Organ preservation with histidine-tryptophan ketogluatarate solution in clinical pancreas transplantation: an update of the indiana university experience.

In May 2003, University of Wisconsin (UW) solution was replaced with Histidine-Tryptophan Ketoglutarate (HTK) solution as the preservation fluid for abdominal organ procurements in our center. Herein we have reported our updated results with HTK in pancreas transplantation. Between May 2003 and October 2006, 152 pancreas transplantations were performed in which 146 used HTK. The procedures were as follows: simultaneous kidney pancreas transplantation (n = 85; 55%), pancreas after kidney transplantation (n = 41; 30%), and solitary pancreas transplantation (n = 20; 15%). Donor and recipient data were collected with primary outcomes as primary nonfunction (PNF), and 30-day and 1-year graft and patient survival. Patient demographics are as follows: age (36 +/- 12 years), gender (males, 89: females, 57), race (white, 135; African American, 11). Mean flush volume was 3.8 +/- 1 L. The mean cold ischemia time was 8 +/- 3 hours. Mean warm ischemia time was 48 +/- 23 minutes. There were no cases of PNF in this cohort. Thirty-day and 1-year patient survival rates were 99% and 95%, respectively. The 30-day and 1-year graft survivals rates were 95% and 93%, respectively. There were 10 grafts lost with 7 vascular complications (6 venous and 1 arterial thrombosis). There were 2 cases of chronic rejection and 1 graft lost to noncompliance. These statistics compare favorably with International Pancreas Transplant Registry reported 1-year survival for pancreas allografts. All other patients were insulin independent by discharge. Serum fasting blood glucose and serial amylase remained comparable at all intervals posttransplantation to those of a historical UW cohort. Within this range of cold ischemia times, HTK appears to provide effective pancreas preservation.

Complications after a 5-year experience with laparoscopic donor nephrectomy: the Indiana University experience.

BACKGROUND: Laparoscopic donor nephrectomy (LDN) is becoming the standard of care for living donor nephrectomy. However, questions have been raised about the safety of LDN for the donor and about the potentially increased rates for ureteral complications experienced by the recipient. In this report, the authors review their 5-year experience with 253 living laparoscopic donor nephrectomies. METHODS: A retrospective chart review was performed for 253 laparoscopic live donors. Graft function and survival were compared using recipient postoperative creatinine values up to 12 months. RESULTS: The overall rate of complications in the investigated series was 10.3%. There were seven intraoperative complications (2.8%), three of which required open conversion. There were 19 postoperative complications (7.5%), three of which required reexploration for bleeding. The majority of complications were minor including 62% grade 1, 8% grade 2, 31% grade 3, and no grade 4 or 5 complications. There were no intraoperative complications in the right-sided donor group. There was a 5% complication rate for patients with a body mass index (BMI) exceeding 25. The findings showed that 11.2% of the recipients had slow graft function, and 4.4% had delayed graft function. Less than 1% of the recipients experienced ureteral stricture requiring permanent stent placement or reoperation. Overall, there was a 2% graft loss rate. CONCLUSIONS: The findings show a low rate of intraoperative and postoperative complications, most of which were minor complications. There was an increase in operative time and hospital stay in the right-sided group, but no increase in complication rate. There was no significant difference in outcome or complication rate for the overweight patients.

In vitro monitoring of in vivo development of human anti-thymoglobulin antibodies by ELISA.

