Decreasing incidence of cancer after liver transplantation-A Nordic population-based study over 3 decades.

Cancer remains one of the most serious long-term complications after liver transplantation (LT). Data for all adult LT patients between 1982 and 2013 were extracted from the Nordic Liver Transplant Registry. Through linkage with respective national cancer-registry data, we calculated standardized incidence ratios (SIRs) based on country, sex, calendar time, and age-specific incidence rates. Altogether 461 cancers were observed in 424 individuals of the 4246 LT patients during a mean 6.6-year follow-up. The overall SIR was 2.22 (95% confidence interval [CI], 2.02-2.43). SIRs were especially increased for colorectal cancer in recipients with primary sclerosing cholangitis (4.04) and for lung cancer in recipients with alcoholic liver disease (4.96). A decrease in the SIR for cancers occurring within 10 years post-LT was observed from the 1980s: 4.53 (95%CI, 2.47-7.60), the 1990s: 3.17 (95%CI, 2.70-3.71), to the 2000s: 1.76 (95%CI, 1.51-2.05). This was observed across age- and indication-groups. The sequential decrease for the SIR of non-Hodgkin lymphoma was 25.0-12.9-7.53, and for nonmelanoma skin cancer 80.0-29.7-10.4. Cancer risk after LT was found to be decreasing over time, especially for those cancers that are strongly associated with immunosuppression. Whether immunosuppression minimization contributed to this decrease merits further study.

Impaired intention-to-treat survival after listing for liver transplantation in children with biliary atresia compared to other chronic liver diseases: 20 years' experience from the Nordic countries.

Biliary atresia (BA) is the most common indication for LT in children. We investigated whether this diagnosis per se, compared to other chronic liver diseases (OCLD), had an influence on patient survival. Data from 421 Scandinavian children, 194 with BA and 227 with OCLD, listed for LT between 1990 and 2010 were analyzed. The intention-to-treat survival and influencing risk factors were studied. Patients with BA had higher risk of death after listing than patients with OCLD. The youngest (<1 year) and smallest (<10 kg) children with the highest bilirubin (>510 µmol/L), highest INR (>1.6), and highest PELD score (>20) listed during 1990s had the worst outcome. Given the same PELD score, patients with BA had higher risk of death than patients with OCLD. For adolescents, low weight/BMI was the only prognostic marker. Impaired intention-to-treat survival in patients with BA was mainly explained by more advanced liver disease in younger ages and higher proportion of young children in the BA group rather than diagnosis per se. PELD score predicted death, but seemed to underestimate the severity of liver disease in patients with BA. Poor nutritional status and severe cholestasis had negative impact on survival, supporting the "sickest children first" allocation policy and correction of malnutrition before surgery.

De Novo Donor-Specific HLA Antibody Formation in Two Patients With Crigler-Najjar Syndrome Type I Following Human Hepatocyte Transplantation With Partial Hepatectomy Preconditioning.

Clinical hepatocyte transplantation is hampered by low engraftment rates and gradual loss of function resulting in incomplete correction of the underlying disease. Preconditioning with partial hepatectomy improves engraftment in animal studies. Our aim was to study safety and efficacy of partial hepatectomy preconditioning in clinical hepatocyte transplantation. Two patients with Crigler-Najjar syndrome type I underwent liver resection followed by hepatocyte transplantation. A transient increase of hepatocyte growth factor was seen, suggesting that this procedure provides a regenerative stimulus. Serum bilirubin was decreased by 50%, and presence of bilirubin glucuronides in bile confirmed graft function in both cases; however, graft function was lost due to discontinuation of immunosuppressive therapy in one patient. In the other patient, serum bilirubin gradually increased to pretransplant concentrations after ≈600 days. In both cases, loss of graft function was temporally associated with emergence of human leukocyte antigen donor-specific antibodies (DSAs). In conclusion, partial hepatectomy in combination with hepatocyte transplantation was safe and induced a robust release of hepatocyte growth factor, but its efficacy on hepatocyte engraftment needs to be evaluated with additional studies. To our knowledge, this study provides the first description of de novo DSAs after hepatocyte transplantation associated with graft loss.

