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Challenges in cni inhibitor

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this is review of CNI utilization in child with kidney transplant the pros and cons

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Challenges in cni inhibitor

  1. 1. Challenges in CNI inhibitor in kidney transplantation Dr Nahid Rahimzadeh Pediatrics Nephrology Rasoul-e-Akram hospital
  2. 2. Calcineurin inhibitors  After the 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. 3.  In the earliest 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. 4.  Acute and chronic 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. 5.  At one year, 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. 6. RISK FACTORS  Several factors 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. 7.  Despite their efficacy 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. 8. PREVENTION OF CHRONIC CNI NEPHROTOXICITY  Reduced exposure to calcineurin inhibitors  Therapies with unclear benefit  Fish oil  arginine and canola oil  Calcium channel blockers  Renin-angiotensin system inhibitors
  9. 9.  Therapies with no benefit:  Pentoxifylline  Thromboxane synthesis inhibitor
  10. 10.  In our center( 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. 11. Complication PRES/CNI toxicity GI disturbances PTDM BK virus ↑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