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

1. Challenges in CNI inhibitor in
kidney transplantation
Dr Nahid Rahimzadeh
Pediatrics Nephrology
Rasoul-e-Akram hospital

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.  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.  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.  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. 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.  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. 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.  Therapies with no benefit:
 Pentoxifylline
 Thromboxane synthesis inhibitor

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. 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