Current and future treatment of amyloid diseases.

There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross-ß-sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases, current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer's disease is a neurodegenerative disorder with extracellular amyloid ß-peptide (Aß) fibrils and intracellular tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with passive and active immunotherapy, and small molecules to inhibit Aß formation and aggregation or to enhance Aß clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent Aß aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However, the underlying pathology is linked to the aggregation and progressive accumulation of islet amyloid polypeptide as fibrils and oligomers, which are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be conducted to determine their efficacy in vivo. The transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases compromising multiple organ systems, caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, nonamyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as a promising treatment.

Improved survival in liver transplant recipients receiving prolonged-release tacrolimus in the European Liver Transplant Registry.

This study was a retrospective analysis of the European Liver Transplant Registry (ELTR) performed to compare long-term outcomes with prolonged-release tacrolimus versus tacrolimus BD in liver transplantation (January 2008-December 2012). Clinical efficacy measures included univariate and multivariate analyses of risk factors influencing graft and patient survival at 3 years posttransplant. Efficacy measures were repeated using propensity score-matching for baseline demographics. Patients with <1 month of follow-up were excluded from the analyses. In total, 4367 patients (prolonged-release tacrolimus: n = 528; BD: n = 3839) from 21 European centers were included. Tacrolimus BD treatment was significantly associated with inferior graft (risk ratio: 1.81; p = 0.001) and patient survival (risk ratio: 1.72; p = 0.004) in multivariate analyses. Similar analyses performed on the propensity score-matched patients confirmed the significant survival advantages observed in the prolonged-release tacrolimus- versus tacrolimus BD-treated group. This large retrospective analysis from the ELTR identified significant improvements in long-term graft and patient survival in patients treated with prolonged-release tacrolimus versus tacrolimus BD in primary liver transplant recipients over 3 years of treatment. However, as with any retrospective registry evaluation, there are a number of limitations that should be considered when interpreting these data.

Plasma levels of stromal cell-derived factor-1 (CXCL12) and circulating endothelial progenitor cells in women with idiopathic heavy menstrual bleeding.

STUDY QUESTION: Do plasma levels of stromal cell-derived factor-1 (CXCL12, sometimes termed SDF-1) and the numbers of circulating endothelial progenitor cells (EPCs), EPC colony-forming units (EPC-CFU) and mature endothelial cells (ECs) differ between women with idiopathic heavy menstrual bleeding of endometrial origin (HMB-E) and controls and are they related to plasma levels of other angiogenic growth factors? SUMMARY ANSWER: Angiogenesis is altered in women with HMB-E, characterized by a reduction in mean plasma levels of CXCL12, a low number of EPCs-CFUs and a high level of circulating ECs. WHAT IS KNOWN ALREADY: Plasma levels of CXCL12 are significantly higher during the proliferative than the secretory phase of the menstrual cycle in healthy women and exhibit a negative correlation with blood EPC-CFUs. STUDY DESIGN, SIZE, DURATION: A prospective cohort study in a university hospital setting. Between 2008 and 2009 10 HMB-E patients were recruited from Karolinska University Hospital. Ten healthy women were also included in the analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ten healthy control women and 10 HMB-E patients, all with regular menstrual cycles, provided 4 blood samples during a single menstrual cycle: 2 in the proliferative phase, 1 at ovulation and 1 in the secretory phase. We assessed plasma levels of CXCL12, vascular endothelial growth factor A(165) (VEGFA), basic fibroblast growth factor (bFGF) and granulocyte and granulocyte-macrophage colony-stimulating factors by ELISA. We counted circulating EPC-CFUs by culture, and ECs and EPCs by flow cytometry and immunostaining for cell surface markers. MAIN RESULTS AND THE ROLE OF CHANCE: Plasma levels of CXCL12 were significantly lower in HMB-E patients compared with control women (P < 0.0001), with a significant decrease (P = 0.013) between the proliferative phase and ovulation. VEGFA showed a trend towards the same decreasing pattern as CXCL12, although not statistically significant (P = 0.086), whereas systemic VEGFA levels in control women remained unchanged across the different phases of the menstrual cycle (P = 0.473). HMB-E patients had a lower number of EPC-CFUs compared with control women (P = 0.014), with a positive correlation between the level of CXCL12 and EPC-CFUs (r = 0.428; P = 0.047). Whilst the level of circulating endothelial cells in HMB-E patients was higher than in control women, this did not reach statistical significance. In contrast, the levels of the hematopoietic/EPC marker CD34 were significantly lower in HMB-E patients than control women (P < 0.020). LIMITATIONS, REASONS FOR CAUTION: Small sample, unknown source of CXCL12, unknown balance between influx and efflux of EPCs from bone marrow and to the endometrium. WIDER IMPLICATIONS OF THE FINDINGS: Our results indicate that CXCL12 may play an important role in physiological angiogenesis in the endometrium, and that low and dysregulated levels of CXCL12 in women with HMB-E could affect vessel quality, integrity and repair. STUDY FUNDING/COMPETING INTEREST(S): Financial support was provided through the regional agreement on medical training and clinical research (ALF) between the Stockholm County Council and Karolinska Institutet (number 20110258). This study was also supported by grants from the Swedish Labor Market Insurance. The authors have no conflict of interest to declare.

