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Biology of Graft Rejection & Damage

For patients undergoing kidney transplantation, there are many risks from both within the body and from external threats that may result in rejection, injury, or failure of the graft and jeopardize patient outcomes. These risks relate to many different biological pathways and systems at play within our bodies. The immune system is the most well recognized risk. Because it is designed to monitor and attack invading foreign elements to protect the body, it is not able to distinguish that the transplanted kidney is there to help. Carrying on with its duties, the immune system will mount an attack on the graft, leading to an inflammatory response and eventual damage to the graft, unless blocked by medications to suppress the immune system and prevent this from happening.

Knowing exactly what the right dose of these medications is for each patient is challenging. If not enough medication is used, the immune system will still be able to attack the graft. Conversely, if too much medication is used, there is a significantly increased risk of infection and cancer development. Identifying the appropriate dose for each patient is further complicated by the fact that every patient is different. Some may have a very active immune system, which would require them to have a higher dose of immune-suppressing drugs or to be treated with them for longer durations. Other patients may have immune systems that naturally have a reduced response and require less assistance. Aside from the immune system, other systems may also cause harm when they become imbalanced or malfunction.

For example, when blood flow is disrupted, often is the case with transplants, oxygen and nutrient delivery to and from the graft is interrupted, which further introduces stress upon the graft. Chronic inflammation also poses a significant long-term threat to graft survival. Injury to the graft recruits inflammatory immune cells to the injured sites, which promotes their secretion of pro-inflammatory molecules. These pro-inflammatory molecules further stimulate immune activation and immune cell infiltration and inflammation within the graft—a vicious cycle that can increase tissue damage.

Importantly, there are also systems that can help reduce the risk of graft rejection, such as cellular and tissue repair pathways that strengthen the graft’s ability to recover from damaging events. These repair mechanisms can support a return to balance by reducing inflammation and promoting recovery from damage. Patients with robust repair pathways and an immune system that is less likely to attack a graft may benefit from reduced doses of immunosuppressant therapies. Although high-risk patients with acute graft rejection are generally easier to diagnose because patients are often symptomatic and warning signs are usually detected in post-procedure tests, these tests are late indicators of compromises on kidney health. Additionally, patients with intermediate risk may have rejection occurring that goes undetected in post procedure tests due to their lack in sensitivity—posing a silent risk to their long-term outcomes. Altogether, graft tolerance is a complex process, and outcomes are governed by a continuum of delicate balancing acts between many integrated mechanisms and systems, ranging from cellular repair and regulation of inflammation to tissue regeneration and immune system suppression.