tacrolimus and Nephritis--Interstitial

Polyomaviruses are increasingly recognized as important human pathogens. Among those, BK virus has been identified as the main cause of polyomavirus-associated nephropathy (PVAN), a major cause of renal allograft failure. PVAN has also been well described in the setting of non-renal solid organ transplantation. The reports of PVAN after hematopoietic stem cell transplantation (HCT) are surprisingly very few. Here, we describe a patient with treatment-related myelodysplastic syndrome who received an unrelated donor HCT after ablative conditioning and in vivo T cell depletion with alemtuzumab. He developed a biopsy-proven BK nephropathy, which contributed to his renal failure. Leflunomide as well as cidofovir were given at different times, both in combination with intravenous immunoglobulin. Both treatments were effective in reducing the BK viral load, the cystitis symptoms and both stabilized but did not really improved the renal function. The patient was still dialysis-dependent when he died from Pseudomonas sepsis 13 months after HCT. A critical review of the literature and the treatment modalities for post-HCT PVAN are provided.

Topics: Antiviral Agents; BK Virus; Cystitis; Cytomegalovirus Infections; Fatal Outcome; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hepatorenal Syndrome; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Failure, Chronic; Lymphoma, Follicular; Male; Middle Aged; Myelodysplastic Syndromes; Nephritis, Interstitial; Polyomavirus Infections; Postoperative Complications; Reoperation; Tacrolimus; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous

Drug-related renal damage is manifold in its origin, clinical picture and prognosis. The disorder can manifest itself as a purely functional phenomenon with tubular elimination of amino acids, enzymes, protein, glucose and electrolytes, or it is due to reversible hemodynamic changes; on the other hand, it may be accompanied by cell necrosis and inflammation. Hemodynamic, toxic, immunologic, or mechanically obstructive mechanisms or a combination of these play a pathogenetic role. It is important to know the renal parameters before and monitor them during treatment with nephrotoxic drugs; to avoid concomitant administration of two or more nephrotoxic drugs; and to make the diagnosis as well as terminate exposure rapidly.

Topics: Analgesics; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Contrast Media; Cyclosporine; Humans; Kidney Diseases; Kidney Function Tests; Kidney Tubular Necrosis, Acute; Nephritis, Interstitial; Tacrolimus

This study aimed to determine the predictive factors of BK virus viremia/nephropathy in kidney transplant recipients and to evaluate the effects of low-dose tacrolimus plus everolimus.. This study included 3654 kidney transplant recipients. The patients were divided into 2 groups: group 1 were BK virus negative (n = 3525, 96.5%) and group 2 were BK virus positive (n = 129, viremia 3.5%, nephropathy 1%). Predictive factors were determined by receiver operating characteristic curve analysis and logistic regression models.We also divided and analyzed patients with BK virus viremia/nephropathy into 2 groups according to immunosuppressive changes. Group 2a had been switched to low-dose tacrolimus plus everolimus (n = 54, 41.9%), and group 2b had been switched to other immunosuppressive protocols (n = 75, 58.1%).. We found that use of anti-T-cell lymphocyte globulin and tacrolimus, deceased donor transplant, and rejection were predictive factors for BK virus viremia/nephropathy. In addition, patients who had low-dose calcineurin inhibitor plus mammalian target of rapamycin inhibitor regimens showed a low rate of BK virus development(only 6.2% of all cases). In Group 2a, both the BK polyomavirus-associated nephropathy rate (n = 23 [42.6%] vs n = 12 [16%] in group 2b; P = .001) and viral load (DNA > 104 copies/mL) (n = 49 [90.7%] vs n = 27 [36%] in group 2b; P = .001) were increased versus group 2b. Graft function, graft survival, viral clearance, and rejection rate were similar between the groups after protocol change.. BK virus viremia/nephropathy rate was lower in patients who received low-dose calcineurin inhibitor plus mammalian target of rapamycin inhibitor protocols; the low-dose tacrolimus plus everolimus switch protocol after BK virus was more effective and safe than other protocols.

