Cytomegalovirus Disease After Liver Transplant-A Description of a Treatment-Resistant Case: A Case Report and Literature Review.

Cytomegalovirus (CMV) infection is a common complication in solid organ transplant recipients. In patients receiving immunosuppressive treatment, CMV may lead to life-threatening organ complications or graft loss. We describe a case of 31-year-old CMV-seronegative patient who underwent liver transplant from a CMV-seropositive donor with an early acute resistant rejection of the transplanted organ followed by primary CMV infection, despite prophylaxis, and its severe organ complications. Routine treatment of acute allograft rejection through increasing the base immunosuppression and then administering methylprednisolone infusions did not yield significant therapeutic effect. This resulted in anti-thymocyte globulin and ultimately proteasome inhibitor introduction. The cholestasis remitted and liver parameters improved. But 4 weeks later the patient was admitted again due to incorrect liver function tests. Blood tests revealed high CMV viral load, and primary CMV infection was diagnosed. On diagnosis the patient was treated with ganciclovir (GCV) intravenously. As GCV resistance was suspected based on clinical premises, foscarnet (FOS) and leflunomide (LFM) were implemented with concomitant cautious immunosuppression reduction due to the history of recent graft rejection. Despite aggressive treatment introduction, viral clearance was not obtained. Ultimately the patient died due to respiratory distress resulting from lung fibrosis, most probably owing to CMV diseases with Pneumocystis jiroveci coinfection. The presented case proves the importance of strictly following the rules of prophylaxis, especially in patients with a high risk factor of CMV infection development. A quick diagnosis, implementation of appropriate treatment, and fast reaction to the lack of satisfying therapeutic effect can be the key to a successful treatment.

Durability of virologic response, risk of de novo hepatocellular carcinoma, liver function and stiffness 2 years after treatment with ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin in the AMBER, real-world experience study.

We followed for 2 years patients treated with direct-acting agents (DAA) to assess long-term durability of virologic response, improvement of liver function, reduction in liver stiffness (LS) and risk of hepatocellular carcinoma (HCC). The study included patients from 16 hepatologic centres involved in the AMBER, investigator-initiated study on treatment of chronic hepatitis C patients within a programme preceding EU registration of ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin. A total of 204 patients among 209 from the primary study were enrolled, 200 with available testing at 2-year follow-up (2yFU) with undetectable HCV RNA (198 responders and 2 nonresponders retreated). During 2yFU, 4 patients died, 17 had hepatic decompensation and 3 needed liver transplantation. De novo hepatocellular carcinoma was diagnosed in 4 and its recurrence in 3 patients. Significant decreases in bilirubin, MELD, Child-Pugh scores and liver stiffness, and increases in albumin level were observed during 2yFU. Strengths of the study were a fixed period of post-treatment follow-up, prospective character of the study and high proportion of available patients from the primary study. The major weaknesses were lack of a comparative arm and relatively insufficient number of patients for subsets analysis. In conclusion, 2-year follow-up confirmed durability of virologic response after treatment of HCV infection with ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin. It was accompanied by significant improvement of major measures of hepatic function and reduction of hepatic stiffness. Successful therapy did not prevent hepatic decompensation, HCC or death in cirrhotics that support the need for longer than 2-year monitoring for possible disease progression.

Treatment of HCV infection in Poland at the beginning of the interferon-free era-the EpiTer-2 study.

