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

Table 1 Tacrolimus intra-patient variability in heart transplantation: Main findings

Heart transplantation
Ref.	Sample size	Donor type	Tac-IPV, assessment	Outcome
Gueta et al[22], 2018	72	Deceased	CV	High trough level variability is associated with higher rates of graft rejection, and trough level variability during the first year is associated with increased risk of rejection after HT
Shuker et al[23], 2018	86	Deceased	MAD	A high IPV was not associated with the development and progression of cardiac allograft vasculopathy or development of acute cellular rejection
González-Vílchez et al[24], 2022	1581	Deceased	CV	IPV levels had limited influence on mid-term outcomes in heart transplant, however high IPV may predispose to rejection in initially stable patients
Baker et al[25], 2019	67	Deceased	TTR	Higher TTR was not associated with a lower rate of Acute Cellular Rejection within the first 30 d after heart transplant
Pollock-Barziv et al[26], 2010	144	Deceased	SD	Associated Tac IPV with late rejection as well as worse patient and graft survival, but it is worth to mention that few heart transplant recipients were included in this study
Sirota et al[27], 2021	118	Deceased	SD	SD ≥ 3 is associated with increased risk of poor outcomes

CV: Coefficient of variability; HT: Heart transplant; MAD: Mean absolute deviation; TTR: Time in therapeutic range; SD: Standard deviation.

Table 2 Tacrolimus intra-patient variability in lung transplantation: main findings

Lung transplantation
Ref.	Sample size	Donor type	Tac-IPV assessment	Outcome
Gallagher et al[28], 2015	110	Non specified	SD	Patients with highly variable trough tacrolimus levels in the second half of the first post-transplant year will likely have similar variability in the second year and are at high risk for subsequent chronic lung allograft dysfunction and death
Kao et al[29], 2021	157	Non specified	CV and TTR	The results suggest that tacrolimus TTR, time in therapeutic range, and variability are not related to the presence of ACR in LTRs
Ensor et al[30], 2018	292	Non specified	TTR	Tacrolimus TTR was predictive of clinical outcomes of ACR, CLAD, infection, and death in lung transplant recipients at 1 yr in this investigation after adjusting for potential confounders
Katada et al[31], 2022	90	Living and deceased	TTR	A lower tacrolimus TTR is a predictor of late acute rejection

SD: Standard deviation; TTR: Time in therapeutic range; ACR: Acute cellular rejection; LTR: Lung transplant rejection; CLAD: Chronic lung allograft dysfunction.

Table 3 Tacrolimus intra-patient variability and liver transplantation: Main findings

Liver transplantation
Ref.	Sample size	Donor	Tac-IPV assessment	Outcome
Lieber et al[18], 2013	988	Not specified	SD	Non-adherence among liver transplant recipients is associated with increased risk of graft failure
Stuber et al[19], 2008	96	Not specified	SD	The SD has utility of monitoring routine tac blood levels in pediatric recipients for detecting non-adherence prior to clinical rejection
Venkat et al[32], 2008	101	Not specified	SD	Variations in tac blood levels is associated with an increased risk of late allograft rejection in pediatric recipients
Shemesh et al[33], 2017	400	Both living and deceased donor	SD; MLVI	MLVI predicts late acute rejection in pediatric liver transplantation recipients
de Oliveira et al[34], 2017	50	Both living and deceased donor	SD; MLVI	MLVI may be a nice indicator of the risk of medication non-adherence in child-age
Defrancq et al[35], 2019	41	Both living and deceased donor	CV	High Tac IPV may be associated with adverse patient outcomes. Also, there is some impact of biological factors on IPV and therapy adherence
Christina et al[36], 2014	150	Not specified	SD; MLVI	The MLVI is associated with and can predict rejection, possibly related to non-adherence in adult recipients
Del Bello et al[37], 2018	116	Deceased donor only	CV	Tac IPV could be useful to identify patients with a greater risk of graft rejection and pf developing de novo DSA after liver transplantation
Rayar et al[38], 2018	812	Deceased donor only	CV	High CV of Tac concentrations was found to be predictive of Tac-related toxicity and poorer survival
van der Veer et al[39], 2019	326	Both living and deceased donor	CV	High IPV in Tac exposure beyond 6 mo after liver transplantation was not associated with imune-mediated graft injury
Dopazo et al[40], 2022	140	Deceased donor only	CV	High IPV between the third and sixth months appears to be an early and independent predictor of poorer liver transplant outcomes
Kim et al[41], 2022	636	Both living and deceased donor	CV	High Tac IPV was associated with increased risks of overall mortality and HCC recurrence in liver transplantation recipients with HCC

SD: Standard deviation; CV: Coefficient of variation; MLVI: Medication level variability index; DSA: Donor-specific antibodies; HCC: Hepatocellular carcinoma.

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.

Table 5 Tacrolimus intra-patient variability in pancreas and bone marrow transplantation: Main findings

Kidney and pancreas, and bone marrow transplant
Ref.	Sample size	Donor type	Tac-IPV Assessment	Outcome
Torabi et al[69], 2020	39	Both living and deceased donor	CV	The once daily LCPT dosing may facilitate medication adherence and result in improved long-term outcomes
Marco et al[70], 2022	128	Living donor only	CV	Determination of Tac IPV soon after alloHSCT could be useful in identifying greater risks of aGVHD

CV: Coefficient of variation; LCPT: LCP-tacrolimus; alloHSCT: Allogeneic stem cell transplantation; aGVHD: Acute graft-vesus-host disease.