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Background: As opposed to most solid-organ transplant recipients, patients with acute liver failure exhibit a pretransplant health status more comparable with the general population, and any posttransplant cardiovascular risk excess should thus be more attributable to transplantation-related factors alone., Methods: This study compared the cardiovascular risk of 77 consecutive patients with acute liver failure at 5 years after liver transplantation with that of the general population using age, sex, and residence area-standardized prevalence ratios (SPR)., Results: At least one cardiovascular risk factor developed in 92% of patients. Treated hypertension, observed in 71% of patients at 5 years, was more common among patients than controls (SPR, 2.73; 95% confidence interval [CI], 2.06-3.55), whereas the 61% prevalence of dyslipidemia and 3% prevalence of impaired fasting glucose were significantly less frequent among patients (SPR, 0.69; 95% CI, 0.51-0.92 and SPR, 0.29; 95% CI, 0.04-1.00). The 5-year prevalence of diabetes (10%), overweight (32%), and obesity (13%) deviated nonsignificantly from controls (SPR 1.90, 0.85, and 0.58). Antibody therapy associated with a 1.49-fold increase in the risk of hypertension (95% CI, 1.15-1.94) and a 6.43-fold increase in the risk of diabetes (95% CI, 1.18-34.9). Immunosuppression-type, steroids, acute rejection, retransplantation, or graft steatosis revealed nonsignificant risk alterations., Conclusions: Liver transplantation and associated immunosuppression evidently cause hypertension, and possibly elicit diabetes in susceptible individuals. Conversely, the often reported transplantation-associated increased burden of overweight/obesity and dyslipidemia might relate mostly to other factors.

Background: Acute liver failure (ALF) is a significant cause of liver transplantation. We have previously reported that human herpesvirus-6 (HHV-6) was found in most livers of patients with ALF of unknown origin ending up with liver transplantation. In this study, we investigated the posttransplant HHV-6 infection of the liver graft in these patients., Methods: Thirty-two patients transplanted due to ALF were included in this retrospective study. Twelve of the 15 patients with unknown cause and four of 17 patients with a known cause of ALF had HHV-6 antigens in the explanted liver. Altogether, 18 patients had some pretransplant evidence of HHV-6. After transplantation, the patients were frequently monitored for the viruses, and biopsy histology was performed in every case of graft dysfunction. HHV-6 was demonstrated in liver tissue by immunohistochemistry., Results: During the follow-up of 6 months, hepatic HHV-6 infection was demonstrated in 9 of the 18 patients, at a mean 19 days (6-38 days) after transplantation. All patients with posttransplant HHV-6 showed graft dysfunction. In biopsy histology, seven out of these nine patients demonstrated viral infection, one of them also having CMV antigens in the liver. None of those patients without evidence of pretransplant HHV-6 showed HHV-6 in the posttransplant biopsies. Posttransplant HHV-6 was not treated and the virus had no effect on 1-year patient or graft survivals., Conclusion: Pretransplant hepatic HHV-6 infection of patients with ALF is a risk factor for posttransplant HHV-6 infection and liver dysfunction, but has no effect on 1-year graft or patient survival.

Background: In patients with acute liver failure (ALF) of unknown cause, viral infections are believed to be involved. This study investigates the involvement of human herpesvirus-6 (HHV-6)., Methods: Thirty-two patients with ALF who underwent transplantations during a 6-year period were studied for viruses in biopsies from their explanted livers. Non-A to non-E hepatitis (unknown) ALF was the reason for transplantation in 15 patients, and another 17 patients with a known disease from the same time period served as controls. The explanted livers were examined for hepatitis viruses and other possible viral agents. HHV-6 antigens were demonstrated in the livers and blood mononuclear cells by immunoperoxidase staining., Results: Of the 15 patients with ALF of unknown cause, 12 (80%) demonstrated HHV-6 antigens in the liver. Most of these patients (10/12) also demonstrated HHV-6 antigenemia. The predominant histologic finding of HHV-6 infection was moderate to severe portal lymphocytic infiltration. HHV-6 was found in 4 of 17 control patients, and cytomegalovirus was found in 2 of 17 control patients (in the blood and explanted liver). No other viruses were found in the livers of the patients with ALF., Conclusions: HHV-6 was found in most explanted livers of patients with ALF of unknown cause. HHV-6 antigenemia was associated with HHV-6 antigens in the liver. Only a few control patients displayed HHV-6 in the liver. These observations indicate that HHV-6 may be one of the causes of ALF.

