undertaken in 53 patients in each group between randomization and year 5, with a mean (SD) of 2.6 (1.7) and 2.2 (1.4) biopsies per patient in the everolimus and CsA groups, respectively. In the everolimus and CsA groups, investigator-initiated biopsies showed (i) BPAR in 12.3 and 7.5% (p = 0.182) of patients, respectively, with episodes graded mild in 22/24 and 18/20 cases (ii) CsA toxicity lesions in 4.5 and 10.3% of patients (p = 0.076) (iii) antibody-mediated rejection in 0.6 and 2.7% of patients (p = 0.204), respectively.ConclusionsThis analysis of histological findings in the ZEUS study to 5 years after kidney transplantation shows no increase in antibody-mediated rejection under everolimus-based therapy with a lower rate of CNI-related toxicity compared to a conventional CsA-based regimen, and confirms the preponderance of mild BPAR seen in the main study after the early switch to CsA-free everolimus therapy.Trial registrationClinicalTrials.gov NCT00154310. Date of registration: September 12, 2005.

Role for primary immunosuppression with everolimus after pulmonary transplantation

PurposeEverolimus is a proliferation signal inhibitor used for triple immunosuppressive therapy following solid organ transplantation. Its positive benefits, such as reduction of acute rejection episodes and reduced nephrotoxicity have been shown in kidney- as well as heart transplantation. However the role of everolimus is less well defined in lung transplantation. We thus wished to study the effect of primary immunosuppression with everolimus in a preclinical large animal lung transplantation model. MethodsLeft-sided single lung transplantation from MHC-mismatched donors was performed in 11 adult minipigs. Intravenous pharmacologic immunosuppression was maintained for 28 days with 1.5 mg/kg/d methylprednisolone, 1.0 mg/kg/d azathioprine and cyclosporine A (blood levels 300-500 ng/ml; CsA group; n = 5). A further group (CsA + Ev; n = 6) received methylprednisolone, CsA (200–300 ng/ml) and Everolimus (5–10 ng/ml). Immunosuppression was discontinued on postoperative day (POD) 28. Graft survival was monitored by sequential chest X-rays, bronchoscopies and transbronchial biopsy histology. ResultsAll animals survived the 28 day course of immunosuppressive therapy and showed healthy grafts on POD 28. Median allograft survival in the CsA group was 55 ± 15 days. CsA + Ev grafts showed median survival of 49 ± 86 days (p = 0.37). ConclusionWhereas everolimus might be advantageous as maintenance immunosuppressive agent, this data does not support an important role for everolimus in the immunosuppressive induction phase following lung transplantation.

Renal Function Changes Under Everolimus Plus Cyclosporine or Everolimus Plus Tacrolimus After Heart Transplantation

Everolimus (EVR) can be used with calcineurin inhibitors to reduce the risk of renal dysfunction, with similar immunosuppressive effect. In this study, we compared renal function after heart transplantation (HT) under EVR with cyclosporine (CSA) or tacrolimus (TAC). Between 2004 and 2014, EVR with CSA or TAC was used in 117 HT at the National Taiwan University Hospital. After HT, all patients received corticosteroid, EVR (C0 target 3–8 ng/mL) and CSA (C0 blood level 100–200 ng/mL), or TAC (Co blood level 5–10 ng/mL). Renal function was evaluated before HT, every month after HT for up to 1 year, and then every 3 months for up to 2 years. Blood-drug levels of EVR, CSA, and TAC were also monitored simultaneously with renal function. The estimated mean glomerular filtration rate (eGFR) was 76.5 mL/min/1.73 m2 before HT. After HT, the eGFR was 64 mL/min/1.73 m2 at the third month, and 64 mL/min/1.73 m2 at the end of first year. The difference was significant between pre-HT and post-HT (P = .00) during the first year. No significant differences were noted between the CSA and TAC groups. Careful monitoring of blood-drug level and renal function is crucial after heart transplantation. It is concluded that under close monitoring blood-drug level and renal function, it is possible to reach acceptable postoperative renal function with no difference of renal function between EVR plus CSA and EVR plus TAC.

