Chronic Graft Dysfunction Research Articles

Population Pharmacokinetics Analysis of Mycophenolic Acid in Adult Kidney Transplant Patients With Chronic Graft Dysfunction

The aim of this study is to develop a population pharmacokinetic model for total and free mycophenolic acid (MPA) in adult kidney transplant patients with chronic graft dysfunction to understand the contribution of potentially relevant covariates to the inter- and the intraindividual variability of MPA in these patients. Twenty patients received mycophenolate mofetil orally up to 1 g twice daily were enrolled in this prospective pharmacokinetic study. Two hundred twenty-nine total and 257 free concentration-time points were determined using reversed-phase high-performance liquid chromatography/ultraviolet at 21 days and 6 months after initiation of mycophenolate mofetil therapy. Data were analyzed using nonlinear mixed effects modeling. A two-compartment model, with zero-order input and first-order elimination from the central compartment, which combined total and free concentration, was selected. Intersubject variability (ISV) was estimated on the clearance, central volume of distribution, and intercompartmental clearance. Only body weight (WT, kg), occasion, and albumin concentration (mg/L) were kept as covariates in the final model. The population pharmacokinetic parameters were: clearance, 0.27 x WT (L/h) on Day 21 and 0.233 x WT (L/h) at 6 months (ISV, 51%; interoccasion variability, 47%); central distribution volume, 47.6 L (ISV, 31%); intercompartmental clearance, 33.1 L/h (ISV, 128%); peripheral distribution volume, 724 L; duration of infusion, 0.64 (hours), and binding capacity, 0.0012 L/mg. The multiple regression analysis between free and total MPA concentration led to the following model: free MPA concentration (mg/L) = 0.31 + 0.02 total MPA concentration (mg/L) - 0.007 albumin (g/L). The large inter- and intravariability of MPA raises questions about the value of the use of therapeutic monitoring and limited sampling strategies as currently practiced. Moreover, none of the data presented here could justify measurement of free concentration for therapeutic drug monitoring.

Primary Graft Dysfunction: Definition, Risk Factors, Short- and Long-Term Outcomes

Primary graft dysfunction (PGD) is a form of early lung graft dysfunction that is a major cause of early morbidity and mortality following lung transplantation. Survivors of PGD have decreased long-term lung function and an increased risk of developing bronchiolitis obliterans syndrome (BOS), a manifestation of chronic graft dysfunction. This article reviews the current definition, contributing factors, and guidelines for grading clinical PGD, as well as controversies surrounding them. The current literature examining clinical risk factors for PGD is summarized, as are studies exploring molecular and biochemical markers for PGD prediction and severity. Studies examining the short- and long-term effects of PGD on lung transplant outcomes are reviewed. Lastly, we highlight the emerging concepts in lung transplantation that will potentially impact PGD incidence and outcomes.

A 50% reduction in cyclosporine exposure in stable renal transplant recipients: renal function benefits

Although cyclosporine maintenance therapy reduces the risk of acute rejection and increases short-term graft survival in renal transplant recipients, its associated nephrotoxicity increases the risk of chronic graft dysfunction. The dose that allows an optimal risk-to-benefit ratio has not been established. This multicentre study enrolled stable renal allograft recipients receiving cyclosporine and mycophenolate mofetil without corticosteroids in their second year post-transplant. Patients were randomized to a cyclosporine dose targeted to a standard area under the concentration-time curve (AUC)(0-12 h) (usual exposure, n = 104) or 50% of the study standard AUC(0-12 h) (low exposure, n = 108) using a three-point pharmacokinetic sampling. The primary endpoint was the percentage of patients with treatment failure at 24 months (graft loss/acute rejection/nephrotoxicity/>15% serum creatinine level increase). Treatment failure was reported in 37 out of 101 (37%) patients in the usual-exposure and 19 out of 106 (18%) patients in the low-exposure groups (P = 0.003). Mean estimated glomerular filtration rate decreased from baseline to 2 years with usual exposure and increased with low exposure (P < 0.001). Mean systolic and diastolic blood pressures were lower with low exposure (P = 0.03 and P = 0.008, respectively). In renal transplant recipients receiving maintenance therapy without corticosteroids, a minimization strategy using three-point pharmacokinetic sampling to reduce and maintain cyclosporine exposure to 50% of the usual levels is safe and reduces the risk of graft dysfunction.