Background: The number of registries is increasing, but few of them perform reliability audits by comparing the data contained in the database with data contained in hospital charts., Methods: The European Liver Transplant Registry (ELTR) cocoordinating committee appointed an independent team to check the reliability of data contained in ELTR. Centers were selected at random. Ten percent of each center's files were selected at random, and 25 items per file were checked during the site visits. The rates of completeness and inconsistencies and the agreement between ELTR and charts were established. We also assessed the correlation between the quality of data and the visited centers' activity., Results: Seven hundred thirty-four files from 21 centers have been audited between June 1998 and June 2001. The rate of ELTR completeness was 95%, and the rate of consistency between charts and ELTR was 98%. The agreement between the ELTR and charts review was very good for all conditions (kappa value < or =0.81). However, comparisons of rates between items indicated that specific items, mostly cause of death or graft failure and patient outcome, should be targeted for improvement. No significant correlation was found between the quality of data and the experience of visited centers. The mean (min-max) and median cost per audited file were EUR 60 (8-150) and EUR 44, respectively., Conclusion: The results of audit visits indicate that ELTR data are reliable, and the scientific results of ELTR can be considered credible and representative of liver transplantation in Europe. The method could serve as a model for auditing a registry.

Background: Activated protein C (APC) exhibits anticoagulant and antiinflammatory properties. We studied the kinetics and magnitude of protein C activation in clinical liver transplantation and the interaction of this activation with neutrophil and monocyte activation., Methods: In 10 patients undergoing liver transplantation, we measured plasma protein C and APC levels, neutrophil and monocyte CD11b and L-selectin expression, and leukocyte differential counts pre-, intra-, and postoperatively. Samples of blood entering and leaving the liver were obtained simultaneously to assess changes across the liver., Results: Protein C level was low preoperatively (65%, range 39%-141%) and remained low throughout surgery. Compared with the preoperative level (107%, range 78%-161%), APC level increased during liver reperfusion (471%, range 183%-917%, P=0.05). A transhepatic decrease in protein C level (-16%, range -45%-5%, P=0.007), but not in APC level, occurred during initial liver reperfusion. At the same time, neutrophil and monocyte activation took place in the liver., Conclusions: Despite protein C deficiency, patients with liver insufficiency are able to maintain normal APC levels. During reperfusion, protein C consumption occurs in the liver without concomitant hepatic release of APC, indicating a shortage of APC in the reperfused liver. The process consuming protein C and APC may be related to the simultaneous ongoing neutrophil and monocyte activation within the liver graft, indicating a regulatory role for APC in inflammation.

Background: Liver transplantation (Tx) has become an alternative treatment of malignant childhood liver tumors, and the importance of careful pretransplantation evaluation has been emphasized. Anti-alpha-fetoprotein (AFP) imaging has been suggested for evaluation of adult patients with AFP-positive tumors., Methods: Antibody imaging utilizing Tc-99 m-labeled monoclonal anti-AFP Fab' fragments was used to demonstrate pathologic uptake in hepatoblastoma (HB)., Results: Radical operation or liver Tx was not possible after four cycles of chemotherapy in a child with HB because of a single extrahepatic metastasis. Chemotherapy was continued, and reevaluation with anti-AFP imaging demonstrated a pathologic uptake only in the liver. Subsequently, a right liver lobe resection was performed. Along with a new rise in serum AFP, repeated anti-AFP imaging revealed active liver tumor but no metastases. A liver Tx was performed, and the child is well with a normal serum AFP level 18 months after the operation., Conclusion: This is the first case of pediatric HB in which anti-AFP imaging has been successfully used for patient management.

Background: Cytomegalovirus (CMV) infection has been linked to acute and chronic rejection. We have previously shown that concomitant rat cytomegalovirus (RCMV) infection increases portal inflammation and bile duct destruction in rejecting rat liver allografts. Many of the pro-inflammatory effects of CMV have been attributed to the immediate early (IE) proteins of CMV. We wanted to investigate whether RCMV and IE-1 gene expression persist in the liver graft in our model., Methods: Liver transplantations were performed from PVG (RT1c) into BN (RT1n) rats. One day after transplantation, the rats were infected with RCMV. No immunosuppression was given. The graft infection was studied by viral culture, immunofluorescence, DNA in situ hybridization and RT-PCR for the detection of IE-1 mRNA at various time points., Results: RCMV caused an active infection from 5 days to 2 weeks after transplantation, during which infectious virus was found in the graft. Thereafter the cultures were negative. RCMV antigens and DNA were found in hepatocytes, endothelial, inflammatory, and bile duct cells during the active infection. At 4 weeks, RCMV DNA positive hepatocytes, endothelial, inflamma tory, and bile duct cells could still be found, but in much smaller quantities. IE-1 mRNA expression was, however, only detected during the active infection, not at 4 weeks postinfection., Conclusions: RCMV IE-1 expression does not persist in the graft after the active infection, although some viral DNA can be detected in the graft up to 4 weeks. In our model, the CMV-induced increase in graft damage does not seem to require the continued expression of IE-1.

