Assessing Benchmarks For Allosure And Allomap Testing in Simultaneous Kidney & Pancreas Transplant Recipients.

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.