tacrolimus and Caliciviridae-Infections

Diarrhea is a frequent but overlooked complication of kidney transplantation. Diarrhea is repeatedly neglected, often considered by patients and clinicians an unavoidable side effect of immunosuppressive regimens. It is, however, associated with a significant impairment in life quality. Severe and chronic posttransplant diarrhea may lead to dehydration, malabsorption, rehospitalization, immunosuppression, noncompliance, and a greater risk of graft loss and death. There is thus a need to optimize and standardize the management of posttransplant diarrhea with consistent diagnostic and therapeutic strategies. A recent study has suggested that the increased sensitivity of molecular tools might help in early pathogen identification and guidance of antimicrobial treatment. Most bacterial and protozoan infections are readily curable with appropriate antimicrobial agents; cryptosporidiosis and C. difficile infections may however be complicated by relapsing courses. In addition, identification of enteric viral genomes in stool has further reduced posttransplant diarrhea of unknown origin. Chronic norovirus-related posttransplant diarrhea, arising from the interplay of the virus and immunosuppressive drugs, has emerged as a new challenge in the field. Prospective and controlled studies are necessary to evaluate the efficacy and safety of innovative anti-norovirus therapeutics, as well as optimal immunosuppressive regimens, to enable viral clearance while preventing rejection and donor-specific antibody formation. This review seeks to provide a basis for the design of future clinical prospective studies.

Topics: Caliciviridae Infections; Clostridioides difficile; Cryptosporidiosis; Cytomegalovirus Infections; Diarrhea; Humans; Kidney Transplantation; Norovirus; Tacrolimus; TOR Serine-Threonine Kinases

Topics: Caliciviridae Infections; Diabetes Mellitus, Type 1; Diagnosis, Differential; Diarrhea; Disease Progression; Drug Tapering; Feces; Fluid Therapy; Gastroenteritis; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Multiplex Polymerase Chain Reaction; Mycophenolic Acid; Pancreas Transplantation; Prednisone; Sapovirus; Tacrolimus

Norovirus is a major cause of acute gastroenteritis worldwide and has emerged as an important issue of chronic infection in transplantation patients. Since no approved antiviral is available, we evaluated the effects of different immunosuppressants and ribavirin on norovirus and explored their mechanisms of action by using a human norovirus (HuNV) replicon-harboring model and a surrogate murine norovirus (MNV) infectious model. The roles of the corresponding drug targets were investigated by gain- or loss-of-function approaches. We found that the calcineurin inhibitors cyclosporine (CsA) and tacrolimus (FK506) moderately inhibited HuNV replication. Gene silencing of their cellular targets, cyclophilin A, FKBP12, and calcineurin, significantly inhibited HuNV replication. A low concentration, therapeutically speaking, of mycophenolic acid (MPA), an uncompetitive IMP dehydrogenase (IMPDH) inhibitor, potently and rapidly inhibited norovirus replication and ultimately cleared HuNV replicons without inducible resistance following long-term drug exposure. Knockdown of the MPA cellular targets IMPDH1 and IMPDH2 suppressed HuNV replication. Consistent with the nucleotide-synthesizing function of IMPDH, exogenous guanosine counteracted the antinorovirus effects of MPA. Furthermore, the competitive IMPDH inhibitor ribavirin efficiently inhibited norovirus and resulted in an additive effect when combined with immunosuppressants. The results from this study demonstrate that calcineurin phosphatase activity and IMPDH guanine synthase activity are crucial in sustaining norovirus infection; thus, they can be therapeutically targeted. Our results suggest that MPA shall be preferentially considered immunosuppressive medication for transplantation patients at risk of norovirus infection, whereas ribavirin represents as a potential antiviral for both immunocompromised and immunocompetent patients with norovirus gastroenteritis.

Topics: Antiviral Agents; Calcineurin; Calcineurin Inhibitors; Caliciviridae Infections; Cell Line; Cyclosporine; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Mycophenolic Acid; Norovirus; Ribavirin; Tacrolimus; Tacrolimus Binding Protein 1A; Virus Replication

No treatment for NVE is available. Immunocompromised patients with NVE treated with OHIG (12 cases) were retrospectively identified and matched 1:1 by age and gender with immunocompromised patients with NVE not treated with OHIG (12 controls). Chi-squared test, t-test, bivariate conditional linear regression analyses, and Kaplan-Meier curve were performed. A total of 58.3% patients were small bowel transplant (SBT) recipients. Although not statistically significant, cases compared with controls were more likely to have had induction therapy (p = 0.25, OR = 65.3), higher peak tacrolimus levels (p = 0.43, OR = 1.04), SBT (p = 0.30, OR = 65.3), prior NVE (p = 0.42, OR = 2.0), TPN support (p = 0.42 OR = 2.0), and decrease in immunosuppression (p = 0.14, OR = 5.0). Treatment with OHIG favored resolution of diarrhea (p = 0.078, OR = 65.3) and decreased stool output seven days after treatment compared with controls (mean difference 11.95 mL/kg/day, p = 0.09). OHIG did not impact total time to resolution of diarrhea (mean 12.08 vs. 11.91 days; p = 0.63), length of hospital stay (p = 0.31, OR = 1.05), or cost of hospitalization (p = 0.32, OR = 1.0). We show a potential role of OHIG treatment for NVE. Resolution of diarrhea and decreased stool output were observed at seven days; no benefit was found for length of hospital stay or hospital cost.

Topics: Administration, Oral; Adolescent; Biopsy; Caliciviridae Infections; Case-Control Studies; Child; Child, Preschool; Female; Gastroenteritis; Hospitalization; Humans; Immunoglobulins; Immunosuppression Therapy; Infant; Intestines; Length of Stay; Male; Norovirus; Tacrolimus