Postoperative pain relief following laparoscopic tubal sterilization with silastic bands

The value of urine flow cytometry (UFC) in diagnosing acute renal allograft rejection (AR) was recently established in a prospective double-blind study. In this study, we report the 1-year follow-up of three groups of patients identified during the previous study: group 1--stable patients (no ARs) with persistently negative UFCs (n=7); group II--patients who had early ARs (<3 months after transplantation), with positive UFCs that completely normalized with antirejection therapy (n=8); group III--stable patients (no ARs) with positive UFCs (n=7). By definition, group III consists of patients previously considered to have "false positive" UFCs. All patients received standard immunosuppressive therapy, with regimens that included cyclosporine at doses adjusted to maintain target levels. Serum creatinine (SCr) levels (mg/dl) were similar in all three groups at 1 month after transplantation. However, at 1 year after transplantation, SCr was 1.4 +/- 0.2 in group I, 2.0 +/- 0.9 in group II, and 1.9 +/- 0.3 in group III (P=0.004 group I vs. group III). There were no ARs clinically diagnosed during this follow-up period in any of the three groups of patients, but there were significantly higher SCr increments among group III patients after the 1 year of follow-up. The detection of an active urine sediment by flow cytometry in "clinically stable" allograft recipients may indicate ongoing, subclinical acute rejection activity, which in this study was found to be associated with worse renal function at the end of the first posttransplant year as compared with patients with persistently negative UFCs. Increased immunosuppression may be indicated for these patients with persistently positive UFCs.     

A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group

BACKGROUND: Tacrolimus (FK506), a macrolide molecule that potently inhibits the expression of interleukin 2 by T lymphocytes, represents a potential major advance in the management of rejection following solid-organ transplantation. This randomized, open-label study compared the efficacy and safety of tacrolimus-based versus cyclosporine-based immunosuppression in patients receiving cadaveric kidney transplants. METHODS: A total of 412 patients were randomized to tacrolimus (n=205) or cyclosporine (n=207) after cadaveric renal transplantation and were followed for 1 year for patient and graft survival and the incidence of acute rejection. RESULTS: One-year patient survival rates were 95.6% for tacrolimus and 96.6% for cyclosporine (P=0.576). Corresponding 1-year graft survival rates were 91.2% and 87.9% (P=0.289). There was a significant reduction in the incidence of biopsy-confirmed acute rejection in the tacrolimus group (30.7%) compared with the cyclosporine group (46.4%, P=0.001), which was confirmed by blinded review, and in the use of antilymphocyte therapy for rejection (10.7% and 25.1%, respectively; P<0.001). Impaired renal function, gastrointestinal disorders, and neurological complications were commonly reported in both treatment groups, but tremor and paresthesia were more frequent in the tacrolimus group. The incidence of posttransplant diabetes mellitus was 19.9% in the tacrolimus group and 4.0% in the cyclosporine group (P<0.001), and was reversible in some patients. CONCLUSIONS: Tacrolimus is more effective than cyclosporine in preventing acute rejection in cadaveric renal allograft recipients, and significantly reduces the use of antilymphocyte antibody preparations. Tacrolimus was associated with a higher incidence of neurologic events, which were rarely treatment limiting, and with posttransplant diabetes mellitus, which was reversible in some patients.     

Diagnosis of emphysema in patients with chronic bronchitis: a new approach

Aerosol-derived airway morphometry (ADAM) and aerosol bolus dispersion (D) are altered in patients or animal models with lung emphysema. This study was performed to examine the sensitivity and specificity of ADAM and D in the detection of emphysema in vivo compared with conventional lung function parameters. The study comprised patients with chronic obstructive bronchitis (COB) without emphysema (group COB; n=19, age 56+/-8 yrs, forced expiratory volume in one second (FEV1)/vital capacity (VC) 66+/-12% predicted) and patients with chronic bronchitis with high-resolution computed tomography-confirmed emphysema (group COB-E; n=20), age 65+/-7 yrs, FEV1/VC 44+/-16% pred). Using monodisperse aerosol particles ADAM assessed the calibres of peripheral airspaces, while D measured convective gas mixing. Among all lung function parameters, ADAM and D showed the highest sensitivity and specificity for separating patients with COB from those with COB-E (area under the receiver operating characteristics curve (pROC) 0.99 and 1.0, respectively). In patients with COB aerosol parameters did not differ from those found in the control group, whereas patients with COB-E exhibited a two-fold increase in peripheral airspace dimensions compared with subjects with COB (0.86+/-0.07 versus 0.37+/-0.02 mm, p=0.0001) and an increase in D by >50% (541+/-74 versus 345+/-42 cm3, p=0.0001). In conclusion, aerosol-derived airway morphometry and aerosol bolus dispersion are powerful tools in the differential diagnosis of chronic obstructive pulmonary disease.     

