Evidence Of Chronic Rejection Research Articles

Circulating Exosomes with Lung Self-Antigens, Kα1Tubulin and Collagen V, and Immune Responses to Lung Self-Antigens Precedes Histological Evidence of Chronic Rejection Following Orthotopic Murine Lung Transplantation

Purpose Lung transplantation (LTx) is a treatment option for end-stage pulmonary diseases. Despite improvements in surgical techniques and post-transplant (Tx) immunosuppression, LTx continues to have one of the poorest long-term outcomes compared to other solid organ Tx, with five year survival of about 50%. Methods Using an orthotopic single LTx model of B6D2F1/J to DBA/2J strain combination, we demonstrate that >80% of transplanted animals developed histological signs of chronic rejection by day 30 of the transplanted lung but not native. We collected blood at days 7, 14, 28, and 30 and serum was tested by ELISA for development of antibodies to lung self-antigens (SAgs), Collagen V (Col-V) and K-alpha 1 Tubulin (Kα1T). Results Significantly elevated levels of antibodies to Col-V and Kα1T were demonstrable on day 14 when there was no histological evidence for chronic rejection of the transplanted lungs. Circulating exosomes were isolated from sera collected on days 7 and 14 which demonstrated increased levels of lung SAgs by western blots in the exosomes isolated from day 14 sera. These results clearly demonstrate that not only antibodies to lung SAgs are present in sera from day 14, but also circulating exosomes with Col-V and Ka1T are easily demonstrable in sera collected on day-14. Semi-quantitation of western blot by densitometry further demonstrated significantly increased levels of exosomes with lung SAgs starting from day 14 until sacrifice on day 30. Splenocytes isolated following sacrifice demonstrated specific reactivity to lung SAgs with significantly high frequency of IFN-γ (Col-V 109±2.5, Kα1T 101±5.5) and TNF-α (Col-V 39±1.5, Kα1T 53±5.5) secreting cells by ELISPOT. Conclusion Taken together our results demonstrate that circulating exosomes with lung SAgs and de novo development of antibodies to lung SAgs occurs prior to histological evidence of chronic rejection in this murine model of chronic rejection following orthotopic single LTx suggesting that circulating exosomes with lung SAgs can contribute in the pathogenesis of chronic rejection following LTx. Further, our data suggests that circulating exosomes with lung SAgs could be a potential biomarker for patients at risk for developing chronic rejection following human LTx.

Successes and lessons learned after more than a decade of upper extremity and face transplantation

This review aims to present the most recent updates on face and upper-extremity allotransplantation. To date, 27 face and more than 89 upper-extremity allotransplantations have been performed. Both the face and hand transplants restored form, function and patients' social integration. The complications were comparable with solid organs; however, face transplantation, as well as the combination of face and double hand transplantation, presented with significant morbidity and mortality. Evidence of chronic rejection was confirmed in hand transplants, but it has not been reported yet for facial transplantation. Novel immunosuppressive protocols have allowed a decrease in the number and dosages of traditional immunosuppressants. With increased awareness that following face and hand transplantation, the return of function is more important than anatomical restoration of the missing parts, there has been an important shift in the ethical debate weighing the risks and benefits of face and hand allotransplantation. Early results after face and upper extremity transplantation are promising, with 5-year survival rates greater than in solid organ transplants. However, these procedures still need to be closely monitored and the outcome data should be rigorously reported to the central patient registry database to allow continuous surveillance.

Long-Term Follow-Up in Composite Tissue Allotransplantation: In-Depth Study of Five (Hand and Face) Recipients

Composite tissue allotransplantations (CTAs) have clinically shown little, if any, evidence of chronic rejection. Consequently, the effect of chronic rejection on bones, joints, nerves, muscles, tendons and vessels may still have undescribed implications. We thoroughly assessed all allograft structures by histology, magnetic resonance imaging, ultrasonography and high resolution peripheral quantitative computed tomography scan in four bilateral hand-grafted patients (10, 7, 3 and 2 years of follow-up, respectively) and in one facial allotransplantation (5 years of follow-up). All the recipients presented normal skin structure without dermal fibrosis. Vessels were patent, without thrombosis, stenosis or intimal hyperplasia. Tendons and nerves were also normal; muscles showed some changes, such as a variable degree of muscular hypotrophy, particularly of intrinsic muscles, accompanied by fatty degeneration that might be related to denervation. In the majority of hand-grafted patients graft radius and recipient tibia showed a decrease in trabecular density, although in the graft radius the alterations also involved the cortices. No deterioration of graft function was noted. In these cases of CTA no signs of chronic graft rejection have been detected. However, the possibility that chronic rejection may develop in CTA exists, highlighting the necessity of close continuous follow-up of the patients.

