Morphology of ischemic acute renal failure, normal function, and cyclosporine toxicity in cyclosporine-treated renal allograft recipients

To characterize morphologic changes in the early post-transplant period in cyclosporine-treated renal allograft recipients, we examined biopsies from three groups of cyclosporine-treated patients: normal function (N = 9), ischemic acute renal failure or "acute tubular necrosis" (N = 12), and cyclosporine toxicity (N = 7). Groups were compared with each other and with previously studied groups of azathioprine-treated patients and native kidney patients. The interstitial infiltrate commonly observed in normally functioning azathioprine-treated grafts was not observed in normally functioning cyclosporine-treated grafts, but two of nine such grafts had a significant venulitis, a change also seen in three of the patients with cyclosporine nephrotoxicity. "Acute tubular necrosis" (ATN) in cyclosporine-treated graft recipients was characterized by focal necrosis of complete tubular cross sections, a finding normally rare in other types of ATN, and by shedding into the tubular lumen of tubular cells with non-pyknotic nuclei, a finding supporting our previous observation of detachment of viable tubular cells in ATN but not in the normal kidney. Hyaline arteriolar thickening was the only morphologic finding on biopsy which distinguished patients with cyclosporine nephrotoxicity from other groups. In summary, the morphologic changes observed in cyclosporine-treated renal allograft recipients with ATN or normal function are quite different from those observed in azathioprine-treated patients. Cyclosporine appears to enhance the tubular injury observed in ATN. Hyaline arteriolar thickening is the main distinguishing feature of cyclosporine nephrotoxicity.     

Clinical and histopathologic examination of renal allografts treated with tacrolimus (FK506) for at least one year

BACKGROUND: We clinically and pathologically analyzed renal allografts from 1 9 renal transplant patients treated with tacrolimus (FK506) for more than 1 year. METHODS: Twenty-six renal allograft biopsy specimens from 1 9 renal transplant patients who underwent transplantations between 1991 and 1993 were evaluated. Thirteen biopsies were performed from stable functioning renal allografts with informed consent (nonepisode biopsy) and the other 13 were from dysfunctional renal allografts with a clinical indication for biopsy (episode biopsy). RESULTS: The main pathologic diagnoses (some overlap) were acute rejection (AR; n = 4), chronic rejection (CR; n=5), AR+CR (n =4), recurrent IgA nephropathy (n =5), normal findings (n =2), minimal-type chronic FK506 nephropathy (n = 9), and mild-type FK506 nephropathy (n = 11). Of the nonepisode biopsies, 7 and 4 biopsies showed minimal-type and mild-type chronic FK506 nephropathy, respectively. Chronic FK506 nephropathy consisted of rough and foamy tubular vacuolization (5 biopsies), arteriolopathy (angiodegeneration of the arteriolar wall; 20 biopsies), focal segmental glomerulosclerosis (4 biopsies) and the striped form of interstitial fibrosis (11 biopsies). The serum creatinine levels of patients in the mild-type chronic FK506 nephropathy group, which included 7 episode biopsies, were statistically higher than those in the minimum-type chronic FK506-nephropathy group (P< 0.001). CONCLUSIONS: This study demonstrates that chronic FK506 nephropathy consists primarily of arteriolopathy manifesting as insudative hyalinosis of the arteriolar wall, and suggests that mild-type chronic FK506 nephropathy is a condition which may lead to deterioration of renal allograft function.     

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.     

Adult heart transplantation under tacrolimus (FK506) immunosuppression: histopathologic observations and comparison to a cyclosporine-based regimen with lympholytic (ATG) induction