Determinants of late allograft nephrectomy

When loss of graft function occurs more than six months after transplantation, allograft nephrectomy is not routinely performed at the time of graft failure. It is usually performed only on those patients who subsequently develop specific complications. However, little is known about the characteristics that make patients more likely to require allograft nephrectomy. The purpose of our study was to identify risk factors for the subsequent need for allograft nephrectomy in patients with graft failure occurring more than 6 months after transplantation. Forty-one patients were studied. Inclusion criteria were: loss of graft function > or = 6 months after transplantation, resumption of dialysis and initiation of weaning from immunosuppression. Thirty patients were treated with cyclosporine + prednisone +/- azathioprine and 11 with azathioprine + prednisone. Mean follow-up time was 17.8 months, ranging from 6 months to 6.1 years. Recipient age, sex and race, original renal disease, donor, donor source (cadaveric vs living related), HLA compatibility, levels of panel reactive antibodies, occurrence of initial delayed graft function, causes of graft failure and tapering of immunosuppression were similar in patients with and without allograft nephrectomy. Using univariate analysis, allograft nephrectomy was found to be significantly more frequent in patients with a history of 2 or more episodes of acute rejection than in patients with no rejection episode: 83% vs 30% (p = 0.03). In addition, allograft nephrectomy was found to be significantly more frequent if the immunosuppressive regimen included cyclosporine (62% vs 27.3%; p = 0.04). Using multivariate analysis however, the number of previous episodes of rejection was found to be the only significant predictor for allograft nephrectomy. None of the other variables considered in the multivariate analysis, including the type of immunosuppressive therapy, was identified as a significant predictor for the need to perform allograft nephrectomy. In summary, the need for late allograft nephrectomy was correlated with the number of previous episodes of acute rejection. Patients with a history of numerous rejection episodes should thus be considered more likely to require allograft nephrectomy once immunosuppression is withdrawn. Possible interventions to reduce or prevent the need for nephrectomy include more gradual tapering of immunosuppression at the time of graft failure or indefinite low-dose immunosuppressive therapy.     

Heart transplantation in Chagas' disease. 10 years after the initial experience

BACKGROUND: Heart transplantation (HT) as a therapeutic option for end-stage chronic Chagas' heart disease (CCHD) is controversial. Reactivation of Trypanosoma cruzi infection and recurrence of the disease in the allograft are likely to occur. Furthermore, active myocarditis has been reported to predispose patients to an increased incidence and severity of rejection. METHODS AND RESULTS: We prospectively investigated the long-term follow-up of 10 patients with CCHD who underwent HT. Immunosuppression was based on cyclosporine A and azathioprine. T cruzi reactivation was prevented with benzonidazole. Besides allograft rejection surveillance, T cruzi infection was monitored through blood tests, myocardial biopsies, and serological tests. Over a mean follow-up period of 34 +/- 38 months (range, 73 to 124 months), 7 patients are alive and in NYHA functional class I. Life expectancy was 78% for the second year and 65% for 10 years. Rejection was less frequent in chagasic than in age- and sex-matched control patients (mean +/- SD, 1.60 +/- 1.26 versus 5.70 +/- 1.89 episodes per patient, respectively; P = .0001); decreased severity of rejection was also observed (P = .006). T cruzi parasitemias detected on three occasions were successfully treated with benzonidazole. There were no signs of recurrence of the disease in the allograft. CONCLUSIONS: These results suggest an important role of HT in the treatment of CCHD. There was a low frequency of T cruzi infection reactivation and no signs of recurrence of the disease in the allograft. The surprisingly decreased rejection incidence and severity require further studies for elucidation.     

