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Emerging Role of Genetics in Kidney Transplantation

Zanoni, Francesca; Obayemi, Joy E; Gandla, Divya; Castellano, Giuseppe; Keating, Brendan
The advent of more affordable genomic analytical pipelines has facilitated the expansion of genetic studies in kidney transplantation. Advances in genetic sequencing have allowed for a greater understanding of the genetic basis of chronic kidney disease, which has helped to guide transplant management and address issues related to living donation in specific disease settings. Recent efforts have shown significant effects of genetic ancestry and donor APOL1 risk genotypes in determining worse allograft outcomes and increased donation risks. Genetic studies in kidney transplantation outcomes have started to assess the effects of donor and recipient genetics in primary disease recurrence and transplant-related comorbidities, while genome-wide donor-recipient genetic incompatibilities have been shown to represent an important determinant of alloimmunity. Future large-scale comprehensive studies will shed light on the clinical utility of integrative genomics in the kidney transplantation setting.
PMID: 39710162
ISSN: 1523-1755
CID: 5767092

Balancing equity and human leukocyte antigen matching in deceased-donor kidney allocation with eplet mismatch

Mankowski, Michal A; Gragert, Loren; Keating, Brendan; Lonze, Bonnie E; Segev, Dorry L; Montgomery, Robert; Gentry, Sommer E; Mangiola, Massimo
Human leukocyte antigen-level matching in US kidney allocation has been deemphasized due to its role in elevating racial disparities. Molecular matching based on eplets might improve risk stratification compared to antigen matching, but the magnitude of racial disparities in molecular matching is not known. To assign eplets unambiguously, we utilized a cohort of 5193 individuals with high-resolution allele-level human leukocyte antigen genotypes from the National Kidney Registry. Using repeated random sampling to simulate donor-recipient genotype pairings based on the ethnic composition of the historical US deceased-donor pool, we profiled the percentage of well-matched donors available for candidates by ethnicity. The prevalence of well-matched donors with 0-DR/DQ eplet mismatch was 3-fold less racially disparate for Black and Asian candidates and 2-fold less for Latino candidates compared to 0-ABDR antigen mismatches. Compared to 0-DR antigen mismatch, 0-DR eplet mismatch was 1.33-fold more racially disparate for Asian and 1.28-fold more for Latino, with similar disparity for Black candidates, whereas 0-DQ eplet mismatch reduced disparities, showing 1.26-fold less disparity for Black, 1.14-fold less for Latino, but 1.26-fold higher for Asian candidates. The prevalence of well-matched donors for candidates of different ethnicities varied according to which molecules were chosen to define a low-risk match.
PMID: 39631566
ISSN: 1600-6143
CID: 5781742

Family-base rare variant association analysis in Saudi Arabian hydrocephalus subjects using whole exome sequencing

Ammar, Ahmed; Bubshait, Dalal K; Al Ojan, Abdulrazaq; Alshari, Shuroq A; Cyrus, Cyril; Alanazi, Rawan; Al Ghamdi, Mohammed A; Keating, Brendan J; Al-Anazi, Abdulrahman; Al Qahtani, Noorah H; Al-Ali, Amein K
BACKGROUND:Hydrocephalus is a highly heterogeneous multifactorial disease that arises from genetic and environmental factors. Familial genetic studies of hydrocephalus have elucidated four robustly associated hydrocephalus associated loci. This study aims to identify potential genetic causation in cases of hydrocephalus, with or without spina bifida and Dandy Walker Syndrome (DWS), using family-based rare variant association analysis of whole exome sequencing. METHODS:We performed whole exome sequencing in 143 individuals across 48 families where at least one offspring was affected with hydrocephalus (N.=27), with hydrocephalus with spina bifida (N.=21) and with DWS (N.=3), using Illumina HiSeq 2500 instrument. RESULTS:No pathogenic or putative pathogenic single-nucleotide variants were evident in the four known hydrocephalus loci in our subjects. However, after examining 73 known hydrocephalus genes previously identified from literature, we identified three potentially impactful variants from the cohort. Using a gene panel comprising variants in known neural tube defects loci, we identified a total of 1024 potentially deleterious variants, of which 797 were missense variants and 191 were frameshift variants, 36 were stop gain/loss variants. A small portion of our family pedigree analyses yielded putative genetic signals which may be responsible for hydrocephaly elated phenotypes, however the low diagnostic yield may be due to lack of capture of genetic variants in the exonic regions i.e. structural variants may only be evident from whole genome sequencing. CONCLUSIONS:We identified three potentially impactful variants from our cohort in 73 known hydrocephalus genes previously identified in literature.
PMID: 37158713
ISSN: 1827-1855
CID: 5479012

