MDSC; the Most Important Cell You Have Never Heard Of.

The myeloid-derived suppressor cell (MDSC) is the 'queen bee' of the tumor microenvironment. MDSCs protect the cancer from the patient's immune system, make the tumor resistant to immunotherapy, and allow the tumor to thrive while the patient withers away. Eliminating MDSCs should improve response rates to cancer therapy and patient survival.

Physiological and pharmacological stimulation of pancreatic islet hormone secretion in type I diabetic pancreas allograft recipients.

Successful heterotopic and denervated pancreas allograft transplantation (PAT) often results in normoglycemia and peripheral hyperinsulinemia in insulin-dependent (type I) diabetic recipients. The contribution of altered hepatic insulin extraction (HIE) to the resulting hyperinsulinemia in such patients remains uncertain. Furthermore, whether the denervated pancreas allografts exhibit beta-cell hyperresponsiveness to physiological and pharmacological stimulation is controversial. We evaluated beta-cell function and HIE after successful whole cadaveric PAT with systemic venous drainage in 13 type I diabetic patients before and after mixed-meal and intravenous glucose and glucagon administration. The results were compared with those of 5 nondiabetic patients with kidney transplantation only, who had native innervated pancreases with portal insulin delivery and were receiving an equivalent triple immunosuppressive therapy (cyclosporin, azathioprine, and prednisone), and 7 healthy control subjects with no family history of diabetes. After PAT, fasting and poststimulation serum glucose concentrations were normalized. PAT was associated with marked basal hyperinsulinemia (3- to 8-fold) as assessed by immunoreactive insulin (IRI) levels in type I diabetic patients (mean +/- SE 345 +/- 43 pM) compared with control subjects (43 +/- 14 pM) and nondiabetic kidney-transplantation patients (129 +/- 38 pM). After mixed-meal ingestion, the mean incremental integrated insulin area was similar in PAT patients (18 +/- 3 nM.min) compared with kidney-transplantation patients (20 +/- 4 nM.min) and healthy control subjects (21 +/- 3 nM.min). Basal serum C-peptide levels were significantly greater in PAT (1.72 +/- 0.13 nM) and kidney-transplantation (2.15 +/- 0.33 nM) patients than in healthy control subjects (0.50 +/- 0.10 nM; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

RDP58 is a novel and potentially effective oral therapy for ulcerative colitis.

BACKGROUND: RDP58 is a novel anti-inflammatory d-amino acid decapeptide that inhibits synthesis of proinflammatory cytokines by disrupting cell signaling at the pre-MAPK MyD88-IRAK-TRAF6 protein complex. We therefore evaluated its efficacy and safety in parallel multicenter, double-blind, randomized concept studies in ulcerative colitis (UC). METHODS: In the first trial, 34 patients with mild to moderate active UC were randomized (1:2) to placebo (n = 13) or RDP58 100 mg (n = 21). In the second trial, 93 similar patients were randomized (1:1:1) to placebo (n = 30) RDP58 200 mg (n = 31), or RDP 300 mg (n = 32). In both studies, treatment success was defined as a simple clinical colitis activity index score of no more than 3 at 28 days. Sigmoidoscopy and rectal biopsy (at baseline and 28 days) and safety measures (baseline and 28 and 56 days) were other endpoints. RESULTS: Treatment success on RDP 100 mg was 29% versus 46% on placebo (P = 0.46). There were no significant differences in sigmoidoscopy or histology score. In the second study, treatment success on the higher doses of RDP58 (200 and 300 mg) was 71% and 72%, respectively, versus 43% on placebo (P = 0.016). Improvements in sigmoidoscopy scores (41% on 200 mg and 46% on 300 mg versus 32% on placebo) did not reach significance, but histology scores improved significantly (P = 0.002) versus placebo. Overall, adverse events were no different between placebo (3.3 +/- 2.4) and RDP58 (2.7 +/- 1.4, 300-mg group). CONCLUSIONS: RDP58 at a dose of 200 or 300 mg, but not 100 mg, was effective in mild-to-moderate UC. RDP58 was safe and well tolerated, and its novel action makes it an attractive potential therapy.