Background: Human herpesvirus (HHV)-6 has recently been reported in liver transplant patients. It infects and causes dysfunction in hepatic transplants, which provides serious differential diagnostic problems between allograft rejection and viral infection. The diagnosis of posttransplantation HHV-6 infection is usually based on serology or on polymerase chain reaction detection of viral DNA in peripheral blood specimens. However, serology does not tell the exact time of the infection, and detection of viral DNA by polymerase chain reaction may also indicate a latent infection in seropositive patients. Here we report the diagnostic use of frequent monitoring of HHV-6 antigenemia after liver transplantation., Methods: Altogether 622 blood specimens from 51 consecutive adult liver transplant patients were analyzed. The diagnosis was based on demonstration of HHV-6-specific antigens in peripheral blood mononuclear cells using immunoperoxidase staining and monoclonal antibodies and on serology., Results: During the first year (7-280 days) after transplantation, HHV-6 infection was diagnosed in 11 (22%) of 51 patients. HHV-6 early antigens, as well as HHV-6 variant B antigens, were detected in all 11 patients. HHV-6 diagnosis was confirmed by serology. The episode of HHV-6 antigenemia usually lasted for several weeks together with mild, if any, clinical signs of the infection. A significant graft dysfunction was associated with HHV-6 antigenemia in 8 of 11 patients, and viral antigens were also detected in the liver biopsy specimens of 3 of these patients., Conclusions: An active HHV-6 infection can be diagnosed from peripheral blood by detection of virus-specific antigens in mononuclear cells. HHV-6 antigenemia correlated with seroresponse.

Background: Infectious complications are a major cause of morbidity and mortality after organ transplantation. There are several reports on infections during the first months after transplantation, but there are very few data regarding infections in long-term survivors of pediatric organ transplantation., Methods: The incidence and type of infections were retrospectively analyzed in 56 children who underwent 59 liver or renal transplantations. Follow-up was begun when the patient was sent home after a successful operation. All of the children received triple immunosuppression., Results: During a mean follow-up of 4.8 years (total, 286 patient years), 1540 episodes of infection were recorded. The median incidence was 4.8 episodes/patient year. The greatest number was seen in the smallest children, 3 to 6 months after transplantation. Viral upper respiratory tract infections were the most common problem, accounting for half of the episodes (2.7 episodes/patient year). Gastroenteritis was the second most common viral infection. Only 45 episodes of infection with herpesviruses were recorded, and seven of those were caused by cytomegalovirus. Otitis media and sinusitis were the most common bacterial infections and complicated upper respiratory infection in 23% of episodes. Thirty-nine episodes of urinary tract infections were diagnosed, thirty-one in children with renal transplants. Other bacterial infections were rare, and only three episodes of verified bacterial sepsis were diagnosed., Conclusion: The frequency and type of infections in children with liver and renal transplants who are on triple immunosuppression are quite similar to those in age-matched healthy children.

Background: During experimental liver transplantation, neutrophil sequestration results in increased oxygen free radical production and correlates inversely with graft viability. Neutrophil activation in clinical liver transplantation is poorly understood., Methods: We assessed leukocyte sequestration and transhepatic differences of neutrophil and monocyte CD11b expression, neutrophil free radical production, and plasma concentrations of interleukin 6 and interleukin 8 in nine patients during liver transplantation., Results: Significant hepatic neutrophil sequestration occurred during initial graft rewarming with portal blood, after inferior vena cava declamping, and after hepatic artery declamping (all P<0.05). A positive transhepatic difference (i.e., outcoming - ingoing) in CD11b expression of neutrophils was observed after portal vein declamping (51+/-32 relative fluorescence unit [RFU]) and in CD11b expression of monocytes during initial graft rewarming (67+/-86 RFU, both P<0.05). A transcoronary increase in both unstimulated (74+/-80 RFU) and N-formyl-methionyl-leucylphenylalanine-stimulated (112+/-168 RFU) neutrophil free radical production took place after hepatic artery declamping (both P<0.05). A negative transcoronary difference of interleukin 6 occurred during initial graft rewarming (-192+/-176 pg/ml) and a positive difference of interleukin 8 occurred after hepatic artery declamping (17+/-23 pg/ml, both P<0.05)., Conclusions: Hepatic sequestration and transhepatic activation of neutrophils, and hepatic production of interleukin 8 occur during clinical liver transplantation. A splanchnic influx of interleukin 6 occurs to the graft, possibly modulating neutrophil-mediated graft reperfusion injury.

