Renal Transplant Rejection Clinical Trial
Official title:
Addition of kSORT Assay in the Follow-up of Patients After Kidney Transplantation
This study evaluates the addition of "Kidney Solid Organ Rejection Test" (kSORT), in the clinical follow-up of renal transplant recipients, compared to clinical standard surveillance in the first two years after kidney transplantation. The design of the study is a partially blinded, randomized control trial of patients with living and deceased donor. The recruitment will be in a third level attention hospital in Mexico city (Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán). The main outcomes are the rate and grade of acute rejection, histologic chronic index of the one year protocol biopsy and glomerular filtration rate.
I. Background Kidney transplantation is the treatment of choice in patients with end stage
renal disease in need of function replacement therapy, and in whom there is no absolute
contraindication to the procedure. The current figures reported in the USA on post-transplant
graft survival at one year, are 95% in cases of living donor (LD) recipients and 90% in
deceased donor (DD) recipients3; the mean calculated survival of these grafts has increased
and is currently 14 years in LD and 11 years in DD recipients. The fact that graft survival
hinges on multiple immune and non-immune factors is well recognized; however, the main cause
of graft loss is solidly linked to its rejection, with evidence of involvement of the immune
humoral response in most cases (specific antibodies against HLA antigens).
The main cause of acute graft dysfunction is acute rejection (AR). Several studies have
associated episodes of this entity with chronic structural injury and subsequent functional
impairment. Thus, timely diagnostic certainty is pivotal so as to optimize immunosuppressive
therapy and preserve graft function. To date, the only tool available to confirm AR is graft
biopsy and its established histological diagnostic criteria8. However, this diagnostic tool
has limitations resulting mainly from sampling errors and costs. Furthermore, about 10% of
patients with normal graft function have evidence of AR in protocol biopsies, so centers that
do not use this follow-up modality in kidney transplant recipients (KTR) are unable to
document this immune phenomenon. Ideally, an AR non-invasive, diagnostic tool would be of
utmost use in KTR follow-up since it would preclude the need for graft biopsies and
efficiently support the management of immune suppressors. Therefore, the systematic
performance of a highly specific and sensitive assay reflecting AR, would allow for the
timely detection of this immune phenomenon compared to the current standard (biopsy).
Moreover, the systematic use of a tool with these characteristics would allow stratification
of the immunological risk as well as proactive adjustment of immunosuppressor drug dosages,
potentially limiting chronic injury and improving the graft's survival.
The background to the proposed study is based on the extensive line of research conducted by
Dr. Sarwal et al. They have recently published results10 on monitored pediatric kidney
transplant recipients. Biomarkers of gene panels in peripheral blood detected by microarray
were discovered in a single institution and subsequently validated by quantitative-PCR in 12
pediatric kidney transplant programs. A total of 367 individual blood samples, each paired to
a graft biopsy for blinded centralized classification, were analyzed (115 with acute
rejection, 180 with stable kidney graft function, and 72 with other causes of graft injury).
Among the genes differentially expressed in microarrays, quantitative-PCR analysis of a set
of 5 genes (DUSP1, PBEF1, PSEN1, MAPK9 and NLTR) classified acute rejection with great
precision. The 5 gene model has a sensitivity of 91%, specificity of 94%, positive predictive
value of 83%, negative predictive value of 97% and a 92% precision when differentiating acute
rejection samples from other phenotypes (stable and no acute rejection, no acute rejection/
non-stable). Interestingly, 8/12 samples from patients with borderline rejection on biopsy,
were classified as acute rejection with the 5 gene model. The frequent prediction of the
phenotype in borderline rejection biopsies suggests that pre-clinical injury in acute
rejection could also be identified by quantitative-PCR in peripheral blood samples, thus
allowing earlier treatment of these patients.10 The fact that this model predicts acute
rejection in both cellular and humoral immune injury modalities, is of utmost relevance.
Moreover, these genes in peripheral blood, strongly linked to graft rejection, do not
correlate (are independent) with many demographic, clinical, treatment modalities and
bacterial/viral infection parameters.
The 5 genes are centered on leukocyte trafficking and T/B cell activation and are mostly
expressed in monocytes, activated in the peripheral circulation; they reflect injury response
mechanisms to cellular oxidative stress (DUSP1), apoptosis (MAPK9), IL2-dependent cytolytic
gene activation (NKTR), increased cell adhesion via the e-cadherin/catenin complex (PSEN1)
and smooth muscle vascular cell injury (PBEF1).
The authors pointed out that the study was conducted in a pediatric and young adult
population, in whom rejection may be more aggressive due to the disparity between the adult
transplanted organ and the pediatric recipient, or as a result of poor treatment adherence in
adolescent recipients, leading to a stronger immune response. Thus, the 5-gene model would
require further evaluation in order to determine its diagnostic potential of acute rejection
in patients of all ages, in larger patient cohorts and in association with different
immunosuppressant regimes.
