Relationship Between Tacrolimus Blood Levels andCOVID-19 Pandemic in Kidney Transplant Recipients
T. Inoue1, K. Unagami,2,3, K. Omoto3,4, H. Ishida2.3, K. Tanabe3
1Tsukuba Nephrplogy Clinic, Ibaraki

Tsukuba , Japan

2Department of Organ Transplant Medicine, Tokyo Women’s Medical University, Tokyo, Japan
3Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan

4Yochomachi Clinic , Tokyo, Japan

BackgroundThe novel coronavirus 2019 infection (COVID-19) has been a challenge for society and health systems
worldwide since the WHO declared a pandemic in March 2020. In Japan, COVID-19 prompted Tokyo torestrict on the free movement of people in March 2020.
Kidney transplant recipients are at high risk for critical COVID-19 due to chronic immunosuppression andcoexisting conditions. Efforts have been invested in the development of mitigation strategies and manage
the acute phase of COVID-19, however, the management of KTx recipients around COVID-19 pandemic
is uncertain.
TAC is a current key drug mainly used as an immunosuppressant for KTx recipients . Lower TAC
concentration or high intrapatient variability of TAC is one of the causes of acute rejection through thedevelopment of de novo donor-specific anti-human luekocyte antigen (HLA) antibodies (dnDSAs) .

The aim of this study is to evaluate relationship between tacrolimus blood levels and COVID-19 Pandemic
in kidney transplant recipients.

Materials and Methods
This single-center retrospective observational study included 1088 patients who had undergone
kidney transplantation at the Department of Urology of Tokyo Women’s Medical University before
August 2018. All patients were followed up at Yochomachi Clinic in Tokyo.
Of these patients, 180 were excluded: reinitiation of dialysis, recipients taking a twice-daily TAC,
recipients treated with Cyclosporine, recipients who did not undergo regular follow-up(regular renal
biopsies and/or regular monitoring). Thus 908 patients were included in this study.
We evaluated the effects of coronavirus pandemic on clinical outcomes such as tacrolimus bloodlevel, renal function, and rejection in kidney transplant recipients, comparing pandemic data with
non-pandemic data obtained between September 2019 and August 2020 in our institute. An unpairedt test was used, and p <0.05 was regarded as statistically significant.

Patients screened
n=1088180 patients excluded due to・reinitiation of dialysis(n=31)
・ recipients taking a twice-daily TAC (n=119)・ recipients treated with Cyclosporine (n=17)
・No follow-up recipients(n=13)

Enrolled patients
n=908

Immunosuppressive Regimen
Beginning a week before transplantation, all patients were treated following a triple immunosuppressive
protocol including TAC (0.1 mg/kg/day), mycophenolate mofetil (MMF; 1500 mg/day if body weight was
˂50 kg, 2000 mg/day if ≥50 kg) and methylprednisolone (MP; 20 mg/day).
Recipients received basiliximab as an induction immunosuppression therapy, administered on the day oftransplantation and on postoperative Day 4 . If the transplant was ABO incompatible, a single dose ofrituximab (200 mg) was administered within 3–4 days before the operation.
Plasma exchange (PE) was performed according to a protocol used for ABO-incompatible transplantation
or before transplantation in patients with a history of sensitization . This protocol involves a total of two or
three sessions before surgery to reduce the anti-A/B antibody titer to ≥1:32 . Some patients also received
preoperative PE therapy to prevent recurrence of their original kidney disease, such as focal segmental
glomerulosclerosis (FSGS). Intravenous immunoglobulin (IVIG) therapy was also performed for highly
sensitized cases. Antithymocyte globulin was not used for induction in our institute.

Initial target trough level:
6-8 ng/ml

Maintenance target trough level:
4-6 ng/ml

TAC
MMF

1500mg/day

2000mg/day
0.1mg/kg/day
500mg
250
12520mg

MP80 60
402084basiliximab
20mg-7Tx714(day)Patients received a once-daily dose of a prolonged-release formulation (Graceptor; Astellas Fujisawa).
The dose was adjusted to maintain a trough level of TAC in whole blood of 8–12 ng/mL during the firstmonth after KTx, 7–9 ng/mL during the second and third months and 4–6 ng/mL thereafter.

Results
Table1.

Clinical features in kidney transplant recipients

Variable

Value

Total number

908

Age, years(SD)54.7(12.5)

Male, n, %603(61.5)

Elapsed time after transplantation, years(SD)9.1(6.3)

Diabetic mellitus, n, %130(13.2)

Living kidney transplantation, n, %935(95.4)

ABO incompatible, n, %120(12.2)

Serum creatinine, mg/dl(SD)1.56(1.02)

Table2.

