BACKGROUNDThe efficacy and safety of immunosuppression for idiopathic membranous nephropathy (IMN) are still controversial. Recent studies showed tacrolimus is effective in the treatment of IMN. To evaluate the efficacy and safety of tacrolimus (TAC) for IMN, we conducted a meta-analysis of published medical literatures.

METHODSStudies addressing the effect of tacrolimus in IMN were searched on PUBMED, EMBASE, The Cochrane Library, and ClinicalTrials.gov (March 2013). Trials comparing tacrolimus with corticosteroid versus control group (cyclophosphamide with corticosteroid) were included. The quality of the studies was assessed using Jadad method. Statistical analyses were performed using Review Manager 5.2 and the results were summarized by calculating the risk ratio (RR) for dichotomous data or the mean difference (MD) for continuous data with 95% confident interval (CI).

RESULTSA total of four studies (259 patients) were included. It was shown that therapy with tacrolimus plus corticosteroid had a higher complete remission rate compared to therapy with cyclophosplamide plus corticosteroid (RR = 1.53, 95% CI: 1.05-2.24, P < 0.05), but not significant on total remission, partial remission and adverse effects. Also, no significant alterations were observed in proteinuria and serum albumin level between the two groups. During the entire follow-up period, serum creatinine level remained stable in both groups without = 50% increase in its level.

CONCLUSIONSTAC is more effective than cyclophosphamide (CTX) by achieving complete remission in patients with IMN. Multi-ethnic RCTs are needed to evaluate its long-term efficacy and safety.

Adrenal Cortex Hormones ; therapeutic use ; Cyclophosphamide ; therapeutic use ; Glomerulonephritis, Membranous ; drug therapy ; Humans ; Immunosuppressive Agents ; therapeutic use ; Tacrolimus ; therapeutic use

Humans ; Tacrolimus/therapeutic use* ; Lupus Erythematosus, Systemic/drug therapy* ; Immunosuppressive Agents/therapeutic use* ; Treatment Outcome

OBJECTIVETo systematically evaluate the clinical effects of cyclosporine A (CsA) and tacrolimus, which are calcineurin inhibitors, on lupus nephritis.

METHODIn this study, the clinical trials on treatment of lupus nephritis with cyclosporine A and tacrolimus published until May 2010 were searched at www.guideline.gov, www.nice.org.uk, mdm.ca/cpgsnew/cpgs/index.asp, www.show.scot.nhs.uk, www.nzgg.org.nz, www.eguid elines.co.uk, www.gin.net, Cochrane library, EMBASE, MEDLINE, Wanfang database, Chinese Journal full-text Database, Chongqing Weipu Database by using the methods of Cochrane systematic review. At the same time the information from related journals, professional data and network were hand-searched. The homogeneous evaluation was performed by meta-analysis.Statistical analysis of clinical data was performed by using RevMan 4.2 software provided by the Cochrane Collaboration.

RESULTA total of 214 reports were found, while only 7 randomized controlled trials met the inclusion criteria, 4 of them were on the treatment with CsA (treatment group) and cyclosporine (CTX) group (control group), and 3 of them were the on treatment with FK506 (treatment group) and CTX group (control group). There were 148 reports in the treatment of CsA and CTX group, while 185 reports in the treatment of FK506 and CTX group. Both CsA and tacrolimus group could decrease daily urinary protein. Tacrolimus group was good at reducing daily urinary protein as compared with CTX group, and the difference was statistically significant (Z = 2.8, P = 0.005), but there was no significant difference between CsA and CTX groups (Z = 1.08, P = 0.28). Tacrolimus group was good at complete remission as compared with CTX group (Z = 3.64, P = 0.0003), partial remission was similar in both groups (Z = 0.53, P = 0.6), and tacrolimus group was good at total remission (Z = 2.2, P = 0.03). There was no significant difference between CsA and CTX group in side effect within a short period, while FK506 had less side-effect than CTX group.

CONCLUSIONCompared with the treatment with CTX, tacrolimus was good at reducing daily urinary protein. CsA and CTX were similar in reducing daily urinary protein in the treatment of lupus nephritis. Tacrolimus resulted in better total remission than CTX and had less side effect. CsA and CTX groups were similar in side effect. On the whole, calcineurin inhibitor could significantly decrease daily urinary protein, and tacrolimus was better in treatment and had less side-effect than CTX. However, large scale, multicenter, well-designed clinical trials should be adopted to further confirm the conclusions.

