Rapid Resolution of Donor-Derived Glomerular Fibrin Thrombi After Deceased Donor Kidney Transplantation.

The aim of this study was to determine the clinical and histologic outcomes related to transplanting kidneys from deceased donors with glomerular fibrin thrombi (GFT). We included all cases transplanted between October 2003 and October 2014 that had either a preimplantation biopsy or an immediate postreperfusion biopsy showing GFT. The study cohort included 61 recipients (9.9%) with GFT and 557 in the control group without GFT. Delayed graft function occurred in 49% of the GFT group and 39% in the control group (p = 0.14). Serum creatinine at 1, 4, and 12 months and estimated GFR at 12 months were similar in the two groups. Estimated 1-year graft survival was 93.2% in the GFT group and 95.1% in the control group (p = 0.22 by log-rank). Fifty-two of the 61 patients in the GFT group (85%) had a 1-month protocol biopsy, and only two biopsies (4%) showed residual focal glomerular thrombi. At the 1-year protocol biopsy, the prevalence of moderate to severe interstitial fibrosis and tubular atrophy was 24% in the GFT group and 30% in the control group (p = 0.42). We concluded that GFT resolves rapidly after transplantation and that transplanting selected kidneys from deceased donors with GFT is a safe practice.

Challenges to research and innovation to optimize deceased donor organ quality and quantity.

Solid organ transplantation is encumbered by an increasing number of waitlisted patients unrequited by the current organ supply. Preclinical models suggest that advances in deceased donor management and treatment can increase the quantity and quality of organs available for transplantation. However, the science of donor intervention and the execution of high quality, prospective, multi-center, randomized-controlled trials are restricted by a myriad of logistical challenges mired in regulatory and ethical ambiguity. By highlighting the obstacles to conducting research in deceased donors, this report endeavors to stimulate the creation of a multi-disciplinary framework to facilitate the design, implementation and supervision of innovative trials that increase the quantity and/or quality of deceased donor organs.

Do Patient Assessments of Hospital Quality Correlate With Kidney Transplantation Surgical Outcomes?

BACKGROUND: Currently, transplant patients have limited metrics available to understand transplant center quality. Graft and patient survival do not capture the patient experience, and patients may use more general consumer assessments of hospital care to help select transplant centers. We evaluated whether consumer assessments of hospital quality correlate with short- and long-term kidney transplant center performance. MATERIALS AND METHODS: CMS uses the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) to publicly report patients' perspectives on hospital care. We merged 2012 SRTR kidney transplant (n = 200 centers), HCAHPS and American Hospital Association survey data. Center performance was determined by variation in observed-to-expected (O/E) ratios for 1-month and 1-year graft failure. We used multivariate regression to determine whether HCAHPS measures correlate with center performance, after risk-adjusting for structural characteristics and volume. RESULTS: Center-specific graft failure varied significantly (30 day O/E range: 0-4.1). At 30 days, compared to average centers, cleanliness (OR = 1.26, P = .001), patient recommendation (OR = 1.18, P = .005), and high overall ratings (OR = 1.11, P = .036) predicted high performance. Poor nursing-patient communication (OR = 0.70, P = .030), lower cleanliness (OR = 0.67, P < .001), poor overall ratings (OR = 0.79, P = .038), and no recommendation (OR = 0.68, P = .019) correlated with average/low performance. There was no significant correlation between HCAHPS measures and 1-year outcomes. CONCLUSIONS: The association between hospital consumer assessments of hospital care and center performance after kidney transplantation is limited. More specific metrics oriented to capturing transplant patient perspectives may be valuable in further defining transplant quality.

Development of mechanisms for drug excretion.

Renal excretion of many drugs is less in the newborn than what would be predicted in terms of body weight. This is due, in part, to low renal blood flow and glomerular filtration rate during the immediate newborn period. In the first weeks to months of postnatal life, renal vascular resistance decreases and blood flow increases. Subsequently, the glomerular filtration rate increases. During this time, drug elimination may also be affected by qualitative and quantitative differences in binding of drugs to plasma proteins. In addition, drug elimination may be prolonged due to an immature ability in the newborn to transport or metabolize drugs in the kidney. Recent evidence demonstrated that drugs administered pre- or postnatally may alter the rate of renal excretion of drugs in the newborn. Such effects are of great concern to the clinician and underscore the importance of monitoring drug blood levels in these patients. From another perspective, the ability to stimulate drug excretion has been used as a tool to study basic renal physiology. Quantitative patterns of development coupled with the use of substrate stimulation provided evidence for at least three transport systems for organic anions in the proximal tubule. Similar technics provided preliminary data linking drug metabolism and organic anion transport in the proximal tubule, whereas an obligatory, rate-limiting role for ligandin in anion transport could not be established.