Gastric mucosal calcinosis. Calcified aluminum phosphate deposits secondary to aluminum-containing antacids or sucralfate therapy in organ transplant patients.

We have noticed calcium deposits (gastric mucosal calcinosis, or GMC) in the superficial gastric mucosa of 28 organ transplant patients (OTPs) (11 liver, seven bone marrow, four kidney, three kidney/pancreas, two heart, and one each of liver and kidney transplant) who underwent endoscopic biopsies. The deposits were tinctorially similar to cytomegalovirus inclusions, ranged from 40 to 250 mu in diameter, and were present just beneath the surface epithelium at the tips of the foveolae. An x-ray microanalysis showed that these mucosal deposits contained the elements aluminum, phosphorus, calcium, and chlorine. Clinical chart review showed that all OTPs with GMC were taking aluminum-containing antacids or sucralfate. Review of biopsies from gastric ulcer patients found GMC in a significantly smaller percentage than in transplant patients (32.7% vs. 5.1%, p < 0.0002). In addition, all three ulcer patients with calcified deposits were chronic renal failure patients on long-term aluminum-containing antacid therapy. Gastric mucosal calcinosis appears to be caused by aluminum phosphate accumulation secondary to antacid or sucralfate therapy in organ transplant patients. The presence of GMC in OTPs and chronic renal failure patients rather than other gastric ulcer patients is most likely due to the longer duration of therapy with aluminum-containing compounds in the former two patient groups. The clinical relevance of GMC remains to be seen. In theory, however, accelerated bone demineralization via loss of phosphates and absorption of aluminum in the gastrointestinal tract may be a consequence of long-term aluminum-containing antacid or sucralfate therapy.

OKT3 for primary therapy of the first rejection episode in kidney transplants.

The improvement in one-year graft survival has allowed transplant centers to focus on long-term graft survival. A study of 665 primary cadaveric kidney transplants from a single center treated with cyclosporine demonstrated that patients did not develop chronic rejection if there was not an episode of acute rejection. This study is a retrospective review of 314 consecutive kidney transplants from a single center to determine if early, aggressive treatment of the first episode of acute rejection will improve graft survival without increasing recipient morbidity. The course of 314 consecutive kidney transplants performed during a 27-month period (245 CAD and 68 living-related) was studied. Demographic characteristics were equivalent between the two groups, and all patients received sequential quadruple immunosuppression using ALG and CsA. Patient and graft survivals at 2 years were 89.7% and 84%, respectively. At least one rejection episode occurred in 41% of the patients, one-half within 30 days of transplant. Rejection episodes were treated by oral prednisone taper, primary ALG or OKT3, or "rescue" therapy with ALG or OKT3. Graft survival in the 52 recipients treated with OKT3 for primary treatment of first rejection episode was 20% better than the 50 patients treated with PRED (P = 0.0847). Comparing the 39 recipients of primary CAD kidneys treated with primary OKT3 vs. 38 treated with PRED demonstrated a 32% improvement in 2-year graft survival (P = 0.033). There was no increase in second rejection episodes in patients treated with OKT3. Renal function was equivalent in patients with rejection regardless of type of antirejection therapy used. Of patients treated for rejection, 22% had symptomatic CMV infections, which were divided equally between the two groups. Eighty-two patients received a single course of OKT3, 28 received two courses, and 2 patients received OKT3 three times. Only two patients developed antimurine antibodies that required abandoning OKT3 for the treatment of rejection. This study clearly demonstrates that the early use of OKT3 as primary treatment of rejection results in significant improvement of 2-year graft survival in recipients of first CAD kidney transplants. There is no increase in episodes in CMV in patients treated with OKT3 as primary therapy and no increase in patient mortality. Early use of OKT3 does not prevent or decrease incidence of subsequent rejection episodes. Renal function in surviving grafts is not improved in patients treated with OKT3 vs. PRED.(ABSTRACT TRUNCATED AT 400 WORDS)

Donor race does not affect cadaver kidney transplant survival--a single center experience.