Efficacy and safety of maribavir dosed at 100 mg orally twice daily for the prevention of cytomegalovirus disease in liver transplant recipients: a randomized, double-blind, multicenter controlled trial.

Maribavir is an oral benzimidazole riboside with potent in vitro activity against cytomegalovirus (CMV), including some CMV strains resistant to ganciclovir. In a randomized, double-blind, multicenter trial, the efficacy and safety of prophylactic oral maribavir (100 mg twice daily) for prevention of CMV disease were compared with oral ganciclovir (1000 mg three times daily) in 303 CMV-seronegative liver transplant recipients with CMV-seropositive donors (147 maribavir; 156 ganciclovir). Patients received study drug for up to 14 weeks and were monitored for CMV infection by blood surveillance tests and also for the development of CMV disease. The primary endpoint was Endpoint Committee (EC)-confirmed CMV disease within 6 months of transplantation. In a modified intent-to-treat analysis, the noninferiority of maribavir compared to oral ganciclovir for prevention of CMV disease was not established (12% with maribavir vs. 8% with ganciclovir: event rate difference of 0.041; 95% CI: -0.038, 0.119). Furthermore, significantly fewer ganciclovir patients had EC-confirmed CMV disease or CMV infection by pp65 antigenemia or CMV DNA PCR compared to maribavir patients at both 100 days (20% vs. 60%; p < 0.0001) and at 6 months (53% vs. 72%; p = 0.0053) after transplantation. Graft rejection, patient survival, and non-CMV infections were similar for maribavir and ganciclovir patients. Maribavir was well-tolerated and associated with fewer hematological adverse events than oral ganciclovir. At a dose of 100 mg twice daily, maribavir is safe but not adequate for prevention of CMV disease in liver transplant recipients at high risk for CMV disease.

Hepatocyte transplantation for inherited metabolic diseases of the liver.

Inherited metabolic diseases of the liver are characterized by deficiency of a hepatic enzyme or protein often resulting in life-threatening disease. The remaining liver function is usually normal. For most patients, treatment consists of supportive therapy, and the only curative option is liver transplantation. Hepatocyte transplantation is a promising therapy for patients with inherited metabolic liver diseases, which offers a less invasive and fully reversible approach. Procedure-related complications are rare. Here, we review the experience of hepatocyte transplantation for metabolic liver diseases and discuss the major obstacles that need to be overcome to establish hepatocyte transplantation as a reliable treatment option in the clinic.

Liver transplantation with grafts from controlled donors after cardiac death: a 20-year follow-up at a single center.