Treatment of hypercholesterolemia in the Watanabe rabbit using allogeneic hepatocellular transplantation under a regeneration stimulus.

Numerous studies have reported successful allotransplantation of hepatocytes. However, none have shown long-term correction of a liver-related metabolic defect. In this study, we used a method of regional hepatocyte transplantation and subsequent induction of transplanted cell proliferation by regeneration response in the transplant-bearing liver lobes. New Zealand White rabbits were used as cell donors and Watanabe heritable hyperlipidemic (WHHL) rabbits were used as cell recipients (2 x 10(8) cells/rabbit). All recipient rabbits were maintained on daily cyclosporine. Two weeks after baseline serum cholesterol determination, group I WHHL rabbits (n = 7) received an infusion of cells into the right lateral liver lobe, and a loose ligature was placed around the portal venous branch supplying the anterior lobe. After 1 week, to allow engraftment, the portal venous branch was ligated, which resulted in the atrophy of the affected liver parenchyma and induction of hyperplasia in the transplant-bearing liver tissue. Group II rabbits (n = 6) were transplanted with New Zealand White hepatocytes without portal branch ligation (PBL) and group III rabbits (n = 4) were subjected to sham transplantation (saline) and PBL. The experimental period extended to 150 days after transplantation. All WHHL rabbits transplanted with normal hepatocytes showed reduction in serum cholesterol and low-density lipoprotein (LDL) levels. Group I (PBL-stimulated) recipients demonstrated a more pronounced and sustained effect than group II animals (P < 0.05). Group III controls showed only a slight, typical for aging decrease in serum cholesterol. Group I recipient livers perfused with LDL labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate (DiI) showed much higher numbers of DiI-LDL-positive hepatocytes than those of group II recipients. In conclusion, a liver regeneration stimulus enhanced the population of transplanted hepatocytes and their functional effect in a large animal model of inborn error of liver metabolism.

Transplantation of hepatocytes for prevention of intracranial hypertension in pigs with ischemic liver failure.

Intracranial hypertension leading to brain stem herniation is a major cause of death in fulminant hepatic failure (FHF). Mannitol, barbiturates, and hyperventilation have been used to treat brain swelling, but most patients are either refractory to medical management or cannot be treated because of concurrent medical problems or side effects. In this study, we examined whether allogeneic hepatocellular transplantation may prevent development of intracranial hypertension in pigs with experimentally induced liver failure. Of the two preparations tested--total hepatectomy (n = 47), and liver devascularization (n = 16)--only pigs with liver ischemia developed brain edema provided, however, that animals were maintained normothermic throughout the postoperative period. This model was then used in transplantation studies, in which six pigs received intrasplenic injection of allogeneic hepatocytes (2.5 x 10(9) cells/pig) and 3 days later acute liver failure was induced. In both models (anhepatic state, liver devascularization), pigs allowed to become hypothermic had significantly longer survival compared to those maintained normothermic. Normothermic pigs with liver ischemia had, at all time points studied, ICP greater than 20 mmHg. Pigs that received hepatocellular transplants had ICP below 15 mmHg until death; at the same time, cerebral perfusion pressure (CPP) in transplanted pigs was consistently higher than in controls (45 +/- 11 mmHg vs. 16 +/- 18 mmHg; p < 0.05). Spleens of transplanted pigs contained clusters of viable hepatocytes (hematoxylin-eosin, CAM 5.2). It was concluded that removal of the liver does not result in intracranial hypertension; hypothermia prolongs survival time in both anhepatic pigs and pigs with liver devascularization, and intrasplenic transplantation of allogeneic hepatocytes prevents development of intracranial hypertension in pigs with acute ischemic liver failure.

Dose-dependent modification of 1,1-dichloroethylene toxicity by acetone.

The ability of acetone to potentiate the toxicity of 1,1-dichloroethylene (DCE) in male rats was investigated. A biphasic potentiation of DCE-induced hepatotoxicity was observed; low doses (5 and 10 mmol/kg, p.o.) of acetone were active, whereas higher doses (15 and 30 mmol/kg) were not. Nephrotoxicity was not affected.

Cadmium toxicity in the isolated perfused rat liver.