Complexity volumes of splittable groups

Using graph of groups decompositions of finitely generated groups, we define Euler characteristic type invariants which are non-zero in many interesting classes of hyperbolic, limit and CSA groups, including elementarily free groups and one-ended torsion-free hyperbolic groups whose JSJ decomposition contains a maximal hanging Fuchsian vertex group.

Effects of Atorvastatin and Carvedilol on Chronic Cyclosporine Nephrotoxicity in Rats

Background: To evaluate possible renoprotective effects of carvedilol and atorvastatin in CsA induced kidney injury in a rat model. Methods: Twenty-two rats were divided into five groups. Control, CsA, CsA+karvedilol, CsA+Atorvastatin, CsA +karvedilol+atorvastatin groups. Drugs were given for 21 days. Results: Serum BUN and creatinine were significantly higher in the CsA group compared to control and were significantly lower in the CsA+carvedilol+atorvastatin group compared to CsA group. Tissue MDA levels were found to be lower in group 3, 4 and 5 than in CsA group. Tissue SOD in CsA +carvedilol and CsA+atorvastatin groups were found higher than the control and CsA groups. Tissue NO levels were found to be higher only in CsA+carvedilol+atorvastatin group compared to CsA group. Apical budding, hyaline casts and apoptosis in the tubular system was significantly higher in the CsA group than in the treatment groups. Osteopontin showed strong positivity especially in the CsA group. Osteopontin density was lower in the treatment group. Conclusions: This is the first study to evaluate MDA, SOD and NO at tissue level for carvedilol in cyclosporine nephrotoxicity. Carvedilol and atorvastatin may contribute to the reduction of renal injury in chronic CsA nehropathy. These agents have provided a protective effect on renal functions especially in combined treatment.

Comparison of patient and graft survival in tacrolimus versus cyclosporine-based immunosuppressive regimes in renal transplant recipients – Single-center experience from South India

Studies have shown better graft function and reduced acute rejection rates among renal transplant recipients who were on Tacrolimus (Tac)-based immunosuppression regimens as compared to cyclosporine (CsA)-based regimens in the first year. However, the long-term follow-up data did not reveal better outcomes in the Tac-based regimens. In view of the short term benefits, the trend has been to change to Tac-based regimens off late. Data from the Indian subcontinent are, however, sparse. We, therefore, looked at our data to ascertain if Tac-based regimen does have better outcomes in our population. We studied a total of 108 individuals who underwent renal transplantation between January 2007 and June 2013, with a mean follow-up of 38.22 months (comparable to both groups). In our group, males constituted 77.8%,; and among the 108 individuals, 16.7% were diabetics. New-onset diabetes after renal transplantation was more common in the Tac group (21 vs. 12 and was statistically significant [P = 0.03]). At the last follow-up, serum creatinine was higher in the CsA group (1.77 mg/dl vs. 1.35 mg/dl) and was statistically significant (P = 0.03). Individuals requiring hemodialysis were also significantly higher in the CsA group (9 vs. 2; P = 0.05). The patient survival was similar in both groups (1-year and 5-year follow-up); however, graft survival was better in Tac group as compared to CsA group (0.94 vs. 0.88 at 1 year and 0.85 vs. 0.72 at 5 years).

The Effect of Mycophenolate Mofetil versus Cyclosporine as Combination Therapy with Low Dose Corticosteroids in High-risk Patients with Idiopathic Membranous Nephropathy: a Multicenter Randomized Trial.

