J. Sperl, M. Kreidlova, D. Merta, K. Chmelova, R. Senkerikova and S. Frankova:
Paritaprevir/Ritonavir/Ombitasvir Plus Dasabuvir Regimen in the Treatment of Genotype 1 Chronic Hepatitis C Infection in Patients with Severe Renal Impairment and End-Stage Renal Disease: a Real-Life Cohort
Kidney Blood Press. Res., 43(2):594-605, Apr 2018
Chronic hepatitis C (HCV) virus infection reactivates under immunosuppressive drugs and therefore has a negative impact on long-term survival of kidney transplant recipients. Treatment-induced clearance of hepatitis C virus (HCV) in kidney transplant candidates prevents virus reactivation after transplantation. Paritaprevir/Ritonavir/Ombitasvir with Dasabuvir (PrOD) represents a highly effective treatment regimen for HCV genotype 1 (GT1), also suitable for patients with end-stage renal disease (ESRD). Serious drug-drug interactions may represent a limiting factor of this regimen. The aim of this retrospective study was to evaluate safety, efficacy and drug-drug interactions management associated with PrOD treatment in the Czech real-world cohort.
Emphasizing concomitant medication adjustment, we described the treatment course with PrOD regimen in 23 patients (4 with CKD4 and 19 on maintenance haemodialysis) infected with HCV GT1 (21 GT1b, 2 GT1a), 18 males and 5 females with an average age of 53.7 years. Six patients had compensated liver cirrhosis and 3 of them were liver transplant recipients.
All 23 patients completed the 12-week treatment and achieved sustained virological response 12 weeks after the treatment (SVR12 rate 100%). None of the patients presented with a significant decrease in haemoglobin level, white blood cell and platelet count during the treatment period. The most frequent adverse events were nausea, hypotension, diarrhoea, and hyperkalemia. Four patients presented with a serious adverse event unrelated to the antiviral drugs (salmonellosis, non-functional kidney graft rejection, early gastric cancer, renal cyst infection, initiation of haemodialysis). Concomitant medication had to be modified with the treatment initiation in 10 out of 23 (43.5%) patients (calcium channel blockers, ACE inhibitors, statins, diuretics, tacrolimus); four patients required further adjustment of antihypertensive drugs or tacrolimus dosage on-treatment.
PrOD regimen demonstrated an excellent efficacy and good tolerability. Both prospective adjustment of concomitant medication and further on-treatment adjustment allowed for a safe treatment course.
E. Kieslichova, S. Frankova, M. Protus, D. Merta, E. Uchytilova, J. Fronek and J. Sperl:
Acute Liver Failure due to Amanita phalloides Poisoning: Therapeutic Approach and Outcome
Transplant. Proc., 50(1):192-197, 2018
Amanita phalloides poisoning is a potentially fatal cause of acute liver failure. The aim of this study was to analyze the impact of initial patients' characteristics and different treatment modalities on the outcome of patients with liver failure caused by Amanita poisoning.
We retrospectively evaluated 23 patients admitted to our center between July 2007 and August 2016.
Mean time interval between Amanita phalloides ingestion and the onset of gastrointestinal symptoms was 12.48 ± 9.88 hours and the interval between ingestion and hospital admission 26.26 ± 15.14 hours. The treatment was intiated by oral decontamination using activated charcoal followed by intravenous rehydration and high doses of intravenous N-acetylcysteine and silibinin. Fourteen patients (61%) underwent extracorporeal elimination method. Ten patients had plasmapheresis, 1 patient had hemoperfusion, and 5 patients had fractionated plasma separation and adsorption. Seven patients who met King's College Criteria were listed for urgent liver transplantation; one of them died before transplantation. Six patients underwent liver transplantation; the mean waiting time was 6.5 ± 12.0 days (range, 1-31 days). One patient died 2 months afterward. All 16 patients who did not meet King's College Criteria and received conservative treatment survived.
Our results documented a good prognostic value of standard King's College Criteria for indication of urgent liver transplantation in acute liver failure caused by Amanita phalloides poisoning. Fractionated plasma separation and adsorption may contribute to low mortality on the waiting list. Intensive care and extracorporeal elimination methods seem to be crucial points of the conservative treatment.