Calcineurin Inhibitors ; Cyclosporine ; therapeutic use ; Enzyme Inhibitors ; therapeutic use ; Humans ; Lupus Nephritis ; drug therapy ; Tacrolimus ; therapeutic use

Corticosteroid, alkylating agents, like cyclophosphamide and chlorambucil, have been used to treat idiopathic nephrotic syndrome for more than fifty years, changing the outcome of these children. However, with long-term use of steroid, especially high dosages, they have unbearable side effects. Newer agents like cyclosporine A, levamisole, tacrolimus, mycophenolate mofetil, have been used to spare those unwanted side effects. In the choice of drugs, the benefits obtained will have to be evaluated against possible side effects, with drug cost also taken into consideration. Though most steroid sensitive nephrotic children may run a relapsing course, have a good prognosis with many becoming non-relapsers or infrequent relapsers in adulthood, the treatment approach should aim at using the minimal amount of drug required to keep patient in remission to tie them over childhood. As for steroid resistant nephrotic syndrome children, especially for focal segmental glomerulosclerosis (FSGS), because of possible grave prognosis of going into end-stage renal failure, more aggressive approach should be adopted, including the use of strong immunosuppressants, such as, cyclosporine, tacrolimus, or mycophenolate mofetil if necessary. The long-term goals of treatment, other than those of physical and medical conditions, should also consider the growth, education, and psychological impact of the disease and side effects of drugs on the child, especially during an adolescent period, so as to allow them having normal development into adulthood.
Child ; Cyclosporine ; therapeutic use ; Drug Therapy, Combination ; Female ; Humans ; Levamisole ; therapeutic use ; Male ; Nephrotic Syndrome ; drug therapy ; Prednisolone ; therapeutic use ; Tacrolimus ; therapeutic use

OBJECTIVETacrolimus (FK506) is an immunosuppressive drug, which is widely used to prevent rejection of transplanted organs. However, chronic administration of FK506 leads to hypertension in solid organ transplantation patients, and its molecular mechanisms are much more complicated. In this review, we will discuss the above-mentioned molecular mechanisms of FK506-induced hypertension in solid organ transplantation subjects.

DATA SOURCESThe data analyzed in this review were mainly from relevant articles without restriction on the publication date reported in PubMed. The terms "FK506" or "tacrolimus" and "hypertension" were used for the literature search.

STUDY SELECTIONOriginal articles with no limitation of research design and critical reviews containing data relevant to FK506-induced hypertension and its molecular mechanisms were retrieved, reviewed and analyzed.

RESULTSThere are several molecular mechanisms attributed to FK506-induced hypertension in solid organ transplantation subjects. First, FK506 binds FK506 binding protein 12 and its related isoform 12.6 (FKBP12/12.6) and removes them from intracellular ryanodine receptors that induce a calcium ion leakage from the endoplasmic/sarcoplasmic reticulum. The conventional protein kinase C beta II (cPKCβII)-mediated phosphorylation of endothelial nitric oxide (NO) synthase at Thr495, which reduces the production of NO, was activated by calcium ion leakage. Second, transforming growth factor receptor/SMAD2/3 signaling activation plays an important role in Treg/Th17 cell imbalance in T cells which toget converge to cause inflammation, endothelial dysfunction, and hypertension following tacrolimus treatment. Third, the activation of with-no-K(Lys) kinases/STE20/SPS1-related proline/alanine-rich kinase/thiazide-sensitive sodium chloride co-transporter (WNKs/SPAK/NCC) pathway has a central role in tacrolimus-induced hypertension. Finally, the enhanced activity of renal renin-angiotensin-aldosterone system seems to play a crucial role in the pathophysiology of FK506-induced hypertension.

CONCLUSIONFK506 plays a predominant role in the pathophysiology of hypertension in solid organ transplantation subjects.

Humans ; Hypertension ; chemically induced ; Immunosuppressive Agents ; adverse effects ; therapeutic use ; Organ Transplantation ; adverse effects ; Tacrolimus ; adverse effects ; therapeutic use

Modified Release (MR) tacrolimus is an extended release formulation of tacrolimus (Prograf (R) ) administered once daily in the morning. In healthy volunteers, the MR tacrolimus formulation given qd AM and Prograf administered twice daily (bid) have a similar exposure (AUC) and trough levels (Cmin), with a reduced peak level (Cmax). Subsequently, pharmacokinetic studies were performed in stable kidney and liver transplant recipients converted from Prograf bid to MR tacrolimus qd AM. The steady-state tacrolimus exposure and target trough level range of MR tacrolimus were equivalent to Prograf after a mg-for-mg daily dose conversion in these two groups of patients, and there is a high correlation of exposure to trough levels for both Prograf and MR tacrolimus, as well as significantly less intra-subject variability in exposure after conversion to MR tacrolimus. These results indicate that stable kidney and liver transplant recipients can be safely converted from standard Prograf twice daily dosing to the same mg- for-mg daily dose of MR tacrolimus once daily in the morning. Hopefully a once daily dosing regimen of tacrolimus can improve patient compliance while maintaining effective immunosuppression.
Delayed-Action Preparations ; Humans ; Immunosuppressive Agents/*administration & dosage/therapeutic use ; *Kidney Transplantation ; *Liver Transplantation ; Tacrolimus/*administration & dosage/therapeutic use

