Nada Kanaan

Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants

BACKGROUND & AIMS Hepatitis E virus (HEV) infection can cause chronic hepatitis in recipients of solid organ transplants. However, the factors that contribute to chronic infection and the outcomes of these patients are incompletely understood. We performed a retrospective analysis of data from 17 centers from Europe and the United States that described the progression, outcomes, and factors associated with development of chronic HEV infection in recipients of transplanted solid organs. METHODS We studied data from 85 recipients of solid organ transplants who were infected with HEV. Chronic HEV infection was defined by the persistent increases in levels of liver enzymes and polymerase chain reaction evidence of HEV in the serum and/or stool for at least 6 months. RESULTS Fifty-six patients (65.9%) developed chronic hepatitis. Univariate analysis associated liver transplant, shorter times since transplant, lower levels of liver enzymes and serum creatinine, lower platelet counts, and tacrolimus-based immunosuppressive therapy (rather than cyclosporin A) with chronic hepatitis. On multivariate analysis, the independent predictive factors associated with chronic HEV infection were the use of tacrolimus rather than cyclosporin A (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.49-1.97; P = .004) and a low platelet count at the time of diagnosis with HEV infection (OR, 1.02; 95% CI, 1.001-1.1; P = .04). Of patients with chronic hepatitis, 18 (32.1%) achieved viral clearance after the dose of immunosuppressive therapy was reduced. No HEV reactivation was observed after HEV clearance. CONCLUSIONS HEV infection causes chronic hepatitis in more than 60% of recipients of solid organ transplants. Tacrolimus therapy is the main predictive factor for chronic hepatitis. Dose reductions of immunosuppressive therapy resulted in viral clearance in more than 30% of patients.

Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring.

Background With effective agents available to prevent posttransplantation acute organ rejection, medication adherence becomes a key factor for successful treatment outcomes after renal transplantation. A once-daily, modified-release oral formulation of tacrolimus has been developed to simplify dosing and improve medication adherence. Methods Adherence Measurement in Stable Renal Transplant Patients Following Conversion From Prograft to Advagraf is a randomized multicenter controlled trial to evaluate adherence between a tacrolimus once-daily regimen and a tacrolimus twice-daily regimen using an electronic monitor to document drug intake. After enrolment, all patients continued the twice-daily regimen for 3 months and then were randomized 2:1 between the two formulations and followed for 6 months. Adherence was decomposed into patients’ persistence and implementation of each regimen. Results Two hundred nineteen patients (45% male; 3±2 years after transplantation) were analyzed (145 once daily and 74 twice daily). At 6 months after randomization, 81.5% of the once-daily group and 71.9% of the twice-daily group remained persistent with the treatment (P=0.0824). Among patients who remained engaged with the regimen, 88.2% of the once-daily group and 78.8% of the twice-daily group (P=0.0009) took the prescribed number of daily doses. When the patients took the twice-daily regimen, the average percentage of missed doses was 11.7% in the morning and 14.2% in the evening (P=0.0035). Conclusions Regimen implementation of tacrolimus once daily is significantly superior to the twice-daily regimen. There was a residual prevalence of suboptimal adherence that will have to be countered by means other than reformulation and regimen simplification. Electronically compiled dosing histories provide detailed data on patient adherence that can be used for efficient medication management.

Progression of Coronary Artery Calcification and Thoracic Aorta Calcification in Kidney Transplant Recipients

BACKGROUND Vascular calcification independently predicts cardiovascular disease, the major cause of death in kidney transplant recipients (KTRs). Longitudinal studies of vascular calcification in KTRs are few and small and have short follow-up. We assessed the evolution of coronary artery (CAC) and thoracic aorta calcification and their determinants in a cohort of prevalent KTRs. STUDY DESIGN Longitudinal. SETTING & PARTICIPANTS The Agatston score of coronary arteries and thoracic aorta was measured by 16-slice spiral computed tomography in 281 KTRs. PREDICTORS Demographic, clinical, and biochemical parameters were recorded simultaneously. OUTCOMES & MEASUREMENTS The Agatston score was measured again 3.5 or more years later. RESULTS Repeated analyzable computed tomographic scans were available for 197 (70%) KTRs after 4.40 ± 0.28 years; they were not available for the rest of patients because of death (n = 40), atrial fibrillation (n = 1), other arrhythmias (n = 4), refusal (n = 35), or technical problems precluding confident calcium scoring (n = 4). CAC and aorta calcification scores increased significantly (by a median of 11% and 4% per year, respectively) during follow-up. By multivariable linear regression, higher baseline CAC score, history of cardiovascular event, use of a statin, and lower 25-hydroxyvitamin D(3) level were independent determinants of CAC progression. Independent determinants of aorta calcification progression were higher baseline aorta calcification score, higher pulse pressure, use of a statin, older age, higher serum phosphate level, use of aspirin, and male sex. Significant regression of CAC or aorta calcification was not observed in this cohort. LIMITATIONS Cohort of prevalent KTRs with potential survival bias; few patients with diabetes and nonwhites, limiting the generalizability of results. CONCLUSION In contrast to previous small short-term studies, we show that vascular calcification progression is substantial within 4 years in prevalent KTRs and is associated with several traditional and nontraditional cardiovascular risk factors, some of which are modifiable.