Cellular dynamics in pig-to-human kidney xenotransplantation

Pan, Wanqing; Zhang, Weimin; Zheng, Binghan; Camellato, Brendan R; Stern, Jeffrey; Lin, Ziyan; Khodadadi-Jamayran, Alireza; Kim, Jacqueline; Sommer, Philip; Khalil, Karen; Weldon, Elaina; Bai, Jiangshan; Zhu, Yinan; Meyn, Peter; Heguy, Adriana; Mangiola, Massimo; Griesemer, Adam; Keating, Brendan J; Montgomery, Robert A; Xia, Bo; Boeke, Jef D
BACKGROUND:Xenotransplantation of genetically engineered porcine organs has the potential to address the challenge of organ donor shortage. Two cases of porcine-to-human kidney xenotransplantation were performed, yet the physiological effects on the xenografts and the recipients' immune responses remain largely uncharacterized. METHODS:We performed single-cell RNA sequencing (scRNA-seq) and longitudinal RNA-seq analyses of the porcine kidneys to dissect xenotransplantation-associated cellular dynamics and xenograft-recipient interactions. We additionally performed longitudinal scRNA-seq of the peripheral blood mononuclear cells (PBMCs) to detect recipient immune responses across time. FINDINGS/RESULTS:Although no hyperacute rejection signals were detected, scRNA-seq analyses of the xenografts found evidence of endothelial cell and immune response activation, indicating early signs of antibody-mediated rejection. Tracing the cells' species origin, we found human immune cell infiltration in both xenografts. Human transcripts in the longitudinal bulk RNA-seq revealed that human immune cell infiltration and the activation of interferon-gamma-induced chemokine expression occurred by 12 and 48 h post-xenotransplantation, respectively. Concordantly, longitudinal scRNA-seq of PBMCs also revealed two phases of the recipients' immune responses at 12 and 48-53 h. Lastly, we observed global expression signatures of xenotransplantation-associated kidney tissue damage in the xenografts. Surprisingly, we detected a rapid increase of proliferative cells in both xenografts, indicating the activation of the porcine tissue repair program. CONCLUSIONS:Longitudinal and single-cell transcriptomic analyses of porcine kidneys and the recipient's PBMCs revealed time-resolved cellular dynamics of xenograft-recipient interactions during xenotransplantation. These cues can be leveraged for designing gene edits and immunosuppression regimens to optimize xenotransplantation outcomes. FUNDING/BACKGROUND:This work was supported by NIH RM1HG009491 and DP5OD033430.
PMID: 38776915
ISSN: 2666-6340
CID: 5654702

Integrative multi-omics profiling in human decedents receiving pig heart xenografts