Inhaled gentamicin reduces airway neutrophil activity and mucus secretion in bronchiectasis

To investigate whether aerosolized gentamicin (GM) prevents myeloperoxidase (MPO)-mediated airway injury and mucus hypersecretion, a short course of aerosol therapy (3 d) with GM 40 mg or 0.45% saline (saline) twice per day was conducted. Twenty-eight patients with bronchiectasis and mucus hypersecretion after adequate chest care and hydration were enrolled in a randomized, double-blind fashion. MPO levels in sputum collected on arising were determined by fluorometric assay at 655 nm before and after treatment. The sputum MPO level significantly decreased in patients receiving aerosolized GM, from 0.22 +/- 0.04 to 0.14 +/- 0.04 U/g (n = 15), but not in patients with saline inhalation (0.23 +/- 0.03 to 0.17 +/- 0.02 U/g; n = 11). The daily sputum amount significantly decreased from 94.6 +/- 21.6 to 58.1 +/- 17.8 ml (n = 13, p < 0.01) in the GM group, whereas it increased from 78.6 +/- 25.4 ml to 120.5 +/- 33.9 ml (n = 11, p < 0.05) in the saline group. The change in the amount of daily sputum was related to that in the sputum MPO level in the GM group (r = 0.61; p < 0.01). Inhalation of GM, but not saline, significantly (p < 0.05) increased the value of peak expiratory flow (PEF) from 186.4 +/- 25.1 to 216.4 +/- 26.4 L/min and decreased the variability of PEF from 24.6 +/- 5.1 to 6.1 +/- 2.3 %. The nocturnal desaturation and the 6-min walking distances were also significantly improved in the GM group (11.2 +/- 3.8 to 0.6 +/- 0.5 min/h; 324.9 +/- 43.1 to 408.1 +/- 25.9 m; p < 0.05; respectively), but not in the saline group. Subjective improvements in the Borg scale and self-sputum assessment were found in the GM group only. In conclusion, aerosolized GM is effective in improving airway hypersecretion and inflammation in patients with bronchiectasis.     

Heterogeneity of coronary flow reserve in the examination of multiple individual allograft coronary arteries

BACKGROUND: Epicardial and resistance vessel function in the transplanted heart has been evaluated primarily in regions supplied by a single vessel. Heterogeneity of flow among multiple perfusion fields as a marker of early endothelial dysfunction in the microcirculation has not been evaluated previously. This study tested the hypothesis that increased variability of coronary flow reserve (CFR) among multiple vascular regions would be associated with allograft coronary vasculopathy. METHODS AND RESULTS: One hundred six posttransplant patients undergoing cardiac catheterization had measurement of CFR in at least 3 major epicardial vessels. Patients were divided into those with minimal angiographic abnormalities (n=37) and those with no angiographic abnormalities (n=69). The ranges, coefficients of variation, and univariate and multivariate regression analyses of CFR were computed to determine the major clinical factors influencing the degree of variability. The abnormal angiographic group was older (54+/-11 versus 47+/-13 years; P<0.003), had older hearts (35+/-11 versus 27+/-10 years; P<0.005), and were further posttransplant (1626+/-1022 versus 931+/-984 days; P<0.0009). There was no difference in global CFR between groups (normal, 3.4+/-0.8 versus abnormal, 3.4+/-0.7; P=NS). The coefficient of variation of CFR was higher for the abnormal group (16.3+/-8.6% versus 11.0+/-5.5%; P<0. 0006). Univariate and multivariate predictors of increased variability in CFR included angiographic abnormalities, patient age, and body mass index. Both angiographic abnormalities and an elevated CV of CFR were predictive of a combined end point of death, congestive heart failure, or subsequent development of >/=50% coronary stenosis. CONCLUSIONS: These data demonstrate that increased variability of CFR is associated with discernible allograft coronary arteriopathy and is predictive of outcome in patients after heart transplantation.     

Follicular fluid immunoreactive-inhibin concentrations in relation to follicular diameter and estradiol-17 beta, progesterone and testosterone concentrations in individual ovarian follicles in buffalo, Bubalus bubalis