Thymoglobulin (rATG), polyclonal immunoglobulin, is prepared from rabbits immunized with human thymocytes. It is effective in prevention and treatment of renal allograft rejection. Human antibodies against antilymphocyte preparations can reduce efficacy by accelerating drug clearance or by inducing serum sickness. We developed an enzyme-linked immunosorbent assay (ELISA) to study posttreatment development of anti-rATG. In an Institutional Review Board-approved trial, we tested 101 allograft recipients for anti-rATG antibodies. Patients received rATG intravenously at 1.25 to 2.0 mg/kg/d for 2 to 14 days. Serum samples were obtained pretreatment and at weeks 1, 2, 4, 6, and months 3 and 6 post-rATG. ELISA plates were coated with rATG (10 microg/mL). Samples were diluted 1:100 and tested in quadruplicate. Positive samples were titrated. Horseradish peroxidase-conjugated (HRPO) affinity-purified goat anti-human immunoglobulin G (H&L) antibody reacted with bound human antibody. A chromagenic substrate for HRPO was added and optical density (OD, 490 nm) was read. An OD of twice the negative control was considered positive. Mean ODs of negative and positive controls were 0.113 +/- 0.030 and 1.042 +/- 0.196, respectively. Ten patients had detectable anti-rATG before rATG administration (1:100). Thirty-five of 101 patients (35%) developed anti-rATG antibody. Patients showed an initial positive anti-rATG antibody from days 8 to 59 after infusion and titers from 1:100 to 1:4000. In spite of rATG's postulated anti-B-cell activity, this study confirms that rATG induces sensitization at a frequency and titer seen with other xenogeneic antilymphocyte antibodies. Formation of such antixenoantibodies can have a negative impact on treatment response and hence warrant monitoring.

Follow-up experience using histidine-tryptophan ketoglutarate solution in clinical pancreas transplantation.

In May 2003, at Indiana University, the standard cold preservation solution University of Wisconsin (UW) solution was replaced by histidine-tryptophan ketogluatarate (HTK) solution. Earlier, we presented our initial experience with HTK in pancreas preservation with an analysis of the first 10 pancreas transplants. Here we report updated results with HTK in pancreas transplantation over the past 18 months. Between May 2003 and March 2005, a total of 87 pancreas transplants were performed with 78 of these organs utilizing HTK. Seventy five patients received 78 organ transplants. Surgical procedures performed were: simultaneous kidney pancreas transplantation (n = 50, 64%), pancreas after kidney transplantation (n = 19, 24%), solitary pancreas transplantation (n = 9, 12%). Donor and recipient data were collected with primary outcomes as primary nonfunction and 30-day graft and patient survivals, and compared to the UW cohort from our original report. Donor and recipient demographics were similar. Mean follow-up time is 12 +/- 6 months. The mean cold ischemia time was 9 +/- 3 hours. There were no cases of primary graft nonfunction. Thirty-day and 1-year patient survivals were 99% and 93%. The 30-day and 1-year graft survivals were 96% and 93%. There were five grafts lost, including three within the first month (two venous and one arterial thrombosis). There was one case of chronic rejection and one noncompliance. All other patients were insulin-independent by discharge. Serum fasting blood glucose and serial amylase remained comparable at all intervals posttransplantation. Within this range of cold ischemia time, HTK appears to provide effective pancreas preservation.

Comparison of histidine-tryptophan ketoglutarate and University of Wisconsin solutions as primary preservation in renal allografts undergoing pulsatile perfusion.

INTRODUCTION: University of Wisconsin (UW) solution is the standard preservation solution for organ transplantation. Histidine-tryptophan ketogluatarate (HTK) solution has been used increasingly for kidney, pancreas, and liver transplantation. This study compared HTK and UW used during kidney procurement with subsequent pulsatile perfusion. METHODS: Between January and October 2003, 91 deceased renal and simultaneous kidney pancreas transplants were performed (UW, n = 41, and HTK, n = 50). There were no differences with regard to donor and recipient demographics or cold ischemia. RESULTS: Delayed graft function occurred in 3 (7%) of UW and 4 (8%) of HTK-preserved kidneys (P = NS). There were no significant differences between patient or graft survival. There was an anticipated difference between total preservative volumes used (HTK: 4.1 +/- 1.0 vs UW: 3.0 +/- 0.5; P < .005). CONCLUSION: UW and HTK appear to have similar efficacy in kidney preservation with pulsatile perfusion. HTK preservation solution can be used safely in conjunction with pulsatile preservation for cold storage of renal allografts.