154: Restrictive Allograft Syndrome (RAS): A Subset of Bronchiolitis Obliterans Syndrome (BOS) or a Distinct Entity?

Pulmonary function tests (PFTs) of BOS show obstructive changes; FEV1 and FEV1/FVC decline with stable or increased TLC. However, some patients with chronic graft dysfunction show restrictive changes with parallel declines in TLC and FEV1, and stable FEV1/FVC. The prevalence and putative mechanisms of this Restrictive Allograft Syndrome (RAS) were studied.

Recipient Toll-like receptors contribute to chronic graft dysfunction by both MyD88- and TRIF-dependent signaling

Toll-like receptors (TLRs) recognize specific molecular patterns derived from microbial components (exogenous ligands) or stressed cells (endogenous ligands). Stimulation of these receptors leads to a pronounced inflammatory response in a variety of acute animal models. Chronic allograft dysfunction (CAD) was regarded as a candidate disease to test whether TLRs influence chronic fibrosing inflammation. Potential endogenous renal TLR ligands, specifically for TLR2 and TLR4, have now been detected by a significant upregulation of glucose regulated protein (GRP)-94, fibrinogen, heat shock protein (HSP)-60, HSP-70, biglycan (Bgn) and high-mobility group box chromosomal protein 1 (HMGB1) in the acute and chronic transplant setting. In a genetic approach to define the contribution of TLR2 and TLR4, and their adaptor proteins MyD88 and TRIF [Toll/interleukin (IL)-1 receptor domain-containing adaptor-protein inducing interferon beta], to CAD, kidney transplantation of TLR wild-type grafts to recipients who were deficient in TLR2, TLR4, TLR2/4, MyD88 and TRIF was performed. TLR and adaptor protein deficiencies significantly improved the excretory function of chronic kidney grafts by between 65% and 290%, and histopathologic signs of chronic allograft damage were significantly ameliorated. T cells, dendritic cells (DCs) and foremost macrophages were reduced in grafts by up to 4.5-fold. The intragraft concentrations of IL-6, IL-10, monocyte chemotactic protein-1 (MCP-1) and IL-12p70 were significantly lower. TLR-, MyD88- and TRIF-deficient recipients showed a significant reduction in fibrosis. alpha-smooth muscle actin (alpha-SMA)-positive cells were decreased by up to ninefold, and collagen I and III were reduced by up to twofold. These findings highlight the functional relevance of TLRs and their two major signaling pathways in graft-infiltrating mononuclear cells in the pathophysiology of CAD. A TLR signaling blockade may be a therapeutic option for the prevention of CAD.

Role of Peritubular Capillaries and Vascular Endothelial Growth Factor in Chronic Allograft Nephropathy

Objective To investigate the role of peritubular capillary damage and vascular endothelial growth factor (VEGF) in chronic allograft injury and to evaluate their correlation with clinical factors. Patients and Methods The study included 56 patients who underwent transplantation between 1987 and 2004 and experienced chronic graft dysfunction. CD34 (peritubular capillaries) and VEGF were evaluated at histologic analysis. Patients were classified into 3 groups: 47 with chronic allograft injury, 9 with pure cyclosporine toxicity, and 26 who served as the control group (time 0 biopsy). Results Compared with the control group, CD34 total expression in chronic nephropathy was indirectly proportional to Banff stage ( P < .05), and VEGF was increased in chronic allograft injury grade I or II or nephrotoxicity ( P < .05). CD34 expression was correlated with age ( P < .007) and number of acute rejection episodes ( P = .005). A negative correlation was observed between expression of CD34 and of VEGF ( P < .001). Low expression of CD34 was associated with risk of graft loss of 1.45 (95% confidence interval, 1.15–7.24; P = .04). Conclusion Peritubular capillaries decreased progressively with development of chronic allograft injury. The VEGF demonstrated a bimodal behavior, increasing at the onset of nephropathy and decreasing in the final stages. Loss of peritubular capillaries was associated with worse graft survival and overexpression of VEGF.

