Long-term outcomes in immunologically low-risk kidney transplant recipients using tacrolimus.
Extension study of: Tacrolimus monotherapy in immunologically low-risk kidney transplant recipients: a pilot randomized-controlled study.

Kidney transplantation is the treatment of choice for patients with end-stage
kidney disease. Current immunosuppressive drugs have allowed for 5-year patient
survival of approximately 90% (1, 2). Malignancy and infectious diseases are
feared and well-known side effects of the immunosuppressive burden after
transplantation (3-6). The total amount of immunosuppression, and especially
the use of induction therapy has proven to increase the risk of mortality (7).
Attempts to address these issues by lowering the total immunosuppressive load
must be weighed against the risk of rejection.
We have investigated this balance by unrolling the *Tacrolimus monotherapy in
immunologically low-risk kidney transplant recipients: a pilot
randomized-controlled* study (NL 2014-46834.078.14). In this main study
immunologically low risk-kidney transplant recipients are randomized to either
tacrolimus (TAC) or tacrolimus with mycophenolate mofetil (MMF) 6 months after
kidney transplantation. Outcomes measures are clinical data, vaccination
responses, questionnaires and immunological markers. This main study will
result in two patients cohorts of approximately 40 patients each on two
different immunosuppressive regimens. By extending their follow-up we are able
to study long term donor-specific and third party reactivity in an extension
study.
The measurement of donor-specific antibodies (DSA) as assessed by Luminex
single-antigen beads is an established marker of activity of the indirect
pathway of allorecognition. In immunologically high-risk kidney transplant
recipients de novo DSA are associated with inferior graft outcomes (8). Weaning
of immunosuppressive drugs has been associated with the appearance of DSA (9,
10). Shaprio et al. used the development of DSA as a monitoring tool to
identify patients who breached tolerance to a weaning of immunosuppressive
drugs (10). However, these studies included *immunological standard-risk*
patients after T-cell depleting induction therapy. Whether DSA monitoring in
immunological low-risk patients is of any benefit in the Dutch situation
remains to be clarified. The measurement of DSA till 10 years after
transplantation can add in the understanding of this B-cell-mediated damage to
the graft.
In the main study patients are vaccinated against pneumococcal infection at 12
months after transplantation. The *Gezondheidsraad* (medical advisory board to
the Dutch government) has released a recommendation on pneumococcal
vaccination in elderly patients in February 2018 (11). The board advices the
government to extend the national vaccination program with PPV23 vaccination
(pneumococcal vaccine) for people aged 60 once every 5 years till the age of
75. The majority of patients in the TACmono study is above the age of 60.
Their vaccination data in this study offer an opportunity to study this
*Gezondheidsraad* recommendation in a category of patients using
immunosuppressive drugs. In the main study the difference in vaccination
response is studied between patients treated with tacrolimus alone or in
combination with mycophenolate mofetil. The persistence of protective antibody
levels after pneumococcal vaccination is unclear, especially with the use of
immunosuppressive drugs. By measuring the pneumoccal antibody titer 3 and 5
years after vaccination the persistence of the vaccination response can be
studied, along with the differences in this response in the two
immunosuppressive regimens. Furthermore, by repeating the PPV23 vaccination 5
years later as in the *Gezondheidsraad* recommendation, the boost of the
antipneumoccal response can be studied. A repeated titer measurement one year
after the boosted vaccination can further explore the antibody dynamics in the
different immunosuppressive cohorts.