BACKGROUND: Tacrolimus (FK506) is an effective immunosuppressant for human heart transplantation, but information about its effects on cardiac allograft and nonallograft kidney and liver histopathologic study is limited. METHODS: We therefore reviewed 1145 endomyocardial biopsy specimens and eight autopsy results from 80 heart transplant recipients who received tacrolimus as baseline immunosuppression. These were compared with 619 endomyocardial biopsy specimens and four autopsy results from 51 patients treated with cyclosporine-based immunosuppression with lympholytic induction (CLI) by use of rabbit anti-thymocyte globulin. Twenty-one histologic features including the International Society for Heart and Lung Transplantation histopathologic grade were retrospectively assessed without knowledge of the treatment regimen. The lymphocyte growth index on biopsy specimens obtained from these patients was also compared. RESULTS: In general, there were no qualitative differences in the histopathologic appearance of various allograft syndromes between tacrolimus- and CLI-treated patients. Thus histopathologic criteria used to diagnose various graft syndromes are applicable under tacrolimus immunosuppression. However, early (between 10 and 30 days) after transplantation, biopsy specimens from patients treated with tacrolimus showed a significantly higher percentage of inflamed fragments (p = 0.02), the inflammation tended to be more severe (p = 0.09), and the rejection grade tended to be slightly higher (p = 0.08). In contrast, during the late transplantation period (275 to 548 days), biopsy specimens from patients treated with CLI showed a significantly higher percentage of inflamed fragments (p = 0.03), more severe inflammation (p = 0.03), higher rejection grades (p = 0.01), and a higher frequency of Quilty lesions (p = 0.05). Although overall freedom from any grade 3A or higher rejection was greater in the CLI-treated arm, tacrolimus was successfully used to treat refractory rejection in three patients from the CLI-treated arm. Concern has been raised in the literature about the possibility of tacrolimus being a direct hepatotoxin and an accelerant of allograft obliterative arteriopathy. However, no evidence to support either of these contentions was detected in this patient population. In contrast, tacrolimus is clearly nephrotoxic, although similar to cyclosporine in this regard. CONCLUSIONS: Tacrolimus is an effective immunosuppressive drug for heart transplantation. The cardiac allograft histopathologic study of patients treated with tacrolimus immunosuppression does not significantly differ from those given conventional, cyclosporine-based triple therapy with lympholytic induction.     

Pathology of idiopathic megarectum and megacolon

BACKGROUND: Central venulitis denotes a histologic lesion of the allograft liver characterized by perivenular and subendothelial mononuclear inflammation of the terminal hepatic venules associated with varying degrees of perivenular hepatocyte dropout. Although this lesion has generally been considered a manifestation of acute rejection, some have suggested that it instead represents tacrolimus hepatotoxicity. METHODS: We therefore compared the clinicopathologic features of 30 episodes of isolated central venulitis with 22 episodes of combined central venulitis and typical portal acute rejection occurring in 27 patients. Nineteen of the patients received tacrolimus and eight received cyclosporine as primary immunosuppression. RESULTS: No significant differences were found between the two groups, except that isolated central venulitis more often displayed a mild inflammatory component (P=0.007) with small lymphocytes as the predominant cell type (P=0.002). None of the patients had tacrolimus or cyclosporine levels that exceeded the therapeutic range, and none had other clinical evidence of drug toxicity. Usual antirejection therapy was instituted in all but two episodes; response was evident in 93% (28 of 30) of the isolated central venulitis and 86% (19 of 22) of the central venulitis-portal acute rejection group, with histologic regression documented in all follow-up specimens (four and five, respectively). Due to persistent central venulitis, two cyclosporine patients were switched to tacrolimus, with prompt resolution. CONCLUSIONS: These findings are inconsistent with the concept that central venulitis represents drug toxicity and indicate instead that it is a form of acute allograft rejection.     