Mechanism Analysis of Long-Term Graft Survival by Monocarboxylate Transporter-1 Inhibition

Monocarboxylate transporter (MCT)-1, a member of a family of molecules, transports monocarboxylates such as lactate. Inhibiting MCT-1 leads to long-term graft survival in rodent heart transplantation and induces tolerance. We evaluated an MCT-1 inhibitor, AS2495674, in a rat heart transplant model and analyzed its underlying mechanism. AS2495674 was tested on rat lymphocytes to determine its effect on lactate accumulation, proliferation, and immunoglobulin production. The effect of AS2495674 on graft survival was tested on the Brown Norway to Lewis rat strain combination with a second heart transplantation to test donor-specific suppression. Histology and ex vivo analyses were done to examine the AS2495674 effects on the immune response. In vitro, AS2495674 resulted in lactate accumulation, inhibited lymphocyte proliferation, and prevented immunoglobulin production. AS2495674 induced long-term allograft survival with little evidence of chronic rejection and induced donor-specific suppression. Evaluation of the allograft and peripheral T lymphocytes from the AS2495674 group compared with that of vehicle showed (1) decreased donor-specific T lymphocyte response, (2) more forkhead box P3+ (Foxp3+) and CD45RA+ cells in the allograft, (3) higher gene expression of chemokines and chemokine receptors in the allograft, and (4) preferential inhibition of Foxp3(-) cells with little or no effect on Foxp3+ cells. AS2495674 prevents acute rejection, reduces features of chronic rejection, and induces tolerance. Our data suggest that the mechanism of AS2495674 involves generating a tolerogenic graft environment by preferentially targeting T effector cells while sparing the generation of T regulatory cells.

The Innsbruck Hand Transplant Program: Update at 8 Years After the First Transplant

We herein provide an update on two bilateral hand and one bilateral forearm transplants with emphasis on immunosuppression (IS), function, morphology, and graft vascular changes at 8 years and 2 years after bilateral hand and 5 years after bilateral forearm transplantation. Between March 2000 and May 2006, three patients underwent bilateral hand or forearm transplantation at our institution. Following induction therapy with antithymocyte globulin (ATG) ( n = 2) or alemtuzumab ( n = 1), tacrolimus, prednisolone ± mycophenolate mofetil (MMF) were given for maintenance IS. Later, tacrolimus ( n = 1) or MMF ( n = 1) was replaced by sirolimus/everolimus for long-term IS. Clinical follow-ups with evaluation of hand function, skin biopsies, X-ray, ultrasound, angiography, computed tomography angiography, electrophysiological studies, and somatosensory evoked potentials were performed at regular intervals. Three, six, and three rejection episodes were successfully treated with bolused steroids, anti-CD25 or anti-CD52 antibodies. Subsequently, skin histology remained normal without any evidence of chronic rejection. Hand function continuously improved during the first 3 years and since then remained stable with minor improvements. Investigation of hand arteries revealed no signs of occlusion or stenosis. Motor and intrinsic hand muscle function continues to improve in all patients. Protective sensation was observed in all patients; however, discriminative sensation was only accomplished after hand but not forearm transplantation. No life-threatening adverse events occurred. Despite immunologic challenging postoperative courses, patients are now free of rejection with moderate levels of IS and good functional results. No signs indicating chronic rejection have been encountered.

