Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04855422 |
| Other study ID # |
2021-12823 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
July 14, 2021 |
| Est. completion date |
July 2025 |
Study information
| Verified date |
December 2023 |
| Source |
Montefiore Medical Center |
| Contact |
Enver Akalin, MD |
| Phone |
877.287.3536 |
| Email |
eakalin[@]montefiore.org |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
This is a non-randomized, non-interventional, prospective pilot cohort study to monitor SPK
patients post-transplant to determine if non-invasive measures using dd-cfDNA (Allosure) and
AlloMap can assess an array of immune panels to predict and confirm the development of
allograft injury and rejection in either organ.
Aims of the study
1. To develop and validate AlloSure and AlloMap in SPK transplant recipients with stable
allograft function and in diagnosis of acute TCMR and ABMR in either organ
2. To assess the ability of AlloSure and AlloMap to determine early discordant rejection in
SPK recipients
3. To investigate AlloSure and AlloMap in SPK transplant recipients with diagnosis of BKV
viremia
Description:
Currently, one the challenges of durable glucose management after pancreas transplantation is
the ability to accurately and expediently diagnose early rejection to prevent unnecessary
damage to the graft. This assessment is further complicated in combined organ
transplantation. Simultaneous pancreas and kidney (SPK) transplantation accounts for most of
the utilized pancreas grafts. However, both grafted systems (kidney and pancreas) are not
subject to equal immunologic pressures even though they are theoretically presented with
similar environments. Historically, the diagnosis of pancreatic rejection was assumed to be
tethered to the presence of concomitant kidney rejection. The two organs were believed to
reject in tandem. As such, many centers use sentinel biopsy of the kidney to determine
rejection in the one or both organs. More recently, many studies have called into question
this management strategy as there appears to be increasing evidence that both organs can
reject independently of one another.
The presence of two organs allows for many combinations of rejection: both organs may undergo
acute rejection known as concordant rejection or one organ may undergo acute rejection
independently of the other organ known as discordant rejection. Kidney or pancreas rejection
may occur in any time frame after SPK and can greatly affect graft survival. In order to
clinically determine rejection in SPK recipients we monitor serum amylase, lipase, glucose,
creatinine and proteinuria. Abnormalities in these labs in conjunction with clinical changes
often are the indication for biopsy to determine the presence of rejection. More importantly,
histology dictates treatment regimen and course. Invariably, SPK recipients sometimes present
with normal creatinine and renal function, but with abnormal pancreatic enzymes. In most
cases, the kidney biopsy would precede any discussion of pancreas biopsy due to the
aforementioned notion of concordant rejection between organs. Certainly, biopsy proven
rejection in the kidney with pancreatic enzymatic leak would necessitate aggressive
anti-rejection therapy given the high likelihood of pancreatic involvement. However, many
times these renal biopsies would be normal and lead to a quandary of how vigorously to pursue
further evaluation of the pancreas.
Pancreas graft biopsy is not a common practice, but has been reported to be performed
percutaneously, transcystoscopically if the pancreas was anastomosed to bladder,
endoscopically, and laparoscopically in a few small series. Most centers use Interventional
Radiology for CT guided pancreas biopsy. More importantly, there have been reported cases of
complications for pancreas biopsies, mainly stemming from intraabdominal bleeding requiring
surgical intervention [1]. In an effort to reduce potential patient morbidity from pancreatic
biopsy, non-invasive tools like AlloSure that assesses donor-derived cell-free DNA (dd-cfDNA)
and AlloMap; a gene expression-profiling test may provide an attractive alternative.
Currently dd-cfDNA analysis (AlloSure, CareDx®) in the kidney has shown promise. While the
gold standard at present remains histologic assessment of kidney tissue, this may be changing
as acceptance of dd-cfDNA grows. Dd-cfDNA analysis is advantageous as it is a noninvasive,
less costly, and a potentially safer way to assess allograft rejection. Additionally, the
easier accessibility of testing dd-cfDNA can enable more frequent testing, which can
elucidate a more accurate progression of rejection rather than a biopsy which is only a
snapshot in time. For renal analysis the recommended dd-cfDNA cutoff value is 1.0% to
diagnose active rejection (positive and negative predictive values are 61% and 84%). While it
seems reasonable that discordant rejection may apply to similar levels of dd-cfDNA seen in
kidney alone rejection, concordant rejection levels of dd-cfDNA are unclear.
