Adjuvants, Immunologic ; adverse effects ; therapeutic use ; Azathioprine ; adverse effects ; therapeutic use ; Cyclosporine ; adverse effects ; therapeutic use ; Glucocorticoids ; adverse effects ; therapeutic use ; Humans ; Mycophenolic Acid ; adverse effects ; analogs & derivatives ; therapeutic use ; Tacrolimus ; adverse effects ; therapeutic use

Treatment of myelodysplastic syndrome (MDS) remains unsatisfactory. It is possible that immunosuppressive therapy might be effective for a certain subset of patients with MDS. In this review 105 patients with MDS who were treated with cyclosporin A (CsA) including 90 RA, 5 RARS, 10 RAEB, were analyzed. The dose of CsA was 2 - 12 mg/(kg x d) for at least three months. Hematological improvement was observed in 64 patients (61%), and complete remission was observed in 14 patients (13.3%). These results indicated that CsA immunosuppressive therapy may be useful for IPSS low, intermediate-1 and intermediate-2 MDS patients.
Cyclosporine ; adverse effects ; therapeutic use ; Humans ; Immunosuppressive Agents ; therapeutic use ; Myelodysplastic Syndromes ; drug therapy ; immunology

OBJECTIVETo reveal interventions for chronic cyclosporine A nephrotoxicity (CCN) and provide new targets for further studies, we analyzed all relevant studies about interventions in renal cell apoptosis.

DATA SOURCESWe collected all relevant studies about interventions for cyclosporine A (CsA)-induced renal cell apoptosis in Medline (1966 to July 2010), Embase (1980 to July 2010) and ISI (1986 to July 2010), evaluated their quality, extracted data following PICOS principles and synthesized the data.

STUDY SELECTIONWe included all relevant studies about interventions in CsA-induced renal cell apoptosis no limitation of research design and language) and excluded the duplicated articles, meeting abstracts and reviews without specific data.

RESULTSThere were three kinds of intervention, include anti-oxidant (sulfated polysaccharides, tea polyphenols, apigenin, curcumin, spirulina, etc), biologics (recombinant human erythropoietin (rhEPO), a murine pan-specific transforming growth factor (TGF)-beta-neutralizing monoclonal antibody1D11, cartilage oligomeric matrix protein (COMP)-angiopoietin-1 and hepatocyte growth factor (HGF) gene), and other drugs (spironolactone, rosiglitazone, pirfenidone and colchicine). These interventions significantly improved the CCN, renal cell apoptosis and renal dysfunction through intervening in four apoptotic pathways in animals or protected renal cells from apoptosis induced by CsA and increased cell survival through respectively four pathways in vitro.

CONCLUSIONSThere are three group interventions for CCN. Especially anti-oxidant drugs can significantly improve CCN, renal cell apoptosis and renal dysfunction. Many drugs can improve CCN through intervening in Fas/Fas ligand or mitochondrial pathway with sufficient evidences. Angiotensin II, nitric oxide (NO) and endoplasmic reticulum (ER) pathways will be new targets for CCN.

Animals ; Apoptosis ; drug effects ; Chronic Disease ; Cyclosporine ; adverse effects ; Humans ; Immunosuppressive Agents ; adverse effects ; Kidney ; drug effects ; pathology ; Mitochondria ; physiology ; Nitric Oxide ; physiology ; Signal Transduction ; fas Receptor ; physiology

OBJECTIVETo evaluate the efficacy and safety of cyclosporine A(CsA) in the treatment of refractory nephrotic syndrome (RNS) in children.

METHODSThe Cochrane library, PubMed, EMBASE, CBMdisk, CNKI and VIP were searched from the time when the databases were established to December 31, 2008. Reports on RCTs on treating RNS in children with CsA were collected. Data were extracted and assessed independently by three reviewers. The methodological quality of included RCTs was assessed by the revised Jadad-scale (including randomization, allocation concealment, blinding method and withdrawal). Meta-analysis of homogenous RCTs was managed by using RevMan4.2.3.