Topics: BK Virus; Calcineurin Inhibitors; Everolimus; Humans; Immunosuppressive Agents; Kidney Transplantation; Nephritis, Interstitial; Polyomavirus Infections; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases; Transplant Recipients; Tumor Virus Infections; Viremia

Adjustment of immunosuppression is the main therapy for BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) after kidney transplantation (KT). Studies of BKPyV-specific T cell immune response are scarce. Here, we investigated BKPyV-specific T cell immunity in KT recipients diagnosed with BKPyVAN.. All adult KT recipients with BKPyVAN diagnosed at our institution from January 2017 to April 2018 were included. Laboratory-developed intracellular cytokine assays measuring the percentage of IFN-γ-producing CD4. We included 12 KT recipients diagnosed with BKPyVAN (7 proven, 4 presumptive, and 1 possible). Those with presumptive BKPyVAN had a median plasma BKPyV DNA load of 5.9 log10 copies/ml (interquartile range [IQR]: 4.9-6.1). Adjusted dosing of mycophenolic acid and tacrolimus with (86%) or without (14%) adjunctive therapies were implemented after diagnosis. There was a significantly higher median percentage of IFN-γ-producing CD4. We observed a marginal trend of BKPyV-specific CD4

Topics: Adult; BK Virus; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; DNA, Viral; Female; Graft Rejection; Humans; Immunosuppressive Agents; Interferon-gamma; Kidney Transplantation; Male; Middle Aged; Nephritis, Interstitial; Polyomavirus Infections; Tacrolimus; Transplantation, Homologous; Viral Proteins

Cannabidiol (CBD), a major purified nonpsychoactive component of cannabis with anticonvulsant properties, was approved by the U.S. Food and Drug Administration (FDA) in June 2018 as an adjuvant treatment for refractory epilepsy (Epidiolex; GW Pharmaceuticals). CBD is metabolized by cytochrome P450 (CYP)3A4 and CYP2C19 with a growing body of evidence suggesting it is also a potent inhibitor of these pathways. We report for the first time a significant drug-drug interaction between the purified CBD product and tacrolimus. A participant in a CBD clinical trial for epilepsy who was also receiving tacrolimus showed an approximately 3-fold increase in dose-normalized tacrolimus concentrations while receiving 2000-2900 mg/day of CBD. Our report delineates an important concern for the transplant community with the increasing legalization of cannabis and advent of an FDA-approved CBD product. Larger studies are needed to better understand the impact of this drug-drug interaction in solid organ transplant recipients.

Topics: Adult; Cannabidiol; Drug Interactions; Epilepsy; Female; Humans; Immunosuppressive Agents; Nephritis, Interstitial; Prognosis; Tacrolimus

Topics: Biopsy; Bipolar Disorder; Cyclosporine; Female; Glomerular Filtration Rate; Humans; Kidney Transplantation; Lithium; Middle Aged; Nephritis, Interstitial; Renal Insufficiency; Risk; Risperidone; Tacrolimus; Treatment Outcome; Valproic Acid

The aim of this study was to observe the effect of sirolimus (SRL) on calcineurin inhibitor (CNI)-induced nephrotoxicity in the aging process by using renal expression of KLOTHO, an antiaging gene. METHODS.: Mice were treated with vehicle (VH; 1 mL/kg/day of olive oil), cyclosporine A (CsA; 30 mg/kg/day), or tacrolimus (FK; 1 mg/kg/day) with or without SRL (0.3 mg/kg/day) for 2 weeks. KLOTHO expression was evaluated by using reverse-transcriptase polymerase chain reaction, immunoblotting, and immunohistochemistry. Oxidative stress was evaluated by using immunohistochemistry and urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG). The calcium metabolism was evaluated by using renal ectopic calcification, serum intact parathyroid hormone level, and renal fibroblast factor 23 (FGF23) expression.. Treatment with CsA or FK alone significantly decreased KLOTHO expression and increased urinary 8-OHdG excretion compared with VH treatment but SRL treatment did not. Treatment SRL+CsA or SRL+FK further decreased KLOTHO expression and increased urinary 8-OHdG excretion compared with treatment of CsA or FK alone. There was a strong correlation between KLOTHO expression and urinary 8-OHdG excretion (r=-0.893; P<0.001). Treatment of CsA or FK alone increased renal ectopic calcification and serum intact parathyroid hormone level and decreased renal FGF23 expression compared with VH treatment (P<0.05) but SRL treatment did not. Treatment with SRL+CNI aggravated these parameters compared with CNI alone.. SRL accelerates the CNI-induced oxidative process by down-regulating the renal antioxidant KLOTHO expression in the kidney.