Clinical outcome between pandemic and non-pandemic
non-pandemic

pandemic

P valueinterval between hospital visit ,week(SD)5.5±2.6

7.3±4.5

2.68×10-14

rate of changes in oral medication, %(SD)

7.7(3.4)

6.0 (6.7)

0.450

rate of deviation from the target trough level, %(SD)

35.4(28.5)

38.3(27.3)

0.134

coefficient of variation, %(SD)

15.4(7.2)

14.8(7.6)

0.162

Serum creatinine, mg/dl(SD)1.56±1.0

1.60±1.1

0.481

Biopsy-proven rejection

030.084

・Rate of changes in oral medication was defined as the number of tacrolimus dose changes divided by the number ofhospital visits during the observation period.
・Rate of deviation from the target trough level was defined as the number of the blood concentration of tacrolimus
deviated from the target trough level (4-6 ng / ml) divided by the number of hospital visits.

・Coefficient of variation(CV)(%)=(δ(standard deviation; SD)/μ(mean))×100
This is an indicator of variations in tacrolimus blood levels1).

Enrolled patients
n=908

Group1n=441

Group2n=467

Enrolled patients were further divided into two groups according to the mean hospital visit interval
after the COVID-19 pandemic.The average interval was less than 6 weeks in group 1 and morethan 6 weeks in group 2.

Table3. Clinical features in kidney transplant recipientsgroup1group2

number441

467

Age, years(SD)54.0(12.7)

54.5(12.9)

0.513

Male, n, %284(64.4)

300(64.2)

0.960

Elapsed time after transplantation, years(SD)7.3(5.0)

10.5(6.2)

9.41×10-7

Diabetic mellitus, n, %57(12.9)47(10.0)

0.211

Living kidney transplantation, n, %425(96.4)444(95.1)

0.327

ABO incompatible, n, %62(14.1)

55(11.8)

0.323

Serum creatinine, mg/dl(SD)1.58(1.1)

1.65(1.2)

0.522

Table4. Clinical outcome between group1 and group2

group1group2

P valuerate of changes in oral medication, %(SD)

7.7(3.4)

6.0 (6.7)

0.001

rate of deviation from the target trough level, %(SD)

35.4(28.5)

38.3(27.3)

0.850

coefficient of variation, %(SD)

15.4(7.2)

14.8(7.6)

0.525

Serum creatinine, mg/dl(SD)1.56±1.0

1.60±1.1

0.156

300.114

Biopsy-proven rejection

P valueDiscussion
In this study, the interval between hospital visits for kidney transplant patients was extended after COVID19 pandemic, however, serum creatinine levels, incidence of biopsy-proven rejection, tacrolimus bloodconcentration were not significant different between pandemic data and non-pandemic data.
Patients in Group 1 had a shorter period after kidney transplantation and needed to change tacrolimus
doses more frequently. There were three acute rejection cases that occurred during the observation period,
all of which were Group 1 patients.
As demonstrated by a population-based registry study of >4,000 patients with a diagnosis of COVID-19
who were receiving kidney replacement therapy, COVID-19-associated mortality is 19.9% in kidneytransplant recipients2). In general terms, optimal disease management is still being debated, and thetherapeutic approach still lacks significant evidence3).
In kidney transplant recipients, mitigation strategies to reduce the risk of exposing patients to the virus
remain paramount. Remote care, telemedicine and minimization of blood tests may be helpful4).

Limitation
・The dose and blood concentration of immunosuppressants except for
TAC were unknown.
・Patients less than 1 year after kidney transplantation at high risk of
COVOD-19 are excluded.
・In this study, the patients were followed up for 6 months after
COVID-19 pandemic, therefore the long-term clinical outcome was notevaluated.

Conclusion

In kidney transplant recipients, bloodlevels of tacrolimus were maintained attarget trough levels during COVID-19pandemic.

Reference1)Emilio Rodrigo, et al. Within-Patient Variability in Tacrolimus Blood Levels Predicts Kidney Graft
Loss and Donor-Specific Antibody Development. Transplantation. 2016 Nov;100(11):2479-2485.

2)Jager KJ, et al. Results from the ERA-EDTA Registry indicate a high mortality due to COVID-19
in dialysis patients and kidney transplant recipients across Europe. Kidney Int. 2020 Dec; 98(6):1540–1548.
3)Federico Alberici, et al. Management of Patients on Dialysis and With Kidney Transplantation
During the SARS-CoV-2 (COVID-19) Pandemic in Brescia, Italy. Kidney Int Rep. 2020 Apr
4;5(5):580-585.
4)Annette Bruchfeld, et al. The COVID-19 pandemic: consequences for nephrology. Nat RevNephrol. 2021 Feb;17(2):81-82.