Improving KIdney Transplantation with Cellular Therapy Study

Immune Tolerance, Kidney Transplant Rejection

The i-KITCaT study aims to harness cellular therapies to favourably alter the immunological response to in AKI in transplantation. Kidney transplantation offers the best survival and quality of life outcomes for patients with end-stage kidney disease but requires life-long immunosuppression. Efforts to increase the donor organ pool means accepting kidneys which have been subjected to medical and surgical factors culminating in acute kidney injury (AKI). There is no treatment to modify the maladaptive injury process following an AKI insult, and this subjects the new kidney to increased risk of needing dialysis in the first 7 days of transplantation, rejection, and shortened transplant survival. Tolerogenic dendritic cells (TolDC) are currently used in phase I/II clinical trials and are safe for patients receiving a kidney transplant from the same donor as these cells. These trials focus on transplant tolerance, but we will re-purpose TolDCs to favorably alter the disease course following AKI and limit injury following transplantation. Furthermore, if the patient's own cells (rather than from a third-party donor) can be used, this avoids supply limitations and potential sensitization risk. We will compare the functional characteristics of TolDC generated from control (healthy) and kidney disease (chronic kidney disease (CKD), dialysis and transplantation).

This observational, cohort study will be conducted at Westmead Hospital * 3 visits over 24-months per participant. * each consenting participant will donate 20 - 50ml of peripheral blood per visit. * recruit n = 20 per study group (control, CKD, dialysis, and transplant). Aims include: 1. Compare generation of therapeutic grade tolerogenic dendritic cells (TolDC) from peripheral blood mononuclear cells derived from controls (healthy) and patients with kidney disease (CKD, dialysis, or transplantation). 2. Perform testing of TolDC phenotype, tolerogenic capacity and yield. 3. Generate hypothesis for different mechanisms of TolDC function not yet described for further characterisation to support future research Research plan: * Peripheral blood mononuclear cells (PBMC) will be isolated from blood by Ficoll gradient and ultrapure magnetic bead sorting. * PBMC will be tested for purity (other unwanted immune cells) and microbiological contaminants before added to specialized DC media to generate TolDC. * TolDC will have in depth functional characterization including flow cytometry, cytokine expression, genomic sequencing, and in-vitro testing protocols. * TolDCs will be co-cultured with human renal cells to test protective capabilities across different AKI stimuli/insults. This allows selection of ideal PBMC donors to generate functionally desirable TolDC for subsequent use in i-KITCaT studies.

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