Multi-drug resistant strains as etiological agents of urinary tract infections in patients after solid organ transplantation.

Introduction: Urinary tract infections (UTIs) caused by multi-drug resistant strains are a serious and growing problem in organ transplant (TX) recipients. Aim of the study: The aim of the study was to assess the prevalence and risk factors of UTIs caused by multi-drug resistant strains in hospitalized patients after kidney or liver transplantation in a large transplant center. Material and methods: 392 cases of UTIs in patients after kidney or liver TX hospitalized in 2014, 2015 and 2016 were analyzed. Among the assessed cases of UTIs, 66.07% occurred in women, 33.93% - in men, 80.1% - in kidney TX recipients and 19.9% - in liver TX recipients. The median age of the patients was 57.51 years and the median time since TX was 41.44 months. Results: Most episodes of UTIs were observed during the first year after TX - 121 (30.78%) of cases. A total of 506 pathogens were cultured: 345 Gram-negative bacteria (68.182%), 146 Gram-positive bacteria (28.854%) and 15 fungi (2.964%). More than one pathogen was found in 25.51% of urine cultures. Among bacteria (n=491), a resistance mechanism was detected in 166 (33.81%) pathogens (133 Gram-negative and 33 Gram-positive). The most common etiological agents were: E. coli ESBL- (23.72%), K. pneumoniae ESBL+ (17.19%), E. faecalis (11.27%) and E. faecium (7.71%). Diabetes was present in 129 (35.46%) of patients, and the number of UTI cases was similar in the group with and without diabetes. Conclusions: Compared to the general population, in hospitalized patients after kidney or liver transplantation UTIs occur more often in men and are more often caused by Gram-positive bacteria. In 33.81% of cases UTIs are caused by multi-drug resistant strains, predominantly Gram-negative bacteria.

Breaking Antimicrobial Resistance: High-Dose Amoxicillin with Clavulanic Acid for Urinary Tract Infections Due to Extended-Spectrum Beta-Lactamase (ESBL)-Producing Klebsiella pneumoniae.

BACKGROUND Carbapenems are the primary treatment for urinary tract infections (UTIs) caused by extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae. However, the recurrence rate is high, and patients often require rehospitalization. We present the results of an observational study on patients with recurrent UTIs who were treated in an outpatient setting with maximal therapeutic oral doses of amoxicillin with clavulanic acid. MATERIAL AND METHODS All patients had pyuria and ESBL-producing K. pneumoniae in urine culture. The starting dosage was 2875 g of amoxicillin twice daily and 125 mg of clavulanic acid twice daily. We down-titrated the doses every 7-14 days and continued prophylactic therapy with amoxicillin/clavulanic acid at 250/125 mg for up to 3 months. We defined therapeutic failure as ESBL-positive K. pneumoniae in urine culture during therapy and recurrence as positive urine culture with the same strain within 1 month after the end of treatment. RESULTS We included 9 patients: 7 kidney graft recipients, 1 liver graft recipient, and 1 patient with chronic kidney disease. We observed no therapeutic failures and no recurrences in the study group during the study period. In 1 case, the patient experienced a subsequent UTI caused by ESBL-producing K. pneumoniae 4 months after completing the therapy. CONCLUSIONS In conclusion, it is possible to break the resistance of ESBL-producing K. pneumoniae strains with high doses of oral amoxicillin with clavulanic acid. Such treatment could be an alternative to carbapenems in select cases.

Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) with a New Pathogenic Variant in TNFRSF1A Gene in a Family of the Adult Male with Renal AA Amyloidosis-Diagnostic and Therapeutic Challenge for Clinicians.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) belongs to systemic autoinflammatory diseases (AIDs). Many of these syndromes are genetically conditioned and can be inherited. Diagnosis relies on clinical symptoms and should be confirmed by genetic testing. One of the most serious complications is AA amyloidosis. We present the diagnostic route of a 33-year-old male with AA amyloidosis and his children, leading to diagnosis of monogenic autoinflammatory syndrome, confirmed by genetic analysis. A novel variant of the in-frame insertion type in one allele of TNFRSF1A gene was found by whole exome sequencing and confirmed by Sanger sequencing, which allowed a diagnosis of TRAPS. Three-dimensional modeling was used to assess the structural changes introduced into TNFR1 molecule by the insertion. The analysis of the 3D model revealed that accommodation of the 4AA insert induces misalignment of three cysteine bridges (especially the C70-C96 bridge) in the extracellular domain, leading to putatively misfolded and improperly functioning TNFR1. Three of the patient's daughters inherited the same variant of the TNFRSF1A gene and presented TRAPS symptoms. TRAPS is a very rare disease, but in the presence of suggestive symptoms the genetic diagnostic workout should be undertaken. Early diagnosis followed by appropriate clinical management can prevent irreversible complications.