Schmauch, Eloi; Piening, Brian; Mohebnasab, Maedeh; Xia, Bo; Zhu, Chenchen; Stern, Jeffrey; Zhang, Weimin; Dowdell, Alexa K; Kim, Jacqueline I; Andrijevic, David; Khalil, Karen; Jaffe, Ian S; Loza, Bao-Li; Gragert, Loren; Camellato, Brendan R; Oliveira, Michelli F; O'Brien, Darragh P; Chen, Han M; Weldon, Elaina; Gao, Hui; Gandla, Divya; Chang, Andrew; Bhatt, Riyana; Gao, Sarah; Lin, Xiangping; Reddy, Kriyana P; Kagermazova, Larisa; Habara, Alawi H; Widawsky, Sophie; Liang, Feng-Xia; Sall, Joseph; Loupy, Alexandre; Heguy, Adriana; Taylor, Sarah E B; Zhu, Yinan; Michael, Basil; Jiang, Lihua; Jian, Ruiqi; Chong, Anita S; Fairchild, Robert L; Linna-Kuosmanen, Suvi; Kaikkonen, Minna U; Tatapudi, Vasishta; Lorber, Marc; Ayares, David; Mangiola, Massimo; Narula, Navneet; Moazami, Nader; Pass, Harvey; Herati, Ramin S; Griesemer, Adam; Kellis, Manolis; Snyder, Michael P; Montgomery, Robert A; Boeke, Jef D; Keating, Brendan J
In a previous study, heart xenografts from 10-gene-edited pigs transplanted into two human decedents did not show evidence of acute-onset cellular- or antibody-mediated rejection. Here, to better understand the detailed molecular landscape following xenotransplantation, we carried out bulk and single-cell transcriptomics, lipidomics, proteomics and metabolomics on blood samples obtained from the transplanted decedents every 6 h, as well as histological and transcriptomic tissue profiling. We observed substantial early immune responses in peripheral blood mononuclear cells and xenograft tissue obtained from decedent 1 (male), associated with downstream T cell and natural killer cell activity. Longitudinal analyses indicated the presence of ischemia reperfusion injury, exacerbated by inadequate immunosuppression of T cells, consistent with previous findings of perioperative cardiac xenograft dysfunction in pig-to-nonhuman primate studies. Moreover, at 42 h after transplantation, substantial alterations in cellular metabolism and liver-damage pathways occurred, correlating with profound organ-wide physiological dysfunction. By contrast, relatively minor changes in RNA, protein, lipid and metabolism profiles were observed in decedent 2 (female) as compared to decedent 1. Overall, these multi-omics analyses delineate distinct responses to cardiac xenotransplantation in the two human decedents and reveal new insights into early molecular and immune responses after xenotransplantation. These findings may aid in the development of targeted therapeutic approaches to limit ischemia reperfusion injury-related phenotypes and improve outcomes.
PMID: 38760586
ISSN: 1546-170x
CID: 5654102

Improving long-term kidney allograft survival by rethinking HLA compatibility: from molecular matching to non-HLA genes

Mattoo, Aprajita; Jaffe, Ian S; Keating, Brendan; Montgomery, Robert A; Mangiola, Massimo
Optimizing immunologic compatibility in organ transplantation extends beyond the conventional approach of Human Leukocyte Antigen (HLA) antigen matching, which exhibits significant limitations. A broader comprehension of the roles of classical and non-classical HLA genes in transplantation is imperative for enhancing long-term graft survival. High-resolution molecular HLA genotyping, despite its inherent challenges, has emerged as the cornerstone for precise patient-donor compatibility assessment. Leveraging understanding of eplet biology and indirect immune activation, eplet mismatch calculators and the PIRCHE-II algorithm surpass traditional methods in predicting allograft rejection. Understanding minor histocompatibility antigens may also present an opportunity to personalize the compatibility process. While the application of molecular matching in deceased donor organ allocation presents multiple technical, logistical, and conceptual barriers, rendering it premature for mainstream use, several other areas of donor-recipient matching and post-transplant management are ready to incorporate molecular matching. Provision of molecular mismatch scores to physicians during potential organ offer evaluations could potentially amplify long-term outcomes. The implementation of molecular matching in living organ donation and kidney paired exchange programs is similarly viable. This article will explore the current understanding of immunologic matching in transplantation and the potential applications of epitope and non-epitope molecular biology and genetics in clinical transplantation.
PMCID:11480002
PMID: 39415982
ISSN: 1664-8021
CID: 5718652

Immune response after pig-to-human kidney xenotransplantation: a multimodal phenotyping study