Risk factors for high blood lead levels among the general population in Taiwan

BACKGROUND: Tacrolimus (FK506) may represent a major advance in the management of allograft rejection after solid organ transplantation. In August 1994 a European heart transplantation pilot study was initiated to assess the efficacy and safety of tacrolimus when administered exclusively through an oral route. METHODS: Eighty-two heart transplant recipients were randomized to treatment (2:1 ratio) with either tacrolimus- (n=54) or cyclosporine-based therapy (n=28). RESULTS: No significant differences were evident between the two treatment groups in either rejection or survival rates at 1 year. Kaplan-Meier estimates of the freedom from rejection were 26.3% and 18.5%, respectively, for the tacrolimus and cyclosporine treatment groups (p=.444). Survival rates were 79.6% and 92.9% (p=.125). At 3 of the 5 centers, patients received antithymocyte globulin during the immediate postoperative period and fared better than those who did not (with acute rejection-free rates of 49.2% and 26.7% for tacrolimus and cyclosporine, respectively [p=.080], as opposed to 7.1% and 8.3% [p=.965]; patient survival rates of 84.6% and 93.3% [p=.382] vs 75.0% and 92.3% [p=.243]). The overall rates of infection, impaired renal function (31.5% vs 21.4%), and glucose intolerance (7.0% vs 4.3%) did not differ significantly between the tacrolimus and cyclosporine treatment groups. Tacrolimus seemed to possess an advantage with regard to a reduced requirement for antihypertensive therapy (59.5% vs 87.5%, p=.025). CONCLUSIONS: Immunosuppression with oral tacrolimus provides a viable alternative to treatment with cyclosporine, particularly when administered in conjunction with antibody therapy. Further studies are warranted to optimize the administration of tacrolimus in this indication.     

Fluoroquinolones as treatment for patients with lower respiratory tract infections caused by Streptococcus pneumoniae

BACKGROUND: Mycophenolate mofetil (MMF) has been previously shown to prevent functional deterioration in an experimental model of chronic renal allograft rejection. METHODS: In this retrospective case-control study, patients with chronic rejection who were receiving cyclosporine or tacrolimus and who had MMF added to their immunosuppressive regimen were compared with patients with chronic rejection who were not receiving MMF. Patients were matched for serum creatinine levels and transplant duration at the time MMF was begun. RESULTS: In the MMF group, the average dose of MMF was 1482 mg/day with an average duration of 19.3 months. Over 36 months, including 12 months before MMF and up to 24 months on MMF, there was no difference in serum creatinine levels between the two groups. Cyclosporine levels and dose were no different. CONCLUSIONS: In this small, retrospective, preliminary study, adding MMF to maintenance immunosuppression provided no clear benefit to renal allograft recipients with established chronic rejection. Larger prospective randomized studies are needed.     

Caspases mediate tumor necrosis factor-alpha-induced neutrophil apoptosis and downregulation of reactive oxygen production

BACKGROUND: Cyclosporine (CSA) has improved patients and organ-graft survival rates, but its chronic nephrotoxicity is still an issue. Although prolonged vasoconstriction could contribute to chronic CsA tubulointerstitial changes by producing chronic ischemia, this relationship has been difficult to demonstrate thus far, and cellular origin and mediators of these structural alterations remain ill-defined. METHODS: As a part of a clinical trial in kidney transplant recipients on triple immunosuppressive therapy (CsA, azathioprine and steroid), which includes renal biopsy as "per protocol," 22 patients enrolled between 12 and 24 months posttransplantation underwent renal hemodynamic evaluation by measuring glomerular filtration rate and renal plasma flow by the plasma clearance of unlabeled iohexol and the renal clearance of para-aminohippuric acid, respectively. In parallel, the CsA pharmacokinetic profile was also determined. A week later, a protocol biopsy of kidney graft was performed. Light microscopy examination and localization of endothelin-1, RANTES, monocyte chemoattractant protein-1 gene expression by in situ hybridization in the graft specimens were evaluated and related to the pattern of histologic lesions. RESULTS: Ten out of 22 kidney transplant recipients who underwent the protocol biopsy had CsA nephrotoxicity, eight had chronic rejection, and four had no lesions at histological examination. The total daily exposure to CsA was higher in patients with CsA nephrotoxicity than in those with chronic rejection or no lesions at biopsy. Renal function was preserved in the CsA toxicity group as compared with the chronic rejection group, despite some degree of renal hypoperfusion. Tubular atrophy and striped interstitial fibrosis were found in all patients with light microscopical evidence of CsA nephrotoxicity, whereas glomerular and arteriolar lesions were less frequent. Intense staining for endothelin-1, RANTES, and monocyte chemoattractant protein-1 mRNAs selectively localized at tubular epithelial cells was found in biopsies taken from patients with CsA nephrotoxicity, but not in the chronic graft rejection group, whose tubuli had only minimal staining for RANTES mRNA on a few occasions. CONCLUSION: Long-term CsA administration to kidney allograft recipients leads to tubulointerstitial injury independently of its vascular effect. The possible contribution to the development of interstitial fibrosis of inflammatory and growth factors released by tubular cells in which CsA accumulates is proposed.     