Higher Concentrations of Cyclosporine Metabolites in Liver Transplant Recipients With a History of Viral and Bacterial Infections.

BACKGROUND: Infection remains a serious clinical problem in liver transplant (LTX) recipients. A higher risk of infection is connected with immunosuppression therapy. The aim of the study was to assess the relationships between infections' incidence and concentrations of cyclosporine (CsA) metabolites after LTX. METHODS: Forty-three liver transplant recipients receiving CsA were included in the study. With the use of liquid chromatography combined with tandem mass spectrometry, concentrations of CsA and its metabolites were measured: dihydroxylated cyclosporine metabolites (DiHCsA), trihydroxylated cyclosporine metabolites (TriHCsA), demethylcarboxylated cyclosporine metabolites (DemCarbCsA), AM1, AM9, and AM4N. The study protocol conformed with the Declaration of Helsinki. RESULTS: Patients with a history of Epstein-Barr virus (EBV) infection had higher DiHCsA, TriHCsA, DemCarbCsA, AM1/CsA, DiHCsA/CsA, TriHCsA/CsA i DemCarbCsA/CsA in comparison with group without such infection (P = .049, P = .037, P = .006, P = .018, P = .005, P = .027, and P = .026, respectively). LTX recipients with a history of all viral infections had higher DiHCsA, TriHCsA, DiHCsA/CsA, TriHCsA/CsA than patients without viral infections (P = .013, P = .021, P = .013, and P = .048, respectively). Multivariable analysis showed that AM1, DiHCsA, TriHCsA, DemCarbCsA, AM4N/CsA had positively influence on the incidence of all viral infections (ß = 0.0302, P = .0328; ß = 0.0699, P = .0453; ß = 0.6781, P = .0382; ß = 0.6767, P = .0414; and ß = 0.8307, P = .0267, respectively). In multivariable analysis, patients with a history of all bacterial infections had higher AM1 and higher AM1/CsA in comparison with LTX recipients without such infections (ß = 0.0118, P = .0279; and ß = 0.0099, P = .036, respectively). CONCLUSION: In liver transplant recipients with a history of viral or bacterial infections higher concentrations of CsA metabolites were found. Possibly CsA metabolites could be used to assess the risk of infection in patients after liver transplantation. It should be confirmed in further investigations.

Shear Wave Elastography Performance in Noninvasive Assessment of Liver Cirrhosis in Liver Transplant Recipients With the Recurrence of Hepatitis C Infection.

BACKGROUND: The recurrence of hepatitis C (HCV) after liver transplant (LTX) leads to graft fibrosis and cirrhosis. Liver biopsy remains the criterion standard for their diagnosis and monitoring. Our objective was evaluation of shear wave elastography (SWE) in patients with HCV recurrence after LTX and its comparison with histopathologic fibrosis assessment scoring systems. METHODS: A total of 101 LTX recipients with HCV recurrence (42 women [41.6%] and 59 men [58.4%]) were evaluated by graft biopsy specimens (Ishak, Scheurer, and meta-analysis of histologic data in viral hepatitis [Metavir] score) and SWE (liver stiffness). Median age of patients was 59.4 years; median time from LTX was 84.9 months. The study protocol conforms with the Declaration of Helsinki. RESULTS: Median liver stiffness was 21.3 kPa. To differentiate between liver fibrosis and cirrhosis, patients were divided into 2 subgroups: Ishak score fibrosis (1-4 [85.2%]) and cirrhosis (5-6 [13.9%]); Scheurer score fibrosis (0-3 [85.2%]) and cirrhosis (4 [12.9%]); Metavir score fibrosis (0-3 [85.2%]) and cirrhosis (4 [14.9%]). We have observed statistically significant differences between liver fibrosis and liver cirrhosis groups defined on the basis of Ishak, Scheurer, and Metavir scoring systems: 20.8 kPa vs 29.6 kPa (P = .001), 20.7 kPa vs 30.3 kPa (P = .0005), and 20.7 kPa vs 28.8 kPa (P = .002), respectively. CONCLUSIONS: Our results indicate that SWE may be useful in differentiating patients with advanced cirrhosis from those with fibrosis and may be helpful in the noninvasive diagnosis and monitoring of HCV recurrence after LTX.

