Development Of Graft Dysfunction Research Articles

A 5-year single-center experience in heart transplantation in Rostov oblast

Objective: to evaluate the outcomes of heart transplants performed at Rostov Regional Clinical Hospital within five years.Materials and methods. Between 2017 and 2022, 29 orthotopic heart transplants (HT) were performed in our clinic. Heart failure was caused by postinfarction cardiosclerosis (21 cases, 72.4%) and dilated cardiomyopathy (8 cases, 27.6%). Among the recipients, 27 (93.1%) were men and 2 (6.9%) were women. Mean age was 53.14 ± 8.7 years (34 to 67 years). All patients received quadruple-drug immunosuppressive therapy, including induction with monoclonal antibodies; calcineurin inhibitor, mycophenolic acid, and corticosteroid were used after HT.Results. In-hospital mortality was 10.34% (n = 3). The causes of death were multiple organ failure and infectious and septic complications. After discharge, 4 (13.8%) recipients died over 5 years. Rejection reaction with the development of graft dysfunction (3 recipients, 75%), infectious and septic complications (1 recipient, 25%) were the causes of death in the long-term period. The survival rate was analyzed according to the Kaplan–Meier estimate. One-year survival was 80.9%. Three-year survival rate corresponded to the 5-year survival rate – 70.56%. Five-year survival of patients surviving the first year after HT was 86.1%. Maximum follow-up period was 64 months.Conclusion. HT continues to be the gold standard for patients with end-stage heart failure. Five-year HT experience in our center has shown a survival rate that is comparable to that of the International Society for Heart and Lung Transplantation (ISHLT).

BK virus in kidney transplant recipients with graft dysfunction

ABSTRACT This study was to estimate the viral load of BK virus (BKV) in the urine and blood of Kidney transplant recipients (KTRs) with graft dysfunction and its effect on the development of graft dysfunction. This analysis included all KTR outpatients who visited the clinic at Urology and Nephrology Center during their routine follow-up visits from September 2017 to May 2019. A total of 100 patients were divided into 62 KTR patients with kidney dysfunction (case group) vs. 38 KTR patients without kidney dysfunction (control group). BKV DNA quantification in urine and plasma samples was examined in all patients by the real time PCR method. The BKV DNA was detected in the urine samples of 5 patients, all with kidney dysfunction (8%) vs. none in the control group. The BKV viral load of the 5 cases ranged from 105 to 244000 copies/ml. The BKV DNA was not detected in the blood samples of the 5 urine-positive cases. It was concluded that all patients with kidney dysfunction should be screened for BKV in their urine samples to prevent the development of BKV-caused nephropathy and further graft failure.

Biomarkers of tolerance and immunological monitoring in liver transplantation

Introduction. We reviewed the literature data on clinical and laboratory parameters that allow predicting the development of operational tolerance in liver transplant recipients after their complete weaning from immunosuppressive therapy. The aim was to identify possible biomarkers of tolerance in liver transplant recipients with the successful complete weaning from immunosuppression for subsequent implementation in routine clinical practice. The cellular, humoral, and molecular markers of the liver transplant recipients who were completely withdrawn from immunosuppressive therapy without the development of graft dysfunction were estimated. The authors underlined the necessity of clinical trials for identifying biomarkers of the operational tolerance development.

Immunosuppression Strategies in the Treatment of Hepatocellular Carcinoma in Virgen de las Nieves University Hospital

BackgroundWe describe an observational, retrospective study that included patients who underwent a liver transplantation (LT) for hepatocellular carcinoma (HCC) in our center between 2004 and 2012. MethodsClinical variables were recorded for donors and recipients as diagnosis and treatment, immunosuppressive therapy, toxicity, graft dysfunction, recurrence, and exitus. Fifty-eight patients were analyzed. The mean age was 57 ± 8 years. The viral etiology of HCC was 50% (n = 29), alcoholic 26% (n = 15), and others, 24% (n = 14). Regarding initial immunosuppressive strategy (IS), 51 patients (87.9%) were treated with standard regimen with corticosteroids (CS) and tacrolimus (TA), compared with 7 patients with impaired renal function (12.1%) who underwent a delayed therapy with calcineurin inhibitors (CNI) + mycophenolate mophetil (MMF) + CS. Concomitant use of anti-CD25 monoclonal antibodies was less than 10%. Regarding maintenance, 43 patients (74.1%) were treated with MMF + CNI versus 15 treated only with TA (25.9%). ResultsRecurrence of HCC was approximately 12%: 7 patients (2 hepatic only, 5 also extra-hepatic). Exitus was established in 19 patients (32.75%); only 3 patients (5.17%) were attributable to HCC. Bivariate studies were conducted according to the initial IS (standard regimen versus delayed therapy) and maintenance therapy (MMF + TA versus TA alone), with no differences in any of them in recurrence, treatment toxicity, graft rejection, and dysfunction. ConclusionsIn our experience with the IS, we found no differences in the development of recurrent disease, treatment toxicity, development of graft dysfunction, or rejection. We believe that individualized immunosuppressive therapy in these patients is safe and effective.