J. Sperl, S. Frankova, M. Kreidlova, D. Merta, M. Tothova and J. Spicak:
Combination of sofosbuvir and daclatasvir in the treatment of genotype 3 chronic hepatitis C virus infection in patients on maintenance hemodialysis
Ther Clin Risk Manag, 13:733-738, 2017
Chronic hepatitis C virus infection (HCV) has a negative impact on the long-term survival of recipients of kidney transplants. HCV should be treated in hemodialyzed patients before their enlistment for kidney transplantation in order to avoid the reactivation of virus after transplantation. Direct-acting antivirals represent the current standard of care in hemodialyzed patients with HCV genotypes 1 and 4; in patients with genotypes 2 or 3, the optimal regimen is yet to be established. Sofosbuvir (SOF) and daclatasvir (DCV) represent an antiviral pangenotypic regimen with favorable pharmacokinetics in hemodialyzed patients. We retrospectively evaluated safety and efficacy of the combination of SOF and DCV in the treatment of genotype 3a chronic HCV in six male patients (mean age of 39 years, range 25-53 years) with end-stage renal disease on maintenance hemodialysis; these patients were treated with a reduced dose of SOF (one half of a 400 mg tablet) and 60 mg of DCV once daily. The anticipated treatment duration was 12 weeks. Initial HCV RNA ranged from 120,000 to 11,000,000 IU/mL. Two of the six patients had compensated liver cirrhosis based on shear-wave elastography result. All of the patients completed a 12-week treatment. Viremia became negative on treatment and remained negative 12 weeks after the end of therapy in all the patients. All of them (6/6, 100%) achieved sustained virological response, including two with cirrhosis and two with HCV RNA >6,000,000 IU/mL. The treatment was well tolerated: none of the patients presented with a serious adverse event requiring hospital admission and none had anemia or any significant changes in blood count. One patient had a short period of diarrhea, which was resolved with antibiotic treatment. The combination of reduced-dose SOF and full-dose DCV, daily, was a safe and effective treatment in our group of hemodialyzed patients infected with HCV genotype 3.
E. Uchytilova, M. Protus, D. Merta, R. Kula, E. Pokorna and E. Kieslichova:
Lack of Impact of Hyperchloremia in Brain-Dead Organ Donors on the Onset of Kidney Allograft Function in the Recipients
Transplant. Proc., 49(6):1262-1269, 2017
Hyperchloremia produces renal vasoconstriction and fall in glomerular filtration rate. In 90% of brain-dead organ donors, diabetes insipidus develops, characterized by inappropriate diuresis, hyperosmolality, and hyperchloremia. The aim of this study was to determine the relationship between the serum concentration of chlorides of the donor and the onset of the function of the kidney allograft in the recipient.
We retrospectively studied 213 donors and kidney allograft recipients. Serum creatinine concentrations and glomerular filtration rates on the 1st, 7th, and 30th days after transplantation of the recipients from hyperchloremic donors were compared with the recipients from normochloremic donors, as well as the incidences of acute tubular necrosis and delayed graft function.
On the 1st day, serum creatinine concentrations of the recipients from hyperchloremic and normochloremic donors, respectively, were 448.2 ± 212.1 μmol/L and 502.2 ± 197.8 μmol/L (P = .1), on the 7th day, 168.6 ± 102.6 μmol/L and 196.9 ± 120.6 μmol/L (P = .13), and on the 30th day, 129.4 ± 43.3 μmol/L and 131.8 ± 43.6 μmol/L (P = .73). The differences were statistically significant. The groups also did not differ significantly in glomerular filtration rates and incidences of acute tubular necrosis and delayed graft function.
In this study, no significant correlation between serum chloride concentrations of the organ donors and the onset of the function of kidney allografts in the recipients was found.
