Giuliano Testa M.D.

Lawrence, M. C., C. M. Darden, S. Vasu, K. Kumano, J. Gu, X. Wang, J. Chan, Z. Xu, B. F. Lemoine, P. Nguyen, C. Smitherman, B. Naziruddin and G. Testa (2019). “Profiling Gene Programs in the Blood During Liver Regeneration in Living Liver Donors.” Liver Transpl 25(10): 1541-1560.

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The human liver’s capacity to rapidly regenerate to a full-sized functional organ after resection has allowed successful outcomes for living donor liver transplantation (LDLT) procedures. However, the ability to detect and track physiological changes occurring during liver regeneration after resection and throughout the restoration process is still lacking. We performed a comprehensive whole-transcriptome RNA sequencing analysis of liver and circulating blood tissue from 12 healthy LDLT donors to define biomarker signatures for monitoring physiological activities during liver regeneration at 14 time points for up to a 1-year procedural follow-up. LDLT donor liver tissue differentially expressed 1238 coding and noncoding genes after resection, and an additional 1260 genes were selectively regulated after LDLT. A total of 15,011 RNA transcript species were identified in the blood in response to liver resection. The transcripts most highly regulated were sequentially expressed within 3 distinct peaks that correlated with sets of functional genes involved in the induction of liver resection-specific innate immune response (peak 1), activation of the complement system (peak 2), and platelet activation and erythropoiesis (peak 3). Each peak corresponded with progressive phases of extracellular matrix degradation, remodeling, and organization during liver restoration. These processes could be tracked by distinct molecular signatures of up-regulated and down-regulated gene profiles in the blood during phases of liver repair and regeneration. In conclusion, the results establish temporal and dynamic transcriptional patterns of gene expression following surgical liver resection that can be detected in the blood and potentially used as biomarker signatures for monitoring phases of liver regeneration.

Jones, B. P., S. Saso, T. Bracewell-Milnes, M. Y. Thum, J. Nicopoullos, C. Diaz-Garcia, P. Friend, S. Ghaem-Maghami, G. Testa, L. Johannesson, I. Quiroga, J. Yazbek and J. R. Smith (2019). “Human Uterine Transplantation: A Review of Outcomes from the First 45 Cases.” BJOG 126(11): 1310-1319.

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Uterine transplantation restores reproductive anatomy in women with absolute uterine factor infertility and allows the opportunity to conceive, experience gestation, and acquire motherhood. The number of cases being performed is increasing exponentially, with detailed outcomes from 45 cases, including nine live births, now available. In light of the data presented herein, including detailed surgical, immunosuppressive and obstetric outcomes, the feasibility of uterine transplantation is now difficult to refute. However, it is associated with significant risk with more than one-quarter of grafts removed because of complications, and one in ten donors suffering complications requiring surgical repair. TWEETABLE ABSTRACT: Uterine transplantation is feasible in women with uterine factor infertility, but is associated with significant risk of complication.

Johannesson, L., A. Wall, J. M. Putman, L. Zhang, G. Testa and C. Diaz-Garcia (2019). “Rethinking the Time Interval to Embryo Transfer after Uterus Transplantation – Duets (Dallas Uterus Transplant Study).” BJOG 126(11): 1305-1309.

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Uterus transplant can allow women to carry their own pregnancy. Because of the transplant operation, infectious disease risks, and immunosuppressive medications, these pregnancies require careful planning. Conditions to achieve before ET include stable uterine graft function, absence of active rejection, stable immunosuppressive medication with agents with low teratogenic risk, and low‐risk status for harmful opportunistic infections. Our experience, the experience of other uterus transplant programmes, and results of successful pregnancies in other solid organ transplant recipients suggest ET could be considered as soon as 3 months after uterus transplantation if the above criteria are met. Given the unique characteristics of uterus transplantation and the recipient population, the transplant‐to‐ET interval should differ from recommendations in other organ and vascular allograft transplantations. The incentive of minimising the recipient‐graft time and concomitant exposure to immunosuppressants in this young, healthy patient population strongly supports shortening the transplant‐to‐ET time. (Excerpt from text, p. 1308; no abstract available.)

Asrani, S. K., L. W. Jennings, W. R. Kim, P. Kamath, J. Levitsky, M. K. Nadim, G. Testa, M. Leise, J. F. Trotter and G. Klintmalm (2019). “Meld-Grail-Na: Glomerular Filtration Rate and Mortality on Liver-Transplant Waiting List.” Hepatology Sep 16. [Epub ahead of print].

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BACKGROUND & AIMS: Among patients with cirrhosis awaiting liver transplantation, prediction of waitlist (WL) mortality is adjudicated by Model for End Stage liver disease-sodium (MELD-Na) score. Replacing serum creatinine (Scr) with estimated glomerular filtration rate (eGFR) in the MELD-Na score may improve prediction of WL mortality, especially for women and highest disease severity. METHODS: We developed (2014) and validated (2015) a model incorporating eGFR using national data (n=17,095) to predict WL mortality. Glomerular Filtration Rate (GFR) was estimated using GfR Assessment In Liver disease (GRAIL) developed amongst patients with cirrhosis (Asrani SK Hepatology.2018; www.bswh.md/grail). Multivariate Cox proportional hazards analysis models were utilized to compare predicted 90-day WL mortality between MELD-GRAIL-Na (re-estimated bilirubin, INR, sodium and GRAIL) vs. MELD-Na. RESULTS: Within 3 months, 27.8% were transplanted, 4.3% died on the WL and 4.7% were delisted for other reasons. GFR as estimated by GRAIL (HR 0.382, 95% CI 0.344-0.424) and the re-estimated model MELD-GRAIL-Na (HR 1.212, 95% CI 1.199-1.224) were significant predictors of mortality or being delisted on the WL within 3 months. MELD-GRAIL-Na was a better predictor of observed mortality at highest deciles of disease severity (>/=27-40). For score >/=32 (observed mortality 0.68), predicted mortality was 0.67 (MELD-GRAIL-Na) and 0.51 (MELD-Na). For women score >/=32 (observed mortality 0.67), predicted mortality was 0.69 (MELD-GRAIL-Na) and 0.55 (MELD-Na). In 2015, use of MELD-GRAIL-Na as compared to MELD-Na resulted in reclassification of 16.7% (n=672) of patients on the WL. CONCLUSION: Incorporation of eGFR likely captures true GFR better than Scr, especially among women. Incorporation of MELD-GRAIL-Na instead of MELD-Na may impact outcomes for 12-17% awaiting transplant and affect organ allocation.

Jones, B. P., S. Saso, A. L’Heveder, T. Bracewell-Milnes, M. Y. Thum, C. Diaz-Garcia, D. A. MacIntyre, I. Quiroga, S. Ghaem-Maghami, G. Testa, L. Johannesson, P. R. Bennett, J. Yazbek and J. R. Smith (2019). “The vaginal microbiome in uterine transplantation.” BJOG Aug 8. [Epub ahead of print].

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Women with congenital absolute uterine factor infertility (AUFI) often need vaginal restoration to optimise sexual function. Given their lack of procreative ability, little consideration has previously been given to the resultant vaginal microbiome (VM). Uterine transplantation (UTx) now offers the opportunity to restore these women’s reproductive potential. The structure of the VM is associated with clinical and reproductive implications that are intricately intertwined with the process of UTx. Consideration of how vaginal restoration methods impact VM is now warranted and assessment of the VM in future UTx procedures is essential to understand the interrelation of the VM and clinical and reproductive outcomes. TWEETABLE ABSTRACT: The vaginal microbiome has numerous implications for clinical and reproductive outcomes in the context of uterine transplantation.