Induction of Supernova-like Explosions by Gamma-Ray Bursts in Close Binary Systems.

We propose that a gamma-ray burst in one member of a binary may induce a supernova-like explosion of a close, white dwarf companion. Such an explosion might be brought about in rather light companions, which cannot undergo the standard accretion-induced explosion. This would give some supernovae associated with gamma-ray bursts an appearance rather unlike that of the typical Type I supernova. GRB 980425, if indeed associated with SN 1998bw, is too weak to have produced the latter through our proposed mechanism.

The Modified Dynamics is Conducive to Galactic Warp Formation.

There is an effect in the modified dynamics that is conducive to the formation of warps. Because of the nonlinearity of the theory, the internal dynamics of a galaxy is affected by a perturber over and above possible tidal effects. For example, a relatively distant and light companion or the mean influence of a parent cluster, with negligible tidal effects, could still produce a significant warp in the outer part of a galactic disk. We present results of numerical calculations for simplified models that show, for instance, that a satellite with the (baryonic) mass and distance of the Magellanic Clouds can distort the axisymmetric field of the Milky Way enough to produce a warp of the magnitude (and position) observed. Details of the warp geometry remain to be explained; we use a static configuration that can produce only warps with a straight line of nodes. In more realistic simulations, one must reckon with the motion of the perturbing body, which sometimes occurs on timescales not much longer than the response time of the disk.

Prostate-specific antigen values and their clinical significance in renal transplant recipients.

BACKGROUND: In the diagnosis of prostate cancer, prostate-specific antigen (PSA) is the most clinically useful tumor marker. Its utility in renal transplant patients is unclear. We hypothesized that PSA values might be affected by the renal function, immunosuppression, or proteinuria. METHODS: Three hundred four PSA values were measured in 166 patients >40 years (53.5 +/- 7.2 years, mean +/- SD, range 44.4 to 76.2). Charts were reviewed for 24-hour creatinine clearance, 24-hour urinary protein, cyclosporine use, age at the time of each PSA test, and evaluation done in response to the PSA result. Analyses used the Mann-Whitney U test and simple regression model. RESULTS: Twenty-five values in 13 patients were >4.0 ng/mL. Of these, 6 patients (6 values) had normal repeat PSA values; 3 patients (11 values) had negative evaluations for prostate cancer; and 4 patients (8 values) were diagnosed with prostate cancer. The latter 4 patients were excluded from the denoted normal group leaving 294 PSA values in 162 patients. The mean normal PSA was 1.3 +/- 1.8 ng/mL, range 0.1 to 20.2. The pretreatment mean PSA for recipients with prostate cancer was 302 +/- 800, range 8.0 to 2,281. An elevated PSA value was associated with a 31% incidence of prostate cancer. There was no association of PSA levels with cyclosporine use, 24-hour creatinine clearance, or 24-hour urinary protein, but there was with age. CONCLUSIONS: Prostate-specific antigen values in renal transplant recipients are similar to those in the general population and are not influenced by cyclosporine or by renal function. We recommend routine measurement of PSA in male transplant recipients.

Oral ganciclovir in pediatric transplant recipients: a pharmacokinetic study.