BackgroundAppropriate immunosuppressive therapy for patients with idiopathic membranous nephropathy (MN) remains controversial. The effect of mycophenolate mofetil (MMF) versus cyclosporine (CsA) combined with low-dose corticosteroids was evaluated in patients with idiopathic MN in a multi-center randomized trial (NCT01282073).MethodsA total of 39 biopsy-proven idiopathic MN patients with severe proteinuria were randomly assigned to receive MMF combined with low-dose corticosteroids (MMF group) versus CsA combined with low-dose corticosteroids (CsA group), respectively, and followed up for 48 weeks. Complete or partial remission rate of proteinuria and estimated glomerular filtration rate (eGFR) at 48 weeks were compared.ResultsThe level of proteinuria at baseline and at 48 weeks was 8.9 ± 5.9 and 2.1 ± 3.1 g/day, respectively, in the MMF group compared to 8.4 ± 3.5 and 3.2 ± 5.7 g/day, respectively, in the CsA group. In total, 76.1% of the MMF group and 66.7% of the CsA group achieved remission at 48 weeks (95% confidence interval, −0.18 to 0.38). There was no difference in eGFR between the two groups. Anti-phospholipase A2 receptor Ab levels at baseline decreased at 48 weeks in the complete or partial remission group (P = 0.001), but were unchanged in the no-response group. There were no significant differences between the two groups in changes in the Gastrointestinal Symptom Rating Scale and Gastrointestinal Quality of Life Index scores from baseline to 48 weeks.ConclusionIn combination with low-dose corticosteroids, the effect of MMF may not be inferior to that of CsA in patients with idiopathic MN, with similar adverse effects including gastrointestinal symptoms.Trial RegistrationClinicalTrials.gov Identifier: NCT01282073

Efficacy and safety of cyclosporine versus tacrolimus in steroid and cyclophosphamide resistant nephrotic syndrome: A prospective study

Calcineurin inhibitors (CNIs) are the preferred drugs for treatment of childhood steroid-resistant nephrotic syndrome (SRNS) who are also resistant to cyclophosphamide (CYC). Although few studies have shown a benefit of one over the other, efficacy and safety of either CNIs (tacrolimus [TAC] or cyclosporine [CSA]) in this special population remained to be assessed in long-term studies. Forty-five children with SRNS who were also resistant to CYC (CYC-SRNS) from January 2006 to June 2011, were included in the study. Patients were treated with CNI either TAC or CSA based on 1:1 allocations and were prospectively observed. Patients who were nonresponsive to CNIs had been treated with mycophenolate mofetil. Outcomes were measured in terms of remission of NS, adverse effects of drugs, and progression of disease. After 6 months of treatment, 16/23 (69.5%) patients on CSA achieved remission and 18/22 (81.8%) on TAC achieved remission (P = 0.3). The side effects hypertrichosis, and gum hyperplasia were significantly less in TAC group as compared to CSA group (P < 0.001). The 1-, 2-, 3-, 4-, and 5-year estimated renal survival (doubling of serum creatinine as event) in CSA group was 96%, 91%, 85%, 54%, and 33% and in TAC group was 96%, 95%, 90%, 89%, and 79%, respectively (P = 0.02). Although TAC and CSA are equally efficacious, TAC has significantly less side effects. The long-term outcome of renal function was significantly better in patients who were treated with TAC as compared to CSA.

The Mechanism of Mitochondria-Mediated Pathway in the Apoptosis of Platelets in Immune-Induced Bone Marrow Failure.

Excessive platelet apoptosis is one of the pathogenic causes of immune-induced bone marrow failure (BMF). The aim of the present study was to explore the role of mitochondria-mediated pathway in the apoptosis of platelets in immune-induced BMF. An immune-induced BMF model was established in mice, which were randomly divided into three groups: normal control (CTL) group, BMF group and cyclosporine (CSA) group (n = 10 in each group). Mice were given 0.027 g/kg CSA daily in the CSA group. Platelet count (PLT), mitochondrial transmembrane potential (ΔΨm), cytochrome C (CytC), phosphatidylserine (PS), calcium ion (Ca²⁺) and expression of proteins of the mitochondrial apoptotic pathway, including Bak, Bax, caspase-3, caspase-8 and caspase-9, was examined and compared. Compared with the CTL group, the BMF group had significantly a lower level of PLC and ΔΨm, but higher levels of CytC, PS, Ca²⁺ and higher expression levels of Bak, Bax, cleaved caspase-9 and cleaved caspase-3 (P < 0.05). CSA restored the above changes in the BMF model (P < 0.05). Further studies showed that intravenous injection of the caspase-9 inhibitor Z-LE(OMe)HD(OMe)-fluoromethylketone (FMK) into the mice could significantly inhibit apoptosis of the platelets and the effect of CSA treatment when compared to the BMF group, and exerted a better protective effect from apoptosis if the caspase-9 inhibitor was combined with the CSA treatment. These results revealed that platelet apoptosis may play an important role in the reduction of platelet of immune-induced BMF probably through the mitochondrial pathway.