RESULTNine RCTs involving 293 participants were included. Six RCTs were assessed as high-quality studies with scores from 4 to 7 and 3 RCTs were assessed as low-quality studies with scores from 1 to 3. Sub-category meta-analysis was based on different clinical types and interventions of RNS in children. Meta-analysis based on included RCTs showed the following results. (1) In children with steroid-dependent or frequent relapse nephrotic syndrome: the short-term efficacy of CsA plus prednisone was better than that of prednisone alone [OR 0.14, 95% CI (0.03, 0.71)]; the short-term efficacy of CsA, cyclophosphamide (CTX) and mycophenolate mofetil had no significant differences, but compared with chlorambucil, CsA had a worse short-term efficacy [OR 6.93, 95% CI (1.53, 31.38)] and a higher relapse rate [OR 0.06, 95% CI (0.01, 0.58)]; maintaining a blood level of CsA between 60 and 80 microg/L during remission period could reduce the long term relapse rate [OR 6.43, 95% CI (1.21, 34.19)]; the incidence of end-stage renal disease (ESRD) or mortality was zero in both groups. (2) In children with steroid-resistant nephrotic syndrome, the short-term efficacy of CsA was better than that of placebo or supportive treatment and CTX, OR and 95% CI were 0.15 (0.02, 0.96) and 0.41 (0.03, 5.00), respectively, but no significant differences were found in the relapse rate and the incidence of ESRD or mortality. (3) Side effects of CsA: the incidence of nephrotoxicity, hypertrichosis and gum hypertrophy was higher in the CsA group than in that of control group, OR and 95% CI were 0.19 (0.05, 0.79), 0.06 (0.02, 0.19), 0.05 (0.02, 0.18), respectively, but no significant differences were found in the incidence of hypertension and liver toxicity.

CONCLUSIONSAvailable evidence showed that CsA could improve short term efficacy in RNS in children, but could not improve long term and endpoint efficacy, therefore CsA could be one of the ideal second-line drugs for RNS in children. There was a trend that the effect of CsA on steroid-dependent or frequent relapse nephrotic syndrome was superior to that on steroid-resistant nephrotic syndrome.

Child ; Cyclosporine ; adverse effects ; therapeutic use ; Humans ; Immunosuppressive Agents ; adverse effects ; therapeutic use ; Nephrotic Syndrome ; drug therapy ; Randomized Controlled Trials as Topic ; Recurrence ; Treatment Outcome

Pancreatitis has not been reported in allogeneic stem cell transplant (allo-SCT) recipients with cyclosporine in China. This article presented a case of acute pancreatitis in a 49-year-old patient with AML-M2a who received allogeneic stem cell transplant from her HLA identical sister. The preparative regimen consisted of busulfan and cyclophosphamide. The cyclosporine A, short-term methotrexate and antilymphocyte globulin (ATG), were used to prevent the graft-versus-host disease (GVHD). Clinical and laboratory signs of acute pancreatitis were found in the patient on day 20 post-transplant. A diagnosis of acute pancreatitis was made although the pancreas was apparently normal at abdominal contrast-enhanced tomography and ultrasonography. She recovered with supportive care and reduction of cyclosporine dose. In conclusion, cyclosporine is the probable cause of pancreatitis in this patient.
Cyclosporine ; adverse effects ; Female ; Hematopoietic Stem Cell Transplantation ; adverse effects ; Humans ; Middle Aged ; Pancreatitis, Acute Necrotizing ; chemically induced ; Postoperative Complications ; chemically induced

OBJECTIVETo investigate the effect of cyclosporin A (CsA) and tumor necrosis factor-α (TNF-α) on cell proliferation of cultured human gingival fibroblasts (GF), and the relationship between gingival inflammation and drug-induced gingival overgrowth.

METHODSHuman GF were cultured in vitro using tissue culture method. then cells from the 4 - 8 th passage were used in the experiment. The cells were cultured and incubated with various concentrations of CsA and TNF-α (A: blank group, B1: 10 µg/L CsA, B2: 50 µg/L CsA, B3: 250 µg/L CsA, B4: 1250 µg/L CsA, C: 5 µg/L TNF-α, D1: 10 µg/L CsA + 5 µg/L TNF-α, D2: 50 µg/L CsA + 5 µg/L TNF-α, D3: 250 µg/L CsA + 5 µg/L TNF-α, D4: 1250 µg/L CsA + 5 µg/L TNF-α) solution for 3, 5 and 7 days. Methyl thiazolyl tetrazolium assay was used to evaluate the cell proliferation in the culture meidiun.

RESULTSThe proliferation of fibroblasts was inhibited when exposed to different concentration of CsA and A value decreased. There was no significant difference between group B1, B2, B3 and the control group, while the A value of group B4 was significantly higher than that of control group (P < 0.01). Fibroblast proliferation was significantly increased while cultured with 5 µg/L TNF-α. A value increased (P < 0.01). When exposed to CsA + TNF-α, A value of group D1, D2, D3 was much higher than that of group A, but was lower than that of group C (P < 0.05). Cell proliferation in group D4 was significantly increased, and significantly different with that in group C (P < 0.01).

CONCLUSIONSCsA did not stimulate the cell proliferation, and high concentration of CsA inhibited cell proliferation. TNF-α can stimulate the cell proliferation. High-concentration CsA + TNF-α can enhance the fibroblast proliferation, which suggests that CsA in certain concentration have amplification effect on TNF-α to stimulate fibroblast proliferation.

