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Cytomegalovirus infection after kidney transplantation
Reischig, Tomáš ; Třeška, Vladislav (advisor) ; Viklický, Ondřej (referee) ; Zadražil, Josef (referee) ; Pazdiora, Petr (referee)
1 SUMMARY Cytomegalovirus (CMV) disease is a common infectious complication in patients after solid organ transplantation. The last decade witnessed major advances in CMV disease prevention. Use of universal prophylaxis or preemptive therapy resulted in a decrease in the incidence of CMV disease from 20-60% to 5-20%. However, the efficacy of preventive approaches in terms of indirect effects of CMV occurrence is problematic. Association with allograft rejection belongs to well documented and clinically extremely important indirect effects of CMV with a prolonged adverse impact on graft survival. Potential mechanisms include overexpression of major histocompatibility complex molecules, growth factors and cytokines, and upregulation of adhesion molecules. A number of questions remain to be answered in evaluating CMV as a risk factor for acute rejection. While CMV disease is associated with an increased incidence of acute rejection, data regarding the role of asymptomatic CMV viremia are controversial. In our research we evaluated the role of CMV in pathogenesis of allograft rejection in the era of modern immunosuppression and CMV prophylaxis as well as optimal preventive strategy to minimize impact of CMV. In the first trial, renal transplant (RTx) recipients were followed prospectively for 12 months to...
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Oxidative and carbonyl stress in kidney diseases
Kratochvílová, Markéta ; Tesař, Vladimír (advisor) ; Průša, Richard (referee) ; Zadražil, Josef (referee)
Aims: 1. Determination of AGEs (Advanced Glycation End products) in patients with various types of nephropathy. 2. Association AGEs with nutritional parameters and anemia. 3. Influence of renal parameters on sRAGE (soluble form of Receptor for Advanced Glycation End products) levels. 4. Technics and proceeding methods of the podocytes cultivation. 5. Determination of urine podocytes. Methods: We determined fluorescent AGEs by spectrofluorometry, sRAGE by Enzyme-Linked ImmunoSorbent Assay (ELISA). Podocytes were passaged and identified immunocytochemically. Podocytes in urine were specified by flow cytometry method. Results: 1. We did not find significant differences in AGEs serum levels among various types of nephropathy, even though the pathogenesis differs. 2. The albumin and prealbumin levels positively and haemoglobin levels negatively correlate with AGEs in patients with CKD grade 1-5, without necessity of dialysis. 3. Serum sRAGE levels are increased in patients with decreased renal function independently on the course of renal disease. 4. We implemented the methods and technics of podocyte cultivation. 5. Urine podocytes observation and confirmation that podocyturia relates to disease activity. Conclusion: We confirmed that AGEs serum levels depend more on renal function than the type of...
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Prediction of graft function development and rejection of transplanted kidney
Wohlfahrtová, Mariana ; Viklický, Ondřej (advisor) ; Zadražil, Josef (referee) ; Reischig, Tomáš (referee)
Improving the short-term results of kidney transplantation did not result in improving the long-term function and survival of kidney allograft. Organ shortage and increasing number of marginal donors remains the key problem in transplant today. The quality of donor organ is critical for graft function development and survival. The aim is to improve understanding to ischemia/reperfusion injury and its consequences, predict delayed graft function and rejection, improve organ allocation strategy and identify patients suitable for safe drug minimization or complete withdrawal of immunosuppressive therapy. Analysis of donor kidneys identified poor tubular cell quality and low survival factor, Netrin-1 expression levels, to be associated with delayed graft function. We confirmed that reperfusion phase of ischemia/reperfusion injury leads to minimal morphological but significant molecular abnormalities. Dissociation observed in histology and molecular pathology finding calls for an integrated approach in donor quality organ evaluation and allocation for transplantation. Significant heterogeneity within donors with expanded criteria was shown and subgroup of organs at low risk of delayed graft function was identified. We suggested donor biopsies to be performed as a routine praxis in all kidneys...
