Clinical trial NCT05816486: BIOtechnology Applied to Renal TRansplantation With IMmunobiogram
Official title: Longitudinal Observational Study to Determine the Correlation Between Patient's Pharmacodynamic Response to Immunosuppressants Measured in Vitro With IMMUNOBIOGRAM and of Rejection in Graft Biopsies in Patients With Renal Transplantation
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Kidney Transplant Failure and Rejection
Keywords: Kidney Transplant Rejection
Immunosuppression
Immune cell bioassay
Pharmacodynamics
Oportunistic infections
Lead sponsor: Biohope Scientific Solutions for Human Health, S.L.
Sponsor class: INDUSTRY
First posted: 2023-04-18
Enrollment: 443
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: 1. Prospective longitudinal cohort: all patients who are to receive a kidney transplant and meet the screening criteria for this study cohort. This cohort will be recruited in sites that routinely perform a Protocol Biopsy (PB) one year after transplant.
2. Cross-sectional cohort: patients in whom an Indication Biopsy (IB) is to be performed due to suspicion of rejection. This cohort may be recruited in all sites participating in the study and patients will be enrolled competitively.
3. Control cohort: cross-sectional cohort to include patients who have received a kidney transplant or a re-transplant less than 5 years before inclusion in the study and have shown a stable clinical course after 6 months post-transplant. An IMBG will be performed coinciding with the study visit.

Brief summary: Immunobiogram (IMBG) is a novel in vitro diagnostic bioassay developed by Biohope Scientific Solutions for Human Health SL, that allows to measure the pharmacodynamic response to individual immunosuppressive drugs in patients with a renal transplantation. Pharmacodynamics can complement the already available pharmacokinetic information on immunosuppressants and enable a more individualized evaluation of the immunosuppressive therapy.

The aim of this study is to evaluate the association between the pharmacodynamic response to individual immunosuppressants taken by the patient measured in vitro with IMBG and the existence of signs of graft rejection in biopsies (upon indication or protocol) performed in a sample of kidney transplant patients.

The main hypothesis is that a lower sensitivity to the immunosuppressive drugs taken by the patient will be associated with a higher probability of rejection.

Detailed description: Immunobiogram (IMBG) is a novel bioassay that allows to measure in vitro the inhibitory effect of a battery of individual immunosuppressants on the patient's immune cells (immunologically stimulated PBMCs).

Studies conducted in kidney transplant patients have shown that IMBG is a valid and accurate instrument, capable of determining each patient's pharmacodynamic response profile to individual immunosuppressive drugs.

Health professionals who monitor kidney transplant patients currently have information only on immunosuppressant pharmacokinetics to adjust the regimen of the immunosuppressants they use to treat the patients to avoid graft rejection. The pharmacodynamic measurement of the in vitro effect of each immunosuppressant in the patient could complement the pharmacokinetic information and enable more personalized approaches.

The main objective of this study is to evaluate the association between the pharmacodynamic response to individual immunosuppressants taken by the patient measured with IMBG and the existence of signs of graft rejection in biopsies (upon indication or protocol) performed in a sample of kidney transplant patients.

A longitudinal follow-up cohort of patients will be recruited from prior to the transplant (at sites that regularly perform a protocol graft biopsy after a year) and a cross-sectional cohort of patients will also be included when an indication biopsy is performed during the first five years after kidney transplantation due to a suspicion of rejection at sites that do not routinely perform protocol biopsies.

Given that one of the main challenges that clinicians face in the follow-up of patients is to reduce the risk of renal graft rejection, while minimizing the incidence of secondary effects related to immunosuppressive therapy, it is proposed as a secondary objective to evaluate in the longitudinal cohort the incidence of "therapeutical failure" due to graft failure or due to the appearance of serious adverse effects attributable to immunosuppression and analyze its relationship with the profile of sensitivity to immunosuppressants taken by the patient measured with IMBG.

It will be also evaluated if the IMBG sensitivity to immunosuppressive drugs measured pretransplant predict the ocurrence of rejection or adverse events during the first year postransplant.

Finally, the changes over time presented by the IMBG in various determinations and the correlation between IMBG results and other lymphocyte activation parameters obtained by flow cytometry will be analyzed.

Eligibility criteria: Inclusion Criteria:

Longitudinal cohort:

1. Patients \> 18 years of age.
2. Candidate to receive a kidney transplant or re-transplant.
3. Patients in whom it is planned to routinely perform a protocol biopsy one year after the kidney transplant for which there is no contraindication at the time of inclusion in the study.
4. Patients in whom a pre-transplant blood sample can be drawn that is viable for the processing of an IMBG.
5. Patients who give their written informed consent to participate in the study.

Cross-sectional cohort:

1. Patients \> 18 years of age.
2. Patients who have received a kidney transplant or re-transplant less than 3 years before inclusion in the study.
3. Patients in whom an indication biopsy is to be performed due to suspicion of rejection.
4. Patients in whom a blood sample can be drawn in a period of time less than 8 days before or after the Indication Biopsy that is viable for the processing of an IMBG.
5. Patients who give their written informed consent to participate in the study.

Exclusion Criteria (PROSPECTIVE AND CROSS-SECTIONAL COHORT):

1. Patient with a double transplant (kidney + other organ).
2. Contraindication for performing a renal graft biopsy.
3. Active autoimmune diseases in the 12 months prior to the study visit (with systemic inflammatory exacerbation in the year prior to study inclusion, despite immunosuppressive therapy).
4. Very elderly cadaver donor transplant (\>80 years of age).
5. Donors in asystole II.
6. Recurrent primary kidney disease in the case of primary focal and segmental hyalinosis or hemolytic-uremic syndrome.
7. Active HIV, HBV or HCV infection or other severe infections (to prevent risks in the processing of samples in conventional laboratories).
8. Concomitant medical conditions that may affect the patient's participation in the study.

