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Challenges in CNI inhibitor in
Dr Nahid Rahimzadeh
After the discovery and clinical use of key CNI compounds
cyclosporine and tacrolimus, graft survival in solid organ transplant
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
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.
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).
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) .
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)
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
Electrolyte and metabolic abnormalities (e.g., glucose intolerance, hyperlipidemia,
Gastrointestinal disturbances (e.g., anorexia, nausea, vomiting)
Neurotoxicities (e.g., tremor, headache, visual abnormalities) and nephrotoxicity
PREVENTION OF CHRONIC CNI NEPHROTOXICITY
Reduced exposure to calcineurin inhibitors
Therapies with unclear benefit
arginine and canola oil
Calcium channel blockers
Renin-angiotensin system inhibitors
Therapies with no benefit:
Thromboxane synthesis inhibitor
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
Female 83 (53.2%), male 73 (46.8%)
PTDM BK virus ↑S Cr ↑ ICP+ headach
1-6mo 1yr 1wk-6mo 2-6mo 6mo-1yr 1-3mo
Focal signs -
CSF findings Nl
Brain imaging acute white
Diagnostic workup MRI,CNI level,EEG
Treatment Taper to stop