Epididymal abscess in renal transplant: uncommon presentation of Klebsiella septicemia

We present a renal allograft recipient 16 months posttransplant with an unusual infectious complication. This gentleman was antihepatitis C virus pretransplant, had a live unrelated transplant, and was taking cyclosporine, mycophenolate mofetil, and prednisolone. He developed diabetes and left scrotal abscess 3 months posttransplant and underwent left orchiectomy. He developed acute right epididymitis progressing to epididymal abscess, septicemia, and acute chronic graft dysfunction. Blood cultures and aspirated pus cultures grew Klebsiella pneumoniae and were treated with intravenous antibiotics, to which he responded. This case highlights an unusual complication in renal transplant and its successful management.

Construction of recombinant adenovirus vector containing a modified gene that codes for human hypoxia-inducible factor-1α without oxygen-dependent degradation domain

The expression of hypoxia-inducible factor-1alpha (HIF-1alpha) in heart allografts is an important mechanism in response to ischemia/reperfusion (I/R) injury which represents the single major non-immunologic factor implicated in pathogenesis of chronic graft dysfunction (CGD). Adenoviral mediated overexpression of HIF-1alpha is a useful way to investigate the molecular mechanisms of I/R injury and the cardiac function during heart transplantation. The oxygen-dependent degradation (ODD) domain of HIF-1alpha can lead to degradation of the HIF-1alpha protein in normoxia. This will be an obstacle to steady expression of HIF-1alpha in heart allograft after transduction. In this study, we obtained the coding sequence of HIF-1alpha without ODD domain (HIF-1alphaDeltaODD) through a PCR-based method, and then generated the HIF-1alphaDeltaODD-expressing adenovirus. In normoxia, adenoviral mediated expression of HIF-1alphaDeltaODD shows constitutive activity in human cardiomyocytes, and can up-regulate heme oxygenase (HO)-1 mRNA levels significantly compared with the group transduced with HIF-1alpha-expressing adenovirus. The constructed HIF-1alphaDeltaODD-expressing adenovirus can be used to transduce allografts in animal studies to investigate the mechanism of CGD and provide a useful model to study the regulation mechanisms of genes regulated by HIF-1alpha alone.

Long‐term outcomes of cytomegalovirus infection and disease after lung or heart–lung transplantation with a delayed ganciclovir regimen

Information is limited on long-term outcomes after preemptive use of ganciclovir to control cytomegalovirus (CMV) infection in lung transplantation. We studied 78 lung recipients who received antithymocyte globulin induction from 1994 to 2000. All patients received six months of oral acyclovir (800 mg TID). This was interrupted three wk post transplantation for a two-wk course of IV ganciclovir. Additional courses of ganciclovir were administered based on serial virological monitoring. CMV-mismatched patients (R-D+) also received four doses of CMV immunoglobulin between weeks 2 and 8. The one yr cumulative risk of CMV disease was 2% (1/61) in CMV seropositive (R+) patients, but was 37% (6/17) in R-D+ patients (p < 0.0001). Over 4.3 yr of follow-up, patients with CMV infection developed more chronic graft dysfunction caused by bronchiolitis obliterans or bronchiolitis obliterans syndrome than patients without CMV infection (p = 0.012). This effect was also apparent in the subgroup of R+ recipients (p = 0.043). Acute rejection and overall survival were not associated with CMV infection. The use of prophylactic acyclovir and short preemptive courses of ganciclovir effectively controlled CMV disease in R+ patients, but was a relative failure in R-D+ patients. CMV infection was significantly associated with chronic graft dysfunction, even in R+ recipients who had good control of CMV symptoms.