Background: Cytomegalovirus (CMV) infection is associated with acute and chronic allograft rejection. We have recently shown that rat CMV increases portal inflammation and bile duct destruction in a model of rat liver allograft rejection. Desferrioxamine (DFO), an iron chelator and antioxidant, has recently been demonstrated to have antiviral as well as immunomodulatory effects in vitro. We therefore investigated whether DFO inhibits (a) CMV infection and (b) graft destruction in our rat model., Method: One day after liver transplantation, PVG (RT1c) into BN(RT1n), the rats were infected with rat CMV (RCMV, Maastricht strain; 10(5) plaque-forming units i.p.). The effects of 100 mg/kg body weight and 200 mg/kg body weight DFO were examined., Results: In the untreated group, the grafts were uniformly RCMV culture-positive. In the group receiving 200 mg/kg DFO, RCMV replication was effectively inhibited. Inflammatory response in the graft, and especially the number of macrophages, was significantly reduced by DFO. Portal inflammation and bile duct destruction were also significantly reduced. In the untreated group, the bile duct epithelial cells were found to be strongly positive for tumor necrosis factor-alpha and this expression was clearly decreased by DFO. In addition, DFO significantly inhibited vascular cell adhesion molecule-1 expression on sinusoidal endothelial cells., Conclusions: Our in vivo transplant study strongly supports the inhibitory effects of metal chelators on CMV infection and their possible usefulness in the treatment of CMV-induced pathogenic changes.

Background: The prognosis for primary epithelial liver tumor in children in whom radical surgery cannot be performed after chemotherapy is poor. Orthotopic liver transplantation has resulted in mortality up to 50%, largely as a result of problems in determining the criteria for transplantation., Methods: We report results on liver transplantation for primary epithelial liver malignancy in five children (mean age at transplantation: 6.0 years). Only patients with inoperable residual tumor in the liver after four cycles of multidrug chemotherapy, but without extrahepatic infiltration or metastases, were considered eligible for transplantation., Results: Mean follow-up was 4.6 years. Patient and graft survival was 100%, with no signs of residual or de novo malignancy., Conclusion: In children with inoperable primary liver malignancy with no extrahepatic tumor growth, orthotopic liver transplantation has an excellent outcome.

Glutathione transferase Alpha (GSTA) is a sensitive indicator of hepatocellular integrity. Its reference range is low (0.7-14 microgram/L) and its half-life is short (1 hr) in serum. We evaluated the changes in GSTA concentration in 18 recipients during and after liver transplantation. The respective liver donors were also included in 13 cases. The baseline GSTA concentrations were normal or slightly elevated in all donors, 1.2-79 micrograms/L (median 5.1 micrograms/L) and recipients, 1.1-34 micrograms/L (median 6.4 micrograms/L). Surgical dissection of donor liver caused a moderate or even large increase in GSTA concentration, peak 80-6500 microgram/L (median 800 micrograms/L). In the recipients the peak of GSTA concentrations varied from 1400 to 47000 micrograms/L (median 5000 micrograms/L), and it was always observed within 45 min after reperfusion of the graft. The highest GSTA values were observed after long cold ischemia and in patients transplanted for acute liver failure. However, they were not associated with early graft dysfunction. There was a correlation between the AUC of GSTA and cold ischemia time in the recipients with chronic nonalcoholic liver failure (r=0.94). There was no correlation between GSTA values in the donors and recipients (r=0.14). The apparent half-life of GSTA in serum was 56 min (median). Perioperative GSTA concentrations in the donors had no obvious predictive value. In the recipients an exceptionally long apparent half-life of GSTA immediately after transplantation or a large second increase in GSTA were predictors of postoperative complications.