An oral formulation of ganciclovir (GAN) has been shown to be effective as prophylaxis of cytomegalovirus (CMV) after liver transplantation in an adult population. There are no data on the use or dose of oral GAN in pediatric transplant recipients. We evaluated the pharmacokinetics of oral GAN in a group of such patients. Nine patients (4 kidney and 5 liver transplant recipients, age 0.9-13 yr) were treated with the commercial formulation of oral GAN after transplant. All patients were considered at risk for CMV disease based on the use of anti-lymphocyte antibody (n = 5), and/or the use of a CMV positive organ in a CMV negative recipient (n = 5) or based on being a recipient of a liver transplant (n = 4). They received oral GAN for 84 +/- 29 d. All recipients had normal renal function as estimated by the Schwartz formula. While on a stable dose of oral GAN for at least 4 d (mean +/- SD 8.4 +/- 7, range 4-27 d), 1-ml serum samples were obtained before and at various times after dosing for the measurement of GAN levels. GAN levels were determined at a central laboratory by high-performance liquid chromatography. In 7 of the patients, a sufficient number of levels were obtained post-dosing to calculate the area under the curve using the linear trapezoidal rule. Cmin, the morning trough concentration, and Cmax, the peak concentration, were determined by inspection. Doses of oral GAN were increased if Cmin levels were less than 0.5-1.0 microgram/ml. Adequate levels of GAN were achieved in these patients at doses of 21.8-38.5 mg/kg or 568-990 mg/m2 every 8 h. There was a better correlation between the maximum GAN blood concentration and body surface area (R2 = 0.52, p = 0.008) than with body weight (R2 = 0.36, p = 0.04). Oral GAN was well tolerated in the 7 patients without evidence of leukopenia, thrombocytopenia, or nephrotoxicity. No CMV disease occurred, although one patient had probable CMV syndrome with the development CMV IgM antibodies. These data suggest that oral GAN may be safely administered to pediatric transplant recipients. With normal renal function, the dosing should be in the range 20-40 mg/kg or 500-700 mg/m2 q 8 h. Further data in children with impaired renal function is required.

Post-transplant diabetes mellitus. The role of immunosuppression.

Immunosuppressive agents increase the risk of death due to coronary disease or stroke by their ability to cause 3 different adverse effects: dyslipidaemia, hypertension and hyperglycaemia. Post-transplant diabetes mellitus has emerged as a major adverse effect of immunosuppressants. As recipients of organ transplants survive longer, the secondary complications of diabetes mellitus have assumed greater importance. There is a need for a precise definition of post-transplant diabetes mellitus to facilitate inter-centre comparison and to study the natural history of post-transplant diabetes mellitus. We recommend broad criteria to define hyperglycaemia, as a fasting blood glucose level of > 400 mg/dl at any point or > 200 mg/dl for 2 weeks, or a need for insulin treatment for at least 2 weeks. We also recommend serial measurements of HbA1c. Cyclosporin and tacrolimus cause post-transplant diabetes mellitus by a number of mechanisms, including decreased insulin secretion, increased insulin resistance or a direct toxic effect on the beta cell. For corticosteroids, the induction of insulin resistance seems to be the predominant factor. However, few studies have examined the mechanism of diabetogenicity at the molecular level. This may hold the key for pharmacological manipulation of current immunosuppressive regimens which may result in decreased metabolic complications. Corticosteroid sparing regimens have been shown to reduce the metabolic complications of immunosuppressants including post-transplant diabetes mellitus. However, their use should be balanced against the increased incidence of transplant rejections. Post-transplant diabetes mellitus may be organ-specific irrespective of the immunosuppressant used. Tacrolimus causes a high incidence of post-transplant diabetes mellitus in recipients of kidney transplants (upto 20% in some reports); the diabetogenicity of cyclosporin-based regimens is comparable with that of tacrolimus-based regimens in recipients of liver transplants. A few clinical studies in which attempts were made to discontinue cyclosporin resulted in an unacceptable loss of the transplant. In the case of tacrolimus, complete withdrawal of immunosuppression may be possible in selected patients with liver transplants. However, post-transplant recipients who may benefit from this approach are difficult to identify. In some early series, patients received doses of tacrolimus that were approximately 2 to 3 times higher than those currently used, which may have resulted in a higher incidence of post-transplant diabetes mellitus. More recently, it has been shown that tacrolimus was successful in salvaging whole pancreatic grafts which were maintained on cyclosporin. Tacrolimus-based immunosuppression as primary therapy was also used with remarkable success in solitary whole pancreas transplants. Strategies to reduce the metabolic complications of immunosuppressants should be pursued aggressively as this will directly lead to a decrease in long term cardiovascular adverse effects.