Endourologic Implants to Treat Complex Ureteral Stenosis After Kidney Transplantation

To evaluate the safety and efficacy of nitinol stents and the Detour extra-anatomical ureteral bypass graft in treatment of ureteral stenosis after kidney transplantation. Eighteen kidney transplant recipients with complex stenosis caused by failure of primary treatment or with high surgical risk or a poorly functioning graft (serum creatinine concentration >2.5 mg/dL) were treated using antegrade percutaneous implantation of nitinol stents (n = 16) or extra-anatomical ureteral bypass grafts (n = 3); 1 patient was treated with both techniques. Mean (range) follow-up of ureteral stents was 51.2 (3-118) months. Patency rate at last follow-up, resumption of dialysis therapy, or death was 75% (12 of 16 patients). In 4 patients (25%), stent occlusion developed, which was treated using a double-J catheter in 2 patients, stent removal and pyeloureterostomy using the native ureter in 1 patient, and implantation of an extra-anatomical bypass graft in 1 patient. Mean follow-up in patients with extra-anatomical ureteral bypass grafts was 32 (8-64) months. One patient developed a urinary tract infection, and another had encrustation with obstruction. Use of nitinol ureteral stents and extra-anatomical ureteral bypass grafts is a safe and effective alternative to surgery for treatment of post-kidney transplantation ureteral stenosis in patients with chronic graft dysfunction, those at high surgical risk, and those in whom previous surgical treatment has failed.

Cause of Death in Pediatric and Infant Heart Transplant Recipients: Review of a 20-year, Single-institution Cohort

As infant and pediatric heart transplantation becomes more common, there is a growing need to better understand the causes of failure or death, if we are to continue to improve the outcome in these children. A multidisciplinary team reviewed all deaths occurring in the cohort of infants and children transplanted during the first 20 years of the Loma Linda Pediatric Heart Transplant program, with 2 additional years of follow-up beyond the 20-year accrual period, and classified them as to cause. There were 169 deaths among 421 recipients, with a median follow-up of 9.7 years. Autopsy was performed in 128 cases. The causes of death, in decreasing order of frequency, included acute rejection (26.0%), infection (16.0%), cardiac allograft vasculopathy (CAV) (14.2%), technical issues (8.3%), acute graft dysfunction (6.5%), neoplasm (7.1%), chronic graft dysfunction (4.7%) and miscellaneous factors (10.1%), and in twelve deaths (7.1%) the cause was unclassified. Acute graft dysfunction and technical issues accounted for nearly two-thirds of the deaths in the first 30 days after transplant, while acute rejection resulted in the largest number of deaths after the first year (30.4%), with CAV a close second (23.5%). Acute graft dysfunction and technical issues were the most frequent cause of early death. Late deaths were most often due to acute rejection and CAV, which differs somewhat from the experience reported in adults. Acute rejection was the single most important cause of late mortality, and resulted in a significant number of late sudden and unexpected deaths.

Proximal tubular dysfunction as an indicator of chronic graft dysfunction

New strategies are being devised to limit the impact of renal sclerosis on graft function. Individualization of immunosuppression, specifically the interruption of calcineurin-inhibitors has been tried in order to promote better graft survival once chronic graft dysfunction has been established. However, the long-term impact of these approaches is still not totally clear. Nevertheless, patients at higher risk for tubular atrophy and interstitial fibrosis (TA/IF) development should be carefully monitored for tubular function as well as glomerular performance. Since tubular-interstitial impairment is an early event in TA/IF pathogenesis and associated with graft function, it seems reasonable that strategies directed at assessing tubular structural integrity and function would yield important functional and prognostic data. The measurement of small proteins in urine such as alpha-1-microglobulin, N-acetyl-beta-D-glucosaminidase, alpha/pi S-glutathione transferases, beta-2 microglobulin, and retinol binding protein is associated with proximal tubular cell dysfunction. Therefore, its straightforward assessment could provide a powerful tool in patient monitoring and ongoing clinical assessment of graft function, ultimately helping to facilitate longer patient and graft survival associated with good graft function.