Eighty-six consecutive liver transplant recipients were prospectively randomized in a double-blind, placebo-controlled antifungal prophylaxis study. Seventy-seven patients received 5 days of prophylaxis starting during the transplantation with either liposomal amphotericin B (AmBisome) 1 mg/kg/day or placebo. Among 40 AmBisome-treated patients, no invasive Candida infection was seen during the first month, compared with 5 invasive Candida albicans infections among 37 control patients (P < 0.05). Furthermore, 1 placebo patient experienced Aspergillus niger pneumonia. Thus, the overall incidence of invasive fungal infections was 0/40 (0%) in the AmBisome group versus 6/37 (16%) in the placebo group (P < 0.01). Patient survival at 30 days was 92% versus 94% for AmBisome- and placebo-treated patients, respectively. One patient experienced backache related to AmBisome infusion. Two patients had transient thrombocytopenia possibly caused by AmBisome treatment. AmBisome was otherwise well tolerated. The total cost for all antifungal drugs used in both groups was equal. However, prophylaxis with AmBisome was $5000 less expensive than treatment of proven invasive fungal infections among placebo patients.

A multicenter randomized trial was performed to compare two immunosuppressive protocols after first ABO-compatible liver transplantation. Forty six patients were randomized to a 14-day treatment with Orthoclone (OKT3) in association with steroids and azathioprine, cyclosporine being progressively introduced on day 11 posttransplant. Fifty patients were randomized to a standard protocol of cyclosporine with steroids and azathioprine. Minimum follow-up was 1 year and graft and patient survivals were updated for the purpose of the study. The cumulative 1-year incidence of acute rejection tended to be greater in the cyclosporine group (75%) than in the OKT3 group (67%), especially when patients who did not receive full-course treatment with OKT3 were excluded (59%). Renal function was better preserved during the first two postoperative weeks in the OKT3 group than in the control group but plasma creatinine levels were comparable in both groups thereafter. The incidence of severe infections was lower in the OKT3 group (13.6%) than in the cyclosporine group (32%). The 4-year incidences of patient and graft survival in the OKT3 group (69% and 61%, respectively) were not different from those in the cyclosporine group (62% versus 54%, respectively). Thus this prospective trial shows that OKT3 immunoprophylaxis is a safe alternative to cyclosporine immunoprophylaxis in unselected recipients of a first liver graft.

Chronic rejection is clinically defined as a gradual but progressive impairment of renal allograft function in the absence of other specific causes. The risk factors predisposing to chronic rejection are incompletely known. In this prospective single-center project, logistic regression analysis was used to study the long-term outcome of 94 consecutive first renal allografts in relation to 10 potential risk factors. Whether serum lipid levels, histopathological changes or the mode of immunosuppressive therapy had a predictive value for chronic rejection was of special interest. The risk factors for renal allograft outcome were determined 2 years after the transplantation, when graft function was still normal, and the results were evaluated 2 years later. Occurrence of acute rejections, cold ischemia time, the high-density lipoprotein cholesterol level, and the high-density lipoprotein and total cholesterol ratio were not significant predictors of graft outcome. In a univariate analysis, triglyceride, total cholesterol, and low-density lipoprotein cholesterol level, and donor age were significantly related to graft outcome. In a logistic regression analysis, triple immunosuppressive therapy was better than any double-drug regimen in preventing the deterioration of renal allografts. Incipient histological changes in graft biopsy, quantitated as the "chronic allograft damage index," was the most important single predictor of chronic rejection. The effect of both the histological changes and low-density lipoprotein cholesterol on adverse graft outcome was level dependent.

Intercellular adhesion molecule-1 (ICAM-1) induction on hepatocytes was investigated in relation to acute liver allograft rejection, CMV infection, and systemic bacterial infections. Twenty-four liver transplant recipients underwent an episode of acute rejection, 13 developed a symptomatic clinical CMV infection, and 7 had bacterial sepsis. Seven recipients without rejection or infection complications were used as controls. All rejection episodes monitored by frequent FNABs were reversible, and lymphocyte and lymphoid blast-dominated with a with peak of inflammation (7.2 +/- 3.9 corrected increment units [CIU]). The rejections were treated with high-dose steroids, and the inflammation subsided within one week. ICAM-1 was demonstrated from fine needle aspiration biopsy (FNAB) preparations by a monoclonal antibody and immunoperoxidase staining. ICAM-1 was not detected on the hepatocytes immediately after transplantation or in control patients, but was always seen during rejection. ICAM-1 appeared 1-5 days before the onset of inflammation in FNAB. The intensity of ICAM-1 expression increased toward the peak of inflammation and subsided together with inflammation. During CMV infection a mild immune activation was seen in FNAB (peak 2.5 +/- 0.8 CIU) and in blood. An intense ICAM-1 induction also preceded the immune activation caused by CMV, and subsided slowly with successful antiviral treatment. In addition, a slight ICAM-1 induction on the hepatocytes was recorded during bacterial sepsis. ICAM-1 induction on hepatocytes appears to be linked with an early phase of immune response, and it even precedes the lymphoid activation of rejection. However, several infections, such as CMV and bacterial infections, raise an immune response and may also induce ICAM-1. In conclusion, ICAM-1 induction on hepatocytes can be considered an early, though unspecific, marker for acute liver allograft rejection.

