Impact of tacrolimus intra-patient variability in adverse outcomes after organ transplantation

Table 4 Tacrolimus intra-patient variability and kidney transplantation: Main findings

Kidney transplantation
Ref.	Sample size	Donor type	Tac-IPV assessment	Outcomes
Borra et al[47], 2010	297	Both living and deceased donor	MAD	Significant relationship between high Tac-IPV and long-term graft failure
Ro et al[45], 2012	249	Both living and deceased donor	MAD	TAC IPV had a significant impact on rejection-free survival. The effect was influenced by CYP3A5 polymorphism
Sapir-Pichhadze et al[44], 2014	356	Both living and deceased donor	MLVI/SD	Increased time-dependent TAC SD may be an independent risk factor for adverse kidney transplant outcomes
O’Regan et al[49], 2016	394	Both living and deceased donor	CV	Inferior renal allograft survival was observed in recipients with higher Tac-IPV
Rodrigo et al[53], 2016	310	Deceased donor only	CV	Tacrolimus level variability is a strong risk factor for dnDSA development and death-censored graft loss
Whalen et al[46], 2017	376	Both living and deceased donor	MAD	Highly variable tacrolimus levels predict worse out- comes postrenal transplantation
Shuker et al[48], 2016	808	Both living and deceased donor	MAD	A high tacrolimus IPV is an independent risk factor for adverse kidney transplant outcomes that can be used as an easy monitoring tool to help identify high-risk RTRs
Vanhove et al[56], 2016	220	Both living and deceased donor	CV	High IPV is related to accelerated progression of chronic histologic lesions before any evidence of renal dysfunction
Rozen-Zvi et al[51], 2017	803	Both living and deceased donor	CV	The combination of high CV and exposure to low drug levels might identify high-risk patients in the early post-transplantation period
Goodall et al[50], 2017	688	Both living and deceased donor	CV	High tacrolimus IPV and clinic nonattendance are associated with inferior allograft survival
Sablik et al[62], 2018	248	Both living and deceased donor	MAD	A high Tac IPV per se does not predispose to the development of chronic active antibody mediated rejection (c-aABMR) but is associated with inferior graft survival once c-aABMR is diagnosed
Seibert et al[57], 2018	1472	Both living and deceased donor	CV	High variability of TAC dose increases risk of acute rejection. High variability of TAC trough increases risk of graft failure
Mo et al[54], 2019	671	Both living and deceased donor	CV	High IPV of Tac is associated with early deterioration of chronic histologic lesions as well as poorer long-term outcomes
Song et al[61], 2019	1241	Living donor only	TTR	Increasing the TTR of tacrolimus in the first year was associated with improved long-term outcomes in living kidney transplants, and TTR may be a novel valuable strategy to monitor tacrolimus exposure
Süsal et al[55], 2019	6638	Deceased donor only	CV	Even in patients with good outcome during the first 3 post-transplant years, a high IPV was associated with inferior graft survival, indicating that a fluctuating tacrolimus trough level at years 1, 2 and 3 post-transplant is a major problem in kidney transplantation
Rahamimov et al[52], 2019	878	Both living and deceased donor	CV	Monitoring CV can help detect the high-risk patients
Gold et al[66], 2020	1419	Deceased donor only	MAD	A more intense and less variable exposure to tacrolimus could improve graft survival strongly in patients with high TAC IPV
Stefanović et al[58], 2020	104	Both living and deceased donor	CV	Combined assessment of tacrolimus IPV and tacrolimus C0/D may categorize patients towards risk of graft deterioration in the long-term post-transplantation period
Stefanović et al[59], 2021	103	Both living and deceased donor	CV	Simultaneous assessment of Tac IPV, C0/D, and CYP3A5 genotype may identify patients at risk of deterioration of graft function in the long-term post-transplantation period
Kim et al[65], 2021	1080	Both living and deceased donor	CV	High tacrolimus IPV significantly increases the risk of graft failure and antibody mediated rejection in patients with high immunological risk
Park et al[63], 2021	1143	Both living and deceased donor	CV	TAC-IPV can significantly affect allograft outcomes even with a high mean TAC-C0
Yin et al[64], 2022	1343	Living donor only	CV	Tac variability score is a novel measure of Tac IPV with higher correlation with graft survival and more convenience in clinical use than CV after kidney transplantation
Baghai Arassi et al[67], 2022	48	Both living and deceased donor	CV	High Tac IPV is associated with an increased risk of dnDSA development and rejection episodes > year 1 posttransplant even in patients with low immunological risk profile
Nuchjumroon et al[60], 2022	188	Both living and deceased donor	CV	No evidence that the CYP3A5 polymorphisms significantly influence tacrolimus IPV during the 6 to 12 mo after kidney transplantation

SD: Standard deviation; CV: Coefficient of variation; MLVI: Medication level variability index; DSA: Donor-specific antibodies; TTR: Time in therapeutic range.