S. Frankova, M. Jirsa, D. Merta, M. Neroldova, P. Urbanek, R. Senkerikova, J. Spicak and J. Sperl
USP18 downregulation in peripheral blood mononuclear cells predicts nonresponse to interferon-based triple therapy in patients with chronic hepatitis C, genotype 1: a pilot study
Ther Clin Risk Manag, 11:1853-1861, 2015
Patients with advanced liver fibrosis owing to chronic hepatitis C virus genotype 1 represent a difficult-to-treat group even if a protease inhibitor is added to pegylated interferon alpha and ribavirin. Therefore, only patients with a high chance of cure should be treated with interferon-based treatment.
Expression of IFNG, IFNLR1, and interferon-sensitive genes CXCL9, IFI16, IFI27, ISG15, and USP18 in peripheral blood mononuclear cells was assessed before and during the initial 12 weeks of treatment. The studied group consisted of 26 treatment-experienced patients of average age of 50 years with advanced liver fibrosis compared to seven healthy volunteers. Fourteen patients were treated with pegylated interferon alpha 2b, ribavirin, and boceprevir and 12 patients with telaprevir. The overall sustained virological response (SVR) rate was 69% (18/26).
A significant difference in the initial expression (median, interquartile range [IQR]) of CXCL9 2.9×, IQR: 1.7-12.4 vs 1.2×, IQR: 0.5-1.8; (P=0.01) IFNG 7.3×, IQR: 1.7-32.6 vs 0.7×, IQR: 0.4-1.3; P=0.002 and USP18 3.7×, IQR: 2.1-7.7 vs 1.4×, IQR: 0.9-1.6; (P=0.03) was found between the SVR and non-SVR groups. Expression of all analyzed genes was progressively increasing during the first 12 weeks of therapy, but a significant difference between SVR and non-SVR group was found only in USP18 expression at week 12 (P=0.001). Initial expression of four genes predicted SVR in univariate analysis (CXCL9 [OR: 12.00, 95% CI: 1.21-118.89], IFI27 [OR: 12.00, 95% CI: 1.21-118.89], IFNG [OR: 10.50, 95% CI: 1.50-73.67], USP18 [OR: 21.00, 95% CI: 2.05-215.18]). In multivariate analysis, only the initial expression of USP18 was identified as a predictor of SVR (P=0.047).
Initial expression of USP18 and the course of its activation could be a reliable predictor of SVR achievement.
J. Sperl, S. Frankova, R. Senkerikova, M. Neroldova, V. Hejda, M. Volfova, D. Merta, O. Viklicky, J. Spicak and M. Jirsa
Relevance of low viral load in haemodialysed patients with chronic hepatitis C virus infection
World J. Gastroenterol., 21(18):5496-5504, May 2015
To identify predictors of sustained virological response in hemodialysed patients treated by PEGinterferon α for chronic hepatitis C, genotype 1.
The sustained virological response (SVR) rate, IL28B genotype, IFNL4 genotype, initial viral load (IVL) and other pretreatment variables in 39 end-stage renal disease patients (ESRD) on maintenance haemodialysis (HD) infected with hepatitis C virus (HCV), genotype 1b, were compared with a control group of 109 patients with normal kidney function treated within the same period. All the patients were treatment naïve and had well compensated liver disease. The ESRD patients received 135 μg of PEGylated interferon α-2a (PegIFN-α) weekly and a reduced dose of ribavirin (RBV) was administered to 23/39 patients with an initial haemoglobin level > 10 g/dL. Control group patients were given standard doses of PegIFN-α and RBV. SVR was assessed as HCV RNA negativity 24 wk post-treatment. A t-test or ANOVA were used for comparisons of the means and a χ(2) test compared the frequencies. Logistic regression was used to determine significant predictors of SVR. Cutoff values for continuous variables were obtained from Receiver Operating Characteristic analysis.