Adult ; Cell Proliferation ; drug effects ; Cells, Cultured ; Cyclosporine ; adverse effects ; pharmacology ; Dose-Response Relationship, Drug ; Fibroblasts ; cytology ; Gingiva ; cytology ; Gingival Overgrowth ; chemically induced ; Humans ; Immunosuppressive Agents ; adverse effects ; pharmacology ; Tumor Necrosis Factor-alpha ; adverse effects ; pharmacology

BACKGROUNDThe relationship between cyclosporine-induced chronic nephrotoxicity (CAN) and renin-angiotensin II in humans is still contradictory. This study was conducted to detect the levels of renin and angiotensin II (ANGII) both in renal tissue and plasma from kidney transplantation patients suffering from CAN.

METHODSTwenty-six patients with allograft biopsy-proven CsA-related chronic nephrotoxicity (CAN group) and chronic rejection (control group) were enrolled in this study. Renal tissues were subjected to immunohistochemical staining with renin and ANGII antibodies. Renin and ANGII plasma levels were measured when the biopsy was performed. The relationship between expression of renin or ANGII and clinicopathological manifestations were also investigated. The cyclosporine plasma level was obtained 2 hours after morning dose (C2). In vitro, human umbilical vein endothelial cells (HUVEC) and rat mesangial cells (MC) were incubated with different concentrations of CsA (0, 250, 500, 1000 microg/L) for 24 hours. Secretion and expression of renin and ANGII was measured by radioimmunoassay or immunohistochemical staining.

RESULTSRenal pathological scores for renin and ANGII expression were significantly higher in specimens of CAN than in controls (P < 0.05). The plasma levels of renin, ANGII and C(2) in the CAN group were higher than the control group, but no significant difference was found ((0.37 +/- 0.12) ng x ml(-1)x h(-1) vs (0.20 +/- 0.10) ng x ml(-1) x h(-1), P = 0.076; (122.69 +/- 26.73) pg/ml vs (121.88 +/- 36.35) pg/ml, P = 0.977; (719.04 +/- 55.89) ng/ml vs (658.80 +/- 90.78) ng/ml, P = 0.196, respectively). In vitro, renin as well as ANGII expression increased significantly in both HUVEC and MC after the cells were incubated with CsA for 24 hours (P < 0.05). CsA also stimulated the secretion of ANGII in HUVEC and MC in a dose-dependent manner.

CONCLUSIONSRenal allograft biopsy is important to differentiate chronic CsA-related nephropathy from chronic rejection. The intrarenal renin angiotensin system plays an important role in CsA-related chronic nephropathy. The histological lesions of CsA nephrotoxicity fail to correspond spontaneously to either the change of C2 level or the change of renin and ANGII plasma level. CsA stimulates the secretion of ANGII and the expression of renin and ANGII in HUVEC and MC. Blockage of RAS may be helpful for therapeutic intervention in the progression of CsA-related chronic nephropathy.

Adult ; Aged ; Angiotensin II ; analysis ; blood ; Cyclosporine ; adverse effects ; Endothelial Cells ; chemistry ; drug effects ; Female ; Humans ; Immunosuppressive Agents ; adverse effects ; Kidney ; drug effects ; pathology ; Male ; Middle Aged ; Renin ; analysis ; blood ; Renin-Angiotensin System ; drug effects

OBJECTIVETo sum up the clinical characteristics of patients with central pontine myelinolysis (CPM) after orthotopic liver transplantation (OLT) and to document the possible causes on CPM.

METHODS142 patients' data with OLT between January 1999 to May 2003 were analyzed retrospectively. The following risk factors during preoperation were analyzed between patients with and without CPM: primary liver disease, preoperative serum sodium level, magnesium level and plasma osmolality, fluctuation degree of serum sodium concentration, and immunosuppressive drugs level etc.

RESULTSA total of 13 (9.2%) neurologic symptoms appeared in 142 patients post operation, including 5 cases (3.5%) with CPM and 8 cases (5.6%) with cerebral hemorrhage or infarct. 2 patients who developed CPM after OLT had hyponatremia history before operation (serum sodium <130 mmol/L), and the mean serum sodium level was (130.6 +/- 5.54) mmol/L. The serum sodium level was significantly lower in CPM than that of patients without neurologic complication or with cerebral hemorrhage/infarct (P <0.05). The rises of serum sodium perioperative 48 h after OLT in patients with CPM was significantly greater than that in patients with cerebral hemorrhage/infarct or no neurologic complication (19.5 +/- 6.54) mmol/L, (10.1 +/- 6.43) mmol/L, (4.5 +/- 4.34) mmol/L, respectively, (P < 0.05). Plasma osmolality increased greatly postoperatively in patients with CPM. Hypomagnesemia was noted in all patients perioperatively, but there was not significant difference among groups. The duration of operation in CPM was longer than in others (492 +/- 190.05) min (P <0.05). Cyclosporin A (CsA) levels were normal in all patients, but there was significant difference between patients with and without neurologic complication (P <0.05).