The first liver transplantation (LTx) in Sweden was performed in 1984, but brain death as a legal death criterion was not accepted until 1988. Between November 1984 and May 1988, we performed 40 consecutive LTxs in 32 patients. Twenty-four grafts were from donors after cardiac death (DCD) and 16 grafts from heart-beating donors (HBD). Significantly, more hepatic artery thrombosis and biliary complications occurred in the DCD group (p < 0.01 and p < 0.05, respectively). Graft and patient survival did not differ between the groups. In the total group, there was a significant difference in graft survival between first-time LTx grafts and grafts used for retransplantation. There was better graft survival in nonmalignant than malignant patients, although this did not reach statistical significance. Multivariate analysis revealed cold ischemia time and post-LTx peak ALT to be independent predictive factors for graft survival in the DCD group. In the 11 livers surviving 20 years or more, follow-up biopsies were performed 18-20 years post-LTx (n = 10) and 6 years post-LTx (n = 1). Signs of chronic rejection were seen in three cases, with no difference between DCD and HBD. Our analysis with a 20-year follow-up suggests that controlled DCD liver grafts might be a feasible option to increase the donor pool.

Once-daily prolonged-release tacrolimus (ADVAGRAF) versus twice-daily tacrolimus (PROGRAF) in liver transplantation.

The efficacy and safety of dual-therapy regimens of twice-daily tacrolimus (BID; Prograf) and once-daily tacrolimus (QD; Advagraf) administered with steroids, without antibody induction, were compared in a multicenter, 1:1-randomized, two-arm, parallel-group study in 475 primary liver transplant recipients. A double-blind, double-dummy 24-week period was followed by an open extension to 12 months posttransplant. The primary endpoint, event rate of biopsy-proven acute rejection (BPAR) at 24 weeks, was 33.7% for tacrolimus BID versus 36.3% for tacrolimus QD (Per-protocol set; p = 0.512; treatment difference 2.6%, 95% confidence interval -7.3%, 12.4%), falling within the predefined 15% noninferiority margin. At 12 months, BPAR episodes requiring treatment were similar for tacrolimus BID and QD (28.1% and 24.7%). Twelve-month patient and graft survival was 90.8% and 85.6% for tacrolimus BID and 89.2% and 85.3% for tacrolimus QD. Adverse event (AE) profiles were similar for both tacrolimus BID and QD with comparable incidences of AEs and serious AEs. Tacrolimus QD was well tolerated with similar efficacy and safety profiles to tacrolimus BID.

Microdialysis monitoring for evaluation of the influence exerted by pneumoperitoneum on the kidney: an experimental study.

BACKGROUND: Laparoscopic donor nephrectomy has become the first choice for living donor kidney transplantation, offering advantages over open donor nephrectomy. This study aimed to evaluate kidney tissue metabolism during and after pneumoperitoneum using a microdialysis technique. METHODS: Eight pigs underwent laparotomy and implantation of two microdialysis catheters: one in the cortex and one in the medulla of the left kidney. After laparotomy, the abdominal wall was closed, and pneumoperitoneum was induced with a constant standard pressure of 16 to 18 mmHg for 4 h, followed by rapid desufflation. In microdialysis samples collected from intrarenal catheters, markers of ischemia (glucose, lactate, pyruvate, and lactate-pyruvate ratio) and the marker of cell membrane injury (glycerol) were monitored. RESULTS: There were no changes in glucose, lactate, or pyruvate level before, during, or after pneumoperitoneum, either in the cortex or in the medulla. Additionally, the calculated lactate-pyruvate ratio did not show signs of ischemia during or after pneumoperitoneum. However, with regard to the marker of cell injury, glycerol increased in the medulla after decompression from 22.57 +/- 3.76 to 35.67 +/- 5.43 mmol/l (p < 0.01). This release of glycerol in the medulla was significantly higher than in the cortex (area under the curve [AUC], 22.18 +/- 4.87 vs 34.79 +/- 7.88 mmol/l; p < 0.01). CONCLUSIONS: The pattern of metabolic changes monitored in the kidney during and after pneumoperitoneum indicates some kind of cell injury predominant in the medulla without any signs of kidney ischemia. This nonischemic injury could be related to hyperperfusion of the kidney after decompression or injury to cells attributable to mechanical cell expansion at the point of rapid decompression.