The aim of the EpiTer-2 study was to analyse patient characteristics and their medication for HCV infection in Poland at the beginning of the interferon-free era. Analysis of data of HCV infected patients treated during the initial period of availability of interferon-free regimens in Poland, who started therapy after 1 July 2015 and had available an efficacy evaluation report before 30 June 2017 was undertaken. A total of 2879 patients with chronic hepatitis C were entered, including 46% with liver cirrhosis. The most common was genotype 1b (86.8%). The study population was gender balanced, the majority of patients were overweight or obese and 69% presented comorbidities, with the highest prevalence that for hypertension. More than half of patients were retreated due to failure of previous therapy with pegylated interferon and ribavirin. Almost two-third of patients received current therapy with ombitasvir/paritaprevir/ritonavir±dasabuvir (OPrD) ±ribavirin. Other patients received mostly sofosbuvir-based regimens including combination with ledipasvir and pegylated interferon and ribavirin for genotype 3-infected patients. Efficacy of treatment in the whole study population measured as intent-to-treat analysis was 95%. The most frequent regimen, administered for patients infected with genotype 1b, was 12 weeks of OPrD, resulting in an SVR rate of 98%. At least one adverse event was reported in 38% of patients, and the death rate was 0.8%. In conclusion, data from the EpiTer-2 study confirmed the excellent efficacy and safety profile of the real-world experience with recently introduced therapeutic options for genotype 1 HCV infection, but demonstrated weakness of the current therapeutic programme regarding genotype 3 infections.

Fibrosing Cholestatic Hepatitis C After Liver Transplantation: Therapeutic Options Before and After Introduction of Direct-Acting Antivirals: Our Experience and Literature Review.

BACKGROUND: Cirrhosis caused by hepatitis C is the most common indication for liver transplantation. The most aggressive form of hepatitis C virus (HCV) relapse after liver transplantation is fibrosing cholestatic hepatitis C, which can be observed in 2% to 15% of recipients. METHODS: Double therapy with peg-interferon and ribavirin was characterized by low antiviral response, rapid fibrosis, and frequent graft failure within 1 year after surgery. RESULTS: Introduction of direct-acting antivirals for HCV treatment allows for more efficient therapy with less adverse reactions, including patients with fibrosing cholestatic hepatitis C. CONCLUSIONS: We present 4 (2.5%) cases of cholestatic viral hepatitis C recurrence in patients undergoing transplantation between 2006 and 2015 at the Transplantation Institute of Warsaw; during this period, 158 liver transplants were performed in patients with cirrhosis caused by HCV infection.

Real-world effectiveness and safety of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin in hepatitis C: AMBER study.

BACKGROUND: Virologic and safety outcomes of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) therapy have shown high sustained virologic response (SVR) rates and good tolerability in most patient populations in pre-registration studies. AIM: To confirm these clinical trial findings in the treatment of genotype 1 and 4 hepatitis C under real-world conditions. METHODS: Patients enrolled for treatment with OBV/PTV/r ± DSV ± RBV based on therapeutic guidelines were included, and the regimen was administered according to product characteristics. Clinical and laboratory data, including virologic response, were collected at baseline, end of treatment (EOT) and 12 weeks after EOT. RESULTS: A total of 209 patients with chronic hepatitis C were enrolled, most were genotype 1b-infected (84.2%) and 119 (56.9%) had liver cirrhosis. Among these, 150 (71.7%) had failed previous anti-viral therapies and 84 (40.2%) were null-responders. At 12 weeks after EOT, SVR was achieved by 207 (99.0%) patients, ranging from 96.4% to 100.0% across subgroups. All Child-Pugh B and post-orthotopic liver transplantation patients achieved SVR. Adverse events occurred in 151 (72.2%) patients and were mostly mild and associated with the use of RBV. Serious adverse events, including hepatic decompensation, renal insufficiency, anaemia, hepatotoxicity and diarrhoea, were reported in eight (3.8%) patients. In five (2.4%) patients, adverse events led to treatment discontinuation. On-treatment decompensation was experienced by seven (3.3%) patients. CONCLUSIONS: The results of our study confirm previous findings. They demonstrate excellent effectiveness and a good safety profile of OBV/PTV/r± DSV±RBV in HCV genotype 1-infected patients treated in the real-world setting.

Dynamic Elastography in Diagnostics of Liver Fibrosis in Patients After Liver Transplantation Due to Cirrhosis in the Course of Hepatitis C.