BACKGROUND: Mycophenolate mofetil reduces episodes of biopsy-proven acute cellular rejection or treatment failure in the first year after kidney transplantation; however, limited data exist regarding the efficacy after lung transplantation. METHODS: In a 2-center, nonrandomized concurrent cohort study (level III evidence), we analyzed the incidence of biopsy-proven acute cellular rejection (International Society for Heart and Lung Transplantation grade > or=A2) and decrement in pulmonary function during the first 12 months after successful lung transplantation. All patients received induction immunosuppression with antithymocyte globulin (< or=5 days' duration), cyclosporine and prednisone, in addition to either mycophenolate mofetil (2.0 g/d) [n=11] or azathioprine (1 to 2 mg/kg per day) [n=11]. RESULTS: During the first 12 months after lung transplantation, the mycophenolate mofetil group experienced significantly fewer episodes of acute cellular rejection than the azathioprine group (0.26+/-0.34 vs 0.72+/-0.43 episodes/100 patient-days [mean+/-SD], p < 0.01; 95% CI for the difference=0.126 to 0.813). The change in forced expiratory volume -1 second [deltaFEV1] (liters) between the 3rd and 12th months after lung transplantation was analyzed for the two treatment groups. For this interval, deltaFEV1 for the mycophenolate mofetil group was +0.158+/-0.497 L vs -0.281+/-0.406 L for the azathioprine group (p < 0.05; 95% CI for difference=+0.0356 to 0.843). During the first year, there was 1 death in each group attributed to bronchiolitis obliterans syndrome with concurrent pneumonia. There were no differences in incidence of cytomegalovirus or bacterial infections between the treatment groups; however, a higher prevalence of aspergillus sp airway colonization in bronchoalveolar lavage fluid was observed for the mycophenolate mofetil group (p < .05). The prevalence of bronchiolitis obliterans syndrome at 12 months was 36% for the azathioprine group vs 18% for the mycophenolate mofetil group (p=NS). CONCLUSIONS: Our preliminary experience with mycophenolate mofetil after lung transplantation suggests a decreased incidence of biopsy-proven acute cellular rejection. Furthermore, less decline in FEV1 after 12 months may suggest a reduced incidence or delayed onset for development of bronchiolitis obliterans syndrome. Prospective randomized trials with low beta error (level I evidence) should be performed to assess the efficacy of mycophenolate mofetil vis-à-vis acute allograft rejection and bronchiolitis obliterans syndrome.     

Circulating vascular cell adhesion molecule-1 in pre-eclampsia, gestational hypertension, and normal pregnancy: evidence of selective dysregulation of vascular cell adhesion molecule-1 homeostasis in pre-eclampsia

The potential of DNase I to increase cystic fibrosis sputum elastase activity and lung damage was evaluated. Sputum from CF patients induced little lung hemorrhage when instilled intranasally in C57BL/6 mice. However, sputum treated in vitro by the addition of 1 mg/ml bovine DNase I showed increased neutrophil elastase activity (7.97 +/- 1.56 versus 3.91 +/- 0.62 microM, p < 0.01) and induced marked lung hemorrhage in mice (bronchoalveolar lavage fluid hemoglobin = 192.8 +/- 40.7 versus 44.5 +/- 12.0 microg/ml, p < 0.01). These effects were not observed with DNase I alone in phosphate buffer and were suppressed by the human neutrophil elastase inhibitor methoxysuccinyl-alanyl-alanyl-prolyl-valine-chloromethylketone (MeOSAAPV-CMK). In vivo administration of 2.5 mg aerosolized recombinant human DNase I to patients with CF resulted in a 2.2-fold increase of sputum elastase activity within 1 h of treatment. Elastase levels returned to pre-rhDNase therapy levels 24 h after aerosol treatment. Sputum collected 1 h after rhDNase on 4 separate days from two of six patients in which elastase levels were highest, induced lung hemorrhage when instilled intranasally in mice. We conclude that DNase I therapy of patients with cystic fibrosis can acutely increase the elastase activity of sputum and also its potential to induce hemorrhage in the murine lung.     

Cytotoxicity and apoptosis in human renal allografts: identification, distribution, and quantitation of cells with a cytotoxic granule protein GMP-17 (TIA-1) and cells with fragmented nuclear DNA