Cinacalcet reduces vascular and soft tissue calcification in secondary hyperparathyroidism (SHPT) in hemodialysis patients

Management of secondary hyperparathyroidism (SHPT) in chronic kidney disease patients on hemodialysis (HD) can be challenging. Conventional treatments can lead to hypercalcemia and hyperphosphatemia, both of which are associated with vascular and soft tissue calcification and increased risk of cardiovascular disease. We report the effect of treatment with the Type II calcimimetic cinacalcet on vascular calcification in a HD patient with SHPT. A 40-year-old male with a 24-year history of kidney failure secondary to mesangial proliferative glomerulonephritis, commenced HD in October 2004 following chronic graft dysfunction. The patient was admitted to hospital with renal insufficiency and metabolic abnormalities. An anatomopathological study showed calcium (Ca) deposits in the alveolar septa, bronchial wall and pulmonary arterioles. Parathyroid methoxy isobutyl isonitrile (MIBI) scintigraphy revealed multiglandular parathyroid disease and an ectopic gland behind the sternal notch. Serum intact parathyroid hormone (iPTH) was repeatedly found to be > or = 2,500 pg/ml, and was accompanied by significant abnormalities in phosphorus (P) and Ca metabolism which were difficult to control. The patient was initially treated with sevelamer, low dose calcium carbonate, a low P and reduced protein diet and high doses of intravenous erythropoietin. In addition, he received HD with a high efficiency membrane for 4.5 hours, 4-times weekly. Treatment with cinacalcet was initiated at 30 mg/day and adjusted to achieve National Kidney Foundation Kidney Disease Outcomes Quality Initiative targets for iPTH, P, Ca and Ca-P product. One year following cinacalcet treatment, a chest x-ray showed a moderate reduction in Ca deposits, a bone X-ray showed a significant reduction in vascular calcifications, and parathyroid MIBI scintigraphy showed a disappearance of ectopic focus and minimal remains of glands. Significant reductions in calcemia were controlled by concomitant modifications to oral Ca supplementation, Ca concentration in the dialysis liquid, and administration of paricalcitriol. In the second year of treatment, iPTH was maintained within the target range, with moderate rises in P and stabilization of serum Ca. An echocardiogram showed an improvement in left ventricular hypertrophy. Chest and hand X-rays showed a progressive reduction in calcifications. Radiology showed an improvement in bone morphology, with reduced trabeculation and better cortical definition in the phalanx bones. In conclusion, the changes in iPTH, P and Ca associated with cinacalcet treatment were accompanied by reduced vascular and soft tissue calcification in this patient. There were no cardiovascular events and the patient experienced a marked improvement in quality of life.

Stromal-Derived Factor-1 Up-regulated the Expression of MIC on Mouse Keratinocyte Stem Cells

Although previous studies have demonstrated that stromal-derived factor-1 (SDF-1) played a key role in chronic graft dysfunction (CGD), the precise mechanisms underlying this process are not clear. In this study, SDF-1 was injected into keratinocyte stem cells (KSCs) which were isolated and purified from neonatal C57BL/6 (H-2b) mice. Adenylyl cyclase (AC) activity of KSCs was measured and expressions of the human major histocompatibility complex (MHC) class I chain-related antigens A and B (MICA, MICB) detected by immunofluorescence. Cultured KSCs were negative for IA/IE MHC class II molecules by immunofluorescence, indicating the absence of any contamination with Langerhans cells and certifying the purity of KSCs. Over a 7-day culture period, SDF-1 up-regulated AC activity to 2.783 ± 0.799, which was higher than that of the control group (1.290 ± 0.476; P < .01). Immunostaining showed that KSCs expressed increased amounts of MICA protein (0.790 ± 0.134 versus 0.200 ± 0.022; P < .01) and MICB protein (0.610 ± 0.832 versus 0.230 ± 0.016; P < .01). Mixed lymphocyte reaction assays showed that KSCs cultured with SDF-1 injection for 7 days stimulated allogeneic T-cell proliferation. The data indicated that SDF-1 may accelerate the ultimate rejection of allogeneic keratinocytes by enhancing MIC through the AC signal pathway.