Black kidney transplant recipients have worse graft survival than white recipients. Speculation regarding etiology has focused on differences in human lymphocyte antigens (HLA). Some suggest that improvements in graft survival would be obtained if donor and recipient race were matched. We reviewed 236 cadaver transplants performed over 9 years at a single center using an HLA-match-driven allocation system and a uniform immunosuppressive protocol to determine the impact of donor race on graft survival. A multivariate analysis of graft survival using patient race, sex, age, transplant number, current and maximum plasma renin activity, donor race, cold ischemia time and HLA mismatch, the need for dialysis, and the presence of rejection as independent variables. Sixty percent of recipients were black, and 82% were primary transplants; 28 kidneys (12%) were from black donors. The 112 patients with the same race donor had identical 5-year graft survival as the 124 who had a different race donor (40%; P = 0.1726). The 5-year survival of the 88 white recipients of white donor organs was better than that of the 120 black recipients of white donor organs (54% vs. 42%, respectively; P = 0.0398). Black recipients (t1/2 = 37 months) did worse than white recipients (t1/2 = 60 months) regardless of organ source (P = 0.023). In the multivariate analysis, neither donor nor recipient race were an independent variable in predicting graft survival. Rejection (RR = 2.9) and the need for dialysis on the transplant admission (RR = 4.1) were the only factors that predicted poor survival. Black recipients had more rejection (P = 0.04) but not more need for dialysis posttransplant regardless of donor race. Donor race did not affect graft survival in this series. The effect of recipient race on graft survival was due to an increased incidence of rejection episodes in black recipients, which was independent of HLA mismatch. These data suggest that improvements in immunosuppression, not changes in allocation, are needed to improve graft survival.

The frequency of rejection episodes after combined kidney-pancreas transplant--the impact on graft survival.

The recipients of combined kidney-pancreas transplants (SPK) are unique because they routinely receive two allografts from the same donor. In a previous study, we found that the long-term graft survival of the two allografts was different, with better graft survival seen in the pancreas allograft. In an attempt to understand the reason for the different graft survival in the recipients of organs from the same donor, we have reviewed the incidence and timing of rejection episodes in 160 consecutive technically successful whole-organ bladder-drained SPK performed at a single institution using a uniform immunosuppressive regimen. Rejection episodes were common. A total of 53% of the recipients had at least one episode of rejection in one of the organs. Multiple rejection episodes requiring hospitalization occurred in 23% of the recipients. The kidney allograft had more frequent rejection episodes than the pancreas allograft: 78 patients had 130 renal rejection episodes while only 50 patients had 65 episodes of pancreas rejection. No rejection episodes occurred in 111 pancreas and 82 kidney grafts (P = 0.0014). Multiple rejection episodes were three times as common in the kidney grafts (20%) than in the pancreas grafts (6%; P = 0.0001). The timing of the first rejection episode was also different. The median time to the first kidney rejection episode was 29 days compared with 39 days to the first pancreas rejection episode (P = 0.0191). Graft survival in the organs was equal when stratified by the number of rejection episodes (none, one, > one) per organ (P = 0.9378). These data suggest that the worse long-term kidney graft survival seen in SPK recipients is due to the greater risk of rejection (relative risk: 2.04; [95% conf. interval: 1.29-3.23]) and a greater frequency of rejection episodes of rejection episodes in the kidney (0.81/patient) compared with the pancreas (0.41/patient). The implications for patient management and the possible reasons for the different rates of rejection are discussed.