Loupy, Alexandre; Goutaudier, Valentin; Giarraputo, Alessia; Mezine, Fariza; Morgand, Erwan; Robin, Blaise; Khalil, Karen; Mehta, Sapna; Keating, Brendan; Dandro, Amy; Certain, Anaïs; Tharaux, Pierre-Louis; Narula, Navneet; Tissier, Renaud; Giraud, Sébastien; Hauet, Thierry; Pass, Harvey I; Sannier, Aurélie; Wu, Ming; Griesemer, Adam; Ayares, David; Tatapudi, Vasishta; Stern, Jeffrey; Lefaucheur, Carmen; Bruneval, Patrick; Mangiola, Massimo; Montgomery, Robert A
BACKGROUND:Cross-species immunological incompatibilities have hampered pig-to-human xenotransplantation, but porcine genome engineering recently enabled the first successful experiments. However, little is known about the immune response after the transplantation of pig kidneys to human recipients. We aimed to precisely characterise the early immune responses to the xenotransplantation using a multimodal deep phenotyping approach. METHODS:We did a complete phenotyping of two pig kidney xenografts transplanted to decedent humans. We used a multimodal strategy combining morphological evaluation, immunophenotyping (IgM, IgG, C4d, CD68, CD15, NKp46, CD3, CD20, and von Willebrand factor), gene expression profiling, and whole-transcriptome digital spatial profiling and cell deconvolution. Xenografts before implantation, wild-type pig kidney autografts, as well as wild-type, non-transplanted pig kidneys with and without ischaemia-reperfusion were used as controls. FINDINGS:cells. Both xenografts showed increased expression of genes biologically related to a humoral response, including monocyte and macrophage activation, natural killer cell burden, endothelial activation, complement activation, and T-cell development. Whole-transcriptome digital spatial profiling showed that antibody-mediated injury was mainly located in the glomeruli of the xenografts, with significant enrichment of transcripts associated with monocytes, macrophages, neutrophils, and natural killer cells. This phenotype was not observed in control pig kidney autografts or in ischaemia-reperfusion models. INTERPRETATION:Despite favourable short-term outcomes and absence of hyperacute injuries, our findings suggest that antibody-mediated rejection in pig-to-human kidney xenografts might be occurring. Our results suggest specific therapeutic targets towards the humoral arm of rejection to improve xenotransplantation results. FUNDING:OrganX and MSD Avenir.
PMID: 37598688
ISSN: 1474-547x
CID: 5598182

Pig-to-human heart xenotransplantation in two recently deceased human recipients

Moazami, Nader; Stern, Jeffrey M; Khalil, Karen; Kim, Jacqueline I; Narula, Navneet; Mangiola, Massimo; Weldon, Elaina P; Kagermazova, Larisa; James, Les; Lawson, Nikki; Piper, Greta L; Sommer, Philip M; Reyentovich, Alex; Bamira, Daniel; Saraon, Tajinderpal; Kadosh, Bernard S; DiVita, Michael; Goldberg, Randal I; Hussain, Syed T; Chan, Justin; Ngai, Jennie; Jan, Thomas; Ali, Nicole M; Tatapudi, Vasishta S; Segev, Dorry L; Bisen, Shivani; Jaffe, Ian S; Piegari, Benjamin; Kowalski, Haley; Kokkinaki, Maria; Monahan, Jeffrey; Sorrells, Lori; Burdorf, Lars; Boeke, Jef D; Pass, Harvey; Goparaju, Chandra; Keating, Brendan; Ayares, David; Lorber, Marc; Griesemer, Adam; Mehta, Sapna A; Smith, Deane E; Montgomery, Robert A
Genetically modified xenografts are one of the most promising solutions to the discrepancy between the numbers of available human organs for transplantation and potential recipients. To date, a porcine heart has been implanted into only one human recipient. Here, using 10-gene-edited pigs, we transplanted porcine hearts into two brain-dead human recipients and monitored xenograft function, hemodynamics and systemic responses over the course of 66 hours. Although both xenografts demonstrated excellent cardiac function immediately after transplantation and continued to function for the duration of the study, cardiac function declined postoperatively in one case, attributed to a size mismatch between the donor pig and the recipient. For both hearts, we confirmed transgene expression and found no evidence of cellular or antibody-mediated rejection, as assessed using histology, flow cytometry and a cytotoxic crossmatch assay. Moreover, we found no evidence of zoonotic transmission from the donor pigs to the human recipients. While substantial additional work will be needed to advance this technology to human trials, these results indicate that pig-to-human heart xenotransplantation can be performed successfully without hyperacute rejection or zoonosis.
PMID: 37488288
ISSN: 1546-170x
CID: 5595152