In conclusion, extending clinical and immunological monitoring beyond one year
after kidney transplantation can add to understanding the outcomes of
immunologically low-risk kidney transplant recipients and the contribution of
tacrolimus and mycophenolate mofetil.
References

1. Ichimaru N, Takahara S. Japan's experience with living-donor kidney
transplantation across ABO barriers. Nat Clin Pract Nephr. 2008;4(12):682-92.
2. Morales JM, Marcen R, del Castillo D, Andres A, Gonzalez-Molina M,
Oppenheimer F, et al. Risk factors for graft loss and mortality after renal
transplantation according to recipient age: a prospective multicentre study.
Nephrol Dial Transpl. 2012;27:iv39-iv46.
3. Piselli P, Busnach G, Fratino L, Citterio F, Ettorre GM, De Paoli P, et al.
De Novo Malignancies After Organ Transplantation: Focus on Viral Infections.
Current Molecular Medicine. 2013;13(7):1217-27.
4. Gutierrez-Dalmau A, Campistol JM. Immunosuppressive therapy and malignancy
in organ transplant recipients - A systematic review. Drugs. 2007;67(8):1167-98.
5. Ak O, Yildirim M, Kucuk HF, Gencer S, Demir T. Infections in Renal
Transplant Patients: Risk Factors and Infectious Agents. Transpl P.
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6. Sanders-Pinheiro H, da Silveira STC, Carminatti M, Braga LSS, Marsicano EO,
Magalhaes GL, et al. Excessive Immunosuppression in Kidney Transplant Patients:
Prevalence and Outcomes. Transpl P. 2012;44(8):2381-3.
7. Rubin RH. Infectious disease complications of renal transplantation. Kidney
Int. 1993;44(1):221-36.
8. Aubert O, Loupy A, Hidalgo L, van Huyen JPD, Higgins S, Viglietti D, et al.
Antibody-Mediated Rejection Due to Preexisting versus De Novo Donor-Specific
Antibodies in Kidney Allograft Recipients. Journal of the American Society of
Nephrology. 2017;28(6):1912-23.
9. Hoshino J, Kaneku H, Everly MJ, Greenland S, Terasaki PI. Using
Donor-Specific Antibodies to Monitor the Need for Immunosuppression.
Transplantation. 2012;93(11):1173-8.
10. Shapiro R, Zeevi A, Basu A, Tan HP, Kayler LK, Blisard DM, et al.
Alemtuzumab preconditioning with tacrolimus monotherapy - The impact of serial
monitoring for donor-specific antibody. Transplantation. 2008;85(8):1125-32.
11. Gezondheidsraad. Verbindende notitie van Zorginstituut Nederland en
Gezondheidsraad bij adviezen over vaccinatie van ouderen tegen pneumokokken.
956704/1295149/LvR/dva/066-A7. 2018.

This study has been transitioned to CTIS with ID 2024-513394-42-01 check the CTIS register for the current data.

To assess long-term outcomes in low-immunological risk renal transplant
patients beyond one year after transplantation using tacrolimus monotherapy
versus tacrolimus with mycophenolate mofetil.

This study is an extension study of the TACmono study (NL 2014-46834.078.14).
It is an non-therapeutic intervention study with blood sampling at various time
points to assess alloreactivity and vaccination responses, nested in a cohort
study describing clinical outcomes of patients who have completed the main
TACmono study (aim n=76 patients).

1. extra blood tubes will be sampled during routine blood sampling: two vials a
5 ml serum year 4 and 6 after kidney transplantation and one vial a 5 ml serum
7 and 10 years after kidney transplantation.
2. The pneumovax (PPV23) vaccine will be administered during routine follow-up
in the outpatient clinic six years after kidney transplantation.
3. An extra visit will be scheduled 3 weeks thereafter to sample one vial a 5
ml serum.

The risk of the venapunctures is small, as extra blood tubes are taken at time
points when blood is already drawn, except for the anti-pneumococcal titer 3
weeks after revaccination. The risk of a venapuncture is the occurrence of a
bruise after puncture and possible pain-symptoms at the site of puncture.
Vaccination can give local reactions the first day(s): pain, redness and
swelling. Fever, malaise, fatigue and headaches are also reported in the first
week after vaccination. Known history of anaphylactic reactions or
Guillain-Barré syndrome in 6 weeks after vaccination is a contra-indication to
vaccination. The administered pneumococcal vaccine is identical to the vaccine
that participants received one year after kidney transplantation in the main
study.
By participating in this study, patients will have easy access to national and
international recommended vaccinations after transplantation.