Repetitive Gastric Aspiration Leads to Augmented Indirect Allorecognition After Lung Transplantation in Miniature Swine

Lung transplant recipients with documented gastroesophageal reflux disease (GERD) are at increased risk for graft dysfunction. Here, we present the first large-animal model of gastric aspiration after allogeneic lung transplantation and some preliminary data demonstrating the effect of chronic aspiration on the direct and indirect pathways of allorecognition. Left orthotopic lung transplants (n=3) were performed in miniature swine across a major histocompatibility complex class I disparity, followed by 12 days of high-dose cyclosporine A. At the time of transplantation, a transtracheal catheter was placed at the carina, above the bronchial anastomosis. A gastrostomy tube was placed for daily aspiration of gastric contents. Subsequently, graft lungs were instilled with gastric aspirate daily (3 mL/hrX8 hr/day) for 50 days. Recipients were followed up with daily complete blood count, scheduled chest radiographs, and biopsies. In vitro studies, including cell-mediated lympholysis, mixed lymphocyte reactions, and peptide proliferation assays, were performed. Results from these three recipients were compared with those of historical controls (n=6) who were treated identically, except for the tracheal cannulation and simulated gastric aspiration. Two of the experimental animals were euthanized with nonviable lungs soon after the postoperative day 50 biopsy. In both cases the native lung was normal. The third animal survived over 180 days without the evidence of chronic rejection. After immunosuppressive treatment, all animals demonstrated donor-specific hyporesponsiveness by assays of direct alloresponse (cell-mediated lympholysis, mixed lymphocyte reaction). A significant response to synthetic donor-derived class I peptide, however, was seen in all animals. A more pronounced and diffuse response was seen in the animals rejecting their grafts. The historical controls showed medium-term graft survival with evidence of chronic rejection in the majority of animals, as previously reported. In a model of GERD after lung transplantation, a spectrum of clinical outcomes was observed. The in vitro data suggest that acid reflux enhances the indirect alloresponse to processed donor class I antigen, giving mechanistic insight into the manner in which GERD may be deleterious to the transplanted lung.

Liver Allografts Are Toleragenic in Rats Conditioned With Posttransplant Total Lymphoid Irradiation

Posttransplant total lymphoid irradiation (TLI) treatment has been applied to tolerance induction protocols in heart and kidney transplantation models. We examined the efficacy and mechanism of posttransplant TLI treatment in the induction and maintenance of tolerance in a rat orthotopic liver transplantation model. Posttransplant TLI prolonged ACI (RT1(a)) liver allograft survival in Lewis (RT1(b)) hosts, with 50% long-term engraftment without immunosuppression and without evidence of chronic rejection. Injection of donor-type liver mononuclear cells (LMCs) facilitated the prolongation of graft survival, with more than 70% of grafts in LMC recipients surviving more than 100 days without chronic rejection. Recipients with long-term liver allograft survival accepted ACI but not PVG skin grafts. In TLI-conditioned recipients with accepted grafts, apoptosis occurred predominantly in graft-infiltrating leukocytes. In contrast, there were few apoptotic leukocytes in rejecting grafts. Recipients with long-term graft acceptance (>100 days of survival) demonstrated evidence of immune deviation; mixed lymphocyte reaction to ACI stimulator cells was vigorous, but secretion of interferon-gamma and interleukin-2 was reduced. In tolerant recipients, the number of Foxp3(+) CD25(+) CD4(+) regulatory T cells was increased in the liver allograft as well as in the peripheral blood. We conclude that posttransplant TLI induces tolerance to liver allografts via a mechanism involving apoptotic cell-deletion and immunoregulation.

β3 Integrins Regulate Lymphocyte Migration and Cytokine Responses in Heart Transplant Rejection

Integrin alpha v beta 3 is important for cell survival, signaling and migration, particularly during angiogenesis and tumorigenesis, where it has been proposed as a therapeutic target. alpha v beta 3 is up-regulated following transplantation and beta 3 polymorphisms are associated with increased acute kidney rejection, suggesting that alpha v beta 3 may also play a role in transplant rejection. Here, using a model of allogeneic heart transplantation, we show that allograft survival is prolonged in beta 3 integrin-deficient (beta 3(-/-)) mice. This is associated with Th2-type immune responses and reduced T-cell infiltration into grafts and T cells from beta 3(-/-) mice show impaired adhesion and migration, consistent with a role for alpha v beta 3 in transmigration. These studies provide evidence that targeting beta 3 integrins impairs recruitment of effector cells and alters cytokine production, so prolonging graft survival. We also show that low doses of blocking antibodies against leukocyte function associated antigen-1 (LFA-1)/alpha L beta 2 and very late antigen-4 (VLA-4)/alpha 4 beta 1, when combined with deletion of beta 3, lead to long-term survival of allografts with no evidence of chronic rejection. Hence we provide strong mechanistic evidence supporting previous genetic studies, demonstrate the involvement of beta 3 integrins in both acute and chronic rejection and identify beta 3 as a new target for immunosuppressive therapy.

