Subnormothermic Oxygenated Perfusion Optimally Preserves Donor Kidneys Ex Vivo.

INTRODUCTION: The current methods of preserving donor kidneys in nonoxygenated cold conditions minimally protect the kidney against ischemia-reperfusion injury (IRI), a major source of complications in clinical transplantation. However, preserving kidneys with oxygenated perfusion is not currently feasible due to the lack of an ideal perfusion mechanism that facilitates perfusion with blood at warm temperature. Here, we have designed an innovative renal pump circuit system that can perfuse blood or acellular oxygen carrier under flexible temperatures, pressures, and oxygenation. We have tested this apparatus to study optimal conditions of storage of our porcine model of donation after cardiac death (DCD) kidneys. METHODS: Porcine kidneys were retrieved after 30 minutes of cross-clamping renal pedicles in situ. Cessation of blood mimics postcardiac death in humans and simulates DCD warm ischemic injury. Procured kidneys were flushed and subjected to static cold storage (SCS) for 4 hours. For warm perfusion, kidneys were cannulated for pulsatile oxygenated perfusion with blood:PlasmaLyte for 4 hours at 15 °C, 22 °C, and 37 °C. To mimic posttransplant scenario, all kidneys were reperfused with blood for an additional 4 hours at 37 °C. RESULTS: Compared with all other groups, 22 °C perfusion resulted in significant reduction of acute tubular necrosis (ATN), apoptosis, kidney damage markers, Toll-like receptor signaling, and cytokine production. It was associated with maximal renal blood flow and urine output. Kidneys stored at 15 °C thrombosed within 2 hours under this condition. Martius Scarlet Blue staining confirmed that 22 °C was the optimal temperature to minimize hemorrhage and blood clots. CONCLUSION: Our novel study shows that oxygenated perfusion at near-room-temperature provides optimal donor kidney storage conditions.

Long-term results of protocol kidney biopsy directing steroid withdrawal in simultaneous pancreas-kidney transplant patients.

INTRODUCTION: We sought to determine whether protocol biopsies could be used to guide treatment and improve outcomes in simultaneous pancreas-kidney (SPK) patients. METHODS: Between 2004 and 2013, protocol biopsies were performed on SPK patients at 3-6 months and one year post-transplant. Maintenance immunosuppression consisted of a calcineurin inhibitor, anti-proliferative agent, and corticosteroid. Corticosteroid was withdrawn in negative early biopsies, maintained in subclinical/ borderline biopsies, and increased if Banff IB or greater rejection was identified. Endpoints included presence of interstitial fibrosis and tubular atrophy on biopsy at one year (IF/TA), rejection episodes, and renal and pancreas function at five years' followup. RESULTS: Forty-one SPK transplant patients were reviewed and a total of 75 protocol biopsies were identified. On early biopsy, 51% had negative biopsies, 44% had borderline rejection, and 5% had subclinical rejection. Renal and pancreas function were not significantly different at one, two, and five years post-transplant between negative vs. borderline early biopsy patients. No difference in the degree of IF/TA was found between these two groups. CONCLUSIONS: To our knowledge, this is the first study to evaluate protocol biopsies as an investigative tool prior to steroid withdrawal in SPK patients. Our study suggests that there are no detrimental functional or histological effects at five years post-transplant, despite weaning steroids in the negative biopsy group.

Randomized open-label crossover assessment of Prograf vs Advagraf on immunosuppressant pharmacokinetics and pharmacodynamics in simultaneous pancreas-kidney patients.

INTRODUCTION: We assessed the pharmacokinetic and pharmacodynamic impact of converting stable simultaneous pancreas-kidney (SPK) recipients from standard tacrolimus (Prograf) to long-acting tacrolimus (Advagraf). METHODS: In a randomized prospective crossover study, stable SPK recipients on Prograf were assigned to Prograf with 1:1 conversion to Advagraf or vice versa. Demographics, tacrolimus, mycophenolic acid levels, and Cylex CD4 + ATP levels were taken at specified intervals in addition to standard blood work. RESULTS: Twenty-one patients, who were a minimum of 1 year post-transplant, were entered into the study. No difference in tacrolimus or mycophenolic acid levels was noted between patients who were first assigned to Prograf or Advagraf. Additionally, Cylex levels as well as serum creatinine, lipase, and blood sugar levels were unchanged. There were no episodes of rejection during the 6-month study. CONCLUSIONS: It is safe to convert between Prograf and Advagraf 1:1, without major impact on pharmacokinetics or pharmacodynamics in SPK recipients.

A comparison of bloat control methods for genetic programming.

Genetic programming has highlighted the problem of bloat, the uncontrolled growth of the average size of an individual in the population. The most common approach to dealing with bloat in tree-based genetic programming individuals is to limit their maximal allowed depth. An alternative to depth limiting is to punish individuals in some way based on excess size, and our experiments have shown that the combination of depth limiting with such a punitive method is generally more effective than either alone. Which such combinations are most effective at reducing bloat? In this article we augment depth limiting with nine bloat control methods and compare them with one another. These methods are chosen from past literature and from techniques of our own devising. esting with four genetic programming problems, we identify where each bloat control method performs well on a per-problem basis, and under what settings various methods are effective independent of problem. We report on the results of these tests, and discover an unexpected winner in the cross-platform category.

Modification point depth and genome growth in genetic programming.

The evolutionary computation community has shown increasing interest in arbitrary-length representations, particularly in the field of genetic programming. A serious stumbling block to the scalability of such representations has been bloat: uncontrolled genome growth during an evolutionary run. Bloat appears across the evolutionary computation spectrum, but genetic programming has given it by far the most attention. Most genetic programming models explain this phenomenon as a result of the growth of introns, areas in an individual which serve no functional purpose. This paper presents evidence which directly contradicts intron theories as applied to tree-based genetic programming. The paper then uses data drawn from this evidence to propose a new model of genome growth. In this model, bloat in genetic programming is a function of the mean depth of the modification (crossover or mutation) point. Points far from the root are correspondingly less likely to hurt the child's survivability in the next generation. The modification point is in turn strongly correlated to average parent tree size and to removed subtree size, both of which are directly linked to the size of the resulting child.