Topics: Aging; Animals; Calcineurin Inhibitors; Colforsin; Cyclosporine; DNA Primers; Fibroblast Growth Factor-23; Gene Expression Regulation; Glucuronidase; Immunosuppressive Agents; Kidney; Klotho Proteins; Mice; Nephritis, Interstitial; Oxidative Stress; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Sirolimus; Tacrolimus

Topics: Antibodies, Monoclonal; Child, Preschool; Cyclosporine; Diagnostic Errors; Dwarfism; Granuloma; Hematuria; Humans; Immunosuppressive Agents; Infliximab; Male; Nephritis, Interstitial; Nephrosis, Lipoid; Nephrotic Syndrome; Obesity; Prednisolone; Proteinuria; Puberty, Delayed; Recurrence; Remission Induction; Tacrolimus; Tumor Necrosis Factor-alpha

We investigated the effects of daily injection of tacrolimus (FK), an immunosuppressor, or dexamethasone (Dx), an antiinflammatory agent, on renal tubulointerstitial fibrosis in mercuric chloride-treated Brown Norway rats. The tubular lesions observed after one time injection of mercuric chloride were reduced in FK-treatment group, but not in Dx-treatment group. Moreover, FK reduced infiltration of mononuclear cells, especially macrophages, and proliferation of myofibroblasts in renal intestitium and also inhibited renal interstitial fibrosis through the reduction of the expressions of fibrosis-related factors, i.e. plasminogen activator inhibitor-1 and transforming growth factor-beta1. On the other hand, Dx reduced lymphocyte infiltraton, but did not inhibit macrophage infiltration. In addition, Dx did not suppress myofibroblast profiferation, upregulation of fibrosis-related factors, and interstitial fibrosis. From these findings, it is suggested that FK may inhibit renal interstitial fibrosis through inhibition of macrophage infiltration, and that macrophages and myofibroblasts are very important fibrogenic factors in the development of mercuric chloride-induced renal tubulointerstitial fibrosis in BN rats.

Topics: Animals; Anti-Inflammatory Agents; Dexamethasone; Disease Models, Animal; Drug Therapy, Combination; Fibroblasts; Fibrosis; Immunosuppressive Agents; Injections, Subcutaneous; Kidney Tubules; Lymphocytes; Macrophages; Male; Mercuric Chloride; Myocytes, Smooth Muscle; Nephritis, Interstitial; Plasminogen Activator Inhibitor 1; Rats; Rats, Inbred BN; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tacrolimus; Transforming Growth Factor beta; Transforming Growth Factor beta1

Polyoma virus infection in renal transplant recipients has been observed with increasing frequency in recent years. Renal allograft involvement in this condition may occur as a result of primary infection or secondary to reactivation of the latent virus. Interstitial nephritis, ureteric stenosis, rise in serum creatinine and allograft function loss have been attributed to this viral infection.. In this study we reviewed our experience with 8 patients who developed polyoma viral infection confirmed by allograft biopsy. All patients were receiving mycophenolate mofetil as part of the immunosuppression and 7 of the 8 patients were on tacrolimus. All patients have biopsy proven polyoma viral infection. The following therapeutic maneuvers were carried out following the diagnosis of polyoma viral infection: 1) stopping mycophenolate and 2) switching tacrolimus to cyclosporine or reducing the tacrolimus dose to adjust it at a lower therapeutic trough level. The clinical course and outcome of our patients were reviewed in relation to manipulation of immunosuppressive medications.. The incidence of this infection in our transplant program in the last 3 yr was 5.3%. Seventy-five percent of the patients had at least one rejection episode and 63% had more than one rejection episode. The main risk factor for the development of polyoma viral infection was related to the intensity of immunosuppression. The use of antirejection therapy after histological diagnosis of polyoma virus infection was not associated with improvement of renal function despite the histological appearance of acute rejection. Thus, the interstitial nephritis associated with polyoma viral infection appears to be an inflammatory response to the virus rather than acute rejection. Six out of the 8 patients stabilized renal function with reduction in immunosuppression.. Reduction in immunosuppression was associated with the stabilization of renal function when instituted early. However, these patients were left with a degree of allograft dysfunction and their outcome may be significantly compromised. The lack of effective antiviral therapy for polyoma virus may limit the use of newer and more potent immunosuppressive medications.

Topics: Acute Disease; Adult; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Nephritis, Interstitial; Polyomavirus Infections; Risk Factors; Tacrolimus; Tumor Virus Infections

Topics: Basement Membrane; Biopsy; Cadaver; Capillaries; Creatinine; Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Glomerulus; Kidney Transplantation; Kidney Tubules; Lymphocytes; Microscopy, Electron; Nephritis, Interstitial; Retrospective Studies; Tacrolimus; Tissue Donors