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Challenges in cni inhibitor
- 1. Challenges in CNIinhibitor in kidney transplantation Dr Nahid Rahimzadeh Pediatrics Nephrology Rasoul-e-Akram hospital
- 2. Calcineurin inhibitors Afterthe discovery and clinical use of key CNI compounds cyclosporine and tacrolimus, graft survival in solid organ transplant increased significantly. They remain a cornerstone of solid organ transplant pharmacotherapy through inhibition of T-lymphocyte activation and impairment of lymphocyte function and replication . Frequent (i.e., weekly or even twice weekly) laboratory monitoring is often required to adjust total daily dosing to achieve goal trough concentrations.
- 3. In theearliest clinical kidney transplant trials using cyclosporine, a high incidence of oliguric AKI and CNI nephrotoxicity was observed. The risk was greatest with prolonged ischemia time of the donated kidney prior to transplantation . Subsequent trials using lower doses of cyclosporine showed that these problems were dose related.
- 4. Acute andchronic nephrotoxicity are generally similar with both cyclosporine and tacrolimus . However, tacrolimus has less nephrotoxicity with lower doses without compromising overall outcomes . In one trial, 1645 kidney transplant recipients were randomly assigned to one of four immunosuppressive arms: conventional-dose cyclosporine, glucocorticoids, and MMF daclizumab induction therapy, MMF, and glucocorticoids with either low-dose cyclosporine (50 to 100 ng/mL), low-dose sirolimus (4 to 8 ng/mL), or low-dose tacrolimus (3 to 7 ng/mL).
- 5. At oneyear, the low-dose tacrolimus group had the highest mean calculated GFR compared with the other three groups (65 versus 57 to 60 mL/min). The tacrolimus-based regimen was also associated with the lowest allograft rejection and highest allograft survival rates. At three years, the low-dose tacrolimus group continued to have the highest mean calculated GFR (69 mL/min versus 64 to 66 mL/min) .
- 6. RISK FACTORS Severalfactors may contribute to the risk of CNI nephrotoxicity : ●High doses of cyclosporineor tacrolimus ●Older age of donated kidney ●Concomitant use of nephrotoxic drugs, particularly NSAIDs. ●Salt depletion and diuretic use ●Drugs that inhibit cytochrome P-450. ●Drugs that inhibit P-glycoprotein-mediated efflux of CNIs from tubular epithelial cells, thereby increasing local renal exposure to CNIs ●Genetic polymorphisms in the genes encoding CYP3A4/5 (CYP3A4/5) and P-glycoprotein (ABCB1)
- 7. Despite theirefficacy successes, the adverse effects associated with CNIs can be substantial, including: Abnormal hair growth (e.g., alopecia with tacrolimus and hirsutism with cyclosporine) Electrolyte and metabolic abnormalities (e.g., glucose intolerance, hyperlipidemia, hyperkalemia) Gastrointestinal disturbances (e.g., anorexia, nausea, vomiting) Hypertension Neurotoxicities (e.g., tremor, headache, visual abnormalities) and nephrotoxicity Thrombotic microangiopathy
- 8. PREVENTION OF CHRONICCNI NEPHROTOXICITY Reduced exposure to calcineurin inhibitors Therapies with unclear benefit Fish oil arginine and canola oil Calcium channel blockers Renin-angiotensin system inhibitors
- 9. Therapies withno benefit: Pentoxifylline Thromboxane synthesis inhibitor
- 10. In ourcenter( Rasoul-e-Akram hospital), 156 pediatric kidney transplantation( 85 from living donors and 71 from deceased donors) were performed from 2011 to 2019 The mean age of the recipients was 10.7 (SD: 3.52), ranging from 4.5 to 20 years. Female 83 (53.2%), male 73 (46.8%)
- 11. Complication PRES/CNI toxicity GI disturbances PTDM BKvirus ↑S Cr ↑ ICP+ headach Peak incidence after SOT 1-6mo 1yr 1wk-6mo 2-6mo 6mo-1yr 1-3mo Altered mental status * Fever * Focal signs - seizures * CSF findings Nl Brain imaging acute white matter lision Diagnostic workup MRI,CNI level,EEG Treatment Taper to stop medication, treatment HTN