A collection of plasma cells in the skin can represent a broad spectrum of disease entities. Secondary syphilis, primary cutaneous plasmacytoma, primary cutaneous plasmacytosis, cutaneous lymphoid hyperplasia and nodular amyloidosis are considered possible differential diagnoses. The primary cutaneous plasma cell disorders can range from malignant to benign plasma cell neoplasms. The malignant conditions are neoplastic diseases having monoclonal proliferations, rapid progression and fatal outcome while the benign plasma cell disorders usually show polyclonality, chronicity and benign process, including plasmacytosis. We present a case of cutaneous plasmacytosis. The patient was a 34-year-old man, presented with disseminated reddish-brown plaques and nodules on the right side of the hips, inguinal groove, and the thigh. Histopathologically, mature plasma cells perivascular infiltrates were observed mainly in the dermis. Polyclonality of infiltrating plasma cells with coexistence of both kappa and gamma chain-positive cells demonstrated with immunohistochemistry, as well as CD20+++, CD38++++, CD79a++++, CD138++, Ki67<30%. The diagnosis, cutaneous plasmacytosis, was established by the pertinent laboratory findings. Primary cutaneous plasmacytosis was an uncommon reactive lymphoplasmacytic disorder of uncertain etiology. Cutaneous plasmacytosis is a rare disease characterized by peculiar multiple eruptions and hyper gamma globulinemia. It has been mainly described in patients of Japanese descent, with only few reports in Caucasians and Chinese, although information concerning the disorder was limited to individual case reports. Cutaneous plasmacytosis is a rare disorder, which is characterized by multiple red to dark-brown nodules and plaques on the trunk and usually associated with polyclonal hyper gamma globulinaemia. Primary cutaneous plasmacytosis or cutaneous plasmacytosis was thought to be a reactive process with unknown etiology. Histologically, lesions contain dense perivascular infiltration of mature polyclonal plasma cells without any atypia, in the dermis and subcutaneous fat. The clinical course is chronic and benign without spontaneous remission. Available treatments for cutaneous plasmacytosis include psoralen ultraviolet A radiotherapy, systemic chemotherapy and intralesional steroid injection. The patient with cutaneous plasmacytosis in this report was treated with tacrolimus ointment and psoralen ultraviolet A.
Adult ; Humans ; Hyperplasia ; Immunosuppressive Agents/therapeutic use* ; Male ; Plasma Cells ; Plasmacytoma/immunology* ; Skin/pathology* ; Skin Diseases/immunology* ; Tacrolimus/therapeutic use*

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

OBJECTIVE: To evaluate the value of pharmacogenetic testing for improving the efficacy and safety of treatment with cyclosporine, tacrolimus, and cyclophosphamide (CTX) for PLA2R-related membranous nephropathy and for determing individualized and precise treatment plans for the patients. METHODS: A total of 63 patients with PLA2R-related membranous nephropathy hospitalized in the Department of Nephrology at our hospital from January, 2019 to October, 2021 were enrolled in this study. Thirty-three of the patients underwent pharmacogenetic testing before taking the immunosuppressive drugs selected based on the results of genetic screening for sensitive targets, and the other 30 patients were empirically given immunosuppressive drugs according to the guidelines (control group). The clinical efficacy and adverse effects of the immunosuppressive drugs were analyzed for all the patients. The two groups of patients were compared for demographic and biochemical parameters including 24-h urine protein, serum albumin, renal function, and serum anti-phospholipase A2 receptor antibody both before and at 3 months after the beginning of the treatment. RESULTS: Among the 33 patients undergoing pharmacogenetic testing, 51.5% showed a GG genotype for cyclosporine, and 61.6% had an AG genotype for tacrolimus; for CTX, 51.5% of the patients showed a homozygous deletion and 63.6% had an AA genotype. After treatment for 3 months, serum anti-phospholipase A2 receptor antibody, 24-h urine protein, and serum albumin levels were significantly improved in pharmacogenetic testing group as compared with the control group (P < 0.05). CONCLUSION Individualized and precise administration of immunosuppressive drugs based on pharmacogenetic testing better controls proteinuria and serum antiphospholipase A2 receptor antibodies and increases serum albumin level in patients with PLA2R-related membranous nephropathy.
Humans ; Autoantibodies ; Cyclosporine/therapeutic use* ; Glomerulonephritis, Membranous/diagnosis* ; Homozygote ; Immunosuppressive Agents/therapeutic use* ; Pharmacogenomic Testing ; Receptors, Phospholipase A2 ; Sequence Deletion ; Serum Albumin ; Tacrolimus/therapeutic use*

Animals ; Brain ; metabolism ; Humans ; Nerve Regeneration ; drug effects ; Neurodegenerative Diseases ; metabolism ; prevention & control ; Neuroprotective Agents ; metabolism ; therapeutic use ; Tacrolimus Binding Protein 1A ; metabolism ; Tacrolimus Binding Proteins ; metabolism ; therapeutic use