CONCLUSIONSCPM may be more prevalent following liver transplantation. Although the diagnosis of CPM after OLT can be made by complete neurologic evaluation including magnetic resonance imaging (MRI) of the head, the mortality is still very high. The occurrence of CPM may be associated with hyponatremia, rapid rise of serum sodium concentration, postoperative increase of plasma osmolality, the duration of operation and high CsA levels.

Adult ; Aged ; Cyclosporine ; adverse effects ; therapeutic use ; Female ; Humans ; Hyponatremia ; complications ; Immunosuppressive Agents ; adverse effects ; therapeutic use ; Liver Transplantation ; adverse effects ; Male ; Middle Aged ; Monitoring, Intraoperative ; Myelinolysis, Central Pontine ; etiology ; Retrospective Studies ; Sodium ; blood ; Transplantation, Homologous

BACKGROUNDWith the increase of survival in liver transplantation recipients, more patients are at a high risk of developing osteonecrosis, especially in the femoral head, due to immunosuppressive treatment. The purpose of this study was to report the incidence, possible risk factors, and outcome of symptomatic osteonecrosis of the femoral head (ONFH) in adult patients with current immunosuppressive agents and individual protocol after liver transplantation in China.

METHODSA retrospective analysis was performed on 226 adult patients who underwent orthotopic liver transplantation (OLT) at a single liver transplantation institution between January 2004 and December 2008. The posttransplant survival time (or pre-retransplantation survival time) of all the patients were more than 24 months. The possible pre- and post-transplantation risk factors of symptomatic ONFH were investigated and the curative effects of the treatment were also reported.

RESULTSThe incidence of ONFH was 1.33% in patients after OLT. ONFH occurred at a mean of (14 ± 6) months (range, 10 - 21 months) after transplantation. Male patients more often presented with osteonecrosis as a complication than female patients. The patients with lower pre-transplantation total bilirubin and direct bilirubin levels (P < 0.05). There was no difference in the cumulative dose of corticosteroids or tacrolimus between the patients with or without symptomatic ONFH. Patients were treated either pharmacologically or surgically. All patients showed a nice curative effect without major complications during the 18 - 63 months post-treatment follow up.

CONCLUSIONSThe symptomatic ONFH does not occur commonly after adult OLT in the current individual immunosuppressive protocol in China.

Adult ; Aged ; Cyclosporine ; adverse effects ; therapeutic use ; Female ; Femur Head Necrosis ; epidemiology ; etiology ; Humans ; Immunosuppressive Agents ; adverse effects ; therapeutic use ; Liver Transplantation ; adverse effects ; Male ; Methylprednisolone ; adverse effects ; therapeutic use ; Middle Aged ; Osteonecrosis ; epidemiology ; etiology ; Retrospective Studies ; Risk Factors ; Sirolimus ; adverse effects ; therapeutic use ; Tacrolimus ; adverse effects ; therapeutic use ; Young Adult

Cyclosporine (CsA) has improved patient and graft survival rates following solid-organ transplantation and has shown significant clinical benefits in the management of autoimmune diseases. However, the clinical use of CsA is often limited by acute or chronic nephropathy, which remains a major problem. Acute nephropathy depends on the dosage of CsA and appears to be caused by a reduction in renal blood flow related to afferent arteriolar vasoconstriction. However, the mechanisms underlying chronic CsA nephropathy are not completely understood. Activation of the intrarenal renin-angiotensin system (RAS), increased release of endothelin-1, dysregulation of nitric oxide (NO) and NO synthase, up-regulation of transforming growth factor-beta1 (TGF-beta1), inappropriate apoptosis, stimulation of inflammatory mediators, enhanced innate immunity, endoplasmic reticulum stress, and autophagy have all been implicated in the pathogenesis of chronic CsA nephropathy. Reducing the CsA dosage or using other renoprotective drugs (angiotensin II receptor antagonist, mycophenolate mofetil, and statins, etc.) may ameliorate chronic CsA-induced renal injury. This review discusses old and new concepts in CsA nephropathy and preventive strategies for this clinical dilemma
Animals ; Chronic Disease ; Cyclosporine/*adverse effects ; Humans ; Immunosuppressive Agents/*adverse effects ; Kidney/*drug effects/immunology/metabolism/pathology ; Kidney Diseases/*chemically induced/immunology/metabolism/pathology/prevention & control ; Risk Factors ; Signal Transduction/*drug effects