Control cohort:

Inclusion criteria:

1. Patients \> 18 years of age.
2. Patients who have received a kidney transplant or re-transplant less than 5 years before inclusion in the study.
3. A stable course after 6 months post-transplant defined as:

   * Lack of renal impairment (GFR \> 50 ml/min/1.73 m2 and proteinuria \< 300 mg/g)
   * No previous rejection episodes and no graft indication biopsies
   * No positive dnDSA
   * No change in the active principle of immunosuppressive drugs in the last 6 weeks
   * No opportunistic infections in the last 6 months
4. Patients in whom a blood sample can be drawn suitable for IMBG processing.
5. Patients (or their legal representative) who give their written informed consent to participate in the study.

Exclusion criteria:

1. Patient with a double transplant (kidney + other organ).
2. Active autoimmune diseases in the 12 months prior to the study visit (with systemic inflammatory exacerbation in the year prior to study inclusion, despite immunosuppressive therapy).
3. Very elderly cadaver donor transplant (\>80 years of age).
4. Donors in asystole II.
5. Recurrent primary kidney disease in the case of primary focal and segmental hyalinosis or hemolytic-uremic syndrome.
6. Active HIV, HBV or HCV infection or other severe infections (to prevent risks in the processing of samples in conventional laboratories).
7. Concomitant medical conditions that may affect the patient's participation in the study.

Primary outcomes:
measure: Proportion of patients with BPAR in biopsies (following BANFF 2019 criteria) who present Low Sensitivity to the prescribed Immunosupressive drugs in IMBG
timeFrame: 12 months in the prospective follow-up cohort.
Secondary outcomes:
measure: Proportion of patients with impairment in renal function AND BPAR or inflammatory damage in biopsies or the presence of dnDSA in the last determination who present low sensitivity to the individual immunosuppressive drugs in IMBG
timeFrame: 12 months
measure: Proportion of patients with impairment in renal function AND BPAR or inflammatory damage in biopsies or the presence of dnDSA in the last determination who present low sensitivity to all prescribed immunosuppressive drugs in IMBG
timeFrame: 12 months
measure: Proportion of patients with therapeutical failure due to rejection who present low sensitivity to the prescribed immunosuppressive drugs in IMBG
timeFrame: 12 months in the prospective follow-up cohort.
measure: Proportion of patients with with therapeutical failure due adverse effects attributable to immunosuppression who present high sensitivity /or low sensitivity and high doses to the prescribed immunosuppressive drugs in IMBG
timeFrame: 12 months in the prospective follow-up cohort.
measure: Proportion of patients whose pre-transplant IMBG predicts the incidence of events during the patients' follow up
timeFrame: 12 months
measure: Correlation between IMBG values and other lymphocyte activation markers
timeFrame: In the prospective cohort at 3, 6, 9, and 12 months
measure: Distribution of pre-transplant IMBG values and post-transplant at 3, 6, 9, and 12 months
timeFrame: In the prospective cohort at 3, 6 , 9 and 12 months
measure: Adherence to treatment measured with Morisky Green Scale (MMAS).
timeFrame: at 6 and at 12 months
measure: Quality of Life perceived by the patient, measured with EQ-5D-5L questionnaire.
timeFrame: baseline and at 12 months
Other outcomes:
Locations:
city: Brasil
country: Brazil
facility: Hospital Do Rim
city: Grenoble
country: France
facility: University Hospital Grenoble
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Barcelona
country: Spain
facility: Fundació Puigvert
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Cadiz
country: Spain
facility: Hospital Universitario Puerta del Mar
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario 12 Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
city: Valencia
country: Spain
facility: Hospital Universitario Dr. Peset
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
Study officials:
affiliation: Biohope Scientific Solutions for Human Health, S.L.
name: Isabel Portero
role: STUDY_CHAIR
References:
citation: Portoles JM, Jimenez C, Janeiro D, Lopez-Oliva MO, Ortega-Carrion A, Blanquez D, Arribas L, Gomez C, Diez T, Pascual J, Portero I. The Immunobiogram, a Novel In Vitro Assay to Evaluate Treatment Resistance in Patients Receiving Immunosuppressive Therapy. Front Immunol. 2021 Jan 25;11:618202. doi: 10.3389/fimmu.2020.618202. eCollection 2020.
citation: Pascual J, Jimenez C, Krajewska M, Seron D, Kotton CN, Portoles J, Witzke O, Sorensen SS, Andres A, Crespo M, Paz-Artal E, Diez T, Ortega A, Portero I. The Immunobiogram, a novel in vitro diagnostic test to measure the pharmacodynamic response to immunosuppressive therapy in kidney transplant patients. Transpl Immunol. 2022 Dec;75:101711. doi: 10.1016/j.trim.2022.101711. Epub 2022 Sep 9.
citation: Pascual J, Crespo M, Portoles J, Jimenez C, Ortega-Carrion A, Diez T, Portero I. The IMBG Test for Evaluating the Pharmacodynamic Response to Immunosuppressive Therapy in Kidney Transplant Patients: Current Evidence and Future Applications. Int J Mol Sci. 2023 Mar 8;24(6):5201. doi: 10.3390/ijms24065201.