Faculty Bibliography

The understanding of marine microbial ecology and metabolism has been hampered by the paucity of sequenced reference genomes. To this end, we report the sequencing of 137 diverse marine isolates collected from around the world. We analysed these sequences, along with previously published marine prokaryotic genomes, in the context of marine metagenomic data, to gain insights into the ecology of the surface ocean prokaryotic picoplankton (0.1-3.0 μm size range). The results suggest that the sequenced genomes define two microbial groups: one composed of only a few taxa that are nearly always abundant in picoplanktonic communities, and the other consisting of many microbial taxa that are rarely abundant. The genomic content of the second group suggests that these microbes are capable of slow growth and survival in energy-limited environments, and rapid growth in energy-rich environments. By contrast, the abundant and cosmopolitan picoplanktonic prokaryotes for which there is genomic representation have smaller genomes, are probably capable of only slow growth and seem to be relatively unable to sense or rapidly acclimate to energy-rich conditions. Their genomic features also lead us to propose that one method used to avoid predation by viruses and/or bacterivores is by means of slow growth and the maintenance of low biomass.

UNet(SM) , the UNOS data collection and electronic organ allocation system, allows centers to specify organ offer acceptance criteria for patients on their kidney waiting list. We hypothesized that the system might not be fully utilized and that the criteria specified by most transplant centers would be much broader than the characteristics of organs actually transplanted by those centers. We analyzed the distribution of criteria values among waitlist patients (N = 304 385) between January 2000 and February 2009, mean criteria values among listed candidates on February 19, 2009 and differences between a center's specified criteria and the organs it accepted for transplant between July 2005 and April 2009. We found wide variation in use of criteria variables, with some variables mostly or entirely unused. Most centers specified very broad criteria, with little within-center variation by patient. An offer of a kidney with parameters more extreme than the maximum actually transplanted at that center was designated a 'surplus offer' and indicated a potentially avoidable delay in distribution. We found 7373 surplus offers (7.1% of all offers), concentrated among a small number of centers. The organ acceptance criteria system is currently underutilized, leading to possibly avoidable inefficiencies in organ distribution.

INTRODUCTION: Delayed graft function (DGF) and slow graft function (SGF) due to ischemic and reperfusion injury (IRI) are common complications of deceased donor kidney transplantation. We tested whether a panel of serum and urine cytokines represent early biomarkers for DGF and SGF. METHODS: We collected serum and urine samples from 61 patients 48 hours posttransplantation and used a multiplex enzyme-linked immunosorbent assay (ELISA) technique to measure levels of 23 cytokines. Fourteen patients developed poor graft function (PGF), with 6 having DGF and 8 with SGF. RESULTS: Area under receiver operation characteristics curve (AUC) demonstrated the following: serum levels of SCF (0.88) and interleukin (IL) 16 (0.74). CONCLUSIONS: This study showed that a select panel of cytokines measured early post kidney transplantation may predict poor graft function.

OBJECTIVE: No therapy except liver transplantation currently exists for patients with acute liver failure (ALF). The aim of this study was to determine whether pharmacologic mobilization of endogenous hematopoietic stem cells (HSCs) can aid in liver repair and improve survival in an animal model of ALF. METHODS: Rodents were treated with a single near-lethal intraperitoneal injection of carbon tetrachloride (CCl4). After 12 hours, animals were randomized to receive plerixafor and granulocyte colony-stimulating factor (G-CSF), agents known to mobilize marrow-derived stem cells, or saline vehicle injection. Mice were observed for survival, and serial assessment of liver injury by serum transaminase measurements, and histologic analysis was performed. RESULTS: In our ALF model, 7-day survival after injection of CCl4 was 25%. Administration of plerixafor and G-CSF following CCl4 resulted in 87% survival (n = 8, P < 0.05). On serial histopathologic analysis, animals treated with plerixafor and G-CSF demonstrated less hepatic injury compared with control animals. Evaluation of peripheral blood demonstrated an increase in circulating HSCs in response to plerixafor and G-CSF, and immunostaining suggested the infiltration of HSCs into the hepatic parenchyma after stem cell mobilization. CONCLUSIONS: Our results suggest a possible new treatment strategy for patients with ALF, a group for whom either liver transplantation or death is frequently the outcome. Pharmacologic agents that mobilize HSCs may lead to an infiltration of the injured liver with cells that may participate in or expedite liver regeneration. This therapy has the potential to avert liver transplantation in some patients with ALF and may be of benefit in a wide variety of medical and surgical patients with liver injury.

A 43-year-old patient with end-stage renal disease, a hypercoagulable condition and 100% panel reactive antibody was transferred to our institution with loss of hemodialysis access and thrombosis of the superior and inferior vena cava, bilateral iliac and femoral veins. A transhepatic catheter was placed but became infected. Access through a stented subclavian into a dilated azygos vein was established. Desensitization with two cycles of bortezomib was undertaken after anti-CD20 and IVIg were given. A flow-positive, cytotoxic-negative cross-match live-donor kidney at the end of an eight-way multi-institution domino chain became available, with a favorable genotype for this patient with impending total loss of a dialysis option. The patient received three pretransplant plasmapheresis treatments. Intraoperatively, the superior mesenteric vein was the only identifiable patent target for venous drainage. Eculizumab was administered postoperatively in the setting of antibody-mediated rejection and an inability to perform additional plasmapheresis. Creatinine remains normal at 6 months posttransplant and flow cross-match is negative. In this report, we describe the combined use of new agents (bortezomib and eculizumab) and modalities (nontraditional vascular access, splanchnic drainage of graft and domino paired donation) in a patient who would have died without transplantation.

We recently showed that DonorNet 2007 has reduced the efficiency of kidney distribution in the United States, particularly for those with prolonged cold ischemia time (CIT), by requiring systematic allocation of all kidneys regardless of quality. Reliable early identification of those most likely to be discarded or significantly delayed would enable assigning them to alternate, more efficient distribution strategies. Based on 39 035 adult kidneys recovered for possible transplantation between 2005 and 2008, we created a regression model that reliably (AUC 0.83) quantified the probability that a given kidney was either discarded or delayed beyond 36 h of CIT (Probability of Discard/Delay, PODD). We then analyzed two PODD cutoffs: a permissive cutoff that successfully flagged over half of those kidneys that were discarded/delayed, while only flagging 7% of kidneys that were not eventually discarded/delayed, and a more stringent cutoff that erroneously flagged only 3% but also correctly identified only 34%. Kidney transplants with high PODD were clustered in a minority of centers. Modifications of the kidney distribution system to more efficiently direct organs with high PODD to the centers that actually use them may result in reduced CIT and fewer discards.

Human leukocyte antigen (HLA) sensitization and ABO incompatibility continue to pose significant barriers to further expansion of live donor renal transplantation. However, the recent development of effective desensitization protocols and creative paired donation strategies demonstrates that the presence of circulating donor HLA-specific antibodies and the use of ABO incompatible organs should no longer be considered contraindications for renal transplantation. It is estimated that as many as 6,000 patients on the kidney transplant waiting list have incompatible living donors and could benefit from these treatments. Furthermore, as our understanding of these treatment modalities has improved, it is now possible to predict whether desensitization, kidney paired donation or a combination of both will provide an individual patient with their best chance for successful renal transplantation.