Fracture of the occipital condyles and associated craniocervical ligament injury: incidence, CT imaging and implications.

Thin section contiguous axial computer tomography (CT) was used to demonstrate fractures of the occipital condyle and craniocervical ligament injury. During a 12-month period, 55 consecutive patients who had sustained high energy blunt trauma to the head or upper cervical region were examined (38 male and 17 female, age range 3-80 years, median 24 years). If occipital condyle fracture was suspected clinically, CT was performed from C2 to the foramen magnum with two dimensional sagittal, coronal, and curvilinear reconstructions and employing bone and soft tissue windows. Occipital condyle fractures were classified according to Anderson and Montesano types 1, 2 or 3. Injury to the internal craniocervical ligaments was described. Nine of 55 patients had occipital condyle fractures (16.4%). Injury of the alar ligaments was demonstrated in four and tectorial membrane injury in two patients. Three of the nine patients had associated fractures of cervical vertebrae. Five of nine patients had a normal Glasgow coma scale on admission (55%) and in two patients the occupital condyle fracture was the only significant injury. Plain cervical radiographs were non-diagnostic. Two patients had significant pain and limited motion of the craniocervicum several months following injury. In conclusion, CT should be performed where there is a high clinical suspicion of occipital condyle fracture, that is based mainly on the mechanism of injury.

Intraoperative placement of a Wallstent for portal vein stenosis and thrombosis after liver transplantation.

We report a case of orthotopic liver transplantation, in which portal vein thrombosis developed in the immediate postoperative period. Surgical thrombectomy and intraoperative placement of a large caliber Wallstent resulted in long-term patency. The unique feature of this case is the intraoperative placement of the stent via the inferior mesenteric vein under fluoroscopic guidance. The use of a large caliber (16 mm) stent obviated the need for postoperative anticoagulation.

Predictive value of enzyme-linked immunosorbent assay-detected IgG anti-HLA antibodies for pediatric renal allograft rejection.

BACKGROUND: Measurement of panel-reactive antibody (PRA) with an enzyme-linked immunosorbent assay using soluble HLA class I molecules (PRA-STAT) in adult renal transplant recipients predicted graft loss and rejection. We sought to confirm this finding in pediatric recipients, an immunologically distinct group. METHODS: The population consisted of 158 renal transplants in 146 patients (age range, 1-21 years). PRA was determined with PRA-STAT and microlymphocytotoxicity (CDC), using final cross-match sera. An elevated test was defined as > or =5% reactivity. Statistical analysis for rejection used the chi-square test and for graft survival used the log-rank test. RESULTS: Thirty-five patients (22%) had %PRA-STAT > or =5%, compared with 26 (16%) with %PRA-CDC > or =5%. The percentage with elevated %PRA-STAT was found to correlate with subsequent transplantations (first, 15%; second, 67%; third, 75%). Subsequent analyses utilized only the 136 primary recipients, of whom 20 (15%) had %PRA-STAT > or =5% and 16 (12%) had %PRA-CDC > or =5%. Elevated %PRA-STAT correlated with rejection at 3 months (65% vs. 36%), 12 months (84% vs. 50%), and 24 months (84% vs. 54%) (P<0.05). No association was found between elevated %PRA-CDC and rejection. Patients with %PRA-STAT > or =5% vs. %PRA-STAT <5% had graft survival at 1 year of 89% vs. 84%, at 2 years of 88% vs. 77%, and at 3 years of 61% vs. 72% (not significant). CONCLUSIONS: Use of %PRA-STAT > or =5% identifies pediatric recipients who are at increased risk for rejection and may benefit from more potent immunosuppression and/or closer monitoring of graft function.

The arteriovenous fistula for hemodialysis access: gold standard or archaic relic?

