Acute rejection: what do the circulating cells have to say about it?

One of the frequent situations that we face in the renal transplant clinic is the patient in otherwise good condition who presents with a slight rise in serum creatinine. Although this is sometimes due to reversible causes, such as high CNI levels or dehydration, acute rejection is of course in the differential. 

The fact that we still rely on an invasive procedure – the graft biopsy – for formal diagnosis of rejection clearly limits our ability for repetitive monitoring and potentially delays treatment. There is no doubt that a simple, non-invasive assay to monitor the immune status would be of great help in the day-to-day practice. Indeed this is currently a field of intense research in transplantation. We recently provided new insights into this issue. We optimized a simple assay to determine the level of activation of circulating blood mononuclear cells in renal transplant recipients. The method is relatively straightforward: peripheral blood is collected, cells are isolated and incubated overnight; cytokine production by the cultured cells is measured in the cell supernatant. The main objective was to determine if this assay, when used in patients for whom a biopsy was performed for an acute rise in serum creatinine, could identify those that would show histological signs of rejection. We found that the measurement of a single cytokine, IL-6, can predict rejection with a sensitivity of 92% and specificity of 63%. This tool could thus potentially be used to exclude rejection, which would be particularly helpful for low-risk or remote patients. 

Where do we go now? 

This work is a first step towards the development of a clinically useful tool. Ideally, a non-invasive test would be able to identify acute rejection well before the serum creatinine starts to rise. To achieve this, we now need to collect blood samples and study cell activation serially post transplant. What we need to determine more precisely is when the cells become activated before the usual signs of graft dysfunction occur. This will allow us to identify rejection early and by doing so, to prevent further graft damage. Although this sounds simple, from a research perspective this next step implies an enormous investment of human and lab resources. 

Sacha De Serres
Leonardo Riella