The long-term effects of four different immunosuppressive regimens on renal allografts have been investigated up to four years. A total of 128 recipients of first cadaveric renal allograft were randomized, after an initial induction period, to receive either triple drug therapy--i.e., (low-dose) cyclosporine, azathioprine, and methylprednisolone, or any possible combination of two drugs--i.e., Aza plus CsA, Aza plus MP, and CsA plus MP. The actual four-year graft survival rates for the triple therapy, Aza plus CsA, Aza plus MP, and CsA plus MP groups were 72%, 69%, 75%, and 59%, and patient survival rates were 78%, 81%, 81%, and 84%, respectively, with no significant differences. The cumulative number of chronic rejections up to 4 years was 0.09, 0.29, 0.25, and 0.34 per patient per group (P = ns), respectively. At 2, 3, and 4 years posttransplantation, the graft function was significantly worse in the Aza plus MP group compared with the triple therapy group (P < .05). Of the 98 patients who did not have type I or II diabetes at the time of transplantation, 17 developed posttransplantation diabetes mellitus or an abnormal glucose tolerance test within 2 years posttransplantation. All these patients had received steroids and none of the patients without steroids had these abnormalities. At two years the mean cholesterol level was highest in the Aza plus MP group, 6.8 mmol/L and lowest in the group receiving triple therapy, 5.8 mmol/L (P = ns). The use of (low-dose) CsA was not associated with lipid abnormalities or with disturbances in glucose metabolism. A protocol graft biopsy was performed at two years on all functioning kidneys, and the histological changes were scored blindly. No CsA-specific changes, except isometric vacuolation in tubuli, were found. Histological alterations characteristic of chronic rejection were expressed as "chronic allograft damage index." Chronic allograft damage index was lowest in the triple therapy group, 1.5, compared with the other groups, 3.2-4.3 (P = .01), indicating the least histopathological change in the triple therapy group. In conclusion, this long-term study did not show any serious cyclosporine-related side-effects when used in low dose in combination with two other drugs. Some side-effects, such as posttransplant diabetes mellitus and probably some lipid abnormalities, could rather be traced to a higher dose of steroids. Moreover, the triple drug therapy was more efficacious than any double drug regimen in the prevention of chronic histological changes in renal allografts.

Thirty episodes of histologically verified acute vascular rejection in kidney transplant recipients were studied. In 11 grafts the rejection was mainly vascular, whereas in 19 grafts a concomitant cellular rejection was seen. Histological features prognostic for bad outcome were glomerular necrosis and thrombi in the arteries and arterioles. Characteristic findings in transplant cytology, i.e., high number of monocytes and low number of lymphocytes and blast cells were noted prior to the onset of clinical signs of rejection, and this finding was also persisting throughout the rejection episode. The numbers of lymphocytes and blast cells were significantly lower in grafts with a pure vascular rejection than in grafts with a concomitant cellular rejection. Vascular rejection was reversible in 15 cases. As rescue therapy plasmapheresis and added immunosuppression were often successful.

The association of an early steroid-resistant rejection (SRR) with HLA-DR antigens was analyzed in 410 kidney transplantations. A severe SRR leading to a poor (45%) 1-year graft survival (GS) occurred in 22 transplantations (5%). An acute reversible rejection (ARR) with a GS of 94% was found in 80 transplantations (20%). For the 308 (75%) transplantations with no early rejection episodes the GS was 91%. HLA-DR5 and -DR8 present in the donor as incompatible antigens were strongly associated with SRR. Further, a mismatched DR1 from the kidney donor predicted a rejection, either reversible or irreversible. These findings may have practical implications for an early diagnosis of SRR and for considering of rescue therapy whenever transplantation with disparities in these loci has been performed.