Domino liver transplantation: risks and benefits.

Domino liver transplantation, wherein a patient who himself undergoes liver transplantation in turn donates his liver to another recipient, has been performed since the mid-1990 s. Although livers from a handful of metabolic disorders cured by liver transplantation have been used for domino transplantation, familial amyloidotic polyneuropathy (FAP) livers are by far the most common source. FAP is an inherited disorder never presenting its clinical manifestation before the age of 15. In many carriers, the genetic disorder never manifests during lifetime. Thus, only a proportion of patients with FAP develop disease symptoms, which has been the rationale for using such livers for other patients on the waiting list for liver transplantation. According to the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR), only 2 out of more than 500 patients so far have developed symptoms after domino liver transplantation using an FAP liver. Domino recipients with nonmalignant indications for liver transplantation show excellent long-term survivals. With careful selection of recipients, the procedure helps to reduce the organ shortage and the time on the waiting list for patients with malignant disorders.

Ex Vivo Generation of Donor Antigen-Specific Immunomodulatory Cells: A Comparison Study of Anti-CD80/86 mAbs and CTLA4-lg Costimulatory Blockade.

Adoptive transfer of alloantigen-specific immunomodulatory cells generated ex vivo with anti-CD80/CD86 mAbs (2D10.4/IT2.2) holds promise for operational tolerance after transplantation. However, good manufacturing practice is required to allow widespread clinical application. Belatacept, a clinically approved cytotoxic T-lymphocyte antigen 4-immunoglobulin that also binds CD80/CD86, could be an alternative agent for 2D10.4/IT2.2. With the goal of generating an optimal cell treatment with clinically approved reagents, we evaluated the donor-specific immunomodulatory effects of belatacept- and 2D10.4/IT2.2-generated immunomodulatory cells. Immunomodulatory cells were generated by coculturing responder human peripheral blood mononuclear cells (PBMCs) (50 × 106 cells) with irradiated donor PBMCs (20 × 106 cells) from eight human leukocyte antigen-mismatched responder-donor pairs in the presence of either 2D10.4/IT2.2 (3 µg/106 cells) or belatacept (40 µg/106 cells). After 14 days of coculture, the frequencies of CD4+ T cells, CD8+ T cells, and natural killer cells as well as interferon gamma (IFN-γ) production in the 2D10.4/IT2.2- and belatacept-treated groups were lower than those in the control group. The percentage of CD19+ B cells was higher in the 2D10.4/IT2.2- and belatacept-treated groups than in the control group. The frequency of CD4+CD25+CD127lowFOXP3+ T cells increased from 4.1±1.0% (preculture) to 7.1±2.6% and 7.3±2.6% (day 14) in the 2D10.4/IT2.2- and belatacept-treated groups, respectively (p<0.05). Concurrently, delta-2 FOXP3 mRNA expression increased significantly. Compared with cells derived from the no-antibody treated control group, cells generated from both the 2D10.4/IT2.2- and belatacept-treated groups produced lower IFN-γ and higher interleukin-10 levels in response to donor-antigens, as detected by enzyme-linked immunospot. Most importantly, 2D10.4/IT2.2- and belatacept-generated cells effectively impeded the proliferative responses of freshly isolated responder PBMCs against donor-antigens. Our results indicate that belatacept-generated donor-specific immunomodulatory cells possess comparable phenotypes and immunomodulatory efficacies to those generated with 2D10.4/IT2.2. We suggest that belatacept could be used for ex vivo generation of clinical grade alloantigen-specific immunomodulatory cells for tolerance induction after transplantation.

Introduction of hand-assisted retroperitoneoscopic living donor nephrectomy at Karolinska University Hospital Huddinge.