Hepatocellular Carcinoma Is a Negative Predictor of Sustained Viral Response in Liver Transplant Recipients With Hepatitis C Treated With Direct-Acting Antivirals.

INTRODUCTION: Treatment with direct-acting antivirals (DAA) for hepatitis C (HCV) in liver transplant (LTX) recipients is very effective, but some studies showed that the treatment effectiveness might be impaired in patients with hepatocellular carcinoma (HCC). The study aimed to evaluate the predictors of DAA treatment failure in LTX recipients. METHODS: Liver biopsy was done before the treatment in 107 of the 120 patients included. All patients had an abdominal ultrasound and liver elastography performed before and after the therapy. Blood HCV polymerase chain reaction was done before; during; and at 4, 12, and 24 weeks after the treatment. RESULTS: Overall sustained viral response 24 weeks after treatment (SVR24) was 96%. There were 2 patients with HCC at the start of the DAA treatment and 3 cases of HCC recurrence during a 1-year follow-up. Treatment failure was observed in 1/115 (0.9%) patients without HCC and 4/5 (80%) with active HCC (P = .0001). Liver fibrosis and previous interferon treatment had no impact on treatment efficacy. Time to viremia elimination on treatment was shorter in the responder versus nonresponder group (28 vs 58 days, P = .03). CONCLUSIONS: HCC is a negative predictor of DAA therapy success in LTX recipients.

Long-Term Follow-up of Liver Transplant Recipients Treated With Direct-Acting Antiviral Agents for Hepatitis C Recurrence After Transplantation.

BACKGROUND: Treatment of hepatitis C virus (HCV) recurrence after liver transplantation (LTX) with direct-acting antiviral agents (DAA) is effective and leads to sustained viral response (SVR) in most cases. Long-term effect of HCV elimination on LTX function is not clear. The aim of the study was to evaluate the long-term influence of DAA with HCV on the liver function in LTX recipients. METHODS: The study included 120 LTX patients with HCV recurrence. Before starting DAA therapy, all patients underwent liver biopsy and elastography. Biochemical tests and HCV viremia were assessed at baseline, 4, 12, and 24 weeks and 24 months after the end of treatment (EOT). The study protocol conformed with the Declaration of Helsinki. RESULTS: In the HCV genotype 1 (G1) group, 106 patients were treated with ledipasvir/sofosbuvir with ribavirin (RBV), and 3 patients received paritaprevir/ritonavir/ombitasvir/dasabuvir/RBV. All HCV genotype 3 (G3) patients were treated with sofosbuvir/RBV; all HCV genotype 4 (G4) patients were treated with paritaprevir/ombitasvir/RBV. The efficacy of the treatment defined as SVR at week 12 after EOT (SVR12) was 97.3% in G1 group, 75% in G3, and 100% in G4 group. Median alanine (ALT) and aspartate (AST) transaminase before therapy were 44.0 IU/mL and 42.5 IU/mL, respectively. Median ALT and AST at 24 months after EOT were 17 IU/mL and 22 IU/mL, respectively. The lack of transaminases normalization was observed in 10 patients 24 months after EOT. CONCLUSION: The efficacy of DAA therapy of HCV recurrence after LTX is as high as that reported in randomized clinical trials. It is also associated with the improvement of liver function tests during long-term follow-up.

Platelets level variability during the first year after liver transplantation in the risk prediction model for recipients mortality.