CSA Group hydrogen fueling testing trailer to aid station owners

North American hydrogen refueling station owners can now make use of the CSA Group's onsite evaluation testing equipment for hydrogen stations, which is trailer-mounted to provide an efficient alternative for the required testing for compliance with codes and standards.

Flavone from Zhongjiefeng (Herba Sarcandrae Glabrae) inhibits platelet apoptosis in immune-induced bone marrow failure through mitochondrial pathway

ObjectiveTo investigate the effect of Flavone from Zhongjiefeng (Herba Sarcandrae Glabrae) on the platelet number in immune-induced bone marrow failure (BMF) and its mechanism of mitochondrial apoptotic pathway. MethodsImmune-induced BMF model, established in mice, was randomly divided into four groups: normal control group without BMF, BMF control group, cyclosporine (CSA) group and flavone group (n = 10 in each group). Mice were given 0.027 g/kg cyclosporine or 0.2 g/kg flavone lavage daily in either the cyclosporine or flavone group respectively. Platelet count, mitochondrial transmembrane potential (ΔΨ), cytochrome C (Cyt C), phosphatidylserine (PS), changes of calcium ion (Ca2+), and protein expression of mitochondrial apoptotic pathway including B-cell lymphoma-2 (bcl-2) Homologous Antagonist-Killer Protein (Bak), bcl-2-associated X protein (Bax), caspase-3, caspase-8, and caspase-9 were examined and compared. ResultsCompared with the normal control group, the BMF group had significantly lower levels of platelet count, ΔΨ, and expressions of caspase family proteins as well as higher levels of Cyt C, PS, Ca2+, and expressions of Bak and Bax (all P < 0.05). Compared with the BMF group, the CSA and flavone groups had significantly higher ΔΨ and expressions of caspase family proteins (all P < 0.05) whereas the levels of Cyt C, PS, Ca2+, and expressions of Bak and Bax were reduced (all P < 0.05). More importantly, the flavone group had higher levels of Cyt C, Ca2+ and expressions of Bak and Bax compared with the CSA group (all P < 0.05), while the levels of PS and caspase family proteins were reduced (all P < 0.05). ConclusionFlavone from Zhongjiefeng (Herba Sarcandrae Glabrae) significantly increases the platelet number and prevents its apoptosis through mitochondrial pathway.

Protective Role of Apelin Against Cyclosporine-Induced Renal Tubular Injury in Rats

BackgroundCyclosporine (CsA) usually reduces glomerular filtration rate (GFR) but also can induce tubular injury without resulting in GFR reduction. Apelin is an endogenous ligand for the apelin receptor and has diverse physiologic roles related to hemodynamic or metabolic processes. We investigated the renoprotective role of apelin against CsA-induced tubular toxicity in rats. MethodsRats were given CsA (15 mg/kg/day) and/or apelin-13 (15 μg/kg/day) for 7 days via subcutaneous injection. We performed serum and urinary assays of creatinine and neutrophil gelatinase-associated lipocalin (NGAL) to estimate renal injury and performed Western blotting for endothelial nitric oxide synthase and nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) to document the underlying mechanism. ResultsThe CsA-treated group showed increased urinary creatinine excretion, polyuria, and renal glycosuria without GFR reduction, suggesting adequate CsA-induced renal tubular injury. Urinary NGAL excretion also increased significantly in the CsA group. Conversely, apelin attenuated CsA-induced tubular injury and had no effect on urinary NGAL excretion. In histopathologic examination, the apelin-treated group had lower tubulo-interstitial injury scores compared with those in the CsA group. Regarding the effects of apelin, our results indicate that apelin provides protection against CsA-induced tubular injury by activating nitric oxide and/or the NFATc1 pathway. Notably, we also found that CsA inhibits renal glucose reabsorption by reducing Na+-K+ ATPase expression and that apelin reverses reduced renal glucose reabsorption by CsA in tubular cells. ConclusionsOur study demonstrates the renoprotective effect of apelin against CsA-induced renal tubular toxicity and provides novel insights into the effects of CsA and apelin on renal tubular cells.