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Relationship between pH and strong ion difference (SID) in predialysis patients with chronic kidney disease and in patients on chronic haemodialysis
Havlín, Jan ; Matoušovic, Karel (advisor) ; Žabka, Jiří (referee) ; Zadražil, Josef (referee)
SUMMARY: Metabolic acidosis (MAC) is a constant symptom of chronic kidney diesease (CKD) in advanced stages. The Siggaard-Andersen analysis is a traditional method of acid-base balance (ABB) assessment, assessing the metabolic component by means of the base excess and the anion gap (AG). Modern methods of ABB assessment draw upon the theory proposed by Stewart, which is based on the electric neutrality principle. Stewart distinguishes three independent variables determining plasmatic pH: pCO2, strong ion difference (SID) and 3) the total charge of non-volatile weak acids [Atot-]. The aim of this study was to assess the relationship between pH and plasma ion changes associated with ABB disorders in patients with chronic kidney disease using both methods of analysis, and subsequently compare both approaches. The cohort of patients consisted of three groups: 1) the "CKD" group, 60 patients with CKD stage 3 to 4 according to the KDOQI; 2) the "HD" group, 68 patients on chronic hemodiafiltration using dialysate bicarbonate concentration of 32 mmol/L; 3) a control group, 19 healthy volunteers. In all patients we measured parameters necessary for both approaches, in the HD group before and after dialysis treatment. We have found that MAC was present in two thirds of patients in the CKD group. A decrease of...
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Oxidative and carbonyl stress in kidney diseases
Kratochvílová, Markéta ; Tesař, Vladimír (advisor) ; Průša, Richard (referee) ; Zadražil, Josef (referee)
Aims: 1. Determination of AGEs (Advanced Glycation End products) in patients with various types of nephropathy. 2. Association AGEs with nutritional parameters and anemia. 3. Influence of renal parameters on sRAGE (soluble form of Receptor for Advanced Glycation End products) levels. 4. Technics and proceeding methods of the podocytes cultivation. 5. Determination of urine podocytes. Methods: We determined fluorescent AGEs by spectrofluorometry, sRAGE by Enzyme-Linked ImmunoSorbent Assay (ELISA). Podocytes were passaged and identified immunocytochemically. Podocytes in urine were specified by flow cytometry method. Results: 1. We did not find significant differences in AGEs serum levels among various types of nephropathy, even though the pathogenesis differs. 2. The albumin and prealbumin levels positively and haemoglobin levels negatively correlate with AGEs in patients with CKD grade 1-5, without necessity of dialysis. 3. Serum sRAGE levels are increased in patients with decreased renal function independently on the course of renal disease. 4. We implemented the methods and technics of podocyte cultivation. 5. Urine podocytes observation and confirmation that podocyturia relates to disease activity. Conclusion: We confirmed that AGEs serum levels depend more on renal function than the type of...
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Prediction of graft function development and rejection of transplanted kidney
Wohlfahrtová, Mariana ; Viklický, Ondřej (advisor) ; Zadražil, Josef (referee) ; Reischig, Tomáš (referee)
Improving the short-term results of kidney transplantation did not result in improving the long-term function and survival of kidney allograft. Organ shortage and increasing number of marginal donors remains the key problem in transplant today. The quality of donor organ is critical for graft function development and survival. The aim is to improve understanding to ischemia/reperfusion injury and its consequences, predict delayed graft function and rejection, improve organ allocation strategy and identify patients suitable for safe drug minimization or complete withdrawal of immunosuppressive therapy. Analysis of donor kidneys identified poor tubular cell quality and low survival factor, Netrin-1 expression levels, to be associated with delayed graft function. We confirmed that reperfusion phase of ischemia/reperfusion injury leads to minimal morphological but significant molecular abnormalities. Dissociation observed in histology and molecular pathology finding calls for an integrated approach in donor quality organ evaluation and allocation for transplantation. Significant heterogeneity within donors with expanded criteria was shown and subgroup of organs at low risk of delayed graft function was identified. We suggested donor biopsies to be performed as a routine praxis in all kidneys...