A randomized, prospective, double-blinded trial of cyclosporine vs. OG37-325 in cadaveric renal transplantation--a preliminary report.

The efficacy of cyclosporine is documented, but it has side effects that are troublesome. Another compound, OG37-325, has been identified that appears to have similar efficacy, but less nephrotoxicity. This study was designed to address the benefits and toxicities of cyclosporine and OG37-325 in a prospective, randomized, double-blinded trial in cadaveric renal transplant recipients. The preliminary results demonstrate similar outcomes in terms of patient and graft survival, but suggest less nephrotoxicity in the OG37-325-treated patients. Longer follow-up will delineate the utility of OG37-325 in solid-organ transplantation.

Transmission of hepatitis C by kidney transplantation--the risks.

The use of cadaveric organ donors with positive serologic tests for hepatitis C (HCV) has caused considerable debate. We have reviewed the clinical course of 43 EIA1 HCV-negative recipients who received kidney transplants from EIA1 HCV-positive donors (Study). We have attempted to define the rate of HCV-RNA transmission and to determine the frequency of HCV disease transmission as determined by abnormalities in liver function tests. Viral transmission was assessed using serologic assays for HCV antibody formation (EIA1, EIA2, and Matrix--an automated multiple antigen immunoblot assay) and with PCR testing for the presence of HCV-RNA on recipient sera. Liver function was followed longitudinally in the Study patients and compared with a group of 103 kidney recipients of organs from EIA1 HCV-negative donors (Control). Of the Study patients, 56% became PCR-positive for HCV-RNA, suggesting the transmission of HCV-RNA from the HCV-positive donor. Interpretation of serologic tests for HCV was complex. Currently available first (EIA1) and second (EIA2) generation serologic assays were always negative. The multiple antigen immunoblots assay (Matrix) had a high positive predictive value (93%) for the presence of HCV-RNA transmission, but one-third of Matrix-negative Study patients were PCR-positive (sensitivity = 66%). Currently, only 38% of recipients have HCV-RNA, suggesting that the virus may have been cleared by one-third of Study recipients who had circulating virus. Traditional tests of liver function (ALT, AST, AP, and GGT) were of limited use in predicting HCV-RNA transmission. Average AST, AP, and GGT were similar in the two groups. Average ALT was increased (93 I/U and 47 I/U) in Study and Control patients, respectively, but this difference was not significant. Episodes of abnormal liver function (ALT 60-99 IU for > or = 14 days) occurred in 22% of Study and 10% of Control patients (P = NS) and lasted longer in Study compared with Control patients (301 vs. 138 days; P < 0.02). Hepatitis (ALT > or = 100 IU for > 14 days) occurred with an equal frequency (6.5%) in both groups. The presence of HCV-RNA did not predict episodes of abnormal liver function. Fulminant hepatitis or rapidly progressive cirrhosis did not occur in the recipients of organs from HCV-positive donors. These data demonstrate a high efficiency of transfer of HCV-RNA by kidney transplantation from an HCV-positive donor to an HCV-negative recipient. A majority of the patients have asymptomatic HCV infection.(ABSTRACT TRUNCATED AT 400 WORDS)

Detection of cytomegalovirus in liver transplant biopsies. A comparison of light microscopy, immunohistochemistry, duplex PCR and nested PCR.

