Tacrolimus Exposure and Evolution of Renal Allograft Histology in the First Year After Transplantation

Abstract

Tacrolimus has a narrow therapeutic window and is characterized by a large inter-individual variability in bioavailability. The impact of tacrolimus exposure on subclinical evolution of graft histology has not been studied in renal recipients. This analysis included 239 protocol biopsies (obtained at implantation, 3 and 12 months) of 120 consecutive kidney recipients treated with tacrolimus, mycophenolate mofetil (MMF) and corticosteroids. Biopsies were scored according to the Banff 2001 criteria and a chronicity score was calculated. Prospective pharmacokinetic data were included in the analysis (5544 tacrolimus predose blood concentrations and tacrolimus AUC 0−12 at 3 and 12 months). Higher donor age and higher number of human leukocyte antigen-DR (HLA-DR) mismatches were independent predictors of subclinical acute rejection at 3 months, present in 8.7% of patients. The number of HLA-DR mismatches was independently associated with biopsy-proven clinical acute rejection. Biopsy-proven acute rejection episodes and low mean tacrolimus exposure were independently associated with higher increase in chronicity scores between 3 and 12 months after transplantation. This observational study suggests that rejection phenomena and immune-mediated mechanisms remain important in the early progression of chronic allograft pathology. Tacrolimus doses or systemic exposure were not associated with lesions of calcineurin inhibitor nephrotoxicity, suggesting that other factors determine susceptibility to tacrolimus nephrotoxicity.

Acute Tacrolimus-Induced Kidney Insufficiency in Patient After Heart Transplantation

“…Характерным признаком поражения почек на фоне приема ингибиторов кальциневрина является CNI-ассоциированная артериолопатия с сопутствующим склерозом интерстиция [9][10][11].…”

“…Но современная трансплантология неотделима от иммуносупрессивной терапии для предупреждения реакции отторжения трансплан-тата. В последние годы успехи трансплантологии связаны прежде всего с широким использованием в клинической практике ингибиторов кальциневрина (CNI) циклоспорина (СуА) и такролимуса (ТАК), ставших основой различных протоколов иммуно-супрессивной терапии [4,9]. Их действие основа-но на подавлении активации и дифференцировки Т-лимфоцитов.…”

Minimizing Immunosuppression, an Alternative Approach to Reducing Side Effects

“…Recently published results of protocol biopsies obtained from renal transplant recipients on TAC/MMF and steroids demonstrate that the primary determinants of chronic pathological lesions in the renal allograft were low tacrolimus exposure and subclinical acute rejections. This important insight redirects our attention to immunological mediators of chronic allograft injury (11). Therefore, we submit that attribution of all vascular and fibrotic lesions in an allograft biopsy entirely to CNI nephrotoxicity is too simplistic and probably incorrect.…”

“…However, lesions of vascular sclerosis, interstitial fibrosis, and importantly in this observational series, the cumulative incidence of subclinical rejection were significantly greater in patients on CsA and azathioprine (AZA) compared with those on TAC and mycophenolate mofetil (MMF) (8). The fact that immunological factors remain important in the pathogenesis of the attrition of renal allograft function over time is illustrated in a recent study of protocol biopsies in TAC-and MMF-treated renal transplant recipients in whom the occurrence of rejection and low TAC exposure were independent risk factors for the development of chronic pathological lesions in allografts (11). Thus the exact and exclusive contribution of CNI alone to the development of chronic pathological lesions in the renal allograft, and, more relevantly, their role as predominant contributors to failure of the renal allograft over time is not necessarily as unequivocal as has been portrayed.…”

Calcineurin Inhibitor-Induced Renal Allograft Nephrotoxicity

“…An important measure in the prevention of these chronic ABBREVIATIONS CI -Calcineurin inhibitors NFAT -Nuclear factor of activated T cells RAS -Renin-angiotensin system NO -Nitric oxide COX-2 -Cyclogenoxygenase-2 TGF-β -Transforming growth factor beta C 0 -Trough level of CI C 2 -2-hour CI post-dose level AUC 0 to 12 -Area under the time-concentration curve ABCB1 -ATP-binding cassette sub-family B member 1 MDR1 -Multidrug resistance protein-1 NSAIDs -Non-steroidal anti-inflammatory drugs ACE -Angiotensin-converting enzyme changes is the effort to reduce the CI dose as much as possible and carefully monitor plasma levels. A pitfall in CI use is their variable pharmacokinetics, narrow therapeutic range, and individual susceptibility to their toxic effects 8 . CI serum levels therefore often fail to correlate with the extent of kidney damage and manifestation of toxicity can be non-specific or, especially in the first months after the transplantation, the toxic changes can be clinically silent.…”