Chronic Antibody Mediated Rejection of Renal Allografts: Pathological, Serological and Immunologic Features in Nonhuman Primates

The pathogenesis of late renal allograft loss is heterogeneous and difficult to diagnose. We have analyzed renal allografts in nonhuman primates to determine the relationship between alloantibodies and the graft pathology of late graft loss. Seventeen Cynomolgus monkeys were chosen from among those on several protocols for renal allotransplantation with mixed chimerism induction so that animals with and without alloantibodies were included. All animals received transient CD154 blockade and short-term cyclosporine treatment until day 28. Serial blood samples were tested for alloantibodies. Protocol biopsies and autopsy kidneys were scored for pathology and C4d deposition. Group 1, defined by complete lack of C4d deposition (24 tissue samples; 8 recipients), had no detectable alloantibodies (33 serum samples; 1-7 samples per recipient) and no evidence of chronic rejection. Three survived greater than 2 years with normal function and histology. Group 2, defined as having C4d deposition in peritubular capillaries, all made alloantibodies (100%), and most grafts later showed chronic allograft glomerulopathy (89%), and/or arteriopathy (89%). All grafts in Group 2 failed (3-27 months). Pathologic lesions of typical of chronic rejection in humans develop in monkeys, correlate with antecedent alloantibodies/C4d deposition and predict chronic rejection rather than durable accommodation.

Clinical Tolerance: the end of the beginning.

Clinical Tolerance: the end of the beginning.

Accuracy of exhaled nitric oxide (eNO) measurements for the diagnosis of chronic rejection (CR) after lung transplantation (LTx)

CR is the most devastating complication after LTx. It has already been demonstrated that measuring eNO may be helpful in early diagnosing and in guiding the treatment of CR. However, up to now, the accuracy of eNO measurements for the diagnosis of CR has not been reported yet. Thirty-two patients (15 males, 10 SLTx, 15 SSLTx and 7 HLTx), who survived at least 2 y after LTx and from whom we had serial measurements of pulmonary function and eNO were included in the study. They were all taking cyclosporin A or tacrolimus, azathioprine or mofetil and oral steroids. None of them was on inhaled steroids. We evaluated their eNO levels at 2 y after LTx (in case there was no evidence of CR) or at the time of developing CR, according to classical ISHLT-FEV1 criteria. A cut-off value for eNO of ≥15 ppb was used to calculate sensitivity (S), specificity (Sp), positive and negative predictive value (PPV and NPV). Twelve patients developed CR (9 BOS O-p and 3 BOS 1) after a mean of 548±169 days. At the time of diagnosis, they had a mean eNO of 24.3 ± 13.2 ppb (range 15-57), which was significantly different from the value of the CR- negative patients (14.0 ± 6.0 ppb, range 6-30, p = 0.0054, unpaired t-test). Eleven of the 20 CR-negative patients also had an eNO of ≥ 15ppb, resulting in a S of 100%, Sp of 45% and a PPV and NPV of 52 and 100% respectively . If we then assumed that patients had to have at least 2 measurements (3 to 6 weeks apart) of eNO ≥ 15ppb during the 3 months preceding the diagnosi s of BOS, only 4/11 CR- negative patients fulfilled that criterium, resulting in an improvement of Sp (80%) and PPV(73%), however, with some loss of S (92%) and NPV (94%), due to one false negative result. In Conclusion: the accuracy of eNO measurements for the diagnosis of chronic rejection after lung transplantation is high, when patients have 2 values of eNO ≥15ppb with 3-6 weeks in between the measurement.

Chemokines and allograft rejection: narrowing the list of suspects.