Emergency Liver Transplantation in Neonates With Acute Liver Failure: Long-Term Follow-Up

Acute neonatal liver failure is a rare condition that is often fatal. Liver transplantation (LTx) in affected neonates may be life saving, but there are only few data on the long-term outcome of neonatal LTx. We conducted a retrospective study of 11 LTx performed in 10 pediatric patients with acute liver failure in the first month of life. Median age at LTx was 15 days (range: 7-31 days) and median weight was 3.25 kg (range: 2-4 kg). The reasons for liver failure were neonatal hemochromatosis (n=5), hemangioendothelioma (n=2), infection caused by echovirus type 11 (n=1), mitochondrial disorder (n=1), unknown (n=1), and primary nonfunction after LTx (n=1). In 10 patients, LTx organs of deceased donors were used (reduced size n=5, split n=5), and living donor LTx was performed in one neonate. The patients were evaluated with respect to survival, graft function, perioperative complications, and neurodevelopmental outcome. After a median follow-up time of 5 years (range: 1-14 years), 8 of 10 patients (80%) were alive. Seven of them were in good clinical condition and had normal liver function tests. One patient had to undergo retransplantation because of primary nonfunction and another is currently listed for retransplantation because of chronic graft dysfunction. Neurodevelopment was normal in 75% of the surviving patients. Liver transplantation provides good short- and medium-term results in neonatal acute liver failure.

Stratégies immunosuppressives et dysfonction chronique du greffon en transplantation rénale

Chronic graft dysfunction is a major cause of return to dialysis. In the majority of cases, it is correlated with histological signs of cellular and/or humoral rejection, the nephrotoxicity of anticalcineurins, or nonspecific lesions of interstitial fibrosis and tubular atrophy. Although the incidence of acute rejection has considerably decreased, renal toxicity of the calcineurin inhibitors remains problematic. In cases of established nephrotoxicity, the use of non-nephrotoxic immunosuppressors such as mycophenolic acid or the proliferation signal inhibitors makes it possible to reduce or even stop the anticalcineurins. In prevention of anticalcineurin nephrotoxicity, many attempts to minimize or wean patients from them have shown that improvement in renal function is only obtained at the cost of an increase in the incidence of acute rejection. This makes it necessary to select patients who may benefit from anticalcineurin-sparing treatment, based on clinical, histological, and biological markers. Finally, long-term follow-up is also fundamental in order to validate the positive impact on renal function of this strategy in terms of graft survival.

Retransplantation After Single Lung Transplantation

Objective Our lung transplant program started in June 1989 with primary grafts including 21 heart-lung, 11 single lung, and 5 bilateral sequential single lung transplantation. Three patients required retransplantation for single lung and 2 patients for heart-lung grafts. The primary cause of death after lung transplantation is chronic graft dysfunction—bronchiolitis obliteran—though other causes, namely acute graft failure, have been mentioned. Retransplantation is considered to be the only treatment option. In experienced centers, the 1- and 5-year survivals are not as good as for other organ transplantations and for retransplantations the outcome is even worse. Our objective herein was to describe factors to be taken into account for retransplantation in our program, including the timing and indication for retransplantation and the presence of comorbidities. Patients and Methods In our experience of 11 single lung transplantations, 3 (27.3%) were retransplantations. The 3 patients were 3, 5, and 2 years after primary transplantation. The indications were overexpansion of the remaining lung compressing the new lung in one and bronchiolitis obliterans in the others. Results One patient with emphysema died in hospital after retransplantation because of acute myocardial infarction. One patient with lymphangioleiomyomatosis (LAM) disease died of lung complication after sudden cardiac arrest at 1.5 years after retransplantation. One patient with idiopathic pulmonary fibrosis is still alive at 5 years after retransplantation. Conclusions Bronchiolitis obliterans was a common reason for retransplantation among our patients as well as in other reports. Bronchiolitis exists with superimposed infection for years if it is the mild form. However, the clinical setting is progressively worse if it could not be controlled leading to retransplantation. At this stage, progressive deterioration of lung function must be considered because of inadequate therapy for infection. Finally, when there is infection usually both lungs are involved. The decision whether to replace the transplanted lung or the remaining lung is a concern, especially when the donor availability is scarce. In conclusion, lung retransplantation is the only treatment option for severe graft dysfunction, if there is no other therapy that can prolong life. Though bronchiolitis obliterans often is the indication for retransplantation, bronchiolitis itself is the signal of retransplantation.

