A Pilot Clinical Trial to Evaluate the Feasibility and Acceptability of: A Prospective, Unblinded, Randomized-controlled, Multicenter Biomarker Intervention Trial of a Urinary CXCL10 Clinical Surveillance Program in Pediatric Kidney Transplant Recipients for Early Ascertainment and Treatment of Subclinical Allograft Inflammation and Preservation of Kidney Transplant Function

Kidney transplant offers hope to thousands of people living with chronic kidney disease, but the average five-year-old who gets a kidney transplant should expect to need a second transplant before they reach adulthood. In adults, transplantation extends patient survival by 30-40 years compared to dialysis. In children, almost 30% lose the transplant within 5 years, with acute rejection as the most common cause. Despite the urgent need, approaches for monitoring and early acute rejection detection are largely unchanged for the past 20 years. The goal of this study is to introduce innovative monitoring that will permit timely acute rejection diagnosis and effective treatment, preserve kidney function, delay graft failure and spare the lives of children with chronic kidney failure.

In pediatric kidney transplants, a single episode of acute rejection confers up to a 19-fold increased risk of histologically visible scarring, the hallmark sign of progressive graft damage. Acute acute rejection is associated with subsequent development of anti-donor HLA antibodies, and chronic types of antibody-mediated and T cell-mediated acute rejection that are refractory to treatment. Acute rejection is readily treated with IV corticosteroids or depleting anti-thymocyte antibody treatments. These major adverse outcomes from acute rejection can only be mitigated or avoided if acute rejection is 1) identified and treated early before chronic inflammation is established; and 2) treated fully with confirmation that the acute inflammation has resolved.

The reported adverse outcomes relate predominantly to "clinical" presentations of acute rejection, i.e. those cases presenting with already worsening kidney failure. Subclinical acute rejection refers to the earlier phase of acute rejection where inflammation is onset but has not yet led to clinical graft dysfunction. This matters enormously because although acute rejection may be invisible to standard clinical monitoring, early identification and treatment of subclinical acute rejection improves long-term function and allograft survival. Acute rejection is a process, not an event. It starts with acute inflammation, and in the absence of immediate treatment it initiates a cascade of immune cytokine signals that causes memory types of effector cells to mature and leads to the suppression of regulatory types of immune cells that would otherwise promote tolerance to the allograft. This immune cell profile within the kidney is characteristic of chronic rejection and often co-exists in late-detected episodes of acute rejection.

Subclinical acute rejection is typically NOT associated with concurrent chronic inflammation or the presence of donor specific antibodies. With timely treatment of acute rejection, there is better preservation of histology, kidney function and survival . The pivotal trial by Rush et al., demonstrated that treatment of subclinical acute rejection detected by protocol surveillance biopsies improved long term outcome compared to clinical acute rejection monitoring and treatment. Natural history studies in adults and in children confirm the progressive nature of untreated subclinical acute rejection and the superior outcome when it is treated. Whether clinically detected or detected on biopsy surveillance (subclinical), both are considered as "acute rejection" and are treated similarly, based on the histological severity.

Unfortunately, damage related to delayed diagnosis and treatment is compounded by the lack of tools to evaluate treatment response. Although it is not standard, follow-up biopsies after acute rejection treatment reveal that 50-61% of children have persistent acute rejection subclinical 6-8 weeks after treatment - undetected by kidney function monitoring . Earlier diagnosis and treatment are therefore critical to prevent damage and preserve long-term function, as are interventions to ensure that reversal of subclinical inflammation is complete.