Diagnosis of cyst infection in patients with autosomal dominant polycystic kidney disease: attributes and limitations of the current modalities

Cyst infection is a diagnostic challenge in patients with autosomal dominant polycystic kidney disease (ADPKD) because of the lack of specific manifestations and limitations of conventional imaging procedures. Still, recent clinical observations and series have highlighted common criteria for this condition. Cyst infection is diagnosed if confirmed by cyst fluid analysis showing bacteria and neutrophils, and as a probable diagnosis if all four of the following criteria are concomitantly met: temperature of >38°C for >3 days, loin or liver tenderness, C-reactive protein plasma level of >5 mg/dL and no evidence for intracystic bleeding on computed tomography (CT). In addition, the elevation of serum carbohydrate antigen 19-9 (CA19-9) has been proposed as a biomarker for hepatic cyst infection. Positron-emission tomography after intravenous injection of 18-fluorodeoxyglucose, combined with CT, proved superior to radiological imaging techniques for the identification and localization of kidney and liver pyocyst. This review summarizes the attributes and limitations of these recent clinical, biological and imaging advances in the diagnosis of cyst infection in patients with ADPKD.

Carbohydrate antigen 19-9 as a diagnostic marker for hepatic cyst infection in autosomal dominant polycystic kidney disease

The diagnosis of hepatic cyst infection is difficult in patients with autosomal dominant polycystic kidney disease (ADPKD). We hypothesized that carbohydrate antigen 19-9 (CA 19-9), secreted by the biliary epithelium lining the cysts, is overproduced in the case of cyst infection. In this report, we describe 3 patients with ADPKD with hepatic cyst infection, all with functioning kidney transplants, who had markedly increased serum CA 19-9 levels. Furthermore, CA 19-9 level was extremely increased in cystic fluid obtained in 2 of these individuals. Corresponding with clinical improvement, there was a marked decrease in serum CA 19-9 level in all 3 patients. To assess the potential applicability of these findings, serum CA 19-9 was measured in asymptomatic patients with ADPKD with known liver cysts and in controls without ADPKD. Although serum CA 19-9 levels were significantly higher in asymptomatic patients with ADPKD than in controls, they were markedly increased in patients with cyst infection compared with either asymptomatic ADPKD patients or controls. Immunostaining for CA 19-9 showed strong positivity in biliary tree epithelia and cysts of polycystic livers from patients with ADPKD that appeared more intense than in normal livers. Although further study is necessary, these data suggest that serum CA 19-9 level is markedly increased during liver cyst infection in kidney transplant recipients with ADPKD and has potential utility as a diagnostic marker.

Fibroblast Growth Factor-23 and Parathyroid Hormone Are Associated with Post-Transplant Bone Mineral Density Loss

BACKGROUND AND OBJECTIVES Among the multiple factors contributing to bone mineral density (BMD) loss after renal transplantation, hypophosphatemia is increasingly recognized to play an important role. Hypophosphatemia occurs in up to 90% of the renal transplant recipients in the early post-transplant period and is caused by renal phosphate wasting. We hypothesized that a high pretransplant level of the recently described phosphaturic hormone fibroblast growth factor 23 (FGF-23) is a risk factor for accelerated BMD loss occurring within the first post-transplant year. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We performed a two-center observational retrospective cohort study in 127 incident renal transplant recipients. Serum full-length FGF-23, parathyroid hormone (PTH), and parameters of mineral metabolism were determined at the time of transplantation. BMD was assessed by osteodensitometry at the time of transplantation and 1 year later. RESULTS A moderate decrease of BMD was observed during the first post-transplant year. High FGF-23 levels were associated with BMD loss at the lumbar spine and total hip region, whereas low PTH levels were associated with BMD loss at all three regions. Cumulative doses of prednisone and post-transplant serum phosphate level were not correlated with BMD changes. CONCLUSION Our data indicate that patients with a high serum FGF-23 level and/or a low PTH level at the time of transplantation are at risk for increased BMD loss during the first post-transplant year.

Renal transplantation in autosomal dominant polycystic kidney disease

In patients with autosomal dominant polycystic kidney disease (ADPKD) evaluated for kidney transplantation, issues related to native nephrectomy, cystic liver involvement, screening for intracranial aneurysms and living-related kidney donation deserve special consideration. Prophylactic native nephrectomy is restricted to patients with a history of cyst infection or recurrent haemorrhage or to those in whom space must be made to implant the graft. Patients with liver involvement require pretransplant imaging. Selection of patients for pretransplant screening of intracranial aneurysms should follow the general recommendations for patients with ADPKD. In living related-donor candidates aged <30 years and at-risk of ADPKD, molecular genetic testing should be carried out when ultrasonography and MRI findings are normal or equivocal. After kidney transplantation, patient and graft survival rates are excellent and the volume of native kidneys decreases. However, liver cysts continue to grow and treatment with a somatostatin analogue should be considered in patients with massive cyst involvement. Cerebrovascular events have a marginal effect on post-transplant morbidity and mortality. An increased risk of new-onset diabetes mellitus and nonmelanoma skin cancers has been reported, but several studies have challenged these findings. Finally, no data currently support the preferential use of mammalian target of rapamycin inhibitors as immunosuppressive agents in transplant recipients with ADPKD.