INTRODUCTION AND OBJECTIVES: Many scoring systems in liver diseases use static values of liver function parameters. These parameters may change significantly in liver transplant (LTx) recipients over time due to various processes. The study was aimed at building a new model for survival prediction after LTx based on variability of selected parameters. MATERIALS AND METHODS: The study included 450 LTx recipients who survived a minimum one year after transplantation. We analyzed liver enzymes and hematology parameters static values and their variability during the first year after transplantation. Modeling patients' survival was performed using Cox regression. Various sets of parameters (both static and variability and trends values) were tested to predict survival in our study group. Models' performance was measured using the concordance index. RESULTS: The single predictors of the patients survival were the static values of AST with C-index 0.706 (0.5883-0.7494), ALT 0.6102 (0.4843-0.6857) and bilirubin 0.6224 (0.5537-0.6695). High prediction scores were observed for variability in creatinine 0.6023 (0.5409-0.6451), PLT 0.6350 (0.5491-0.7043), RBC 0.5689 (0.5065-0.6213) and WBC 0.6506 (0.5095-0.7124). Our best-fitted and proposed model for patients survival after LTx has C-index 0.8273 (IQR 0.7767-0.8649). The model uses the following indicators for mortality prediction: the static value of AST, variability measure of PLT and trend measures of WBC and PLT. CONCLUSIONS: Adding variability and trend measures increases predictive accuracy in modeling patients survival after LTx. We propose a high-accuracy survival model in which variability and trend of PLT measures in the first year after transplantation are strong predictors of long-term mortality.

Lack of Relationship Between Renal Function and Genetic Variants of CYP3A4, CYP3A5, MDR1, MRP2, UGT1A9, UGT1A8, and UGT2B7 in Patients After Liver Transplantation in a 2-Year Follow-up.

BACKGROUND: The prolonged survival time after liver transplantation (LTX) creates the possibility of the occurrence and development of complications in the late post-transplantation period. Deterioration of renal function is 1 of these complications. The nephrotoxicity of calcineurin inhibitors (CNIs) and their metabolites produced during pharmacokinetic processes in the body is also postulated. The study was aimed at assessment of the relationship between selected single gene polymorphisms (SNPs) for enzymes and transport proteins and change of estimated glomerular filtration rate (ΔeGFR) during 2-year follow-up in LTX patients. METHODS: The study involved 244 patients after LTX (105 women [43.0%] and 139 men [57.0%]) receiving tacrolimus (191; 78.3%) or cyclosporine A (53; 21.7%). The study protocol conforms with the Declaration of Helsinki. RESULTS: We have not observed significant differences of ΔeGFR between groups distinguished based on analyzed genotypes in patients treated with cyclosporine or tacrolimus. CONCLUSION: Genetic variations of CYP3A4, CYP3A5, MDR1, MRP2, UGT1A9, UGT2B7, and UGT2B7 tested in LTX recipients are not associated with kidney function during the 24-month follow-up.

Worsening of Kidney Transplant Function During 2-Year Follow-up Is Associated With the Genetic Variants of CYP3A4, MDR1, and UGT1A9.

BACKGROUND: Calcineurin inhibitors (CNIs), tacrolimus and cyclosporine, undergo pharmacokinetic processes. Enzymes and transport proteins found in various organs are involved. It is possible that genetic polymorphisms of these proteins influence CNIs pharmacokinetics and the generation of CNIs metabolites. CNIs may be nephrotoxic, and it is thought that some CNIs' metabolites may have a similar effect. The study was aimed at the assessment of the relationship between selected gene polymorphisms for enzymes and transport proteins and change of estimated glomerular filtration rate (eGFR) during a 2-year follow-up in kidney transplant (KTX) patients. METHODS: The study involved 366 patients after KTX (160 women; 43.7%) receiving tacrolimus (62.57%) and cyclosporine (37.43%). The mean age was 50.1 years, and the median time after KTX was 60.5 months. The study protocol conformed with the Declaration of Helsinki. The percent of difference between eGFR at baseline and at 24 months (ΔeGFR) was calculated. We evaluated selected genetic polymorphisms of CYP3A4, CYP3A5, MDR1, UGT1A9, UGT2B7, UGT1A8, and MRP2. RESULTS: In the tacrolimus group, there were no significant differences of ΔeGFR between groups distinguished based on analyzed genotypes. In the cyclosporine group, differences were found for CYP3A4∗22 C/C -12.3 (-26.8 to -1.8) versus C/T 13.2 (12.4 to 13.9), P = .034; MDR1 3435C>T C/T -18.2 (-31.5 to -5.7) versus C/C -1.8 (-17.1 to 6.9) vs T/T -8.1 (-18.4 to 12.4), P = .031; and UGT1A9 2152C>T C/C -9.0 (-25.5 to 2.8) versus C/T -26.8 (-31.9 to -24.1), P = .017. CONCLUSION: The study results suggest that in KTX metabolic transformations and transport, especially of cyclosporine, dependence on the genetic variability of CYP3A4, UGT1A9, and MDR1 may contribute to kidney damage.