Beneficial Effects of High-Dose Mizoribine on ABO-Incompatible Living-Related Kidney Transplantation: Two-Year Results by a Japanese Multicenter Study

BackgroundMizoribine (MZ) has been developed as an immunosuppressive agent in Japan, but it has a less-potent immunosuppressive effect up to 3 mg/kg/d. In the previous study, a Japanese multicenter study, we reported that high-dose MZ, at 6 mg/kg/d, with a calcineurin inhibitor was effective and safe in reducing the frequency of cytomegalovirus (CMV)-related events in ABO-incompatible (ABO-i) living-related kidney transplantation (LKT). In the present study, therefore, we investigated the effects of high-dose MZ with a CNI in ABO-i LKT recipients in a Japanese multicenter study. MethodsA total of 37 patients were treated with high-dose MZ (6 mg/kg), a CNI (cyclosporine [CsA] or tacrolimus [Tac]), basiliximab (Bas), rituximab (Rit), and corticosteroids. CsA was started at a dose of 7 mg/kg to maintain blood levels [200 ng/mL (C0), 6000 ng-h/mL (AUC 0–9)]. Tac was started at a dose of 0.2 mg/kg to maintain blood levels [8–10 ng/mL (C0), 100 ng-h/mL (AUC 0–9)]. Bas (20 mg/body) was administrated on day 0 and day 4 after transplantation. Rit (100–200 mg/body) was administrated on day −14 and day −7 before transplantation. MZ was adjusted to maintain target C0 levels of 1.5 to 2.0 μg/mL. ResultsPatient and graft survival rates for 2 years were 100% in the CsA group (n = 22) and 93.3% in the Tac group (n = 15) (not significant, NS). Overall incidence of acute rejection for 2 years was 22.7% in the CsA group and 26.7% in the Tac group. Mean serum creatinine levels at 2 years were 1.29 ± 0.2 mg/dL in the CsA group and 1.21 ± 0.34 mg/dL in the Tac group (NS). The incidence of CMV disease was 0% in both groups, and positive rates of CMV antigenemia were 50.0% and 26.7% in the CsA and Tac groups, respectively (NS). Mean serum uric acid levels were 5.5 ± 1.3 mg/dL and 6.4 ± 1.2 mg/dL at 2 years (NS) in the CsA and Tac groups, respectively. ConclusionsA high-dose MZ regimen including calcineurin inhibitor (CsA or Tac), Bas, Rit, and steroids was effective and safe in reducing the frequency of CMV-related events in ABO-i LKT.

Incidence and outcome of BK polyomavirus infection in a multicenter randomized controlled trial with renal transplant patients receiving cyclosporine-, mycophenolate sodium-, or everolimus-based low-dose immunosuppressive therapy.

It remains unclear whether overall degree of immunosuppression or specific effects of individual immunosuppressive agents are causal for increased occurrence of BK polyomavirus (BKPyV) infection in renal transplant recipients (RTR). A prospective, multicenter, open-label randomized controlled trial in 361 de novo RTR was performed. A total of 224 RTR were randomized at 6months into three treatment groups with dual therapy consisting of prednisolone (Pred) plus either cyclosporine (CsA), mycophenolate sodium (MPS), or everolimus (EVL). Primary outcomes were incidence of BK viruria, BK viremia, and BKPyV-associated nephropathy (BKVAN). From 6months, incidence of BK viruria in the MPS group (43.6%) was significantly higher than in the other groups (CsA: 16.9%, EVL: 19.8%) (P=.003). BKVAN was diagnosed in 3 patients, all treated with MPS (7.8%, P=.001). Longitudinal data analysis showed a lower BKPyV load and a significantly faster clearance of BK viruria in the CsA group compared to the MPS group (P=.03). Treatment with MPS was associated with an increased incidence of BK viruria. Dual immunosuppressive therapy with CsA and Pred was associated with the lowest rate of BKPyV replication and the fastest clearance of the virus.

