About 50% of renal transplant patients will suffer graft loss within 10 years.
Graft loss leads to a critical situation, but overexposure to drugs is not without risk. It leads to medium- and long-term organ damage in patients, with deterioration of quality of life and even death.
For this reason, a different approach is increasingly necessary. Personalization of drug regimens, adapting the type of drug, combination and doses to the “expected” response of patients is essential to minimize the risk of rejection, lack of treatment adherence and the side effects of prolonged overexposure to drugs.
Inadequate control of the alloimmune response triggers chronic rejection, the main reason for late allograft loss. To prevent this, patients undergo continuous treatment with immunosuppressive drugs (IMS), which are also associated with serious adverse effects. Transplant recipients must comply with complex therapeutic regimens that often include one or more immunosuppressive agents.
Currently, immunosuppressive therapy is not based on the individual’s immune alloreactivity profile. Despite the great demographic and clinical heterogeneity of recipients in renal transplantation, IMS selection and dose titration is essentially empirical. Decisions are mainly guided by the recommendations of international clinical guidelines (KDIGO), then adjusted according to peripheral blood drug concentrations and the occurrence of related side effects. However, toxicity and rejection still occur within acceptable concentration ranges.
The current standard of monitoring transplant patients by drug levels is not optimal because it does not take into account the different and individual effects of IMS drugs in each patient. In fact, patients may receive inadequate or insufficient IMS treatment (under-immunosuppression, with increased risk of graft rejection), or more IMS treatment than necessary (over-immunosuppression, with increased risk of serious side effects such as cancer or opportunistic infections).
Immunosuppression, in the case of transplantation, comprises induction and maintenance therapy. Induction consists of the administration of potent anti-rejection drugs at the time of transplantation, when the risk of acute rejection is greatest. Maintenance drugs are used as initial and long-term therapy to prevent acute and chronic rejection.
The main maintenance IMS are:
- Calcineurin inhibitors
- Mycophenolate mofetil/sodium
- mTOR inhibitors, Sirolimus, Everolimus
T lymphocytes are known to play a key role in initiating and mediating alloimmune responses that contribute to acute and chronic allograft rejection. IMS drugs act at different steps of T-cell activation, exerting mainly an antiproliferative effect (such as Mycophenolate mofetil/sodium or Azathioprine) or rather an inhibition of T-cell activation (such as Tacrolimus) .
There is currently no tool in clinical practice to predict the individual patient’s immune response to immunosuppressive drugs. However, some previous publications have shown that a pharmacodynamic approximation of the patient’s immune response to immunosuppressive drugs can be obtained by exposing their activated peripheral blood mononuclear cells (PBMC) to the drugs in an in vitro cell culture procedure. This response is associated with clinical outcomes.
Pharmacodynamics, reports the effects of drugs on immune cells when quantified according to their mechanisms of action.
Following this new model of scientific approach to determine the more adequate treatments, Biohope has developed and patented the IMMUNOBIOGRAM®, an IVD tool to optimize immunosuppressive therapy.
Rationale for the Immunobiogram®
Individual immune response to IMSs can be measured in vitro and correlates with clinical outcomes:
1- A pharmacodynamic approach to measure patients’ response to IMS in vitro is feasible.
- Culture of PBMC for 3-4 days in vitro in the presence of a proliferative stimulus and exposure to serial concentrations of IMS
- Measurement of cell blastogenesis
- Dose-response curves of the in vitro effects of IMS against PBMC proliferation for each patient.
- The curves deviates considerably between patients and IMS, describing a sensitivity/resistance pattern
2- In vitro response to IMS is associated with clinical outcomes
Patients with a resistance profile showed a higher rate of graft loss (p<0.02) and more episodes of acute rejection (p< 0.05)
Based on this rationale, Immunobiogram® was developed as an IVD to improve the experimental technology done previously, and to facilitate its implementation in clinical practice by a new patented process.
Immunobiogram® is not a prognosis biomarker tool. A correlation with clinical outcome is expected, but not a prediction of clinical outcome as the sole variable. Is not a pharmacokinetic test, like immunosuppressant blood levels, but is a pharmacodynamic test. It provides the sensitivity/resistance profile of KT patients circulating PBMCs to a panel of immunosuppressants
Thus, it is expected to correlate with clinical prognosis and should be useful to improve clinical outcome, because medication is mostly the sole factor actionable in clinical management
Immunobiogram® captures approximately the causality linked to the patient risk in renal transplantation derived from response to medication.
- Immunobiogram® test builds on the in-vitro measurement of metabolic activity of immunologically activated PBMCs, as response to individual immunosuppressive drugs.
- It is a quantitative test. The fluorometer reading is automatic and the interpretation is performed through a specific software.
- Immunobiogram® provides clinicians an individual pharmacodynamic information of the effect of each immunosuppressant on patient´ s lymphocytes T activation/proliferation related to a reference population.
- This effect is associated with the risk of rejection related to medication and it can complement the global graft rejection risk evaluation in kidney transplant patients