The hematopoietic stem cell number in the peripheral blood of pediatric recipients correlates with the outcome after living donor liver transplantation.

It has been proposed that circulating HSCs play a role in graft survival after liver transplantation. The aim was to analyze the relationship between the number of HSCs before and after LDLT and liver function, immune biomarkers, and clinical outcomes in pediatric patients. We studied 15 pairs of adult healthy liver donors and pediatric recipients with ESLD. The CD34/CD45+ cell number was measured in the blood via flow cytometry, and plasma levels of immune biomarkers - via ELISA. CD34/CD45+ cell number in the recipients decreased within the first week after LDLT. The cell number before LDLT was negatively correlated with the plasma levels of CRP and the development of graft dysfunction in the early post-transplant period. After LDLT, the CD34/CD45+ cell number was positively correlated with the pretransplant plasma level of sCD40L, a T-cell activation marker. In adult liver donors, the cell number did not change within the first week after liver resection and was lower than in pediatric recipients. The results suggest that in pediatric recipients, the HSC number may be associated with graft function and could be regarded as a potential predictor of the clinical outcome after LDLT.

Clinical Outcomes and Genetic Expression Profile in Human Liver Graft Dysfunction During Ischemia/Reperfusion Injury

IntroductionThis study aims to compare the molecular gene expression during ischemia reperfusion injury. Several surgical times were considered: in the beginning of the harvesting (T0), at the end of the cold ischemia period (T1), and after reperfusion (T2) and compared with graft dysfunction after liver transplant (OLT). MethodsWe studied 54 patients undergoing OLT. Clinical, laboratory data, and histologic data (Suzuki classification) as well as the Survival Outcomes Following Liver Transplantation (SOFT) score were used and compared with the molecular gene expression of the following genes: Interleukin (IL)-1b, IL-6, tumor necrosis factor-α, perforin, E-selectin (SELE), Fas-ligand, granzyme B, heme oxygenase-1, and nitric oxide synthetase. ResultsFifteen patients presented with graft dysfunction according to SOFT criteria. No relevant data were obtained by comparing the variables graft dysfunction and histologic variables. We observed a statistically significant relation between SELE at T0 (P = .013) and IL-1β at T0 (P = .028) and early graft dysfunction. ConclusionsWe conclude that several genetically determined proinflammatory expressions may play a critical role in the development of graft dysfunction after OLT.

TRANSFORMING GROWTH FACTOR 1 IN CHILDREN OF EARLY AGE WITH LIVER TRANSPLANTATION

Transforming growth factor β1 (TGF-β1) plays a key role in the development of the immune response, as well as in the process of liver regeneration. Measuring the level of TGF-β1 may have important clinical implications in liver transplantation, because cytokine concentration in the tissue and in blood plasma varies with different liver diseases. Aim. To analyze the dynamics of TGF-β1 levels in children-recipients with liver transplant from related donors, including from incompatible blood groups. Materials and methods. The study involved 127 children aged 3 to 72 months (median – 8, average age – 12 ± 14 months), including 57 boys and 70 girls, with liver cirrhosis, developed as the result of congenital and hereditary diseases of the hepatobiliary system. All patients underwent transplantation of the left lateral liver sector from living related donors: 98 patients were transplanted fragment of a liver from identical or AB0-compatible donors and 29 – from incompatible donors. The concentration of TGF-β1 was determined by enzyme immunoassay method in blood plasma samples. Results. Average level of TGF-β1 in blood plasma of children with liver cirrhosis, developed as the result of congenital and hereditary diseases of the hepatobiliary system was 5,2 ± 5,5 ng/ml. A month after liver transplantation from a related donor level of TGF-β1 in blood plasma of recipients increased to 8,1 ± 9,6 ng/ml. One year after transplantation, the average level of TGF-β1 in the recipients of liver fragment was 7,7 ± 8,4 ng/ml, and signifi cantly (p = 0,00) differed from the level prior to transplantation. No association between TGF-β1 level in a month and a year after transplantation and the compatibility of the recipient with AB0 donor was found. A correlation (r = –0,23, p < 0,05) between level of TGF-β1 prior to transplantation and the development of graft dysfunction was observed: in recipients with graft dysfunction (16 cases) cytokine level prior to surgery was lower (p = 0,047) than in other recipients. Conclusion . Liver transplantation leads to a signifi cant increase in the level of TGF-β1 in the blood plasma of children and that level is not different in recipients after transplantation of a liver fragment from AB0-compatible and AB0-incompatible donors and in recipients with anti-group antibodies before and/or after transplantation, and without them.