In the present study, we analyzed human renal allografts using immunohistochemical techniques to determine the site, identity, and frequency of (a) cytotoxic and apoptotic cells, as identified by staining for GMP-17 (TIA-1), a component of cytotoxic granules; and (b) DNA fragmentation in situ, as detected by the TUNEL method. In acute cellular rejection (n = 15), GMP-17+ mononuclear cells accounted for 29% +/- 12% of the infiltrating cells in the interstitium (341 +/- 164/mm2) and were significantly more concentrated in tubulitis lesions, where they amounted to 65% +/- 14% of the mononuclear cells (96 +/- 61/mm2) (p < 0.01 versus interstitium). GMP-17+ mononuclear cells were also found in sites of endothelialitis. An estimated 80% of the GMP-17+ lymphocytes expressed CD8, and 10% to 20% expressed either CD4 or the macrophage marker CD14. The latter finding led us to analyze normal peripheral blood monocytes by flow cytometry, all of which were found to contain GMP-17. NK cells and neutrophils, which are known to express GMP-17, were detected only rarely in allografts. Specimens with cyclosporine A toxicity (n = 7) or acute tubular necrosis (n = 13) showed fewer GMP-17+ cells in the interstitium (22 +/- 46/mm2 and 62 +/- 50/mm2, respectively) and tubules (2 +/- 6/mm2 and 10 +/- 10/mm2, respectively) (all p < 0.01 versus rejection). These differences were due largely to less intense mononuclear cell infiltration. In cyclosporine A toxicity, however, the percentages of GMP-17+ mononuclear cells within tubules and the interstitium were significantly lower than in rejection (p = 0.02), whereas in acute tubular necrosis significantly lower percentages were found in the tubules (p = 0.04) but not in the interstitium. Native kidneys with end-stage diabetic nephropathy (n = 5) had very low proportions of GMP-17+ cells in interstitial infiltrates (7% +/- 6%) and in tubules (11% +/- 15%), although the infiltrates were focally intense (517 +/- 355/mm2). TUNEL+ cells were found in acute cellular rejection, predominantly in areas with intense mononuclear infiltrates and also within lesions of tubulitis and endothelialitis. Although some TUNEL+ cells were intrinsic renal cells, most appeared to be infiltrating mononuclear cells, and we were able to detect CD3 in some. In areas of intense cellular infiltration, the percentages of TUNEL+ cells (range, 0.5% to 4.2%) were comparable to those seen in the rat thymus, indicating a high level of apoptosis. Overall, in the allograft samples, the numbers of GMP-17+ cells and TUNEL+ cells were significantly correlated (r = 0.79; p < 0.01). These data provide new evidence that T cell (and possibly macrophage)-mediated cytotoxicity plays an important role in acute renal allograft rejection, particularly in the case of tubular injury, and furthermore suggest that apoptosis may be a mechanism not only for graft cell destruction, but also for elimination of activated T cells in the infiltrate.     

Early cyclosporine monotherapy in liver transplantation: a 5-year follow-up of a prospective, randomized trial

Maintenance of adequate immunosuppression and avoidance of side-effects are the goals of long-term management of all organ-transplanted patients. We here report the final results of a prospective, randomized trial comparing early cyclosporine monotherapy versus double-drug therapy (cyclosporine and steroids) in adult liver transplantation patients. One hundred four patients were randomized 3 months after transplantation either to continue (Group I = 50 patients) or to stop steroids (Group II = 54 patients). Patients on a double-drug regimen were maintained long term on methylprednisolone at a dose of 0.1 mg/kg/d. Target cyclosporine trough levels were between 150 and 250 ng/mL in both groups. Our main points of interest were the prevalence of acute and chronic rejections and steroid-related side-effects in the two groups of patients. Mean follow-up was 41 +/- 16 months (range, 4-68 months). Patient actuarial survival 2 and 5 years after randomization was similar in the two groups (82% vs. 83% and 82% vs. 77%). The prevalence of acute rejections after randomization was, respectively, 8% and 4%. A single episode of chronic rejection was observed only in a patient on long-term steroid therapy. Side-effects of steroid therapy were less frequent in patients weaned off steroids, and when considering hypertension and diabetes, the differences between the two groups were statistically significant. Early cyclosporine monotherapy is a safe undertaking in liver transplantation because it allows a significant reduction of steroid-related side-effects without increasing the risk of acute and chronic rejection. After 5 years, patient survival was similar in patients with or without steroids.     

Beta-adrenergic signal transduction following carvedilol treatment in hypertensive cardiac hypertrophy

Cytokines and cytotoxic agents, including nitric oxide (NO) released by macrophages, play important roles during cardiac allograft rejection. In contrast to agents that suppress T-lymphocyte function, CNI-1493 is a multivalent guanylhydrazone compound that inhibits the synthesis and release of proinflammatory cytokines and NO from macrophages. This study investigated the effects of CNI-1493 on rejecting rat cardiac allografts by using Lewis to Wistar-Furth heterotopic cardiac transplants. CNI-1493 (2 mg/kg i.p., b.i.d.) or vehicle (water) was administered beginning the day before surgery. Rat cardiac allograft survival to cessation of heart beat, apoptosis of cardiac myocytes, degree of myocardial inflammation, and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA), protein, and enzyme activity were studied at days 1, 3, 5, and 7 after transplantation. Allograft survival was increased significantly by 26% from 7.5 +/- 0.8 days in vehicle-treated rats (n = 6) to 9.5 +/- 1.2 days in CNI-1493-treated rats (n = 8, p < 0.05). Apoptotic cells per mm2 myocardium decreased from 2.25 +/- 1.25 to 0.84 +/- 0.49 at day 3 and 31.2 +/- 2.9 to 17.6 +/- 5.43 at day 5 after transplantation with CNI-1493 treatment (p < 0.05). The number of apoptotic myocytes and loss of cardiac muscle cells also decreased significantly at day 5 in the treated animals (p < 0.05). The reduction of myocyte loss at day 5 coincided with a significant decrease of the inflammatory response and reduced macrophage influx (p < 0.05). Myocardial iNOS mRNA, protein, and enzyme levels increased during the course of allograft rejection, and CNI-1493 did not significantly reduce iNOS expression in the rejecting rat allograft. CNI-1493 prolongs allograft survival and reduces myocyte loss, apoptosis, and inflammation during rat cardiac allograft rejection. These effects of CNI-1493 appear to be unrelated to altered NO synthesis but may be related to effects of the drug to inhibit macrophage synthesis of cytokines.     