Isolated perfused livers from male and female Sprague-Dawley rats were exposed to cadmium chloride (50 and 200 microM). Acute hepatotoxicity was investigated by measuring cadmium-induced changes in bile flow, urea synthesis and alanine aminotransferase (ALT) leakage. Cadmium-induced lipid peroxidation was estimated by formation of conjugated dieners and thiobarbituric acid (TBA) reactants. Cadmium, at both concentrations, caused a rapid decrease in bile flow (within 40 min) and complete cholestasis within 70 min exposure in livers perfused from both male and female rats. Cadmium exposure (50 and 200 microM) also resulted in the leakage of ALT into the perfusate within 60 min. In contrast, exposure of isolated rat hepatocytes to as high as 500 microM cadmium did not result in enzyme leakage until 180 min exposure. Sex differences in cadmium-induced cholestasis and ALT leakage were not observed at these concentrations. Malondialdehyde was not detected in the perfusate nor were conjugated dienes detected in liver tissue following 90 min cadmium exposure. These data demonstrate that the isolated perfused rat liver (IPRL) is a sensitive system in which to study chemically induced hepatotoxicity. Cadmium rapidly causes functional alterations and cellular damage in perfused livers from both male and female rats. Cadmium-induced liver injury was apparently not related to lipid peroxidation.

Mechanisms in 2-hexanone potentiation of chloroform hepatotoxicity.

2-Hexanone (2-Hx) is known to potentiate chloroform (CHCl3) hepatotoxicity in part by increasing the bioactivation of CHCl3 to phosgene (COCl2). Treatment of rats with 2-Hx + CHCl3 in vivo did not initiate peroxidation of hepatic fatty acids as determined by formation of conjugated dienes or depletion of unsaturated fatty acids, or as determined by production of malondialdehyde (MDA) in vitro. A 5-fold decrease in the specific activity of succinate-dependent cytochrome c reductase in liver from rats treated in vivo with corn oil (vehicle) + CHCl3 and in rats treated with 2-Hx + CHCl3 indicated that a mechanism independent of CHCl3 bioactivation may add to the hepatotoxic effects which result from the metabolism of chloroform to phosgene.

Renal and hepatic interactions between 2-hexanone and carbon tetrachloride in F-344 rats.

Fisher-344 rats were pretreated with 2-hexanone (HX) and challenged with carbon tetrachloride (CCl4) in a replicated 3 X 4 factorial experiment to determine if HX potentiated CCL4-induced renal and hepatic damage. Rats given both HX and CCl4 demonstrated more severe hepatic injury at 24 and 48 h than did controls. However, in contrast to our experience with chloroform (CHCl3), CCl4-induced renal injury in HX-pretreated rats was only slightly greater than in vehicle-pretreated controls.

Acetone-induced potentiation of trihalomethane toxicity in male rats.

The acute hepato- and nephrotoxic potentials of two trihalomethane water contaminants, bromodichloromethane (BrCHCl2) and dibromochloromethane (Br2CHCl), were determined in male Sprague-Dawley rats. Br2CHCl possessed a greater hepatotoxic and lethal potential than BrCHCl2. However, both Br2CHCl and BrCHCl2 were weak hepatotoxicants as compared to a related trihalomethane, CHCl3. Br2CHCl and BrCHCl2 did not produce liver injury until near-lethal dosages were administered. Neither trihalomethane appeared to produce appreciable kidney injury during the 24-h challenge period. Pretreatment of rats with acetone (15 mmol/kg, p.o.) markedly potentiated the hepatotoxic response to BrCHCl2 and Br2CHCl. The potentiated response observed with acetone plus BrCHCl2 or Br2CHCl was equal to or greater than that observed with acetone plus an approximately equimolar dosage of CHCl3. That is, acetone appeared to convert these weak hepatotoxicants into strong hepatotoxicants.

Relationship between the carbon skeleton length of ketonic solvents and potentiation of chloroform-induced hepatotoxicity in rats.

Previous studies have suggested that ketonic solvents potentiate the hepatotoxic action of CHCl3 in rats. In addition, the relative potentiating capacity of the ketones appeared to be related to the length of their carbon skeleton. To test this hypothesis CHCl3-induced liver injury was evaluated in male Sprague-Dawley rats pretreated (15 mmol/kg, p.o.) with acetone (Ac), 2-butanone (Bu), 2-pentanone (Pn), 2-hexanone (Hx) or 2-heptanone (Hp). After 18 h, a challenging dose of CHCl3, (0.50 or 0.75 ml/kg, i.p.) was given. Liver damage was evaluated 24 h after CHCl3 administration by determining elevations in plasma GPT and OCT activity. Neither Ac, Bu, Pn, Hx, Hp or the CHCl3 challenging dosages produced marked liver injury when given alone. However, each of the ketones potentiated CHCl3-induced liver damage. The severity of the potentiated hepatotoxic response was significantly (positively) correlated with the ketone carbon chain length. These observations suggest that carbon skeleton length may play a role in determining the relative potentiating capacity of ketonic solvents.