The outcome of 64 repeated renal retransplantations (50 third, 13 fourth, and 1 fifth) during a period of 25 years was retrospectively evaluated. The prognosis of third and subsequent grafting was greatly improved if cyclosporine was included in the induction immunosuppressive regimen (one-year graft survival 79.9%, compared with 32.4% if CsA was not used). The onset of graft function was not delayed by CsA and the proportion of never functioning grafts was significantly lower (5.3%) in patients treated with CsA than in those treated without it (43.2%). Survival of the previous grafts for longer than one year favorably influenced the outcome of the subsequent grafts.

Fine-needle aspiration biopsies were used for clinical monitoring of liver allografts; 21 patients with an inflammatory episode of acute rejection (12.0 +/- 3.3 CIU at the peak) were studied; all episodes were reversible. The inflammatory infiltrate consisted mainly of lymphoid cells, including lymphoid blasts, with increased numbers of class II and IL-2-receptor expressing lymphocytes. No lymphoid activation was seen in corresponding blood specimens. A rapid response to antirejection therapy with high-dose steroids was recorded by FNAB. Another group of 7 recipients without rejection developed a severe CMV disease. The CMV disease was associated with mild inflammation in the FNAB (3.2 +/- 0.9 CIU at the peak), but fewer blast cells and activated cell types were recorded in the graft, and blast cells and lymphocyte activation were seen in the blood specimens, as well. The inflammation disappeared from the FNABs during successful antiviral treatment. The cellular findings of rejection and CMV infection were significantly different, and the presence or absence of rejection could be firmly established by FNAB.

We have quantitated the impact of post-transplantation uremia on the antiallograft immune response by transplant aspiration cytology. Sixty-four consecutive renal transplants, treated with a similar immunosuppresive regimen, were aspiration biopsied at 2-day intervals during the first 15 days postoperatively. The patients were allocated into three groups on the basis of their serum creatinine level on the 3rd postoperative day: transplants with a delayed onset of function (highly uremic group, serum creatinine level greater than or equal to 600 mumol/liter; 24 cases), transplants with a partially delayed onset of function (partially uremic group, 200 to 600 mumol/liter; 21 cases), and transplants with an immediate onset of function (nonuremic group, less than or equal to 200 mumol/liter; 14 cases). These three groups were comparable in respect to the mean age, sex ratio, number of HLA-ABC mismatches (DR was not typed), number of pretransplant blood transfusions, and underlying diseases. Seventy percent of the transplants in the high uremic group, 60% in the moderately uremic group, and 60% in the nonuremic group underwent an early inflammatory episode during days 0 to 15 post-transplantation. The date of onset of inflammation was not significantly different in the three groups. However, the size and type of inflammation were significantly different: compared with the transplants in nonuremic patients, the total inflammatory response was slightly (P = 0.272) depressed in the transplants of moderately uremic patients and significantly (P = 0.007) depressed in the transplants of highly uremic patients. This depression was attributable to the depression of the blastogenic response: compared with nonuremic patients the blastogenic response was distinctly (P = 0.059) depressed in the moderately uremic group and significantly (P = 0.003) depressed in the highly uremic group. Instead, the frequency of in situ macrophages was the same in the three groups, or moderately elevated in the highly uremic group (P = 0.079). However, the graft survival was only 40% in the highly uremic group compared with 79% in the nonuremic controls and 81% in the moderately uremic patients (P = 0.016). We conclude that post-transplantation uremia partially impairs the antiallograft immune response, but this impairment is so small that other factors, whose nature cannot be explained on the basis of the present results, overrule the effects of uremia on graft survival.

Serial fine-needle aspiration biopsies (FNAB) were used for clinical monitoring of human liver allografts. Nine liver allograft recipients were monitored with FNAB at 1-3 day intervals. No complications were recorded. All patients underwent at least 1 inflammatory episode of acute rejection; altogether 11 episodes, all reversible, were recorded. The inflammatory infiltrate consisted mainly of lymphoid cells, including lymphoid blasts, with minor involvement of monocytes, monoblasts, and macrophages. Further analysis of lymphoid cell subpopulations by immunoperoxidase techniques demonstrated an increase of T cells during rejection, both the CD4 (T4) and CD8 (T8) subsets were increased. A slight increase of B cells in the graft was also seen. The CD4/CD8 (T4/T8) ratio was first low, peaked at the onset, and decreased toward the end of the episode. No clear correlations to the intragraft cellular events were recorded in corresponding blood specimens. However, an episode of eosinophilia was seen in the blood at the beginning of rejection, correlating with fever in the recipient. Degenerative changes in the parenchymal cells and bile droplets in the hepatocytes, indicating cholestasis and hepatocyte damage, were seen during all episodes of rejection, and these changes persisted even 10 days after the inflammation had subsided. The FNAB-findings correlated well with biochemical laboratory parameters, but the diagnosis of rejection could be established by the FNAB already 1-5 days earlier than elevated serum values indicated liver dysfunction.