Changes in the pancreatic and respiratory functions in cystic fibrosis. The influence of the time of the evolution of the disease

BACKGROUND: Cystic fibrosis is the most frequent congenital disease in Caucasian and is transmitted by recessive autosomic inheritance. It is characterized by affection of different glands of exocrine secretion, particularly the pancreas and the lung. The aim of this study was to analyze the degree of alteration of pulmonary and pancreatic exocrine function in a group of patients with cystic fibrosis in relation to the time of disease evolution. METHODS: Twenty-one patients between 9 and 31 years of age were studied; 11 with an evolution of lower than or equal to 158 months and 10 with an evolution of higher than 158 months (median of the total patients). To study pancreatic exocrine function the BT-PABA test immunoreactive serum trypsin test were used. To evaluate respiratory function FEV1, FVC, FEV1/FVC ratio and PaO2 were used. RESULTS: The results obtained demonstrated that in the group with a lower time of evolution the diagnosis had been carried out at earlier ages (17 +/- 17 months versus 84 +/- 60 months; p = 0.002) and presented a significantly more altered pancreatic exocrine function (BT-PABA: 13 +/- 12% versus 35 +/- 23%; p = 0.013). However, respiratory function was altered in the group with longer time of evolution (FEV1: 68 +/- 20% versus 36 +/- 23%; p = 0.003; FVC: 74 +/- 9 versus 52 +/- 25%; p = 0.013; FEV1/FEV: 77 +/- 19 versus 50 +/- 9%; p < 0.001; PaO2: 84 +/- 16 versus 58 +/- 11%; p < 0.001). CONCLUSIONS: Pancreatic exocrine function is most intensely affected in patients diagnosed with cystic fibrosis at earlier and with shorter times of evolution while patients who have the longest time of evolution and who were diagnosed later in life presented greater changes in respiratory function.     

Histopathologic findings from 2-year protocol biopsies from a U.S. multicenter kidney transplant trial comparing tarolimus versus cyclosporine: a report of the FK506 Kidney Transplant Study Group

BACKGROUND: This paper reports the histopathologic results of 2-year protocol biopsies from patients who were enrolled in the U.S. FK506 kidney transplant study . METHODS: Recipients of cadaveric kidney transplants were randomized to tacrolimus or cyclosporine therapy. Patients active in the trial at 2 years after transplantation were approached for a protocol biopsy. Biopsies were scored by the Banff classification in a blinded fashion by one pathologist. RESULTS: A total of 144 patients (41.3% of those active at 2 years) had a 2-year protocol biopsy performed; 79 patients were treated with tacrolimus and 65 patients were treated with cyclosporine. Evidence of acute rejection was found in seven (8.9%) of the 2-year biopsies in tacrolimus-treated patients and six (9.2%) cyclosporine-treated patients. Chronic allograft nephropathy was found in 49 (62.0%) tacrolimus biopsies and 47 (72.3%) cyclosporine biopsies (P=0.155). There were no apparent histopathologic differences between the tacrolimus and cyclosporine biopsies. The occurrence of chronic allograft nephropathy was significantly higher in patients who received a graft from an older donor (P<0.01), who experienced presumed cyclosporine or tacrolimus nephrotoxicity (P<0.001), who developed a cytomegalovirus infection (P=0.038), or who experienced acute rejection in the first year after transplantation (P=0.045). A multivariate analysis showed that nephrotoxicity and acute rejection were the most significant predictors for chronic allograft nephropathy. CONCLUSIONS: The occurrence of histologic acute rejection was rare at 2 years, confirming the absence of subclinical acute rejection in these late biopsies. A majority of the biopsies showed features consistent with chronic allograft nephropathy that was associated with acute rejection (particularly in cyclosporine-treated patients), nephrotoxicity, and cytomegalovirus infection in the first year. This suggests that nonimmunologic factors, such as drug-induced toxicity, may play an important role in chronic allograft nephropathy.     