Identification of regulatory elements of human alpha 6 integrin subunit gene

BACKGROUND: A study was performed by 17 different U.S. liver transplantation centers to determine the safety and efficacy of conversion from cyclosporine to tacrolimus for chronic allograft rejection. METHODS: Ninety-one patients were converted to tacrolimus a mean of 319 days after liver transplantation. The indication for conversion was ongoing chronic rejection confirmed by biochemical and histologic criteria. Patients were followed for a mean of 251 days until the end of the study. RESULTS: Sixty-four patients (70.3%) were alive with their initial hepatic allograft at the conclusion of the study period and were defined as the responder group. Twenty-seven patients (29.7%) failed to respond to treatment, and 20 of them required a second liver graft. The actuarial graft survival for the total patient group was 69.9% and 48.5% at 1 and 2 years, respectively. The actuarial patient survival at 1 and 2 years was 84.4% and 81.2%, respectively. Two significant positive prognostic factors were identified. Patients with a total bilirubin of < or = 10 mg/dl at the time of conversion had a significantly better graft and patient survival than patients converted with a total bilirubin > 10 mg/dl (P=0.00002 and P=0.00125, respectively). The time between liver transplantation and conversion also affected graft and patient survival. Patients converted to tacrolimus < or = 90 days after transplantation had a 1-year actuarial graft and patient survival of 51.9% and 65.9%, respectively, compared with 73.2% and 87.7% for those converted > 90 days after transplantation. The mean total bilirubin level for the responder group was 7.1 mg/dl at the time of conversion and decreased significantly to a mean of 3.4 mg/dl at the end of the study (P=0.0018). Thirteen patients (14.3%) died during the study. Sepsis was the major contributing cause of death in most of these patients. CONCLUSIONS: Our results suggest that conversion to tacrolimus for chronic rejection after orthotopic liver transplantation represents an effective therapeutic option. Conversion to tacrolimus before development of elevated total bilirubin levels showed a significant impact on long-term outcome.     

Reversal of early acute rejection with increased doses of tacrolimus in liver transplantation: a pilot study

BACKGROUND: In this pilot study, we present the results of treatment of early (3 months after liver transplantation) acute rejection episodes by increasing only the tacrolimus doses. METHODS: Ten patients who received tacrolimus as primary treatment experienced acute mild (one case), moderate (four cases), or severe (five cases) rejection episodes. Tacrolimus dosing was increased 1-2 mg every 1 or 2 days until hepatic enzymes started to improve. Steroid basic daily doses were kept unchanged. RESULTS: With the daily dose of tacrolimus increased by a median 1.89-fold (range: 1.2-5), alanine aminotransferase, bilirubin, and gamma-glutamyltranspeptidase levels rapidly reached normal values within the first month. During a median follow-up time of 19.5 months (range: 14-24), none of the 10 patients died or lost their graft. Control liver biopsies were done 13.5 months (range: 7-19) after rejection episode in all patients, and none demonstrated evidence of rejection or sequela. CONCLUSION: This pilot study suggests that increasing tacrolimus dosage could be considered as treatment against early acute rejection episodes including the severe grade.     

Thromboxane synthase expression in renal transplant patients with rejection

Thromboxane synthase (TS) catalyzes the formation of thromboxane (TxA2) in monocytes/macrophages, platelets, and various tissues. TxA2 is likely to play a role in graft dysfunction due to its vasoconstrictive and platelet aggregatory properties. We studied the expression of TS in 7 normal native kidneys, 29 consecutive renal allograft biopsies (performed for rising serum creatinine, n = 23, and delayed graft function, n = 6), and one transplant nephrectomy specimen with severe acute rejection. TS expression was determined by immunocytochemistry using a monoclonal antibody against human TS, Kon-7. Histologic grading of the transplant biopsy specimens was based on the Banff classification. The degree of TS staining was graded in the glomeruli, interstitium, tubules and vessels from 0 to 3+. Of 29 biopsies, 13 had chronic nephropathy (CN), 6 had acute rejection (AR) with chronic nephropathy (AR/CN), 4 had acute rejection (AR), and 6 had acute tubular necrosis (ATN). TS staining of native kidneys showed sporadic interstitial cells. The biopsy and transplant nephrectomy specimens showed significant staining, predominantly in the glomeruli and interstitium. Positively staining cells appeared to be of macrophage/monocyte lineage by morphology. The mean glomerular staining grade was significantly increased in specimens with AR (2.3 +/- 0.9) and the mean interstitial staining was increased in specimens with AR/CN (2.2 +/- 0.9). Follow-up renal function 6 months post-biopsy showed that patients with higher TS staining grades had a faster decline in graft function. In conclusion, TS expression is increased in patients with acute rejection with or without chronic nephropathy and is associated with more rapid deterioration in function.     