326 - Transplant Associated Thrombotic Microangiopathy in Individuals with Fanconi Anemia

Objective: Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic stem cell transplantation (HSCT) due to vascular endothelial injury. TA-TMA most commonly affects the kidneys resulting in proteinuria, hypertension and often progresses to multi-organ failure in severe cases. We previously identified in our institutional prospective study of TA-TMA a higher incidence of TA-TMA in Fanconi anemia (FA) individuals. We hypothesized that exposure to cyclosporine (CSA), which has been implicated in TA-TMA, may have led to this increase. The goal of our current study was to examine the TA-TMA incidence in FA individuals undergoing HSCT with CSA exposure at our institution and its impact on transplant related morbidity and organ function. Methods: We performed a retrospective chart review in all patients with FA undergoing first unrelated donor T-depleted HSCT (2010-2016) using a busulfan, fludarabine, cyclophosphamide and ATG preparative regimen to identify the incidence of transplant-associated TMA and clinical outcomes. TMA was monitored prospectively and subjects were stratified by cyclosporine use. Results: Forty-two patients underwent unrelated donor t-depleted HSCT using busulfan, fludarabine, cyclophosphamide and ATG during the study period. Additional GVHD prophylaxis with cyclosporine (CSA) was used in the first 29 subjects while subsequent subjects received no additional prophylaxis (n = 13). Incidence of TA-TMA in the CSA and Non-CSA groups was 66% (n = 19/29) and 54% (n = 7/13) respectively (P = .51) and was increased from the overall institutional TA-TMA incidence of 34% (P = .0011). Risk factors for severe TA-TMA were increased in the CSA-group with nephrotic range proteinuria in 53% compared with 14% of the non-CSA group in tested patients and increased complement activation by sC5b-9 levels 100% vs 20%. Median duration of active TA-TMA was longer in the CSA-group at 108 days compared with 38 in the non-CSA group (P = .005). Complications of TA-TMA including hypertension, kidney injury, dialysis, pericardial effusion and pulmonary hypertension were all increased in the CSA group compared to the non-CSA group. Long-term decreased renal function at greater than 1 year post HCST was seen in 40% of the CSA/TMA cohort versus none of the non-CSA/TMA cohort. Conclusion: Incidence of TA-TMA after HSCT is increased in FA compared to other HSCT recipients. Individuals receiving cyclosporine for GVHD prophylaxis had more severe TA-TMA than those who did not receive it, affecting transplant related morbidity and long-term renal function. T cell depletion and other alternatives to CSA may be advantageous to individuals with FA undergoing HSCT.

Calcineurin inhibitors versus cyclophosphamide for idiopathic membranous nephropathy: A systematic review and meta-analysis of 21 clinical trials.