Early cardiac allograft rejection is independent of regional myocardial blood flow

Noninvasive telemetric monitoring of canine heterotopic cardiac allograft unipolar peak-to-peak amplitude (UPPA) has permitted prospective surveillance for rejection; moreover, this technique is able to reliably detect rejection before the development of histologic evidence of myocyte necrosis. This study was performed to determine whether early cardiac allograft rejection and the accompanying decline in allograft UPPA were associated with alterations in regional myocardial blood flow (RMBF). Seven heterotopic, intrathoracic canine cardiac transplantations were performed using triple-drug immunosuppression. Native hearts and allografts were instrumented with right ventricular and left ventricular epicardial screw-in electrodes connected to subcutaneous telemeters. Daily measurement of native and graft UPPA was performed; using radioactive microspheres, native and graft RMBF were determined during the control period and when UPPA had declined by 15%, 30%, and 45%. Graft histologic status was determined by endomyocardial biopsy at the time of RMBF determination. Mean duration of the study was 19.7 +/- 3.9 days. Rejection was documented in all animals. The UPPA was stable in native hearts; UPPA declined in the allografts after the onset of rejection. A biphasic change in allograft blood flow was seen. Initially RMBF increased as UPPA declined; a 30% to 45% reduction in UPPA was associated with a 41% increase in RMBF (p = 0.028 versus allograft control). Subsequently, a significant decline in blood flow was observed for reductions in UPPA greater than 45% (0.68 +/- 0.44 versus 1.07 +/- 0.47 mL.g-1 x min-1 for a 30% to 45% decline in UPPA; p = 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocarditis in children with dilated cardiomyopathy: incidence and outcome after dual therapy immunosuppression

BACKGROUND: The true incidence and prognosis of myocarditis in children with acute dilated cardiomyopathy (DCM) at presentation remains uncertain. This study examines the incidence of lymphocytic myocarditis in a consecutive cohort of children with acute DCM at presentation and outcome after dual therapy immunosuppression with cyclosporine and steroids. METHODS: Twenty-nine consecutive children with acute DCM underwent early endomyocardial biopsy. Children with "definite" myocarditis comprised group I (n = 9) and were treated with cyclosporine and prednisolone. Group II (n = 2) had "borderline" myocarditis, and group III (n = 18) nonspecific histologic findings. Outcome was assessed by echocardiographic measurement of left ventricular end-diastolic dimension and fractional shortening, with follow-up endomyocardial biopsy in group I subjects. RESULTS: Myocardial inflammation with or without myocardial necrosis (groups I and II) was present in 38% of all cases. There were no initial clinical, electrocardiographic, or echocardiographic features to distinguish patients in group I from patients in group III. At presentation, the mean +/- SEM left ventricular end-diastolic dimension and fractional score-Z scores of group I patients were 4.6 +/- 1.7 and -5.1 +/- 0.8, respectively, compared with 0.8 +/- 0.3 and -0.9 +/- 0.4, respectively, at withdrawal of immunosuppression (p < 0.001 for both). Both of these parameters did not differ significantly from normal controls at least follow up. Two group I patients had a biopsy-proven relapse after withdrawal of therapy that responded to reinstitution of immunosuppression. At latest follow-up, all nine group I patients had regained normal left ventricular function compared with four of 18 group III patients (p < 0.001). CONCLUSION: Lymphocytic myocarditis is frequent in children with dilated cardiomyopathy and cannot be predicted from noninvasive investigations. The use of cyclosporine and steroids is associated with a favorable outcome, and a controlled trial of dual therapy immunosuppression in children is therefore warranted.     

Survival after heart transplantation without regular immunosuppression

Seventy renal allograft biopsies were done in 31 patients, routinely at 1, 2, and 3 months posttransplant, and as clinically indicated, using an automated biopsy "gun." The histological diagnosis was made according to the Banff schema, which emphasizes tubulitis and vascular inflammation over mononuclear cell infiltration. Fifty-three biopsies satisfied histological inclusion criteria. Twenty-nine biopsies were obtained from stable patients, defined as those in whom serum creatinine had changed < 10% in 2 weeks, and in whom immunosuppression (cyclosporine, azathioprine, and prednisone) had not been increased in that interval. Of these biopsies, 30% (9/29) showed rejection, which could not have been predicted from pretransplant (HLA mismatch, panel-reactive antibody titer) or posttransplant (cyclosporine and serum interleukin 2 receptor levels) variables. The significance of these early subclinical rejection episodes is unknown, and their effects on long-term graft histology and function are being examined in a controlled study.     