Mycophenolate mofetil decreases rejection in simultaneous pancreas-kidney transplantation when combined with tacrolimus or cyclosporine

BACKGROUND: Historically, the acute rejection rates in simultaneous pancreas-kidney (SPK) recipients have been extremely high (50-80%), with many second and third rejection episodes despite the use of quadruple immunosuppression (antibody induction and cyclosporine [CsA]-azathioprine [AZA]-based maintenance immunosuppression). Although this acute rejection has rarely led to graft loss, it has been a great cause of morbidity and of significantly increased cost. In an attempt to decrease the acute rejection rate and related morbidity in SPK transplant recipients, we compared two "state-of-the-art" immunosuppression regimens in a prospective, randomized, single-center study. METHODS: Patients who received SPK transplants were randomized to receive either tacrolimus (TAC) and mycophenolate mofetil (MMF, n=18) or CsA (Neoral formulation) and MMF (n=18). All patients received OKT3 induction and prednisone, which was tapered to 5 mg/day by 6 months after transplantation. All rejection episodes were biopsy proven. In addition, metabolic control (HgbA1C, hypertension, serum cholesterol), drug toxicity, and infection also were measured. Data were compared with that of a historical group (n=18) who received conventional CsA (Sandimmune formulation) and AZA-based immunosuppression. RESULTS: The incidence of biopsy-proven acute rejection was 11% in both the TAC-MMF and CsA-MMF groups with only two patients in each group experiencing a rejection episode. This rejection rate was significantly decreased from that of the CsA-AZA historical group (77%, P<0.01). There were no significant differences in infection rates, including cytomegalovirus, or in metabolic control (HgbA1C, hypertension, and cholesterol levels). All patients remained on their initial immunosuppression regimen for the first 3 months after transplantation. Between 3 and 6 months after transplantation, three patients were switched from TAC to CsA for recurrent migraine headaches, posttransplant diabetes, and chronic cytomegalovirus infection. Two patients in the CsA-MMF group died of nonimmunologic causes (aspiration pneumonia and arrhythmia) between 3 and 6 months after transplantation. CONCLUSIONS: The data from this study show that MMF treatment significantly decreases the incidence of biopsy-proven acute rejection in SPK transplant recipients compared with AZA-treated historical controls. In addition, we conclude that TAC and CsA (Neoral), when combined with MMF, yield similar, low acute rejection rates with similar graft function and metabolic control.     