A five year retrospective review was undertaken to evaluate the patency rates of arteriovenous fistulae (AVF) in patients with end stage renal disease. From July 1989 through June 1994, 150 fistulae were created in the wrists of 144 patients. Thirty-four percent of the patients had diabetes mellitus. Patient death or irreparable fistulae were considered end points in the study. Patency rates were calculated by the Kaplan-Meier Actuarial Analysis. An analysis to assess the impact of the demographic characteristics, underlying renal disease, and effect of revisions on patency rates was calculated. The results demonstrate a high initial failure rate (less than 1 month) of 13 per cent in the entire cohort undergoing fistulae replacement. The 1 and 5-year patency rates were 56 per cent and 30 per cent, respectively. Diabetics had a significantly lower patency rate at 1 and 5 years (42% and 18%) respectively. Others, who had poor patency rates, include patients 70 years old or greater (40% patency at one year). The results suggest that the AVF should not be the first choice of access in elderly diabetics and that these patients would be better served with other modes of access, such as synthetic conduits or permanent indwelling venous catheters.

Persistence of cyclosporine after withdrawal of the drug in a patient with chronic liver transplant rejection. Role of the monoethylglycinexylidine test.

Patients with chronic rejection of liver allografts may show persistently high cyclosporine levels. This phenomenon may be due to a down-regulation of the P450 cytochrome system. The monoethylglycinexylidine test was useful in confirming this hypothesis.

Zinc deficiency and its repletion following liver transplantation in humans.

Zinc deficiency is common in patients with end-stage liver disease but its prevalence and resolution in liver transplant recipients has not been reported. We hypothesized that with normalization of liver function after transplant, zinc levels should rapidly return to normal, obviating the need for oral supplementation. Serum zinc levels were obtained as part of routine laboratory studies just prior to liver transplantation in 34 patients. Of these, 22 had at least one additional zinc level obtained post-transplant. The charts of these 34 patients were retrospectively reviewed for pre- and post-transplant zinc, albumin, protein, and cholesterol levels, prothrombin times, use of oral zinc supplementation, and patient demographics including age, gender, cause of liver failure, UNOS status at the time of transplant, and the use of a pre-transplant trans-jugular intrahepatic portosystemic shunt (TIPS). Post-transplant, the patients received standard enteral formula for nutrition. The overall zinc level for the group was 37.4 +/- 9.0 micrograms/dl (mean +/- s.d., normal = 60-150 micrograms/dl). Thirty-two of the 34 patients (94%) had a zinc level in the subnormal range. There were no differences in zinc levels between patients with alcoholic and non-alcoholic liver failure, males versus females, UNOS status (low = status 1 and 2, high = 3 and 4), pre-transplant use of TIPS nor correlation between age and zinc level. All 22 patients who had a post-transplant zinc level demonstrated an increase from 40.1 +/- 9.7 micrograms/dl to 68.5 +/- 14.1 micrograms/dl (p < and = 0.0001, paired t-test). Our findings indicate that zinc deficiency, generally profound, should be assumed to be present in every patient with end-stage liver disease awaiting transplant. During the waiting period oral supplementation with zinc should be provided. The degree of deficiency is not effected by cause of liver failure, UNOS status, or the presence of TIPS. Following transplantation, zinc levels rapidly recover, obviating the need for checking levels and oral supplementation.

Metabolic problems in recipients of liver transplants.

We analyzed the metabolic problems in recipients of liver transplants. Immunosuppression consisted of cyclosporine, steroids and azathioprine. With a mean follow up of 3.5 yr, 37% of 71 recipients were rendered permanently diabetic and hyperlipidemic. Recipients who developed posttransplant diabetes had higher cholesterol levels and proteinuria, but decreased creatinine clearance. Transplant recipients who developed posttransplant hyperlipidemia had greater proteinuria, but their sugars and creatinine clearance were comparable to those who did not have hyperlipidemia. The most significant factor responsible for these metabolic complications was the total dosage of prednisone and cyclosporine. There was no effect of risk antigens on the development of diabetes.