Disseminated Varicella Zoster Virus Infection in Adult Renal Transplant Recipients: Outcome and Risk Factors

BACKGROUND Disseminated varicella zoster virus (VZV) infection, whether due to primary infection or reactivation, may be life threatening in renal transplant recipients. The aims of this study were to assess the outcome of disseminated VZV infection in renal transplant recipients and to determine potential risk factors for mortality. METHODS A search of the English literature from 1985 to 2011 using PUBMED was performed. Reports involving renal transplant recipients younger than 16 years of age were excluded. RESULTS A total of 56 adult patients presenting with a disseminated cutaneous or visceral VZV infection was included. Seventy percent of cases occurred within 5 years after transplantation, and 89% within 10 years. Visceral complications including disseminated intravascular coagulation occurred in two thirds of patients. Mortality decreased significantly from 47% in the era before 1995 to 17% after 1995 (P = .04). Risk factors for mortality included visceral involvement, use of azathioprine as immunosuppressant, and longer time between transplantation and VZV infection. VZV seropositivity did not influence fatal outcome. CONCLUSION Disseminated VZV infection can be life threatening in renal transplant recipients with a global mortality rate of 30%. This rate seems to have decreased since 1995. Seropositive VZV patients with disseminated infection are not protected from fatal outcome.

Significant rate of hepatitis B reactivation following kidney transplantation in patients with resolved infection.

BACKGROUND Limited data is available on the risk of hepatitis B virus (HBV) reactivation in patients with resolved infection undergoing kidney transplantation. It is generally thought that this risk is negligible. OBJECTIVES To evaluate the incidence of HBV reactivation in such patients, and the potential risk factors for reactivation. STUDY DESIGN Retrospective cohort study including 93 patients transplanted with a kidney between 1995 and 2007 who had evidence of resolved HBV infection (HBsAg negative, anti-HBc positive, anti-HBs positive or negative, and normal liver enzymes). HBV reactivation was defined as HBsAg reversion with HBV DNA>2000 IU/mL. RESULTS Six patients experienced HBsAg reversion followed by HBV reactivation, 3 within the first post-transplant year. Immunosuppression regimen was similar in patients with and without reactivation. Among patients with reactivation only one was positive for anti-HBs antibodies at time of transplantation; these were progressively lost before reactivation. The odds ratio for reactivation in patients without anti-HBs antibodies at transplantation compared to those with anti-HBs antibodies was 26 (95% CI [2.8-240.5], p=0.0012). In patients with anti-HBs antibody titer above 100 IU/L, no reactivation was observed. CONCLUSIONS Reactivation rate of resolved hepatitis B is not negligible in patients without anti-HBs antibodies at transplantation. We suggest monitoring of liver tests and HBV serology including HBsAg and anti-HBs antibodies after transplantation as well as vaccination pre- and post-transplantation in all patients, including those with resolved hepatitis B, aiming at maintaining anti-HBs antibody level above 100 IU/L.

Sclerostin Serum Levels and Vascular Calcification Progression in Prevalent Renal Transplant Recipients

CONTEXT Vascular calcification (VC) is prevalent and progressive in renal transplant recipients (RTRs). Recent cross-sectional data suggest that activated Wnt signaling contributes to VC. OBJECTIVE The objective was to investigate whether circulating levels of the Wnt antagonist sclerostin associate with progression of VC. DESIGN This was a post hoc analysis of the longitudinal observational Brussels Renal Transplant Cohort study. SETTING The setting was a tertiary care academic hospital. PATIENTS Coronary artery calcification and aorta calcification were measured by multislice spiral computerized tomography in 268 prevalent RTRs (age, 53 ± 13 y; 61% male) at baseline and remeasured in 189 patients after a median follow-up of 4.4 years. Baseline serum sclerostin levels were assessed on stored blood samples. Regression analysis was performed to identify determinants of baseline VC and progression. MAIN OUTCOME MEASURE The main outcome measure was progression of VC. RESULTS VC was present in up to 84% of participants at baseline. Almost half of the patients showed progression of VC, according to Hokanson criteria. The cross-sectional analysis at baseline demonstrated a direct association between sclerostin levels and VC score in univariate analysis, which became inverse after adjustment for age, gender and PTH level. Remarkably, a lower sclerostin level was identified as an independent determinant of a higher baseline aorta calcification score in the final regression model. Moreover, baseline sclerostin levels showed an inverse association with VC progression, at least after adjustment for traditional risk factors. CONCLUSIONS Serum sclerostin levels inversely associated with VC burden and progression in prevalent RTRs after adjustment for traditional risk factors. Our data corroborate previous findings in nontransplanted chronic kidney disease patients and support the notion that sclerostin may be up-regulated in the vascular wall during the VC process as part of a local counterregulatory mechanism directed to suppress VC. Additional clinical and experimental data are required for confirmation.