Dose-adjusted and dose/kg-adjusted concentrations of mycophenolic acid precursors reflect metabolic ratios of their metabolites in contrast with tacrolimus and cyclosporine.

BACKGROUND AND PURPOSE: Therapeutic drug monitoring is a valuable tool supporting immunosuppressive therapy. Significant variation of immunosuppressive drug (ISD) concentrations during their use at similar doses is the basis of dose-normalization strategy. The strategy of dose-adjustment is proposed to identify variability in the rate of ISD metabolism. While the parent drug-to-metabolite ratio (metabolic ratio, MR) represents the rate of formation of individual metabolites. The present study was aimed at evaluation of associations between ISDs' metabolism rate expressed as dose-adjusted concentrations (C/D) and dose/kg-adjusted concentrations (C/D/kg) and MRs of individual metabolites of tacrolimus, cyclosporine A and MPA precursors. EXPERIMENTAL APPROACH: 506 patients have participated: 284 males (56.13%) and 222 females (43.87%); 318 after kidney (62.85%) and 188 after liver transplantation; median age was 51.34 (39.32-59.95) years and median time after transplantation 78.92 (33.87-138.4) months. KEY RESULTS: Generally, we have not observed significant relationships between dose-adjusted and dose/kg-adjusted concentrations and MRs of cyclosporine and tacrolimus. Significant correlations were found for: AM9/CsA and dMC-CsA/CsA in kidney transplant recipients and MIII/Tac, AM1/CsA and AM4N/CsA in liver transplant recipients. In contrast, MRs of mycophenolic acid (MPA) metabolites correlated significantly with MPA C/D and C/D/kg both in kidney and liver transplant recipients. CONCLUSION AND IMPLICATIONS: In conclusion, easily available and easy to use in clinical practice C/D and C/D/kg ratios cannot be considered as parameters directly reflecting the rate of generation of major metabolites of cyclosporine and tacrolimus both in liver and kidney transplant recipients.

Cyclosporine Metabolites' Metabolic Ratios May Be Markers of Cardiovascular Disease in Kidney Transplant Recipients Treated with Cyclosporine A-Based Immunosuppression Regimens.

Cardiovascular disease (CVD) remains one of the primary causes of death after kidney transplantation (KTX). Cyclosporine (CsA) metabolites may play a role in CVD. Metabolic ratio (MR) may be considered a measure of intra-individual differences of CsA metabolism. The study was aimed at analysis of associations of CVD with indices of CsA metabolism: MRs and dose-adjusted CsA concentrations (C/D and C/D/kg). The study was performed in the Department of Immunology, Transplant Medicine, and Internal Diseases of the Medical University of Warsaw and involved 102 KTX recipients. Whole blood concentrations of cyclosporine A, AM1, AM9, AM4N, demethylcarboxylated (dMC-CsA), dihydroxylated (DiH-CsA), trihydroxylated (TriH-CsA) cyclosporine metabolites were determined by liquid chromatography coupled with tandem mass spectrometry. Lower AM9/CsA were observed in diabetics. Patients with coronary disease and/or myocardial infarction had lower dMC-CsA/CsA and higher AM4N/CsA. Supraventricular arrhythmia (SVA) was associated with higher AM1/CsA and AM4N/CsA. Hypertriglyceridemia (hTG) was associated with lower AM9/CsA, higher C/D and C/D/kg. Decrease of AM9/CsA and AM4N and higher D/C were associated with overweight/obesity. Systolic blood pressure (BP) positively correlated with dMC-CsA/CsA and negatively with C/D/kg. Diastolic BP correlated positively with AM1/CsA, dMC-CsA/CsA, DiH-CsA/CsA and TriH-CsA/CsA. We have demonstrated the association of coronary disease/myocardial infarction, SVA, hTG, overweight/obesity and elevated arterial BP with higher MRs of AM1, AM4N, dMC-CsA, DiH-CsA and TriH-CsA, and lower MRs of AM9, which may indicate deleterious and favourable effects of individual CsA metabolites on cardiovascular system and suggest engagement of specific enzymatic pathways.