Living donor kidney transplantation accounts for about 50% of the total number of renal transplantations at our center. From 1999 through 2005, 75 out of 220 living donor nephrectomies were performed with a laparoscopic technique (LLDN). In June 2005, we introduced the technique of hand-assisted retroperitoneoscopic nephrectomy (HARS) for living donors. Since the introduction until the end of 2005, 11 out of 18 living donor nephrectomies (LDN) were performed with HARS. Reduced operation time was observed for the HARS group (mean, 166 minutes) compared with the LLDN (mean, 244 minutes). Two grafts showed delayed function, one in the LLND group and one in the HARS group. No major perioperative or postoperative complications were observed in the HARS group, whereas one patient who underwent LLDN developed severe pancreatitis. So far in our hands HARS is a fast and safe procedure with results comparable with open LDN. Compared to LLDN, we experienced reduced operation time together with the advantage of retroperitoneal access.

Liver transplantation for HCV cirrhosis at Karolinska University Hospital Huddinge, Stockholm.

Hepatitis C virus (HCV)-induced cirrhosis is the major indication for liver transplantation globally, and an increasing indication for liver transplantation in Sweden. We have retrospectively examined the 120 patients transplanted for HCV cirrhosis from 1987 through 2005, including 11 who received more than one graft. The 1-, 3-, and 5-year postoperative survivals for all patients transplanted for HCV with or without hepatocellular cancer (HCC) were 77%, 66%, and 53%, respectively. HCV patients without HCC had a 1-, 3-, and 5-year survivals of 78%, 73%, and 61%, compared with 84%, 79% and 74%, respectively, for patients transplanted with chronic liver diseases without cancer or HCV. The number of patients with HCV cirrhosis transplanted in our center is increasing. Compared with patients transplanted for other chronic liver diseases, we experienced inferior results among patients with HCV cirrhosis.

Antibodies to liver sinusoidal endothelial cells modulate immune responses in liver transplantation.

AIM: Liver sinusoidal endothelial cells (LSECs) have been implicated to play a role in the induction of liver allograft rejections. Here, we studied the clinical consequences of preformed LSEC-reactive antibodies and their functional capacity in modulating T-cell responses. METHODS: Pre- and posttransplant sera and T lymphocytes from 95 liver transplant patients were used in this study. LSECs were isolated from a normal healthy liver. Binding of antibodies to LSECs was detected using flow cytometric analysis. To study whether LSEC antibodies facilitated cell-mediated immunity, a mixed cell culture (MCC) assay was used. Cytokines in the supernatant of MCC were also measured by enzyme-linked immunosorbent assay. Immunohistochemical staining on liver biopsy sections was performed to detect deposition of immunoglobulins in LSEC during rejections. RESULTS: Significantly higher numbers of patients with rejections had LSEC antibodies (35/50, 70%) compared with 8/45 (18%) without rejections (P < .0001). Purified fractions of LSEC antibodies induced the expression of the costimulatory marker CD86 on LSECs. Significantly higher numbers of patients with LSEC antibodies and rejections had an increased proliferation of T cells and markedly decreased levels of transforming growth factor (TGF)-beta in the MCC as compared with those without antibodies and rejections (P < .0001, P < .0001, respectively). Deposition of antibodies in LSECs during rejection episodes was observed in the biopsies of patients with LSEC antibodies but not in those without LSEC antibodies. CONCLUSION: Our data suggest that antibodies to LSEC may facilitate acute liver allograft rejections by down-regulating the immune modulating cytokine TGF-beta and thus up-regulating alloreactive T-cell proliferation.

The correlation between cytological patterns in bile and histological findings in liver transplantation.

The cytological patterns in bile were compared with the histological findings in concomitant specimens from liver transplants. In cases where cytology showed a moderate (n = 10) or high cell density (n = 8), histology demonstrated rejection in 14 of 18 specimens and cholangitis in 4. When the cell density was low (n = 22), histology was nearly normal in 3 specimens and showed cholangitis in 9, while rejection was observed in 10 specimens. Cell density in bile did not correlate quantitatively with the severity of cellular infiltration in the portal triads or with the percentage of bile ducts attacked by inflammatory cells. The results of the present study support our hypothesis that an increased concentration of cells in bile is indicative of liver transplant rejection (sensitivity 58%), while normal cytology does not rule out the possibility of rejection (specificity 75%).