Intrinsic susceptibility of the kidney to acetaminophen toxicity in middle-aged rats.

Acetaminophen (APAP)-induced nephrotoxicity is age-dependent in male Sprague-Dawley (SD) rats: middle-aged (9-12 months old) rats exhibit nephrotoxicity at lower dosages of APAP than do young adults (2-3 months old). The present study was designed to test the hypothesis that the intrinsic susceptibility of renal tissue to APAP toxicity is increased in middle-aged rats. APAP toxicity was evaluated in renal slices from naive 3- and 12-month-old male SD rats incubated with 0-50 mM APAP for 2-8 h. Renal slice glutathione (GSH) and APAP concentrations were determined; renal function was assessed by organic anion (para-aminohippurate, PAH) and cation (tetraethylammonium, TEA) accumulation; and cell viability was assessed by lactate dehydrogenase (LDH) leakage. At each concentration of APAP tested, accumulation of APAP by renal slices was similar in 3- and 12-month-olds. APAP toxicity in renal slices from both 3- and 12-month-old rats was characterized by concentration-dependent increases in LDH leakage. In contrast to APAP nephrotoxicity in vivo, APAP toxicity in renal slices was accompanied by decreased accumulation of PAH and TEA. Additionally, APAP produced marked reductions in renal slice GSH content in a concentration-dependent manner: however, in contrast to APAP nephrotoxicity in vivo, APAP-induced GSH depletion in vitro did not precede cytotoxicity. No consistent age-dependent differences in the time- and concentration-response curves for APAP nephrotoxicity were observed. These data suggest that APAP cytotoxicity in vitro is not increased in 12-month-old rats. However, since the pattern (and mechanisms) of APAP cytotoxicity in vitro appears to be different from that observed in vivo, extrapolation of in vitro cytotoxicity to in vivo nephrotoxicity is limited. Therefore, age differences in intrinsic susceptibility of the intact kidney cannot be excluded as a mechanism contributing to enhanced APAP nephrotoxicity in middle-aged rats.

Clinical experience with a porcine hepatocyte-based liver support system.

UNLABELLED: The only clinically proven effective treatment of fulminant hepatic failure (FHF) is orthotopic liver transplant (OLT). However, many patients die before an organ becomes available. Thus, there is a need for development of an extracorporeal liver support system to "bridge" these patients either to OLT or spontaneous recovery. We developed a bioartificial liver (BAL) based on plasma perfusion through a circuit of a hollow-fiber cartridge seeded with matrix-anchored porcine hepatocytes to treat patients with severe acute liver failure. Two groups of patients were studied. Group 1 (n = 12): patients with FHF. All patients were successfully "bridged" to OLT. "Bridge" time to OLT was 21-96 hr (mean: 39.3 hr). All patients were discharged neurologically intact. Reversal of decerebration was noted in all 11 deep stage 4 coma patients. There was reduction in intracranial pressure (ICP mmHg, 18.2 +/- 2.2 to 8.5 +/- 1.2; p < 0.004) and increase in cerebral perfusion pressure (CPP mmHg, 71.1 +/- 4.0 to 84.7 +/- 2.6; p < 0.006). Laboratory values pre- and post-BAL treatment: glucose (mg/dl) 122 +/- 11 to 183 +/- 21, p < 0.002; ammonia (mumol/l) 155.6 +/- 13.2 to 121.6 +/- 9.5, p < 0.02; total bilirubin (mg/dl) 21.6 +/- 2.8 to 18.2 +/- 2.2, p < 0.001; PT (sec) 23.2 +/- 1.7 to 21.9 +/- 1.0, p < 0.3. Group II (n = 8): patients with chronic liver failure experiencing acute exacerbation. Two patients survived and later underwent OLT. Six patients (not OLT candidates) died 1-14 days after last BAL treatment. Laboratory values pre- and post-treatment: ammonia (mumol/l) 201 +/- 47 to 143 +/- 25, p < 0.06; total bilirubin (mg/dl) 22.8 +/- 5.2 to 19.5 +/- 4.4, p < 0.01; PT (sec) 22.5 +/- 2.0 to 21.8 +/- 1.1, p < 0.6. CONCLUSION: our clinical experience with the BAL suggests that it may serve as "bridge" to OLT in patients with FHF primarily by reversing intracranial hypertension, but it is not a substitute for OLT in patients with end-stage liver disease who are non-transplant candidates.