Low Transfer of Tacrolimus and Its Metabolites into Colostrum of Graft Recipient Mothers.

Currently, the majority of neonates born to organ recipient mothers on chronic immunosuppressive therapy are formula fed. However, over the past few years, evidence has grown, suggesting that breastfeeding might be possible and beneficial. We designed a study assessing the transfer of tacrolimus into the colostrum of posttransplant mothers. We assessed the amount of tacrolimus and its metabolites, M-1 and M-3, that would be ingested by the breastfed neonates. Concentrations of tacrolimus and its metabolites were measured in colostrum from 14 posttransplant mothers as well as in venous cord blood and venous blood of the neonates. Test material analysis was performed by liquid chromatography coupled with mass spectrometry (LC/MS). The amount of ingested formula was registered, which allowed for estimation of the amount of tacrolimus and its metabolites that would be ingested by breastfed infants. The mean amount of tacrolimus that would be ingested by the neonates in maternal milk was 151.4 ng/kg/24 h (standard deviation SD ± 74.39); metabolite M-1: 23.80 ng/kg/24 h (SD ± 14.53); and metabolite M-3: 13.25 ng/kg/24 h (SD ± 9.05). The peak level of tacrolimus and metabolite M-1 in colostrum was noted 8 h after an oral dose (3.219 ng/mL SD ± 2.22 and 0.56 ng/mL SD ± 0.60, respectively) and metabolite M-3 after 6 h (0.29 ng/mL SD ± 0.22). Low concentrations of tacrolimus and its metabolites, M-1 and M-3, in colostrum show that neonates will ingest trace amounts of the drug. Further studies are required to fully assess the safety of breastfeeding by posttransplant mothers.

Circadian and short-term blood pressure abnormalities after liver transplantation.

Liver transplantation remains the only therapeutic method in end-stage liver disease. Cardiovascular system diseases, including arterial hypertension, are considered one of the main risk factors increasing mortality in this population. The aim of the study was the evaluation of circadian blood pressure patterns in liver transplant recipients. In a group of 107 liver transplant recipients, a 24-hour ambulatory blood pressure monitoring (ABPM) was performed. The ABPM revealed arterial hypertension in 88.79% and unsatisfactory blood pressure (BP) control in 71.03% of the study participants. The abnormal circadian BP pattern was observed in 90.65% of liver recipients. The subgroup of patients with preserved BP circadian rhythm was characterized by higher standard deviation (SD) and coefficient of variation (CV) values for 24-hour systolic, diastolic and mean arterial blood pressure (SBP, DBP, and MAP). There were no such differences for other short-term blood pressure variability (ST BPV) parameters: SD and CV of day-time and night-time SBP, DBP and MAP values. Arterial hypertension and circadian BP abnormalities are present in a majority of liver transplant recipients. BP circadian rhythm is not associated with ST BPV parameters assessed separately during awake and sleep period which suggests that both groups of parameters could reflect different cardiovascular phenomena after liver transplantation.

Mycophenolic Acid Metabolites Acyl-Glucuronide and Glucoside Affect the Occurrence of Infectious Complications and Bone Marrow Dysfunction in Liver Transplant Recipients.

