ASN has hosted the world's premier meeting in nephrology for more than 50 years, which was reimagined as a fully digital meeting for Kidney Week 2020. As a transplant nephrologist, I always look forward to the major novelties in kidney transplantation, and this year, I identified three series of presentations.
The first theme of interest focused on precision medicine and molecular studies of kidney allograft injury using single-cell RNA sequencing, proteomics, epigenome-wide microarray analysis, and donor-derived cell-free DNA (dd-cfDNA) technologies to risk stratify outcomes. In a study by Malone et al., single-nucleotide variation and single-cell RNA sequencing was utilized to define immune cell chimerism in the rejecting kidney transplant. The investigators demonstrated that donor origin macrophages and T cells have distinct transcriptional profiles compared to their recipient counterparts, and donor macrophages can persist for years post-transplantation. The same authors used a similar approach, but this time to tubular cells, and presented studies suggesting a role for loop of Henle cells in antibody-mediated rejection through the expression of CXCL12. In another study using compartmental proteomics analyses, Clotet Freixas et al. determined that extracellular matrix injury occurs early in the glomeruli and tubulointerstitium of kidney allografts with antibody-mediated rejection. The group from Mount Sinai, NY, presented a study indicating that single-cell profiling of peripheral blood mononuclear cells could identify immune populations associated with a high risk of early acute rejection. Studies by Kerr et al. highlighted epigenome-wide microarray analysis of pre- and post-transplant methylation profiles in kidney transplant recipients. This indicated that further methylation and transcriptomic analyses could help identify epigenetic risk factors associated with post-transplant complications.
A series of 10 posters presented findings addressing the role of dd-cfDNA monitoring for kidney transplant injury. Briefly, these studies suggested no significant difference in the performance of AlloSure vs. Prospera for the diagnosis of rejection, a transient increase in AlloSure levels after a kidney transplant biopsy, nearly equal performance of Prospera in de novo versus repeat kidney transplant recipients, and a strong correlation between Molecular Microscope (MMDx), class II DSA, microvascular inflammation, and AlloSure. In aggregate, there is promising information on the role of molecular diagnostics and precision medicine in kidney transplant recipients. However, the actual clinical value of these tests remains to be determined.
The second major theme of interest at ASN’s Kidney Week was around tolerance and donor-specific immunosuppression. Dixon Kaufman presented an interim update of the MDR-101-MLK Phase 3 Trial: MERCURY Study. MDR-101 is a novel cellular immunotherapy, able to produce persistent mixed chimerism without graft versus host disease (GvHD). This allows the elimination of all immunosuppression (IS) therapy without rejection. The randomized study evaluated the need for chronic IS therapy in recipients of HLA-matched living donor (LD) kidney transplants as compared to standard of care (SOC). Eligible adult pairs, donors and recipients, of a first kidney allograft from an HLA-identical LD were enrolled and randomized two-to-one to either the Investigational Arm (IA; n=20) or Control Arm (CA; n=10). Donors in the IA received G-CSF mobilization for five days before undergoing apheresis (one or two cycles). IA recipients received ATG conditioning, low-dose total lymphoid irradiation (TLI) over 10 days, IS therapy, and then followed by an infusion of MDR-101 on d11. After 180 days of persistent mixed chimerism, IA subjects initiated a six-month taper of CNI and could withdraw all IS on D365. CA subjects were treated as institutional SOC. As of June 1, 2020, 26 subject pairs (donor/recipient) have been enrolled, comprising 18 pairs randomized to the IA and eight pairs randomized to the CA. MDR-101 infusion was completed in 12 subjects in the IA. To date, nine subjects in the IA have reached Day 180 with six months of positive mixed chimerism, five reached Day 365 and were able to withdraw from all IS, and two lost chimerism — one at Day 545 (off IS) and one at Day 240 continue to wean IS. There have been no events of GvHD, biopsy-proven acute rejection, dnDSA. There have been no graft losses or deaths in either group. These studies suggest that administration of MDR-101 in HLA-identical LD kidney transplant recipients conditioned with ATG and TLI have produced promising results via mixed chimerism without GvHD. Another study, based on donor-specific immunosuppression after modified immune cell infusion, demonstrated a long-lasting increase in regulatory B cells (Breg) at various stages of B cell development, including memory Bregs. In aggregate, these studies suggest that donor-specific immune tolerance may be achieved, at least in low immunological risk patients.
The third and final important theme of research at ASN's Kidney Week addressed racial and social disparities in kidney transplantation. Chu et al. presented data indicating that variation in underlying end-stage renal disease (ESRD) risk distributions by race and/or ethnicity has the potential to produce systematic racial disparities against Black Americans and Hispanics due to under-recognition of the higher progression risk when a singular eGFR threshold is used as a decision point. Brunelli et al. presented information confirming that racial disparities still existed within the kidney transplant process, including downstream of the referral. Similarly, Swift et al. presented how social determinants of health predict patient-reported outcomes in transplant-eligible ESRD patients. In an interesting study by Zanoni et al., the investigators compared the effects of self-reported race versus genetic-African admixture on graft outcomes, and showed that both self-reported race and a genetically-derived continuous measure of African ancestry predict the risk of allograft rejection and failure in multiethnic and genetically diverse cohorts. Finally, in a study of 297 donors by Goggins et al., the investigators showed that the rate of declined authorization for research participation from next of kin was higher among donors from African American ethnicity compared to donors from White or Hispanic backgrounds, especially when donor age was less than 35. In aggregate, these studies highlighted the areas of unmet need to reduce heath and health care disparities in racial and social minorities.
ASN Kidney Week 2020 Reimagined was a success amidst the COVID-19 pandemic. Credit should go to the organizers and ASN leadership for the efforts to adjust, adapt, and move the society forward.
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