The dental assessment of the patient waiting for a liver transplant

Until the last several years liver transplantation was considered an experimental treatment procedure. Nowadays virtually any disease process, that is in terminal stage, is treatable with transplantation. The introduction of cyclosporine in 1980 and the recent use of OKT3 monoclonal antibody now allows a 5-year survival rate of 60-70%. The causes of early death of patients who survive after surgery are infective complications, multiorgan failure and acute rejection of the allograft. In the literature and in our experience, bacterial sepsis is the most common cause of deaths occurring during the first postoperative months while most deaths after one year are generally related to chronic rejection of the allograft. The risk of infection is also increased by the over-immunosuppression of these patients always treated with a high dose of immunosuppressive agents when evidence of acute graft rejection is found. Regarding these problems, patients being prepared for liver transplantation should be evaluated for their dental health. The medical indications of 80 transplant recipients and the current status of liver transplantation are reviewed in this article. We describe the dental status of these patients that should receive indicated dental care before surgery. Most patients (90%) were affected by chronic active hepatitis while the number of primitive cirrhosis was significantly lower. Very poor dental hygiene was found in 85% of patients while 45% were affected by advanced periodontal disease and 12% by a chronic gingivitis. Dental caries were observed in 67% while in 20% of cases endodontic periapical lesions were found and only 2% of these resulted as radicular cysts. Indicated dental care consisted in 87% of cases in dental hygiene instructions, in 85% in scaling and root planing, in 63% in conservative restorations and in 40% in endodontic treatments. Dental treatment guidelines before transplantation are described with particular attention to prevent risk of infection using antibiotic prophylaxis for invasive dental procedures. Dentists, after surgery must be also prepared to deal with excessive bleeding related to a severe liver disfunction; for this purpose an appropriate protocol is also described. The monitoring of oral and general health conditions and the achievement of specific protocols of prophylaxis are helpful in the prevention of complications and are fundamental to obtain the best results with liver transplantation improving the quality of life of these patients.     

Low level of interleukin 10 synthesis during liver allograft rejection

Interleukin 10 (IL-10) is a macrophage and T-cell-derived cytokine with potent immunosuppressive properties. To assess its role in liver allograft rejection, we evaluated the plasma level and in situ production of IL-10 after liver transplantation and designed in vitro studies to asses the effects of IL-10 on the allogeneic response. Normal controls and liver transplant recipients with acute rejection, chronic rejection, other complications (recurrent hepatitis C, biliary complications), or no complications were evaluated. The plasma IL-10 level was measured by an immunoenzymatic technique. IL-10 expression in the liver was detected on frozen liver biopsies by in situ hybridization and immunohistochemistry. Plasma IL-10 levels were not elevated during acute or chronic rejection, when compared with liver recipients with uncomplicated transplants. IL-10 mRNA and protein expressions in the liver graft were restricted to rare scattered sinusoidal cells of transplant recipients with acute or chronic rejection, as well as in those with no complications. In mixed lymphocyte cultures performed with peripheral blood mononuclear cells (PBMC) from normal subjects, IL-10 decreased the cell proliferation in a dose-dependent manner, and this immunosuppression was synergistic with that of cyclosporine or FK506. These findings indicate that IL-10 production is low during allograft rejection. Thus, IL-10 therapy in association with cyclosporine or FK506 might be proposed after liver transplantation.     

Long-term outcome of a prospective randomized trial of conversion from cyclosporine to azathioprine treatment one year after renal transplantation

BACKGROUND: Since the introduction of cyclosporine (CsA), 1-year renal allograft survival has improved, but concern persists about the long-term adverse effects of CsA, especially with respect to renal function and blood pressure. This randomized controlled trial was set up to establish whether withdrawal of CsA would alter long-term outcome. METHODS: Adult patients who, at 1 year after renal transplantation, had a stable serum creatinine of less than 300 micromol/L and who had not had acute rejection within the last 6 months were eligible for entry. Patients were randomized either to continue on CsA (n=114) or to stop CsA and start azathioprine (Aza, n=102). All patients remained on prednisolone. Median follow-up was 93 months after transplantation (range: 52-133 months). RESULTS: There was no significant difference in actuarial 10-year patient or graft survival (Kaplan-Meier), despite an increased incidence of acute rejection within the first few months after conversion. Median serum creatinine was lower in the Aza group (Aza: 119 micromol/L; CsA. 153 micromol/L at 5 years after randomization, P=0.0002). The requirement for antihypertensive treatment was also reduced after conversion to Aza; 75% of patients required antihypertensive treatment at the start of the study, decreasing to 55% from 1 year after randomization in the Aza group and increasing to >80% in the CsA group (55% (Aza) and 84% (CsA) at 5 years after randomization, P<0.005). CONCLUSIONS: Conversion from CsA to Aza at 1 year after renal transplantation results in improvement in both blood pressure control and renal allograft function, and is not associated with significant adverse effects on long-term patient or graft survival.     

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.     