The polymerase chain reaction was used to detect cytomegalovirus (CMV) in 91 formalin-fixed paraffin-embedded needle biopsies from 38 liver transplant patients with allograft dysfunction. Thirty donor liver biopsies served as negative controls. PCR results were compared with light microscopy (LM), immunohistochemical staining (IH) for CMV early and late antigen, and clinical data. Primers to the major immediate early gene (MIE) and the viral DNA polymerase gene were duplex amplified. PCR product was reamplified with a nested primer set for the MIE and confirmed by electrophoretic mobilities and dot blotting. Primers for human beta-hemoglobin were used as internal controls. Seventeen of 38 patients had clinical evidence of cytomegalovirus disease, 12 of these were IH-positive, 14 were LM-positive, 15 were duplex PCR-positive and 17 were nested PCR-positive. In addition, duplex PCR was positive in one patient without other evidence of CMV disease, while nested PCR was positive in 12 such patients. The sensitivity and negative predictive value of nested PCR was 100%--however, the specificities and positive predictive values were only 42.9 and 58.6%, respectively. The control group was completely negative by LM, IH, and duplex PCR, however, 6 of 30 patients were nested PCR-positive. The number of nested-positive, duplex-negative patients without CMV disease was significantly greater in the transplant group versus the control group (12/21 vs. 6/30, P < 0.009). The incidence of IgG seropositivity was also significantly greater in the transplant group versus the controls (29/32 vs. 15/24, P < 0.02). We conclude that nested PCR may be an overly sensitive technique for the detection of clinically relevant CMV disease. A negative nested PCR assay for CMV may, however, help rule-out symptomatic CMV infection in an individual case. Duplex PCR showed little advantage over LM, while IH was confirmatory but did not add any new information in this study.

The effect of verapamil on cellular uptake, organ distribution, and pharmacology of cyclosporine.

Verapamil has been shown to potentiate cyclosporine's effect in inhibiting lectin-stimulated proliferation of murine and human lymphocytes, and in prolonging graft survival in experimental heterotopic cardiac transplantation in rats. A series of experiments were designed to determine whether verapamil's effect occurred by increasing cyclosporine uptake or decreasing cyclosporine's clearance by lymphocytes utilizing human peripheral blood lymphocytes and radiolabeled cyclosporine. Verapamil had no effect. The distribution of radiolabeled cyclosporine was also studied in mice that had been given verapamil (10 mg/kg) 1 hr prior to cyclosporine injection. No significant changes in organ distribution occurred. Lectin-stimulated release of intracellular ionized calcium was studied using a flurometric technique (Quin-2 and Fura-2). Neither cyclosporine nor verapamil had any effect on either lectin-stimulated or phorbol ester-stimulated release of intracellular ionized calcium. Phorbol ester and subproliferative doses of lectin were used to determine the effect of cyclosporine and verapamil on protein kinase C-mediated lymphocyte activation. Cyclosporine inhibited phorbol ester stimulated proliferation and verapamil potentiated this inhibition. Verapamil does not change cell or organ uptake of cyclosporine, and it does not affect the initial increase in intracellular ionized calcium that occurs with lymphocyte activation. Verapamil potentiates cyclosporine in inhibiting protein kinase C-mediated events in lymphocyte activation.

The economic benefit of allocation of kidneys based on cross-reactive group matching.

BACKGROUND: Recently the United Network for Organ Sharing (UNOS) began a pilot study to evaluate prospectively the merits of an allocation of cadaveric kidneys based on broader classes of HLA antigens, called cross-reactive groups (CREG). The objectives of the pilot study consider patient outcomes, but not the potential economic impact of a CREG-based allocation. This study predicts the impact of a CREG-based local allocation of cadaveric kidneys on 3-year Medicare payments and graft survival. METHODS: The UNOS renal transplant registry was merged to Medicare claims data for 1991-1997 by the United States Renal Data System. Average accumulated Medicare payments and graft survival up to 3 years posttransplant for first cadaveric renal transplant recipients were stratified by cross-reactive group mismatch categories. The economic impact was defined as the difference in average 3-year costs per transplant between the current and proposed allocation algorithms. Average 3-year costs were computed as a weighted average of costs, where the weights were the actual and predicted distributions of transplants across cross-reactive group categories. RESULTS: Results suggest that an organ allocation based on cross-reactive group matching criteria would result in a 3-year cost savings of $1,231 (2%) per transplant, and an average 3-year graft survival improvement of 0.6%. CONCLUSIONS: Cost savings and graft survival improvements can be expected if CREG criteria were to replace current criteria in the current allocation policy for cadaveric kidneys, although the savings appear to be smaller than may be achievable through expanded HLA matching.

Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation.

BACKGROUND: Thymoglobulin, a rabbit anti-human thymocyte globulin, was compared with Atgam, a horse anti-human thymocyte globulin for the treatment of acute rejection after renal transplantation. METHODS: A multicenter, double-blind, randomized trial with enrollment stratification based on standardized histology (Banff grading) was conducted. Subjects received 7-14 days of Thymoglobulin (1.5 mg/kg/ day) or Atgam (15 mg/kg/day). The primary end point was rejection reversal (return of serum creatinine level to or below the day 0 baseline value). RESULTS: A total of 163 patients were enrolled at 25 transplant centers in the United States. No differences in demographics or transplant characteristics were noted. Intent-to-treat analysis demonstrated that Thymoglobulin had a higher rejection reversal rate than Atgam (88% versus 76%, P=0.027, primary end point). Day 30 graft survival rates (Thymoglobulin 94% and Atgam 90%, P=0.17), day 30 serum creatinine levels as a percentage of baseline (Thymoglobulin 72% and Atgam 80%; P=0.43), and improvement in posttreatment biopsy results (Thymoglobulin 65% and Atgam 50%; P=0.15) were not statistically different. T-cell depletion was maintained more effectively with Thymoglobulin than Atgam both at the end of therapy (P=0.001) and at day 30 (P=0.016). Recurrent rejection, at 90 days after therapy, occurred less frequently with Thymoglobulin (17%) versus Atgam (36%) (P=0.011). A similar incidence of adverse events, post-therapy infections, and 1-year patient and graft survival rates were observed with both treatments. CONCLUSIONS: Thymoglobulin was found to be superior to Atgam in reversing acute rejection and preventing recurrent rejection after therapy in renal transplant recipients.

An increased incidence of rejection episodes. One of the causes of worse kidney transplantation survival in black recipients.

OBJECTIVE: To evaluate the cause of worse kidney allograft survival in black recipients, which has been the source of considerable interest and debate. DESIGN: Three hundred ninety-two consecutive renal allografts (O HLA mismatch grafts excluded) were reviewed. Of the recipients, 57% were black, 27% received living donor grafts, and 86% received their first transplant. All recipients underwent an oral cyclosporine induction protocol with triple drug maintenance. Crude graft survival, the risk of rejection, and the need for dialysis were determined using donor and recipient demographic and immunologic variables. RESULTS: Graft survival was 84%, 67%, and 50% at 1, 3, and 5 years after the transplantation, respectively. The survival of black recipients was 4%, 11%, and 20% worse than that of white recipients at 1, 3, and 5 years, respectively (P < .002). When only pretransplantation variables were considered, black recipient race was the only variable that predicted graft loss in the multivariate analysis (relative risk [RR] = 1.6, P = .09). When posttransplantation and pretransplantation variables were used, cadaver donor (RR = 1.7), an episode of rejection (RR = 2.6), and the need for dialysis (RR = 2.7) were independent variables that predicted graft loss (P < .001). Black recipient race was a dependent variable. Four pretransplantation variables predicted the risk of dialysis: black race (RR = 3.6), male recipient (RR = 2.1), cadaveric donor (RR = 2.2), and a peak panel-reactive antibody level greater than 30% (RR = 2.8). Three pretransplantation variables predicted the risk of rejection: black race (RR = 1.7), male recipient (RR = 1.6), and a current panel-reactive antibody level greater than 30% (RR = 5.3). CONCLUSIONS: These data suggest that black recipient race is a dependent predictor of renal allograft survival when the posttransplantation events of rejection and dialysis are considered. Black recipients have more immunologic complications after renal transplantation that result in worse graft survival. These results confirm the importance of postallograft events as the major determinants of long-term graft survival and suggest that black recipients are receiving inadequate immunosuppression. These data support attempts to tailor immunosuppressive protocols to recipient pretransplantation risk profiles as a way to improve graft survival in the high-risk recipient.