For these reasons, the same group of investigators undertook a large study to identify a
transcription profile that would unify the kidney transplant recipient population
independently of age, the cause of terminal renal disease, comorbidities, and the type of
immune suppression used in different centers in the USA, Mexico and Europe. The final
selection of 17 genes included 10 genes in the pediatric population and 7 newly identified
genes and allowed the molecular classification of acute rejection in adult and pediatric
patients. They correctly predicted the presence of acute rejection and non-acute rejection in
the different samples collected from patients in various participating study sites, and in
recipients of different ages with no previous data normalization. On the basis of these
observations, a score was generated using 14 of the 17 genes, and with Pearson's correlation
test, a score was attributed to each detected gene and compared with the genetic profile
found in patients with and without rejection, assigning the number +1 or -1. The score ranges
between -13 and +13. Among the patients in whom the score predicted a "high risk of
rejection" (Acute Rejection Risk-Score ≥ 7), 90.24% were correctly classified as acute
rejection, while if the test predicted "a very low risk of acute rejection" (Acute Rejection
Risk-Score ≤ -7), 97.7% were correctly classified as non-acute rejection on the basis of the
biopsy findings. Furthermore, the average predictive probability of acute rejection was
highly significant when comparing acute rejection vs. non-acute rejection in 4 centers
(p<0.0001; p=0.002; p<0.0001; p<00001), respectively. This model equally detected acute
rejections mediated by antibodies as well as those that were cell-mediated, with a high
predictive probability. The prediction of acute rejection was independent of the
post-transplant period duration. These 17 genes are included in the KSORT assay (Kidney Solid
Organ Rejection Test) and the algorithm generating the risk score is known as the kSORT
analysis suit (kSAS).
In a recently published study with data from our Institute, in which the results of biopsies
obtained because of post-transplant dysfunction were reviewed between January 2007 and
December 2011 (n=223), we observed an AR incidence during the first year post-transplant of
11.8% in live donor KTR and of 17.4% in deceased donor graft recipients. Throughout 2013, the
number of kidney transplants performed at the Institute increased to 63 (53% from living
donors, 46% from deceased donors). In accordance with our institutional protocol for the
follow-up of kidney transplant recipients, we currently obtain protocol graft biopsies on the
3rd and 12th month post-transplant. The protocol biopsies are obtained at established
timepoints with the purpose of documenting whether there is any evidence of immunological
activity (sub-clinical) or signs of other pathologies that would require modification of the
immunosuppressive therapeutic regime. We also obtain a graft biopsy at any point in the
post-transplant period if abnormalities in renal function develop, defined as a verified
increase in serum creatinine ≥ 25% over previous baseline values, and in the absence of other
evident pathologies such as obstructive processes of the urinary tract, urinary tract
infections, dehydration, supra-therapeutic blood levels of the used calcineurin inhibitor.
As of May 2013, the date in which the 3rd month protocol biopsy was established, we have
documented an incidence of sub-clinical acute rejections, including borderline and major
rejections according to the Banff classification, of 52% (10/40 biopsies revealed acute
cellular or humoral rejection and 11/40 had borderline injury). This number is unprecedented
at the Institute because protocol biopsies were not previously obtained on the 3rd month.
Currently, all KTR at the Institute receive an induction therapy modality (Thymoglobulin or
Basiliximab), depending on their individual immunological risk and the origin of the graft.
Hence, all live donor KT recipients with a PRA <30% and no HLA donor specific antibodies
(DSA) are treated with Basiliximab (anti-IL2R monoclonal antibody; 2 doses of 20mg each); the
exceptions are KTR sharing 2 haplotypes with their donor and that receive no induction
therapy. All deceased donor graft recipients (independently of the PRA %), live donor KTR
with positive donor-specific HLA antibodies (independently of the PRA %) or with a PRA ≥30%,
are induced with Thymoglobulin (rabbit polyclonal antibody preparation, at a total dose of
4.5mg/Kg). All patients must have a lymphocyte crossmatch test (T/B), a negative CDC-AHG and
those with DSA (Single antigen, Luminex) also require a negative crossmatch by flow
cytometry.
Biopsy-proven acute rejection events are treated with pulses of methylprednisolone for 3
consecutive days. Patients with steroid-resistant acute cellular rejection (biopsy-proven),
are administered Thymoglobulin (1.5 mg/Kg/body weight, for 7 days). Patients with
antibody-mediated acute rejection (humoral rejection) are treated with 3-5 plasmapheresis
(PP) sessions, 100 mg IV Ig per Kg body weight after each PP session and rituximab (anti-CD20
monoclonal antibody) at the end of all PP sessions.
The standard initial and maintenance immunosuppressive regime is Tacrolimus, Mofetil
Mycophenolate and prednisone. The initial Tacrolimus doses are aimed to obtain blood trough
levels of 10 to 15 ng/mL, until the 3rd month post-transplant; subsequently and in the
absence of AR during the first trimester (clinical or by protocol biopsy), the trough levels
are maintained between 8 and 10 ng/mL throughout the first year post-transplant. The
maintenance dose of prednisone is 5 mg daily and that of Mofetil Mycophenolate is 1-1.5 g
daily.
II. Justification In previous paragraphs, we described the KSORT test's high sensitivity and
specificity in the detection of acute rejection. It is now necessary to attempt its transfer
into the clinical setting and to help support treatment decisions, such as increasing immune
suppression based on a positive test result. The impact of this maneuver on efficacy and
safety outcomes will be pivotal in order to incorporate this scrutinizing method into daily
clinical practice. Our Institute has transplanted over 60 patients in the last few years, so
conducting this study in our center is feasible.
III. Hypothesis and aims Hypothesis Adding the kSORT genetic panel to the post-transplant
follow-up will decrease the incidence and severity of acute rejection as well as the
chronicity indices in the yearly protocol biopsy, and will improve the calculated glomerular
filtration rate after a follow-up of two years.
Aims:
To evaluate the safety and efficacy of adding the kSORT test to the surveillance of patients
after kidney transplantation.
;
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