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Selected candidate genes variants with respect to the renal transplantation outcomes
Bandúr, Štěpán ; Viklický, Ondřej (advisor) ; Zadražil, Josef (referee) ; Reischig, Tomáš (referee)
6 Abstract: Renal transplantation outcomes might be influenced by genetic determinants, genes encoding structural and regulatory proteins involved in respective pathophysiological and immunological pathways. CYP3A4/CYP3A5 and ABCB1/MDR1 genes encoding cytochrome P450IIIA and P-glycoprotein, proteins determining bioavailability of immunosuppressants- calcineurin inhibitors and mTOR inhibitors, play important role. Polymorphisms in these genes have been suggested to influence immunosuppressants pharmacokinetics and renal transplant outcomes. The association of CYP3A4 -288A>G, CYP3A5 +6986G>A, ABCB1/MDR1 +1236C>T, +2677G>T>A and +3435C>T polymorphisms with clinical and laboratory endpoints was assessed by using haplotype analysis approach in 1016 patients. Except of HLA-DR mismatch, delayed graft function and kidney graft donor age, [ABCB1/MDR1+1236C;+2677G;+3435T] haplotype was independent predictor of acute rejection, but did not influence kidney graft survival. Homozygotes for the [CYP3A4- 288A;CYP3A5+6986G] haplotype had higher bioavailability of tacrolimus at week one. ABCB1/MDR1 haplotypes did not influence pharmacokinetics, but modified the risk of acute rejection, suggesting that allelic arrangement of the genetic loci was a stronger regulator of P- glycoprotein activity than single polymorphisms....
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Molecular factors of artherogenesis in chronic kidney disease with experimental model of chronic inhibition of Nitric Oxide Synthesis and its Effect of HMG-CoA reductase inhibitoin
Lecian, Dalibor ; Matouš, Bohuslav (advisor) ; Tesař, Vladimír (referee) ; Zadražil, Josef (referee)
The experimental part of the thesis covered the markers involved in nitric oxide deficiency model in rats. The analogue of arginine N-nitro- L -arginine-methyl ester ( L -NAME) was used. L -NAME administration resulted in sustained elevation of BP, decreased GFR, and in higher albuminuria compared to control animals. The administration of hypolipidemic drug - atorvastatin to Wistar rats was studied. The statin used caused lower albuminuria and prevented decreases in GFR in L -NAME rats without having an impact on hypertension. CAV1 protein expression was similar in all groups of rats. In contrast, VEGF expression and RhoA activity was increased in L -NAME-treated animals, and normalized with coadministration of atorvastatin. Clinical part of the thesis focused on the analysis of markers of oxidative stress in obese and non-obese patients with CKD and after kidney transplantation. The patients with CKD had elevated serum concentrations of AGEs, sRAGE and ADMA with the maximal concentrations of AGEs in the patients on hemodialysis. The successful kidney transplantation decreases the AGEs, sRAGE and ADMA concentrations but not to normal value according to general population. Patients with obesity exhibited lower concentrations of sRAGE in CKD as a protective factor for cardiovascular disease. Concentrations of...
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Cytomegalovirus infection after kidney transplantation
Reischig, Tomáš ; Třeška, Vladislav (advisor) ; Viklický, Ondřej (referee) ; Zadražil, Josef (referee) ; Pazdiora, Petr (referee)
1 SUMMARY Cytomegalovirus (CMV) disease is a common infectious complication in patients after solid organ transplantation. The last decade witnessed major advances in CMV disease prevention. Use of universal prophylaxis or preemptive therapy resulted in a decrease in the incidence of CMV disease from 20-60% to 5-20%. However, the efficacy of preventive approaches in terms of indirect effects of CMV occurrence is problematic. Association with allograft rejection belongs to well documented and clinically extremely important indirect effects of CMV with a prolonged adverse impact on graft survival. Potential mechanisms include overexpression of major histocompatibility complex molecules, growth factors and cytokines, and upregulation of adhesion molecules. A number of questions remain to be answered in evaluating CMV as a risk factor for acute rejection. While CMV disease is associated with an increased incidence of acute rejection, data regarding the role of asymptomatic CMV viremia are controversial. In our research we evaluated the role of CMV in pathogenesis of allograft rejection in the era of modern immunosuppression and CMV prophylaxis as well as optimal preventive strategy to minimize impact of CMV. In the first trial, renal transplant (RTx) recipients were followed prospectively for 12 months to...
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