In a double-blind, controlled study 35 herpes simplex virus (HSV) antibody-positive patients were randomized to receive oral acyclovir 200 mg X 4 daily or placebo for 28 days following renal transplantation. The incidence of herpes virus infection was compared in both groups by weekly virus demonstration/isolation testing from throat swabs and urine, and by serum antibody demonstration. None of the 18 patients allocated to acyclovir showed any signs of HSV or varicella zoster virus (VZV) infection during the trial period, whereas 9 of 17 receiving placebo had signs of HSV (P less than 0.001) and 2 of VZV (P less than 0.05) infection. Because of systemic as well as local symptoms of infection in five of the placebo patients, the trial was interrupted and treatment with oral acyclovir instituted. All of them responded well with rapid disappearance of all symptoms. Cytomegalovirus (CMV) was isolated from the urine of two patients in both groups during the trial period; a significant antibody rise was seen later in three of them. There was no evidence of drug-related toxicity during the study.

We have analyzed the inflammatory changes in pig liver allografts and autografts by fine needle aspiration biopsy (FNAB) and correlated the cytological findings with transplant histology and changes in recipient blood. In nonimmunosuppressed piglets (n = 9) the inflammatory episode of rejection occurred promptly, peaked on days 4-7, and thereafter subsided in cases in which the graft was accepted (n = 6). The early inflammatory infiltrate consisted of all major types of inflammatory leukocytes, including T lymphoblasts, B plasmablasts, and plasma cells, lymphocytes and monocytes; macrophages dominated the late inflammatory lesion of irreversible rejection. In piglets that died of rejection (n = 3), the inflammation peaked earlier and the total amount of inflammation, including the frequency of blast cells and mononuclear phagocytes, was higher. These differences were, however, statistically insignificant and not predictive for irreversible rejection. In sham-operated autograft recipients (n = 5) no inflammation was recorded in the graft. Application of cyclosporine (n = 5), significantly suppressed the total inflammation (P = 0.02 and 0.06 on days 4 and 7, respectively) and delayed the peak; in addition, both the blastogenic component (P = 0.08 on day 4) and the mononuclear phagocyte component (P = 0.03 on day 7) were clearly suppressed. These inflammatory changes, recorded by the FNAB, had a close correlation with biopsy histology. On the other hand, determinations of S-ASAT, S-ALAT, and S-AFOS was not correlated with the episodes of rejection, and no characteristic changes were seen in blood cytology during the rejection episodes either.

We have used allogeneic pig liver transplants to investigate the structure of inflammation in acute liver allograft rejection. An inflammatory episode of acute cellular rejection was observed in 9/10 allografts in nonimmunosuppressed recipients, when monitored with simultaneous fine-needle aspiration biopsies (FNAB) and core needle biopsies (NB). The intensity of inflammation in FNAB was quantitated using the corrected increment method and correlated with NB findings. In FNAB, all inflammatory episodes were detected on the 4th day after transplantation with lymphoid blast and lymphocyte infiltration, later accompanied by monocytes and macrophages. Maximal intensity of inflammation was recorded in FNAB on day 14. In NB, histology demonstrated distinct inflammation in the portal area on day 4. The predominantly lymphocytic infiltration, also containing varying numbers of plasma cells, eosinophils, neutrophils and macrophages, reached its maximum 7-14 days after transplantation. With the indirect immunoperoxidase technique, lymphoid cell subpopulation analysis of FNAB demonstrated an increase of both T4 and T8 cells during rejection. The T4/T8 ratio was first low, and increased at the beginning of the episode, on day 4, but decreased again on days 7 and 14. The number of B cells in the graft was also elevated during rejection. The cellular changes in the corresponding blood specimens followed approximately the same lines, although the changes were less prominent. NB immunohistology, using immunoperoxidase and frozen sections, correlated well with FNAB results, and demonstrated a T4 predominance in the portal area on day 4 but a T8 predominance on days 7 and 14. In addition to lymphoid cells, macrophages/granulocytes were also frequent in the portal area and scattered in the parenchyma on days 7 and 14. An additional inflammatory cell component in liver allograft rejection, detectable only in the NB, was eosinophils in the portal area, recorded in maximum on day 14. Taken together, the inflammatory changes in the FNAB and NB were similar, and time-related changes of cellular infiltrate in FNAB and NB correlated closely.