BACKGROUND: Assessment of the dynamics and degree of liver fibrosis in patients after liver transplantation is a basic element in the process of determining transplant survival prognosis. It allows planning and early initiation of prophylaxis or treatment, which translates into increased chances of preventing cirrhosis and of long-term optimal function of the graft. The aim of this study was to compare the results of biopsy and dynamic elastography in diagnostics of transplanted liver fibrosis, as well as determination of the stiffness cut-off point for assessment of significant fibrosis. PATIENTS AND METHODS: The study included 36 patients who had undergone liver transplantation due to cirrhosis in the course of hepatitis C virus (HVC) infection. Fibrosis was assessed in bioptates according to the METAVIR score (F0-F4). Elastography was performed using FibroScan; receiver operating characteristic curve analysis was used to identify the cut-off point for significant fibrosis (≥F2). RESULTS: The median stiffness in kPa for the whole group F0-F4 was 6.3 (range 3.4-29.9); for ≥F2 it was 6.9 (3.4-29.9), whereas for F0-F1 it was 4.4 (3.5-8.0). It was demonstrated that the value of 4.7 kPa in elastography is a statistically significant cut-off point for differentiation between the groups F0-F1 and F2-F4 (sensitivity: 93%, specificity: 57%, positive predictive value: 90%, negative predictive value: 66%), area under the receiver operating characteristic curve: 0.746 (95% confidence interval: 0.53-0.95, P < .05). CONCLUSIONS: Elastography is a promising tool for noninvasive assessment of significant liver fibrosis in patients after transplantation due to cirrhosis in the course of hepatitis C; it allows reduction in the number of biopsies performed.

Pregnancy in a patient with hepatic artery thrombosis after liver transplantation: a case report.

BACKGROUND: Hepatic artery thrombosis (HAT) increases the risk of complications and mortality after liver transplantation. The incidence for HAT is increased in patients with risk factors (vascular reconstructions, coagulation disorders and acute rejection episodes amongst others). Early retransplantation improves the prognosis for patients, but owing to lack of donors, surgical and interventional radiologic attempts to restore the patency of hepatic artery are made. The prognosis for the liver and the patient can also be improved by the development of collateral circulation. CASE REPORT: We describe a case of a 30-year-old woman with hepatic failure owing to Wilson disease. Liver transplantation with the use of vascular conduit made of donor's iliac arteries was complicated by an early HAT. Heterozygous factor V Leiden mutation was confirmed in the patient. Despite surgical and radiologic attempts to restore patency and despite treatment with fractioned heparin and aspirin, the hepatic artery remained occluded. Retransplantation was not considered, even though the patient was planning a pregnancy. After 1 year of observation of stable liver function, conversion from mycophenolate mofetil to azathioprine treatment, the patient was given consent for a high-risk pregnancy. DISCUSSION: The course of pregnancy was uneventful, with normal liver function parameters, without pathological bleedings. The patient was treated with doses of enoxaparin adjusted for the patient's weight. In the 34th week, owing to increasing concentration of bile acids, the pregnancy ended with a cesarean section. The newborn had 10-point APGAR score.

The significance of antiphospholipid antibodies in liver recipients.

BACKGROUND: The presence of antiphospholipid antibodies (APLAs) may be associated with increased thrombotic risk. Liver graft thrombosis may necessitate retransplantation. AIM: To determine the prevalence of APLAs among liver recipients and to investigate the relationship between APLAs and liver graft thrombosis. MATERIALS AND METHODS: We included 33 Caucasian patients aged 22 to 75 years who displayed stable liver graft function (21 women and 12 men). The patients were divided into 2 subgroups: high thrombotic risk subgroup T(-) and at low risk T(+) subgroups. The T(-) included 25 patients, T(+) included 8 recipients with a history of severe thrombosis. We investigated: lupus anticoagulant, anticardiolipin antibodies (aCL), anti-ß2-glycoprotein I antibodies (anti-ß2GPI), antiprothrombin antibodies (immunoglobulin (Ig)G and IgM isotype), protein C and S activities, factor VIII, antithrombin, ADAMTS-13 and anti-ADAMTS-13. The 2 determinations were performed at an interval of 6 months. The mean follow-up was 19.5 ± 4.6 months. RESULTS: The most commonly detected antibodies were anti-ß2GPI IgM (25%) and aCL IgG (15.63%). Comparing the prevalence of APLAs between T(-) and T(+), we observed a significant difference only for aCL IgM (P = .0183), which was not confirmed on a second determination after 6 months. We noted correlations between aCL IgM and number of thrombotic episodes (P = .0040) and between aCL IgM and anti-ß2GPI IgM (P = .0074; rho 0.45). Despite receiving low-molecular-weight heparin or aspirin recurrence of thrombosis occurred in 4 T(+) patients: 3 hepatic artery thrombosis and 1 splenic artery thrombosis. Only 1 patient had APLAs; the other 2, protein C or S deficiency and the fourth, a normal test. CONCLUSIONS: The prevalence of APLAs in liver recipients is greater than that in the general population. The usefulness of APLAs as a marker of thrombosis was not demonstrated suggesting multifactorial etiologies of liver graft thrombosis.