Surgical resection for hepatocellular carcinoma in Cape Town--a clinical and histopathological study

BACKGROUND: The effect of mycophenolate mofetil (MMF) and sirolimus (rapamycin, RAPA) mono- and combination-therapy was examined in prevention of acute heart, pancreas, and kidney allograft rejection and in reversal of ongoing heart allograft rejection in the rat. METHODS: Both drugs were administered orally for up to 30 days. Eleven groups (n=6) were involved in the first part of the heart allografting model. Brown Norway (RT1n) to Lewis (RT1(1)) combination was used in the heart and pancreas transplantation models, whereas Buffalo (RT1b) to Wistar Furth (RT1u) was used in the kidney transplantation model. RESULTS: The naive control group showed a mean survival time of 6.5+/-0.6 days. There were graded dose-responses to monotherapy of MMF 10 and 20 mg(kg/ day (12.5+/-2.6 days; 19.3+/-9.0 days) and RAPA 0.2, 0.4, 0.8, and 1.8 mg/kg/day (19.2+/-2.0 days; 30.0+/-7.3 days; 50.8+/-12.5 days; 51.2+/-2.6 days), respectively (P=0.001). Results with the combined use of drugs indicate that a synergistic or very strong synergistic interaction was produced when compared with monotherapy of MMF or RAPA: MMF 10 mg(kg/day+RAPA 0.2 mg/kg(day (52.7+/-5.7 days, combination index [CI] =0.189), MMF 20 mg(kg/day+RAPA 0.2 mg/kg/day (57.7+/-5.7 days, CI=0.084), MMF 10 mg/kg/day+RAPA 0.4 mg(kg/day (50.2+/-13.5 days, CI=0.453), and MMF 20 mg/kg(day+ RAPA 0.4 mg/kg(day (51.5+/-6.8 days, CI=0.439), respectively. These results were repeatable in the prevention of acute pancreas and kidney allograft rejection in the rat. In the second part of the study of reversal of ongoing acute heart allograft rejection model, the combined treatment of MMF 10 mg/kg(day+RAPA 0.2 mg/ kg(day (35.5+/-16.0 days, CI=0.794) and MMF 20 mg/kg day+RAPA 0.2 mg(kg/day (57.2+/-4.7 days, CI=0.310) represented synergistic interaction compared with monotherapy of MMF or RAPA. CONCLUSIONS: Concomitant therapy of MMF and RAPA produces a synergistic effect in prevention of heart, pancreas, and kidney allograft rejection and in reversal of ongoing heart allograft rejection in the rat.     

The immunopathology and clinical relevance of lymphocyte cultures in liver transplantation

Lymphocytes infiltrating human liver allograft biopsies were expanded in vitro for 3 to 5 days in recombinant IL-2 and then uniformly quantified and phenotypically characterized. The extent of proliferation was correlated with the degree and pattern of lymphocyte infiltration of the source biopsy as well as with the subsequent clinical outcome. Each of the 117 cases was assigned to one of three primary clinical outcome groups based on a retrospective evaluation of the clinical course before and after biopsy. The groups consisted of cases involving viral infection (n = 21), rejection (n = 40), or nonrejection-related allograft dysfunction (n = 56). The rejection group showed significantly greater in vitro expansion of lymphocytes (4201 +/- 685) compared to the nonrejection group (2720 +/- 408, P < 0.05). However, cases from the viral infection group showed the highest overall average lymphocyte growth (6655 +/- 2595, P < 0.05). Immunohistologic evaluation of the source liver transplant biopsy demonstrated increased T-cell infiltration of portal triads primarily by CD8+ T-cells in rejection compared to nonrejection cases (semiquantitative grade 1.3 +/- 0.1 versus 1.0 +/- 0.1, P < 0.05). The viral infection group demonstrated more significant T-cell infiltration (again predominantly CD8+) of the lobules compared to cases without viral infection (1.9 +/- 0.3 versus 1.3 +/- 0.1, P < 0.05). Immunohistologic evaluation of the cultured lymphocytes from the biopsies demonstrated a marked predominance (75% of cultures) of CD8+ T-cells compared to CD4+ T-cells.(ABSTRACT TRUNCATED AT 250 WORDS)