Situational Analysis
Standard non-invasive monitoring to detect kidney injury secondary to
rejection or other causes includes measuring serum creatinine levels and
immunosuppressive drug levels, both of which are insensitive and
nonspecific. Clinical manifestations of severe rejection, such as fever,
pain over the graft, or decreased urine output may be present, but are
infrequent findings with current immunosuppressive regimens. Thus,
current non-invasive monitoring only detects rejection when it is
advanced and only after significant, and potentially irreversible damage
to the graft has occurred. Indication or for cause biopsies are
typically performed to determine the cause of acute renal dysfunction.
Biopsies are expensive, invasive, and suffer from significant
variability in interpretation (12). Moreover, biopsies put patients at
risk for significant complications such as infection, bleeding, and even
graft loss, in addition to being painful and inconvenient (13). However,
indication biopsies remain essential in the management of patients with
renal dysfunction and are used ubiquitously by transplant programs. In
sharp contrast, while a number of transplant programs have adopted the
routine use of surveillance biopsies to detect subclinical acute
rejection (subAR) in patients with stable renal function, several
factors have discouraged other programs from following suit. These
include but are not limited to all the issues stated above, but, in
addition, stable patients undergo indiscriminate biopsies resulting in
negative (unnecessary) invasive procedures the vast majority of the
time. Thus, a non-invasive monitoring strategy that replaces invasive
protocol biopsies is sorely needed and has been the focus of several
investigators in the past few years.
Previous investigators focused on developing non-invasive biomarkers in
the urine and blood to diagnose rejection in patients with graft
dysfunction (clinical acute rejection – cAR) in an attempt to replace
indication biopsies. There are two major fallacies to this approach:
first, while some patients with subAR develop cAR, others exhibit
ongoing subAR causing more chronic graft injury; second, in the absence
of paired biopsies for each sample, it is difficult to be certain that
bio-informatics approaches which yield positive results from these
samples are real. For this reason, we set out to develop a biomarker
specific for subAR by using only blood samples paired with protocol
biopsies in patients with stable renal function.