Immunologic monitoring in lung allograft recipients

To identify patients with increased risk of chronic lung allograft rejection, we assessed the utility of an in vitro biopsy-derived lymphocyte growth assay and serum anti-HLA antibody screening as a complement to currently available methods of monitoring lung allograft recipients. Lymphocyte growth assay was performed on bronchoscopic fragments of tissue cultured in medium with rIL-2. Seventy-nine biopsies from 31 lung transplant recipients were tested by lymphocyte growth assay, and results were correlated with histopathology findings. Positive lymphocyte growth was found in 12/26 (46%) episodes of acute rejection, 5/44 biopsies without rejection (11%), and 0/9 episodes of bronchitis. Positive lymphocyte growth was seen in 7/16 (44%) grade A1 rejections and in 5/10 (50%) grade A2 rejections, as opposed to only 5/44 (11%) grade A0 (no rejection) biopsies (P < 0.01 for both A1 and A2 with respect to A0). Actuarial probability of remaining free from obliterative bronchiolitis (OB)* tended to be higher in patients who did not exhibit lymphocyte growth in biopsies. Sequential samples of sera obtained at the time of the biopsy were screened for lymphocytotoxic anti-HLA antibodies. Twenty-two of 44 recipients (50%) developed anti-HLA antibodies during the first postoperative year, exhibiting greater than 10% reactivity to an HLA reference panel of lymphocytes in four or more consecutive serum samples. Actuarial survival of lung allograft recipients with anti-HLA antibodies (n = 22) was lower than in those without anti-HLA antibodies (n = 22; P = 0.03). Of the 22 antibody producers, 7/12 died as a consequence of OB. Of the 22 non-antibody-producers, 1/2 deaths occurred as a consequence of OB. Anti-HLA antibodies were present in 9/11 instances of OB (82% sensitivity) and in 13/33 patients without OB (61% specificity; P = 0.03). These data indicate that lung transplant recipients with positive lymphocyte growth and anti-HLA antibodies are at an increased risk of chronic allograft rejection.     

Dose-related reversal of acute lung rejection by aerosolized cyclosporine

This study evaluated the effectiveness of aerosolized cyclosporine as rescue therapy for refractory acute rejection in lung-transplant patients that is unresponsive to conventional therapy. Over 2 yr, nine allograft recipients with histologic evidence of persistent acute rejection and worsening pulmonary function were enrolled. Twenty-two patients with similar degrees of unremitting rejection served as historical controls. Aerosolization of cyclosporin A (300 mg in 4.8 ml propylene glycol) using an AeroTech II jet nebulizer was instituted daily for 12 consecutive days followed by a maintenance regimen of 3 d/wk. Cyclosporine and tacrolimus blood and plasma levels were maintained within therapeutic ranges throughout this trial. Efficacy was assessed by histologic grade of rejection, interleukin-6 (IL-6) mRNA expression by graft bronchoalveolar lavage cells, and pulmonary function testing before and during cyclosporine therapy. In seven patients, results were correlated to deposition of cyclosporine aerosol in the allograft(s) as measured by radioisotopic techniques. At a mean of 37 d after initiation of aerosolized cyclosporine, graft histology improved in eight of the nine patients. Cellular IL-6 mRNA expression decreased significantly in seven patients (mean IL-6/actin +/- SD, 40.96 +/- 118 versus 0.33 +/- 0.57 [p = 0.038]). Pulmonary function (FEV1), which had decreased posttransplant (over a mean of 347 d of observation) from a best value of 1.98 +/- 0.8 L to 1.59 +/- 0.6 L (p = 0.0077), improved over time (152 d) to a posttransplant value of 1.90 +/- 0.8 (p = 0.025). In the control subjects, FEV1 inexorably declined over a comparable period of observation (best posttransplant value 2.36 +/- 0.86 to 1.32 +/- 0.53, p < 0.0001). There was a strong correlation between cyclosporine deposition in the allograft and improvement in FEV1 (r = 0.900, p < 0.01). Fewer cycles of pulsed corticosteroids (1.4 +/- 0.9 versus 0.2 +/- 0.4, p = 0.011) and anti-thymocyte globulin 0.8 +/- 0.4 versus 0, p = 0.018) and reduced doses of oral prednisone (10.8 +/- 3.1 versus 6.1 +/- 4.2 mg/d, p = 0.026) were observed during treatment with aerosolized cyclosporine. Episodes of pneumonia also were reduced significantly during aerosol therapy (2.6 versus 0.95 episodes/100 d, p = 0.029). Nephrotoxicity and hepatotoxicity did not occur, and no patients withdrew from the study. Aerosolized cyclosporine appears to be safe and effective therapy for refractory acute rejection, but confirmation by a larger, randomized trial is necessary. The correlation observed between deposition of cyclosporine aerosol and physiologic improvement of lung function suggests that there is a dose-response relationship between the concentration of cyclosporine in the allograft and immunologic tolerance.     

