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.