Comparison of fine-needle aspiration biopsy and histology in human liver transplants.

The findings in 50 fine-needle aspiration biopsies obtained from 27 liver transplants in 24 patients were compared with concomitant histologic findings. When histology showed rejection, rejection was diagnosed in 20 out of 29 FNAB specimens; when rejection was absent histologically, FNAB was negative in 20 out of 21 specimens (sensitivity 69%, specificity 95%). There was a statistically significant correlation between the degree of immunoactivation as reflected by total corrected increment (TCI) in FNAB specimens and the portal triad cell density during rejection, while no correlation existed between the 2 parameters in situations other than rejection. When cholestasis was demonstrated histologically, FNAB showed cholestasis in 30 out of 31 specimens. Furthermore, FNAB showed fatty change in the hepatocytes in 29 out of 43 specimens from livers with histologically evident steatosis. Histology showed necrotic areas in 40 specimens; however, only in 12 concomitant FNAB specimens were necrotic clumps observed. In conclusion, FNAB is a good method for diagnosing acute liver transplant rejection as well as for evaluating intracellular cholestasis or fatty change. Furthermore, TCI seems to reflect the severity of cellular infiltration in the portal triads during rejection.

Renal function before and long after liver transplantation in children.

BACKGROUND: Renal dysfunction occurs in children with liver diseases and renal function is often further impaired after orthotopic liver transplantation (OLT). Inaccurate methods of determining renal function are used in many cases. We studied renal function with accurate methods before and repeatedly after OLT to analyze the effect of the underlying diseases, hypertension, and the immunosuppressive agents. METHODS: A total of 46 children were studied both before and annually after OLT with clearances of inulin and paraaminohippuric acid to determine the glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). The clearance of inulin was also compared with the formula creatinine clearance. RESULTS: GFR and ERPF decreased from before to after OLT and decreased further during the first years after OLT. Patients with extrahepatic biliary atresia and with tumours showed higher GFR 1 year after OLT than those with metabolic and miscellaneous disorders. No significant change in GFR of individual patients occurred from the first to the last values determined at around 1 and 6 years after OLT. No difference in renal function was seen during the first years between patients treated with cyclosporine as compared to those treated with tacrolimus, but 4 years after OLT, the GFR was higher in the tacrolimus-treated patients. Patients on antihypertensive agents had lower GFR than the normotensive ones. There was no agreement between GFR, determined by clearance of inulin, and that calculated on the basis of serum creatinine and the height of the patients. CONCLUSIONS: Renal function is reduced by OLT and decreases further during the first years after OLT. Patients with metabolic disorders and those on antihypertensive treatment have the lowest GFR. Determination of GFR by the formula creatinine clearance is inaccurate in children after liver transplantation.

Bile cytology in orthotopic liver transplantation.

The utility of bile cytology (BC) in the diagnosis of hepatic graft rejection was assessed in 21 liver transplantations in 18 patients. A total of 307 BC specimens were studied; cell density and relative contribution of different cell types were monitored in 130 specimens. The findings in 62 fine-needle aspiration biopsies and 9 core needle biopsies (CNB) from the transplants were compared with those of the BC specimens. For the first 3-5 days after transplantation, BC specimens were cell-rich, containing degenerating cells and polymorphonuclear leukocytes. In uneventful cases, the cellularity of the specimens gradually decreased. Upon rejection, the number of cells increased, with a high percentage of PMN. Occasionally, blasts or macrophages were detected. After antirejection treatment, the cellularity of the specimens decreased. The analysis of the relationship between the findings of BC and FNAB showed that a high cell density was indicative of rejection. However, BC was not as sensitive to rejection as was FNAB. No clear-cut correlation was found between BC pattern and the degree of cell infiltration in portal triads as seen in CNB specimens. Our results indicate that serial bile cytology is valuable as an additional diagnostic method in monitoring hepatic graft rejection.