The distribution of IL28B rs12979860 CC, CT and TT genotypes in the ESRD group was 28.2%, 64.1% and 7.7%, respectively, and 19.3%, 62.4% and 18.3% in the controls. The IFNL4 genotype was in almost absolute linkage disequlibrium with IL28B. The proportion of patients with a low IVL (< 600000 IU/mL) was significantly higher in the ESRD group than in the controls (28/39, 71.8% vs 51/109, 46.8%, P = 0.009), as was the proportion of patients with low IVL in IL28B CC carriers compared with non-CC carriers in the ESRD group (10/11, 90.9% vs 18/28, 64.3%, P = 0.0035). This difference was not found in the controls (7/22, 31.8% vs 44/87, 50.6%, P = 0.9). The overall SVR rate was 64.1% (25/39) in the ESRD group and 50.5% (55/109) in the control group (P = 0.19). 11/11 (100%) and 19/22 (86.4%) IL28B CC patients achieved SVR in the ESRD and control groups, respectively. A statistically significant association between SVR and IL28B and IFNL4 variants was found in both groups. The ESRD patients who achieved SVR showed the lowest IVL [median 21000, interquartile range (IQR): 6000-23000 IU/mL], compared with ESRD individuals without SVR (1680000, IQR: 481000-6880000, P = 0.001), controls with SVR (387000, IQR: 111000-1253000) and controls without SVR (905000, IQR: 451000-3020000). In ESRD, an IVL < 600000 IU/mL was strongly associated with SVR: 24/28 (85.7%) patients who achieved SVR had viraemia below this threshold.
Haemodialysis decreases the viral load, especially in IL28B CC genotype carriers. A low IVL was the strongest predictor of SVR in ESRD patients identified in multivariate analysis.
E. Kieslichova, M. Rocen, D. Merta, M. Kudla, I. Splichal, J. Cap, O. Viklicky and R. Gurlich:
The effect of immunosuppression on manifestations of sepsis in an animal model of cecal ligation and puncture
Transplant. Proc., 45(2):770-777, Mar 2013
The diagnosis of sepsis is difficult in immunocompromised patients owing to their modified response to infection. Our experiment in minipigs was designed to compare responses to sepsis between experimental groups of septic minipigs with and without immunosuppression.
Minipigs with identical baseline parameters were randomized into 3 groups: Sepsis (n = 10); immunosuppression (n = 11), including cyclosporine, methylprednisolone, and mycophenolate mofetil treatment before surgery, and a sham group (n = 6). Sepsis was induced by cecal ligation and puncture (CLP). We recorded selected clinical and laboratory parameters up to 24 hours postoperatively.
All CLP animals developed septic shock with a febrile response, tachycardia, and hypotension requiring noradrenaline administration. The hemodynamic responses to sepsis in septic groups with and without immunosuppression were similar. Noradrenaline infusion was started on average later in the immunosuppression than in the group without immunosuppression; however, the difference was not significant. The kinetics of the plasma levels of most selected cytokines and C-reactive protein were similar in both septic groups. At 10 hours after surgery, the immunosuppression group showed significantly lower interleukin (IL)-6 levels compared with the sepsis group. At 19, 22, and 25 hours after surgery immunosuppressed animals displayed significantly greater increases in IL-10 levels compared with the cohort without immunosuppression.
CLP is a simple, reproducible model of sepsis in minipigs. All CLP animals developed sepsis within 24 hours on average. Significant differences in IL-6 and IL-10 plasma levels were recorded between septic animals with versus without immunosuppression.
R. Gurlich, E. Kieslichova, D. Merta, M. Kudla, J. Cap, I. Splichal, J. Maluskova and M. Rocen:
[Caecal ligation and puncture in the minipig - a model of sepsis induction]
Cas. Lek. Cesk., 151(5):248-253, 2012
Sepsis belongs among the most serious conditions and animal models of sepsis are the basic tools to investigate the pathophysiological response to this condition.
A total of 16 adult minipigs with identical baseline parameters were randomized into two groups. In the sepsis group (n = 10), sepsis was induced using caecal ligation and puncture (CLP). The control group (n = 6) underwent laparotomy without CLP. Selected clinical and laboratory parameters as well as histological findings between the sepsis and control group were subsequently compared.
All animals undergoing CLP developed diffuse peritonitis and sepsis. Compared to the control group, experimental animals showed significant increase of body temperature and heart rate (while) requiring noradrenaline to maintain their perfusion pressure. No significant differences in the monitored biochemical parameters (including C-reactive protein levels) between the two groups were found. Histological findings in organs of experimental animals were consistent with changes of organs seen in sepsis, i.e., centrilobular liver necroses, acute tubular renal necrosis, serous fibrinopurulent exudate, myocardial malacias, and pulmonary edema.