Chemokines and allograft rejection: narrowing the list of suspects.

Requirement of the chemokine receptor CXCR3 for acute allograft rejection.

Chemokines provide signals for activation and recruitment of effector cells into sites of inflammation, acting via specific G protein-coupled receptors. However, in vitro data demonstrating the presence of multiple ligands for a given chemokine receptor, and often multiple receptors for a given chemokine, have led to concerns of biologic redundancy. Here we show that acute cardiac allograft rejection is accompanied by progressive intragraft production of the chemokines interferon (IFN)-gamma-inducible protein of 10 kD (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T cell alpha chemoattractant (I-TAC), and by infiltration of activated T cells bearing the corresponding chemokine receptor, CXCR3. We used three in vivo models to demonstrate a role for CXCR3 in the development of transplant rejection. First, CXCR3-deficient (CXCR3(-/)-) mice showed profound resistance to development of acute allograft rejection. Second, CXCR3(-/)- allograft recipients treated with a brief, subtherapeutic course of cyclosporin A maintained their allografts permanently and without evidence of chronic rejection. Third, CXCR(+/+) mice treated with an anti-CXCR3 monoclonal antibody showed prolongation of allograft survival, even if begun after the onset of rejection. Taken in conjunction with our findings of CXCR3 expression in rejecting human cardiac allografts, we conclude that CXCR3 plays a key role in T cell activation, recruitment, and allograft destruction.

Significant frequencies of T cells with indirect anti-donor specificity in heart graft recipients with chronic rejection.

The purpose of this study was to determine whether T cells with indirect allospecificity could be detected in heart transplant recipients with chronic rejection. Human T-cell clones were used to determine the most effective way to deliver major histocompatibility complex alloantigens for indirect presentation. Seven allograft recipients with evidence of progressive, chronic rejection were selected. Four heart graft recipients with no evidence of chronic rejection were used as controls. Peripheral blood T cells and antigen-presenting cells from the recipients were cultured with frozen/thawed stored donor cells or major histocompatibility complex class I-derived synthetic peptides in limiting dilution cultures and then compared with controls using tetanus toxoid and frozen/thawed third-party cells with no human leukocyte antigens in common with the donor. In 5 of 7 patients analyzed who had chronic rejection, elevated frequencies of T cells with indirect, anti-donor specificity (iHTLf) were detected. No such elevated iHTLf were detected in recipients without chronic rejection. iHTLf can be obtained from human transplant recipients, which supports the contention that the indirect pathway is involved in chronic transplant rejection.

Development of obliterative bronchiolitis after allogeneic rat lung transplantation: implication of acute rejection and the time point of treatment

Background Chronic allograft failure represents the major cause of late morbidity and mortality after solid organ transplantation. Despite the pathological and clinical changes of this disease being well-described, the etiology and the causative factors are still under discussion. Several clinical, as well experimental studies, emphasize the significance of acute rejection. In rat model of left lung allo-transplantation (F344-to-WKY) the influence of acute rejection (AR) on the development of chronic rejection (CR) was studied. Methods In Group I ( n = 25) no immunosuppression was used, while methylprednisolone (MP) (10 mg/kg) was applied in Group II ( n = 20) in the early phase of AR on postoperative Days 9, 10, 11 and in Group III ( n = 20) during AR on Day 14, Day 15, Day 16. The rats were sacrificed on Day 5, Day 15/20, Day 30, Day 60, Day 100 and following HE-staining the extend of AR as well CR was graded according to the working formulation of The International Society of Heart and Lung Transplantation. Results In Group I, AR was found at Day 15 and Day 30 which resolved spontaneously and resulted in CR on Day 60 and Day 100. In Group II, signs of AR were less evident on Day 20, while mild AR persisted on Day 30 and Day 60. On Day 100, normal lung structure was found in all rats. The recipients of Group III showed decreased signs of AR in the early course, however, severe CR was found on Day 60 and Day 100. Extensive airway inflammation with destruction of the subepithelial layer of the smaller airways resulted in severe early obliterative bronchiolitis. Conclusions Untreated severe AR in the early course after lung transplantation results in CR in the F344-to-WKY model. Preventive treatment with MP during the early phase of AR clearly diminishes the degree of AR and the graft recovers completely without any evidence of CR. Late application of steroids during the zenith of AR is successful to control the extent of AR, however, it fails to prevent CR.