Positive selection driving the evolution of a gene of male reproduction, Acp26Aa, of Drosophila: II. Divergence versus polymorphism

BACKGROUND: Sirolimus, a novel immunosuppressant that inhibits cytokine-driven cell proliferation and maturation, prolongs allograft survival in animal models. After a phase I trial in stable renal transplant recipients documented that cyclosporine and sirolimus have few overlapping toxicities, we conducted an open-label, single-center, phase I/II dose-escalation trial to examine the safety and efficacy of this drug combination. METHODS: Forty mismatched living-donor renal transplant recipients were sequentially assigned to receive escalating initial doses of sirolimus (0.5-7.0 mg/m2/day), in addition to courses of prednisone and a concentration-controlled regimen of cyclosporine. We conducted surveillance for drug-induced side effects among sirolimus-treated patients and compared their incidence of acute rejection episodes as well as mean laboratory values with those of a historical cohort of 65 consecutive, immediately precedent, demographically similar recipients treated with the same concentration-controlled regimen of cyclosporine and tapering doses of prednisone. RESULTS: The addition of sirolimus reduced the overall incidence of acute allograft rejection episodes to 7.5% from 32% in the immediately precedent cyclosporine/prednisone-treated patients. At 18- to 47-month follow-up periods, both treatment groups displayed similar rates of patient and graft survival, as well as morbid complications. Although sirolimus-treated patients displayed comparatively lower platelet and white blood cell counts and higher levels of serum cholesterol and triglycerides, sirolimus did not augment the nephrotoxic or hypertensive proclivities of cyclosporine. The degree of change in the laboratory values was more directly associated with whole blood trough drug concentrations than with doses of sirolimus. CONCLUSIONS: Sirolimus potentiates the immunosuppressive effects of a cyclosporine-based regimen by reducing the rate of acute rejection episodes.     

Humoral (antibody-mediated) rejection in lung transplantation

To confirm the existence and characterize the pathologic features of humoral (antibody-mediated) lung rejection, we prospectively studied 55 lung transplant recipients (24 male [44%] and 31 female [56%], age range 14 to 69 years [mean 45]). The time between transplantation and biopsy ranged from 2 to 1546 days (mean 274). We performed direct immunofluorescence with C3, immunoglobulin M, and immunoglobulin G antibodies on frozen sections of 106 transbronchial biopsies and one wedge biopsy and compared the results with 13 explanted lungs, one donor lung, and two controls. The histologic diagnoses of these 107 biopsies included acute cellular rejection (62, 58% [minimal 23, mild 33, moderate 5, and severe 1]), chronic rejection (eight, 7%), chronic vascular rejection (two, 2%), acute vasculitis (five, 5%), cytomegalovirus pneumonitis (two, 2%), acute pneumonia (two, 2%), acute organizing pneumonia (two, 2%), diffuse alveolar damage (one, 1%), no evidence of rejection or infection (30, 28%), lipoid pneumonia (one, 1%), and inadequate for histologic diagnosis (one, 1%). Eighty-nine of 106 (84%) transbronchial biopsies, the wedge biopsy, and control lungs were satisfactory for direct immunofluorescence, because each contained alveolate lung parenchyma and arterioles or venules. There was no demonstrable immunofluorescence in the wall of the blood vessels or in the lung parenchyma in any case. We conclude that (1) transbronchial biopsies and wedge biopsies provide adequate material to evaluate humoral rejection, and (2) in spite of the large population studied, the satisfactory material obtained, and the wide range of histologic diagnoses, we could not demonstrate the occurrence of humoral rejection in the lung.