BACKGROUND Mycophenolic acid (MPA) prodrugs are anti-proliferative immunosuppressive agents commonly used after organ transplantation. Although they are generally well tolerated by patients, adverse effects may occur. It is postulated that MPA metabolites could also contribute to these adverse effects. MATERIAL AND METHODS The objective of this study was the assessment of concentrations of total MPA and its metabolites, phenyl glucuronide (MPAG), acyl glucuronide (AcMPAG) and glucoside (GluMPA), using liquid chromatography combined with mass spectrometry (LC/MS/MS) in two groups: kidney transplant recipients and liver transplant patients. Associations of MPA and its metabolites with adverse effects were analyzed. RESULTS The study group consisted of 211 recipients of liver or kidney transplants who received immunosuppressive therapy, including MPA prodrugs. Multivariant analysis showed a positive influence of MPA on gastroenterotoxicity in kidney transplant recipients. In liver patients, gastroenterotoxicity was associated with lower MPAG concentrations. A positive influence of AcMPAG on bacterial infections in liver transplant patients was observed. In liver transplant recipients, a positive influence of MPA and a negative influence of GluMPA levels on the PLT count were revealed. MPA and its metabolites did not influence the hemoglobin levels in both groups. There were no significant relationships among MPA, its metabolites and WBC counts. CONCLUSIONS In kidney transplant recipients, total MPA trough concentration is associated with gastroenterotoxicity and its monitoring could have important role in management of gastrointestinal complications. The quantification of AcMPAG in liver recipients receiving MPA may be helpful in avoiding bacterial infections. GluMPA seems to have a toxic effect on thrombopoiesis.

Liver Failure Impairs the Intrahepatic Elimination of Interleukin-6, Tumor Necrosis Factor-Alpha, Hepatocyte Growth Factor, and Transforming Growth Factor-Beta.

The strategic location of the liver and its metabolic activity make it a key organ regulating homeostasis. Our purpose was to examine its participation in removal of cytokines: interleukin-6 (Il-6), tumor necrosis factor-alpha (TNF-α), hepatocyte growth factor (HGF), and transforming growth factor-beta (TGF-ß) from the portal circulation in human. 20 liver donors and 20 patients with end-stage liver failure were included in the study. Their blood was collected during liver transplantation from the portal, hepatic, and peripheral vein, and the hepatic artery and cytokines' concentrations were determined. Using the results the mathematical model of cytokine elimination by the liver was developed. In donors significantly lower levels of IL-6, TNF-α, HGF, and TGF-ß were detected in portal blood compared to hepatic vein. In patients with cirrhosis there were no significant differences of IL-6, TNF-α, and TGF-ß levels between portal and hepatic veins. Significantly higher level of HGF in hepatic compared to portal vein was observed. In healthy liver elimination of the cytokines prevailed over their synthesis, as reflected by the positive values of the elimination ratios. In the cirrhotic liver elimination ratios of Il-6, HGF, and TGF-ß were negative indicating the prevalence of intrahepatic synthesis of cytokines over their removal.

[Hypertension in liver transplant recipients]. / Nadcisnienie tetnicze u pacjentów po przeszczepieniu watroby.

Arterial hypertension in liver transplant recipients is diagnosed in approximately 36-100% of cases. The development of arterial hypertension is considered to be the consequence not only of changes in cardiovascular system associated with liver transplantation but also of immunosuppressive treatment and complex physiopathological processes affecting the hormonal system and vascular endothelium. Introduction of ambulatory blood pressure monitoring (ABPM) in liver transplant recipients has contributed to enrichment of the amount of data available on blood pressure physiopathology and epidemiology in this population. In view of specific physiopathological mechanisms engaged in hypertension development, antihypertensive treatment in liver transplant recipients requires a special approach.

[Application of intravenous immunoglobulin preparations (IVIGs) in organ transplantation]. / Zastosowanie dozylnych przeciwcial poliwalentnych (IVIG) w przeszczepianiu narzadów.

In clinical setting intravenous immunoglobulin preparations (IVIGs) are used for over thirty years. They were used initially as a substitutive treatment. Discovering of IVIG immunosuppressive properties has led to its use in the treatment of autoimmune diseases. Since then the range of indications in this group of diseases is becoming wider. With regard to IVIG's multidirectional influence exerted on the immune system it has also find its application in transplantology. In the article IVIG's mechanism of action, possible applications in transplantation and adverse effects are discussed.