To compare the efficacy and safety of calcineurin inhibitors (CNIs) with cyclophosphamide (CTX) in the treatment of idiopathic membranous nephropathy (IMN). A literature search was carried out using PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and three Chinese databases (WanFang Data, Chongqing VIP and China National Knowledge Infrastructure) from inception through June 2016. Randomized controlled trials (RCTs) comparing the efficacy and safety of CNIs with CTX in IMN patients were included. Two authors independently extracted data and assessed the quality of each study. Statistical analyses were performed using Revman 5.3 software. Odds ratio (OR) for dichotomous data and mean difference (MD) for continuous data with 95% confidence interval (CI) were calculated and data were pooled with a random-effect model. A total of twenty-one studies involving 1187 patients were included in this study. CNIs had significant merits in increasing total remission (CSA vs CTX: OR 1.91, 95%CI 1.09 to 3.34, P=0.02; TAC vs CTX: OR 2.95, 95%CI 1.84 to 4.75, P<0.00001), elevating serum albumin (CSA vs CTX: MD 3.83, 95%CI 2.49 to 5.16, P<0.00001; TAC vs CTX: OR 8.57, 95%CI 5.08 to 12.07, P<0.00001) and reducing proteinuria (CSA vs CTX: MD -0.73, 95%CI -1.25 to -0.22, P=0.005; TAC vs CTX: MD -1.7, 95%CI -2.29 to -1.10, P<0.00001) compared with CTX after 6months of treatment. However, no similar results were found after 12months. Moreover, CSA had a higher relapse rate than CTX (OR 3.89, 95%CI 1.53 to 9.92, P=0.004), which was not found in the comparison of TAC and CTX. The incidences of leukopenia, alopecia and liver damage were higher in the CTX group (OR (95%CI): 0.23 (0.09 to 0.59), 0.10 (0.04 to 0.24), and 0.36 (0.19 to 0.69, respectively), whereas the incidences of hirsutism, gingival hyperplasia, worsening hypertension and hyperuricemia were higher in the CSA group (OR (95%CI): 8.64 (1.97 to 37.79, 4.44 (1.09 to 17.99), 4.59 (1.43 to 14.82) and 9.05 (1.53 to 53.36), respectively). Our systematic review demonstrates that CNIs are promising alternatives to CTX for IMN patients, primarily due to their better short-term efficacy and safety. Well-designed clinical trials are needed to further evaluate the long-term efficacy and safety of CNIs and CTX.

Transplant Associated Thrombotic Microangiopathy in Individuals with Fanconi Anemia

Objective: Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic stem cell transplantation (HSCT) due to vascular endothelial injury. TA-TMA most commonly affects the kidneys resulting in proteinuria, hypertension and often progresses to multi-organ failure in severe cases. We previously identified in our institutional prospective study of TA-TMA a higher incidence of TA-TMA in Fanconi anemia (FA) individuals. We hypothesized that exposure to cyclosporine (CSA), which has been implicated in TA-TMA, may have led to this increase. The goal of our current study was to examine the TA-TMA incidence in FA individuals undergoing HSCT with CSA exposure at our institution and its impact on transplant related morbidity and organ function.Methods: We performed a retrospective chart review in all patients with FA undergoing first unrelated donor T-depleted HSCT (2010-2016) using a busulfan, fludarabine, cyclophosphamide and ATG preparative regimen to identify the incidence of transplant-associated TMA and clinical outcomes. Subjects were stratified by cyclosporine use.Results: Forty-two patients underwent unrelated donor t-depleted HSCT using busulfan, fludarabine, cyclophosphamide and ATG during the study period. Additional GVHD prophylaxis with cyclosporine (CSA) was used in the first 29 subjects while subsequent subjects received no additional prophylaxis (n= 13). Incidence of TA-TMA in the CSA and Non-CSA groups was 66% (n=19/29) and 54% (n=7/13) respectively (p=0.51) and was increased from the overall institutional TA-TMA incidence of 34% (p=0.0011). Risk factors for severe TA-TMA were increased in the CSA-group with nephrotic range proteinuria in 53% compared with 14% of the non-CSA group in tested patients and increased complement activation by sC5b-9 levels 100% vs 20%. Median duration of active TA-TMA was longer in the CSA-group at 85 days compared with 41 in the non-CSA group. Complications of TA-TMA including hypertension, kidney injury, dialysis, pericardial effusion and pulmonary hypertension were all increased in the CSA group compared to the non-CSA group.Conclusion: Incidence of TA-TMA after HSCT is increased in FA compared to other HSCT recipients. Individuals receiving cyclosporine for GVHD prophylaxis had more severe TA-TMA than those who did not receive it, affecting transplant related morbidity and long-term renal function. Increased incidence of TA-TMA in individuals with FA may point to novel mechanisms of vascular endothelial injury. Better understanding of these mechanisms may allow for improved transplant risk stratification or new therapeutic approaches in solid tumor therapy. DisclosuresDavies:Novartis: Honoraria.