CHOLESTATIC HEPATITIS (CH) IN LIVER ALLOGRAFTS OF HEPATITIS C (HCV) PATIENTS: HISTOPATHOLOGIC PROGRESSION AND CORRELATION WITH HCV-RNA VIRAL LEVELS

38 PURPOSE: A subset of HCV liver transplant patients develop a severe form of CH. In this study we characterize the histopathologic features on serial biopsies and investigated the role of HCV viral replication in disease progression. MATERIALS and METHODS: Seven cases of CH were identified among patients transplanted for HCV endstage liver disease. CH was defined as hyperbilirubinemia > 5mgs/dl for a duration of > 1 month. No other causes of cholestasis were identified. All biopsies [median #9 (6-12)] were reviewed as well as native explant and allograft explant livers. The tissues were evaluated for multiple histologic features and overall tissue diagnosis. HCV viral load was measured in 28 native explant, 6 allograft explant liver tissues and 2 allograft biopsies with CH using AMPLICOR HCV MONITOR™ test. RESULTS: 5/7 cases of CH required retransplantation. Two died < 1 month following retransplantation of infections. All three surviving retransplant patients had recurrent CH, of these, two cases developed bridging fibrosis 3 and 20 months following retransplantation. The histopathologic progression of CH in the original allografts was similar in all 7 cases. Mild lobular hepatitis is present initially and precedes the development of ballooning degeneration and cholestasis. Ballooning degeneration dominated the histologic picture during the cholestatic phase and culminated in centrizonal collapse. There was no evidence of chronic rejection in any of the biopsies or allografts. The native explant liver tissue of CH cases had significantly higher HCV levels than an unselected group of 21 HCV native explant livers (P<.013). Four cases had levels >25,000 copies/ug DNA, while all non-cholestatic cases had lower levels. Two cases of CH with <10,000 copies/ug DNA in the native explant did not require retransplantation. HCV levels in 3 allograft explants were >20,000 copies/ug DNA. The 2 cases with the highest levels showed the most ballooning. The levels in the 2 biopsies with CH were >50,000 copies/ug DNA, and were higher than in native explant or allograft explant livers. CONCLUSIONS: 1) CH is an aggressive disease with poor prognosis and recurs after retransplantation. 2) The histopathological progression is predictable. 3) HCV RNA levels >25,000/ug DNA in native explant liver tissue is associated with CH in allografts requiring retransplantation.

Retransplantation for recurrent hepatitis C.

Recurrence of hepatitis C virus (HCV) after orthotopic liver transplant (OLT) may be mild or may lead to progressive liver disease requiring retransplantation (re-OLT). Results of re-OLT for hepatitis C are not well known. We analyzed outcomes in 14 patients retransplanted for recurrent hepatitis C. All had evidence of recurrent hepatitis on multiple biopsies. Polymerase chain reaction (PCR) was performed in blood or tissue samples from 12 patients when recurrence was suspected; all 12 were positive for HCV-RNA. Explants showed chronic hepatitis with bridging necrosis in 3 patients, hepatitis with transition to cirrhosis in 2, hepatitis and cirrhosis in 3, and cirrhosis alone in 2. In 2 patients, in whom immunosuppression had been withheld for 4 to 6 weeks, there was also evidence of chronic rejection. Four died of sepsis perioperatively (median, 32.5 days; range, 9-59); pre-OLT, 3 of 4 had renal failure, and 1 had fever with no obvious source of infection. Ten patients did well early after OLT and were discharged. One patient was readmitted 6 weeks after discharge and died of cytomegalovirus (CMV) infection 127 days after re-OLT. One patient with concomitant vanishing bile duct syndrome, probably due to chronic rejection, developed recurrent hepatitis and died of progressive liver failure 161 days after re-OLT. Eight patients are well at a median of 926 days (range, 315-1930) after re-OLT. Three have evidence of mild recurrent hepatitis on liver biopsy, one is overweight with severe steatosis on biopsy, and four have no evidence of recurrent hepatitis. Retransplantation for hepatitis C should be considered a viable option for patients who develop end-stage hepatic dysfunction secondary to recurrent disease and should be performed before development of infectious complications and renal insufficiency.