Notably, the technology behind Allosure has provided several insights into cellular injury
from a variety of milieu. In the study by Shen et al., the dd-cfDNA level in deceased donors
(44.99%) was significantly higher than that in the living donors (10.24%) at initial time, P
< 0.01. Dd-cfDNA level in delayed graft function (DGF) recipients was lower (23.96%) than
that in non-DGF (47.74%) at the initial time, P = 0.89 (19.34% in DGF and 4.46% in non-DGF on
the first day, P = 0.17). There was a significant correlation between dd-cfDNA level at
initial time and serum creatinine (r2 = 0.219, P = 0.032) and warm ischemia time (r2 = 0.204,
P = 0.040). DGF patients experienced a slower decline than non-DGF patients, but both groups
had a rapid decline in dd-cfDNA post-transplant.
However, most importantly it appears that a recurrence of dd-cfDNA level may be indicative of
active rejection [5]. In the case report by Hurkmans et al., it was shown that dd-cfDNA was a
sensitive biomarker to detect rejection in solid organ transplantation in a renal transplant
patient diagnosed with melanoma and taking nivolumab as treatment. Additionally, the utility
of Dd-cfDNA has been studied in the pediatric renal transplant population. In the study by
Puliyanda et al., biopsies were completed when dd-cfDNA > 1.0% or when there was high
clinical suspicion. 19 of 67 patients had dd-cfDNA testing as part of routine monitoring with
a median dd-cfDNA score of 0.37 (IQR: 0.19-1.10). 48 of 67 patients who had clinical
suspicion of rejection had median dd-cfDNA score of 0.47 (0.24-2.15). DSA-positive recipients
had higher dd-cfDNA scores than those who were negative or had AT1R positivity alone (P =
.003). There was no association between dd-cfDNA score and strength of DSA positivity. 7 of
48 recipients had a biopsy with a dd-cfDNA score <1%; two showed evidence of rejection.
Neither DSA nor AT1R positivity was statistically associated with biopsy-proven rejection.
However, dd-cfDNA >1% was diagnostic of rejection with sensitivity of 86% and specificity of
100% (AUC: 0.996, 0.98-1.00; P = .002). In the study by Sigdal et al., urinary dd-cfDNA after
kidney transplantation correlates to the apoptotic injury load of the donor organ. Serial
monitoring of urinary dd-cfDNA has been shown to be a sensitive proxy and biomarker of acute
injury in the donor organ, but fails to have specificity to differentiate between acute
rejection and BK virus nephropathy. Therefore, dd-cfDNA is an appropriate and accurate method
in lieu of a biopsy to assess allograft rejection and injury. However, one of the limitations
of dd-cfDNA is its ability to be detected is inhibited by methylprednisolone.
In addition to dd-cDNA, the quantification of select genes in circulating leukocytes
(AlloMap, CareDx®) has potential to determine rejection. AlloMap has been shown to determine
the risk for rejection in Cardiac Allograft Rejection Gene Expression Observational Trial
(CARGO) and in the subsequent trial known as CARGO II. The current research of AlloMap in
multi-organ recipients reflects a national cohort of 18 heart-kidney, 8 heart-liver, 1
heart-lung matched to 54 heart only recipients. AlloMap Heart® is a panel assay of 20 genes,
11 informative and 9 used for normalization and/or quality control, which produces gene
expression data used in the calculation of an AlloMap Heart test score - an integer ranging
from 0 to 40. Compared with patients in the same post-transplant period, the lower the score,
the lower the probability of acute cellular rejection at the time of testing. Recently a
multivariable gene-expression signature targeting T-cell-mediated rejection in peripheral
blood of kidney transplant recipients was developed. This frugal TCMR-signature was made of
(IFNG, IP-10, ITGA4, MARCH8, RORc, SEMA7A, WDR40A).
The gene expression profiles in renal transplant recipients with BKV viremia have been
investigated by microarrays. This research analyzed entire blood gene expression profiles of
19 BKV viremia patients matched to 14 patients without BKV viremia and showed a significant
higher expression of GRIT, CAT, and NK cell associated transcript. The study results
indicated increased activity of cytotoxic T cells and NK cells in both BKV viremia and
nephropathy that resembled acute rejection and showed potential involvement of both the
innate and adaptive immune system. This study documents to the importance of studying BKV
viremia to exclude the diagnosis due to similar gene expression pattern in blood compared to
rejection. In other study, gene expression profiles of DSA+ renal transplant recipients were
analyzed with and without tissue findings of ABMR and found that DSA+ patients with ABMR has
increased expression of activation, regulation, and differentiation of immune cells (T cells,
NK cells, leukocytes, and interleukins).
Allosure and Allomap tests were not studied in SPK recipients in detail. Cutoff values for
Allosure test could be different in stable SPK recipients compared to kidney transplant
recipients due to additional donor tissue (pancreas and duodenum). It is also unknown, what
would be the Allosure values in pancreas and/or kidney rejection in SPK recipients. It is
also unknow the circulating gene transcripts in SPK recipients with rejection. Using the
similar concept of peripheral blood gene expression by Allomap testing, AlloMap
Kidney/Pancreas could be created.