Interface hepatitis is associated with a high incidence of late graft fibrosis in a group of tightly monitored pediatric orthotopic liver transplantation patients

Chronic graft dysfunction, manifesting with elevated liver enzymes and histological features of interface hepatitis (IH), is being increasingly recognized as a long-term problem after liver transplantation. The aim of this study was to characterize our group of post-orthotopic liver transplantation (OLT) patients with respect to clinical, laboratory, and histological signs of IH. A retrospective study of charts and liver biopsy specimens from patients transplanted between 1986 and 1999 was used. Histological features of IH were found in 29/119 patients at a median interval of 23.9 months (95% confidence interval -28.2 to 52.6) after OLT. All patients with IH had risk factors for chronic rejection, such as steroid-resistant rejection, acute rejection later than 3 months post-OLT, female receiver of male graft, or pretransplant cytomegalovirus (CMV)-positive serology with a CMV-negative donor liver. None of the 29 had features favoring a diagnosis of de novo autoimmune hepatitis, but 4 had isolated hypergammaglobulinemia, and 4 had non-organ-specific autoantibodies without hyperimmunoglobulin G. Sixteen of 29 patients also had features of chronic rejection, such as foam cell arteriopathy, loss of bile ducts, or pericentral fibrosis. After abnormal biopsy, all but 1 patient were switched to tacrolimus. During a median follow-up of 12 years, death occurred in 5, retransplantation occurred in 7, and definite cirrhosis occurred in 4. In conclusion, IH was detected in 24.4% of our patients and was associated with a high degree of fibrosis development. Most likely, IH represents a form of chronic rejection directed against periportal hepatocytes.

Bronchiolitis Obliterans Syndrome: Alloimmune-Dependent and -Independent Injury with Aberrant Tissue Remodeling

Long-term success in lung transplantation continues to be challenged by chronic graft dysfunction, which is manifest as bronchiolitis obliterans syndrome (BOS). The mechanisms of BOS involve both immune-mediated pathways (rejection, autoimmune-like mechanisms), and alloimmune-independent pathways (infection, aspiration, ischemia, primary graft failure), which lead to a fibroproliferative responses. BOS correlates histologically with obliterative bronchiolitis in terminal bronchioles and evidence of aberrant remodeling in the airway epithelium, vasculature, stroma, and lymphoid system. A potentially important mechanism that supports the progressive and therapy-resistant nature of BOS is a continuous cycle of ongoing injury and aberrant remodeling. Namely, anatomical and functional abnormalities induce and exacerbate immune-mediated and alloimmune-independent pathways through various mechanisms (e.g., epithelial remodeling decreases mucociliary clearance that exacerbates aspiration-related injury). From this viewpoint, we review current therapeutic strategies and revisit the role of transplant surgeons in attenuating the initial transplant-related injuries to prevent the lung grafts from entering the remodeling-injury cycle.

Hepatitis C virus, an important risk factor for tuberculosis in immunocompromised: experience with kidney transplantation

Little is known about the role of hepatitis C virus (HCV) infection in the development of tuberculosis (TB) in patients with immunosuppression. We performed a retrospective case-control study (1:4) to investigate by univariate and multivariate logistic regression analysis the importance of HCV infection in the development of TB in a cohort of kidney transplant recipients (KTR). TB was diagnosed in 16 out of 2012 (0.8%) KTR between 1976 and 2004. The percentage of HCV-positive patients was significantly higher in cases than in controls (56.3% vs. 18.8%; P=0.02). By multivariate analysis, the only two independent risk factors associated with the development of TB were the presence of HCV infection (P=0.003; OR=6.5; 95% CI 1.9-23) and serum creatinine over 1.5 mg/dl (P=0.03; OR=4.8; 95% CI 1.1-21). HCV infection and chronic graft dysfunction are important risks factors for TB in KTR.