Diminution du risque de rejet chronique et de variabilité de lʼabsorption avec Néoral® par rapport à Sandimmun®

The inter- and intrapatient variability in cyclosporin pharmacokinetics obfuscates the relationship between therapeutic outcome and administered dose. We defined patients with high pharmacokinetic variability and an increased risk of chronic rejection by means of serial pharmacokinetic profiling of 204 renal transplant patients treated for up to 5 years with cyclosporin doses selected to achieve a target average cyclosporin concentration (Cav). Patients were stratified into cohorts according to high versus low pharmacokinetic variability, which was based on the cut-off values of percentage coefficient of variation (%CV) of the dose-corrected Cav (Cav/mg; 35%) or 0-hour concentration (C0/mg; 53%). These values are the inflection points of curves that express the relationships between true positives (patients with high %CV and chronic rejection) versus false positives (patients with high %CV but no evidence of chronic rejection).

Steroid withdrawal 3 months after liver transplantation - does FK 506 confer any advantage over cyclosporin?

Eighty-one liver recipients were randomised to FK 506 or cyclosporin (CyA) and azathioprine (AzA), both in combination with steroids. Twenty-seven FK 506 and 29 CyA/AzA patients continued in the trial 3 months after transplantation. Steroids were ceased in 23 (85%) FK 506 patients and in 27 (93%) CyA patients. After steroid withdrawal, 2 FK 506 and 4 CyA patients were excluded from the study, all for reasons other than rejection. The median follow-up was 16 months for the FK 506, and 19 months for CyA group. There were no acute rejection episodes or graft losses in the FK 506 group. None of the CyA patients lost their graft but three (13%) had episodes of acute rejection requiring steroids to be recommenced in two cases. There was no evidence of chronic rejection in any of the annual review biopsies in either group. Our results suggested no advantage of FK 506 over CyA in its steroid-sparing effect.

THE DEVELOPMENT OF PROTEINURIA AND FOCAL-SEGMENT AL GLOMERULOSCLEROSIS IN RECIPIENTS OF PEDIATRIC DONOR KIDNEYS

Several reports in animals, and sporadic case reports in humans, have suggested that kidneys with decreased nephron mass may be more susceptible to the development of focal-segmental glomerosclerosis. This prompted a reexamination of our previously reported group of pediatric donor-adult recipient renal transplant combinations. Data were analyzed from 31 adult recipients who had received renal transplants from cadaver pediatric donors (less than 6 years) with graft function for greater than 6 months and no evidence of chronic rejection. These were compared with a control group transplanted during the same period with adult donor kidneys. Immunosuppression consisted of azathioprine/prednisone or quadruple therapy in 16 and 15 patients respectively. End-stage renal disease (ESRD) was secondary to chronic glomerulonephritis (n = 9), diabetes mellitus (n = 6), polycystic kidney disease (n = 5), and miscellaneous causes (n = 11). Twenty patients had radiographic documentation of renal hypertrophy posttransplant. All patients had serial 24-hr urinalysis for protein and creatinine after transplantation during periods of stable renal function. Ten patients had renal biopsies performed at a mean time from transplant to biopsy of 10.4 +/- 1.6 months. Seven recipients had biopsies that revealed glomerulosclerosis at 13 +/- 6 months posttransplant. Protein excretion and serum creatinine in these patients were significantly higher than in control patients (1.6 +/- 0.37 vs. 0.49 +/- 0.15 g/24 hr and 1.96 +/- 0.11 vs. 1.64 +/- 0.09 mg%; P less than 0.03 and P less than 0.01, respectively). Only 3 of 25 control adult donor recipients developed proteinuria greater than 0.8 g/24 hr within 2 years of transplantation vs. 15/31 pediatric donor recipients. No correlations with the etiology of ESRD, age (greater than or less than 40 years), weight, sex, diabetes, hypertension, or the number of acute rejection episodes could be found. Our data suggest that adult recipients of pediatric donor renal transplants may be at greater risk for the development of glomerulosclerosis than those recipients receiving adult donor kidneys.