[Antithrombotic therapy in patients with prosthetic heart valves].

Anticoagulant therapy is an important component of treatment of patients with prosthetic heart valves. The article contains consideration of specific problems of antithrombotic therapy in patients with various types of prostheses and its tactics in different clinical situations. In the absence of national recommendations on the use of anticoagulants in these patients the authors suggest schemes of management based on recent European and American guidelines.

[Left ventricular myocardial hypertrophy after transplantation of the kidney: risk factors and possible regress].

AIM: To study structural-functional changes in left ventricular (LV) myocardium in recipients of renal allograft (RA) after different postoperative period and to specify factors promoting persistence, progression or regression of LV hypertrophy (LVH). MATERIAL AND METHODS: The study included 240 recipients of primary RA (38% females and 62% males, age 16-69 years, mean age 42 +/- 11 years). A prospective study covered 143 patients. RESULTS: LVH was diagnosed in 52% patients. LVH incidence after renal transplantation (RT) had a wave-like dynamics: during 9 months after RT LVH presents in more than 50% patients; after 9-24 months after the operation it fell to 30% and after 3-7 years after the operation it affected at least 2/3 patients. After RT LVH risk factors were age, duration of chronic renal failure (CRF) and pretransplantation dialysis, reduced mass of the operating nephrons, arterial hypertension, anemia, functioning of arterio-venous fistula (AVF) and chronic inflammation syndrome. LVH was also associated with factors specific for RT: RA rejection crises, infections complicating massive immunosuppressive therapy. LVH is also associated with proteinuria which may indicate RA damage and can be considered as a marker of generalized endothelial dysfunction. 2-year and longer follow-up after RT confirmed complete LVH regression in 1/3 of the recipients. LVH regression was observed in normal RA function, normal blood pressure, the absence of proteinuria, hypoalbuminemia, anemia, AVF, infectious complications. CONCLUSION: LVH after RT is multifactorial and can completely regress in a favourable posttransplantation course.

Bisphosphonates are effective prophylactic of early bone loss after renal transplantation.

INTRODUCTION: Rapid bone loss and fractures occur early after solid organ transplantation. We examined the preliminary results of a prospective study evaluating the efficacy of prophylactic use of bisphosphonates in renal allograft recipients. METHODS: Bone mineral density (BMD) was measured at the lumbar spine and the hip by dual energy X-ray absorptiometry at 1, 6, 12 months. Alendronian or risedronian were initiated for patients with osteopenia or osteoporosis at 1 month who had no contraindications to bisphosphonates. The treatment lasted at least 6 months. Sixty-six patients were included in the study; 39 were treated with bisphosphonates (A), and 27 were drug-free (B). Presently, 24 group A and 13 group B patients have completed the 12-month observation period. RESULTS: In group A 53.8% (21) subjects had osteoporosis and 46.2% (18), osteopenia. Mean T-score L(2)-L(4) in group A at 1, 6, and 12 months were: (-)2.22 +/- 1.06; (-)2.07 +/- 1.25; (-)1.89 +/- 1.07, respectively. The T-score increase between 6 and 12 months was significant (P = 0.0014). The relative rise in BMD L(2)-L(4) between 1 and 12 months was 2.26%. In group B mean T-score L(2)-L(4) at 1, 6, and 12 months were: (-)0.26 +/- 1.34; (-)0.80 +/- 1.19; (-)1.2 +/- 1.59, respectively. The T-score decrease between 1 and 12 months in group B was significant (P = .0082). The 12-month relative decrease in femoral neck and trochanter BMD in group B was (-)2.1% and (-)2.75%, respectively. CONCLUSION: Bisphosphonates are effective for prophylaxis of rapid bone loss early after renal transplantation.