Unsupervised mRNA-seq classification of heart transplant endomyocardial biopsies

Romero, Erick; Tabak, Esteban; Fishbein, Gregory; Litovsky, Silvio; Tallaj, Jose; Liem, David; Bakir, Maral; Khachatoorian, Yeraz; Piening, Brian; Keating, Brendan; Deng, Mario; Cadeiras, Martin
BACKGROUND:Endomyocardial biopsy (EMB) is currently considered the gold standard for diagnosing cardiac allograft rejection. However, significant limitations related to histological interpretation variability are well-recognized. We sought to develop a methodology to evaluate EMB solely based on gene expression, without relying on histology interpretation. METHODS:Sixty-four EMBs were obtained from 47 post-heart transplant recipients, who were evaluated for allograft rejection. EMBs were subjected to mRNA sequencing, in which an unsupervised classification algorithm was used to identify the molecular signatures that best classified the EMBs. Cytokine and natriuretic peptide peripheral blood profiling was also performed. Subsequently, we performed gene network analysis to identify the gene modules and gene ontology to understand their biological relevance. We correlated our findings with the unsupervised and histological classifications. RESULTS:Our algorithm classifies EMBs into three categories based solely on clusters of gene expression: unsupervised classes 1, 2, and 3. Unsupervised and histological classifications were closely related, with stronger gene module-phenotype correlations for the unsupervised classes. Gene ontology enrichment analysis revealed processes impacting on the regulation of cardiac and mitochondrial function, immune response, and tissue injury response. Significant levels of cytokines and natriuretic peptides were detected following the unsupervised classification. CONCLUSION/CONCLUSIONS:We have developed an unsupervised algorithm that classifies EMBs into three distinct categories, without relying on histology interpretation. These categories were highly correlated with mitochondrial, immune, and tissue injury response. Significant cytokine and natriuretic peptide levels were detected within the unsupervised classification. If further validated, the unsupervised classification could offer a more objective EMB evaluation.
PMID: 37151104
ISSN: 1399-0012
CID: 5479002

Whole-exome sequencing analyses in a Saudi Ischemic Stroke Cohort reveal association signals, and shows polygenic risk scores are related to Modified Rankin Scale Risk

Alkhamis, Fahad A; Alabdali, Majed M; Alsulaiman, Abdulla A; Alamri, Abdullah S; Alali, Rudaynah; Akhtar, Mohammed S; Alsalman, Sadiq A; Cyrus, Cyril; Albakr, Aishah I; Alduhalan, Anas S; Gandla, Divya; Al-Romaih, Khaldoun; Abouelhoda, Mohamed; Loza, Bao-Li; Keating, Brendan; Al-Ali, Amein K
Ischemic stroke represents a significant societal burden across the globe. Rare high penetrant monogenic variants and less pathogenic common single nucleotide polymorphisms (SNPs) have been described as being associated with risk of diseases. Genetic studies in Saudi Arabian patients offer a greater opportunity to detect rare high penetrant mutations enriched in these consanguineous populations. We performed whole exome sequencing on 387 ischemic stroke subjects from Saudi Arabian hospital networks with up to 20,230 controls from the Saudi Human Genome Project and performed gene burden analyses of variants in 177 a priori loci derived from knowledge-driven curation of monogenic and genome-wide association studies of stroke. Using gene-burden analyses, we observed significant associations in numerous loci under autosomal dominant and/or recessive modelling. Stroke subjects with modified Rankin Scale (mRSs) above 3 were found to carry greater cumulative polygenic risk score (PRS) from rare variants in stroke genes (standardized PRS mean > 0) compared to the population average (standardized PRS mean = 0). However, patients with mRS of 3 or lower had lower cumulative genetic risk from rare variants in stroke genes (OR (95%CI) = 1.79 (1.29-2.49), p = 0.0005), with the means of standardized PRS at or lower than 0. In conclusion, gene burden testing in Saudi stroke populations reveals a number of statistically significant signals under different disease inheritance models. However, interestingly, stroke subjects with mRS of 3 or lower had lower cumulative genetic risk from rare variants in stroke genes and therefore, determining the potential mRS cutoffs to use for clinical significance may allow risk stratification of this population.
PMCID:10042957
PMID: 36973604
ISSN: 1438-7948
CID: 5478992