Safety of simultaneous aortic reconstruction and renal transplantation.

Patients with aortic disease and end-stage renal failure who require both aortic reconstruction and renal transplantation (simultaneously or staged) pose a formidable clinical challenge. Traditionally, the performance of either one of these procedures has been viewed as a relative contraindication to the performance of the other. From 1978 to 1989, eight patients were referred to us with the combination of aortic disease and end-stage renal failure. Seven had aneurysmal disease and one had aorto-iliac occlusive disease. Five patients presented with their diseases sequentially and had two sequential operations, with a mean interval of 4 years between procedures. Three patients presented with their diseases simultaneously and underwent simultaneous aortic reconstruction and living related renal transplantation. All patients were followed up for a mean interval of 4.5 years. By life-table analysis, the 5-year renal graft survival was 100%, the primary aortic graft patency was 82%, and the secondary aortic graft patency was 100%. The only death in this series occurred 11 years after aortic reconstruction and 4 months after a renal transplantation and was due to overwhelming cytomegalovirus sepsis. There were no significant differences between the simultaneous and staged groups in terms of operative mortality, postoperative complications, transplant function, or aortic graft patency. From this experience, we conclude that: (1) patients who present simultaneously with aortic disease and end-stage renal failure can safely undergo simultaneous aortic reconstruction and renal transplantation; (2) patients who present with these two diseases sequentially can undergo a second reconstructive procedure with very low operative morbidity and mortality rates; (3) when these two procedures have been performed sequentially, the second procedure has not significantly altered the 30-day or 5-year results of the first procedure; and (4) the 30-day and 5-year results of each procedure have been excellent regardless of the temporal sequence in which they were performed.

Orthotopic liver transplantation with abdominal situs inversus and dextrocardia.

Anatomic anomalies may present technical difficulties during orthotopic liver transplantation. Abdominal situs inversus was considered a contraindication to liver transplantation. A successful liver transplant in a patient with both situs inversus and dextrocardia is described, along with a technical review.

Histopathologic changes in human small intestine during storage in Viaspan organ preservation solution.

OBJECTIVE: To evaluate the histopathologic changes that occur in human small intestine or time when preserved in Viaspan organ preservation solution. DESIGN: Short segments of human small intestine were placed in standard organ preservation solution (Viaspan) and stored in conditions that mimic the clinical situation associated with clinical organ procurement, preservation, and transplantation. The intestinal segments were removed at sequential time points and placed in 10% formalin. Specimens underwent histopathologic examination to determine time-related changes. SPECIMENS: Short intestinal segments were obtained from seven multiorgan cadaver donors. Specimens were obtained in a way that exactly mimicked small intestinal organ retrieval. RESULTS: Small intestinal histology remained normal for the first 6 hours. After 6 hours, vacuolar separation began to occur between the epithelium and the basement membrane in the upper half of the villi. After 9 hours of cold preservation, epithelial detachment extended deep into the crypts with occasional shedding of cells and villi. CONCLUSIONS: Currently used small intestinal preservation using Viaspan results in considerable histopathologic changes in human jejunum after 9 hours of cold storage. The histopathologic pattern appears normal for the first 6 hours and suggests that preservation times should be limited to this time period when possible.

In vivo potentiation of cyclosporine immunosuppression by calcium antagonists.

We have shown that the addition of verapamil, a calcium channel blocking agent, or trifluoperazine, a phenothiazine, to a regiment using the immunosuppressive agent Cs significantly enhances heterotopic cardiac allograft survival in an ACI to Lewis transplant model. This work verifies previous in vitro work from our laboratory and offers a potential therapeutic strategy to decrease the dose of Cs needed for effective immunosuppression while perhaps lessening its dose-related side effects.