Liquid nitrogen treatment of hand and plantar warts.

The author reports on a study of the liquid nitrogen treatment of warts at the Rutgers University Student Health Center. He demonstrates that liquid nitrogen therapy is a safe, effective treatment method, appropriate for use by nurses and other primary providers in a college health setting.

Robotic resection of choledochocele in an adult with intracorporeal hepaticojejunostomy and Roux-en-Y anastomosis: encouraging progress for robotic surgical treatment of biliary disease.

BACKGROUND: Robotic surgery offers three-dimensional visualization and precision of movement that could be of great value to hepatobiliary surgeons. Previous reports of robotic choledochocele resections in adults have detailed extracorporeal jejunojejunostomies. We describe a total robotic excision of a choledochal cyst with hepaticojejunostomy and intracorporeal Roux-en-Y anastomosis. METHODS: A 58-year-old woman underwent a robotic excision of a small choledochocele with hepaticojejunostomy and intracorporeal Roux-en-Y. RESULT: Port placement was determined via collaborative surgical discussion and previously reported robotic right hepatectomies. Total operative time was 386 min and total robot working time was 330 min. The hepaticojejunostomy was performed using 5-0 PDS suture with parachute-style back wall and running front wall sutures. The jejunojejunostomy was a stapled anastomosis. Estimated blood loss was less than 100 mL. The patient was ambulating and tolerating oral intake on post-operative day 1, and was discharged home on post-operative day 2. CONCLUSIONS: Robotic resection of choledochal cyst with intracorporeal Roux-en-Y anastomosis is feasible, with advantages over open surgery such as superior visualization, precision, and post-operative patient recovery.

Domino liver transplantation in maple syrup urine disease: a case report and review of the literature.

BACKGROUND: Improved outcomes have expanded the indications for liver transplantation, thus aggravating the already limited supply of donor organs. Domino liver transplantation (DLT) has been one strategy to augment the supply of donor organs in cases of inborn errors of metabolism. One such disease is maple syrup urine disease (MSUD), an inherited disorder of branched-chain amino acid (BCAA) metabolism. METHODS: We report on the transplantation of a deceased donor liver into a patient with MSUD, and the sequential transplantation of the explanted liver into a patient with hemophilia A, HIV, hepatitis C, and a low priority on the transplant waiting list. RESULTS: At 30 months, the MSUD recipient has had significant correction of BCAA metabolism on a protein-unrestricted diet and no progression of neuropsychiatric symptoms. The DLT recipient has been cured of hemophilia and has normal BCAA homeostasis. This case provides further evidence that elective orthotopic liver transplantation for MSUD attenuates the disease with restoration of BCAA metabolism, and that DLT in this setting can achieve excellent results in ESLD patients. CONCLUSION: It is possible that domino grafts from patients with MSUD could be used in more conventional recipients, but additional studies and longer-term outcomes are needed to determine the validity of DLT in MSUD.

Genetic differences in Native Americans and tacrolimus dosing after kidney transplantation.

Tacrolimus pharmacokinetics vary due to single nucleotide polymorphisms (SNPs) in metabolizing enzymes and membrane transporters that alter drug elimination. Clinically we observed that Native Americans require lower dosages of tacrolimus to attain trough levels similar to Caucasians. We previously demonstrated that Native Americans have decreased oral clearance of tacrolimus, suggesting that Native Americans may have more variant SNPs and, therefore, altered tacrolimus pharmacokinetic parameters. We conducted 12-hour pharmacokinetic studies on 24 adult Native American kidney transplant recipients on stable doses of tacrolimus for at least 1 month posttransplantation. Twenty-four Caucasian kidney transplant recipients were compared as controls. SNPs encoding the genes for the enzymes (CYP3A4, CYP3A5) and transporters (ABCB1, BCRP, and MRP1) were typed using TaqMan. The mean daily tacrolimus dose in the Native Americans was 0.03 ± 0.02 compared with the Caucasians 0.5 ± 0.3 (mg/kg/d; P = .002), with no significant differences in trough levels, (6.7 ± 3.1 vs 7.4 ± 2.1 ng/dL; P = .4). Many Native Americans, but not Caucasians, demonstrated the 3/*3 - C3435T CC and the *3/*3 -G2677T GG genotype combination previously associated with low tacrolimus dosing. Native Americans required significantly lower tacrolimus doses than Caucasians to achieve similar tacrolimus trough levels, in part due to lower tacrolimus clearance from decreased drug metabolism and excretion.