Tubular and glomerular proteinuria in diagnosing chronic allograft nephropathy with relevance to the degree of urinary albumin excretion.

The diagnosis of chronic allograft nephropathy (CAN) is based on pathological examination according to Banff 97 schema. The aim of the study was to evaluate the usefulness of tubular and glomerular proteinuria for noninvasive recognition of CAN. One hundred and thirty renal allograft recipients (at least 90 days after transplantation) who had undergone diagnostic allograft biopsy were included in the study. Beta2-microglobulin, alpha1-microglobulin, albumin, immunoglobulin G, total protein, and creatinine concentrations were obtained from the second morning urine specimen. Raw data and values calculated per 1 g of creatinine excreted in urine along with time after transplantation, serum creatinine, and its change over a period of 2 months prior to biopsy were taken for analysis. Urine proteins were measured using a nephelometric method. Statistical calculations were performed using MANOVA and stepwise discriminant analysis (SDA). Statistical diagnosis and staging of CAN matched the pathological method in 68% of a preliminary SDA. Therefore patients were divided into normoalbuminuric, microalbuminuric, and macroalbuminuric groups. There was no significant differences between protein excretion, except alpha1-microglobulinuria (CAN 0 vs 2, P = .018; CAN 1 vs 2, P = .041), beta2-microglobulinuria (CAN 0 vs 2, P = .026; CAN 1 vs 2, P = .0033), and total proteinuria (CAN 0 vs 2, P = .042) in the normoalbuminuric group. Nevertheless, diagnoses obtained using SDA were 89%, 91%, and 92% identical to the results of pathological examinations, for normoalbuminuric, microalbuminuric, and macroalbuminuric groups, respectively. In conclusion, tubular and glomerular proteinuria measurements may be useful for a noninvasive CAN diagnosis and staging only with regard to degree of urinary albumin excretion.

Pneumonia in kidney allograft recipients.

Infectious complications, including pneumonia, remain one of the leading causes of morbidity and mortality in kidney allograft recipients. The aim of the study was to evaluate the relationship between pneumonia occurrence and treatment duration and recipient age, cause of native kidney insufficiency, dialysis duration, time between transplantation and onset, HLA matching, PRA immunosuppressive protocol, acute rejection incidence and treatment, kidney function at the pneumonia onset, as well as presence of comorbid conditions. One hundred and twenty pneumonia cases occurred in kidney allograft recipients transplanted between 1991 and 2000 with 12 to 120 months follow-up. Twenty five percentage of pneumonia episodes were diagnosed during the first posttransplant month, 25% between 2 and 6 months, and 25% at 0.5 to 3 years. Treatment duration measured from pneumonia onset to the study endpoint of recovery, which was defined as antibiotic withdrawal, show 50% of patient we cured after 15 days and 75% after 24 days of treatment. The risk of prolonged pneumonia treatment was associated with: second versus first kidney transplantation with RR = 2.3 (P <.02) and medians of treated time 28 versus 15 days; as well as serum creatinine level above 2 mg/dL (RR = 1.4; P <.098). Exposure to enhanced-potency immunosuppressive protocols including induction therapy with mono- or polyclonal antibodies increased the RR = 1.65 (P <.02), and lengthened the time to 18 versus 14 days. Maintenance immunosuppression with agents other than cyclosporine also enhanced the risk. (RR = 2.18; P <.068).