Experimental caecal ligation with a predefined size of the perforation in the intestinal wall is a suitable model for assessing the pathophysiological changes occurring in the body in sepsis.
M. Rocen, E. Kieslichova, D. Merta, E. Uchytilova, Y. Pavlova, J. Cap and P. Trunecka
The effect of Prometheus device on laboratory markers of inflammation and tissue regeneration in acute liver failure management
Transplant. Proc., 42(9):3606-3611, Nov 2010
Prometheus, based on modified fractionated plasma separation and adsorption (FPSA) method, is used in the therapy of acute liver failure as a bridge to liver transplantation. As the therapeutic effect of Prometheus is caused not only by the elimination of terminal metabolites, the aim of the study was to identify the effect of FPSA on the levels of cytokines and markers of inflammation and liver regeneration. Previous studies assessing cytokine levels involved mostly acute-on-chronic liver failure patients. Data concerning markers of inflammation and liver regeneration are not published yet. Eleven patients (three males, eight females) with acute liver failure were investigated. These patients underwent 37 therapeutic sessions on Prometheus device. Before and after each treatment, the plasma levels of selected cytokines, tumor necrosis factor alpha (TNFα), C-reactive protein (CRP), procalcitonin (PCT), hepatocyte growth factor (HGF), and α(1) fetoprotein, were measured, and the kinetics of their plasma concentrations was evaluated. Before the therapy, elevated levels of interleukin (IL)-6, IL-8, IL-10, TNFα, CRP, and PCT were detected. The level of TNFα, CRP, PCT, and α(1) fetoprotein decreased significantly during the therapy. In contrast, an increase of HGF was detected. The decline of IL-6, IL-8, and IL-10 concentrations was not significant. Our results show that Prometheus is highly effective in clearing inflammatory mediators responsible for systemic inflammatory response syndrome and affects the serum levels of inflammatory and regeneration markers important for management of acute liver failure.
E. Kieslichova, O. Schuck, I. Smrckova, J. Granatova, J. Skibova, D. Merta and P. Trunecka:
[Liver transplantation and peri-operative changes to renal function]
Vnitr Lek, 55(12):1126-1134, Dec 2009
Was to analyze in detail perioperative changes of renal function during orthotopic liver transplantation (OLT) and to identify risk factors, that were associated with the need of renal replacement therapy (RRT) during the first week after liver transplantation.
Prospective study of 50 consecutive patients undergoing OLT was performed. Selected laboratory and clinical parameters were monitored prior to the procedure, after reperfusion, at the end of the procedure, and at 12 hours after the procedure. In the first post-transplant week, necessity to use RRT in the presence of acute kidney injury was monitored and the analysis of risk factors for the need for RRT was performed. Patient survival, graft function, need for dialysis and selected laboratory parameters were assessed at one year post-transplant.
During OLT, there was an increase in S(cr) and S(urea), which persisted as late as 12 hours post-transplant. There was a decrease in U(cr) and U(urea) and an increase in S(Na) and S(K). During the procedure any increase in S(cyst) were observed, increase the values were recorded 12 hours after surgery. S(bili) level decreased. There was a rise in the urinary levels of total protein, albumin and beta2-microglobulin. U(prot)/U(cr) increased significantly after reperfusion, with a peak after the procedure. At 12 hours after the procedure, there was a decrease in U(prot)/U(cr), but the values were still many times higher than those seen preoperatively. RRTwas necessary in 14% cases. Risk factors for acute kidney injury requiring RRT included a higher APACHE score, higher BMI, higher preoperative S(cr) and S(urea), hepatorenal syndrome pretransplant, blood loss and intraoperative hemodynamic instability, postoperative complications and dysfunction of the liver graft. One year after OLT, there was no difference in followed laboratory values between patients requiring postoperative RRT and others; no patient was treated with dialysis.
OLT has a major impact on glomerular and tubular renal functions. Our data suggest that patients surviving acute renal injury treated with RRT in the early postoperative period have a high chance of restoring renal function. A sensitive marker of renal injury during OLT seems to be perioperative proteinuria.