The results of biliary reconstructions after liver fragments transplantation

To analyze the results of repeated reconstructions of choleresis after living related liver fragments transplantation. The study included 268 recipients (145 women and 123 men) aged 5 months - 61 years (mean age 16,11 ± 14,62 years) who underwent liver fragments transplantation in the department of liver transplantation of cad. B.V. Petrovskiy Russian Research Surgery Center from 1997 to 2012. Biliary reconstructions were performed at different terms after transplantation in 37 patients (13.81%). Complications followed repeated reconstructions, the initial conditions for biliary anastomosis formation during transplantation, the results of biliary reconstructions after transplantation were analyzed. In most cases despite the prevailing complications there is a combination of various biliary complications requiring biliary reconstruction. It was found that live rfragment used for transplantation, type of primary reconstruction of choler sis, number of bile ducts orifices of graft and biliary anastomoses do not demonstrate statistically significant effect on the incidence of post-transplant biliary reconstructions (p>0.05). Poor prognosis in patients with biliary complications required biliary reconstructionsis determined by the development of graft dysfunction. Early reconstruction before development of liver transplant dysfunction is necessary condition of successful treatment. In the case of graft dysfunction liver retransplantation is unique method of treatment.

Molecular monitoring of alloimmune-mediated injury in kidney transplant patients.

Rapid progress in molecular technology has allowed development of numerous molecular tools to help the clinician to evaluate graft status in kidney transplant patients. This review highlights recent findings, describing the use of molecular approaches to monitor, diagnose, and predict alloimmune-mediated injury in kidney grafts. Both previously identified and newly discovered molecular markers of immune injury have been studied and validated in large multicenter studies. Recent data indicate that measuring specific gene transcripts in noninvasive samples, such as urine or peripheral blood, can identify the occurrence of acute rejection and differentiate this immune-mediated injury from other causes of graft dysfunction. Serial monitoring of urine in stable renal transplant patients may detect the onset of rejection before development of graft dysfunction. Moreover, combining gene expression analysis with conventional histopathologic assessment of grafts can enhance the accuracy of diagnosis and may also help predict graft outcomes. Measuring specific gene transcription in noninvasive clinical samples has the potential to become an important and standard tool to monitor alloimmune-mediated injury in kidney transplant recipients. Prospective studies are ongoing to validate these findings for use of these approaches in clinical settings.

Renal tubular epithelial clusters in voided urine: a potential diagnostic pitfall in renal transplant patients

Urine cytology is often used to screen for polyomavirus in renal transplant patients. There are qualitative cytologic differences between urine from transplant and nontransplant patients, particularly the presence of epithelial cell clusters, that can pose diagnostic difficulty. Voided urine cytology specimens from 100 renal transplant patients and 100 nontransplant patients were reviewed for cell clusters. Immunocytochemistry for renal cell carcinoma marker (RCC) and cytokeratin 7 was performed on 10 recent specimens. Clinical data was reviewed with a focus on evidence of graft dysfunction or malignancy. Eighteen patients (18%) in the renal transplant group and no nontransplanted patients (0%) exhibited cell clusters with characteristic morphology: 3-dimensional cohesive groups; high nucleus-to-cytoplasm ratio; round, eccentrically placed nuclei with a prominent central nucleolus; and granular or vacuolated cytoplasm. Some had significant nuclear atypia. The groups were RCC-positive in 8 of 10 cases, and cytokeratin 7-positive in 6 of 10 cases, which is consistent with renal tubular epithelial clusters (RTECs). Clinical follow-up revealed that 88% (15 of 17) of those with RTECs developed graft dysfunction in a median of 65 days, compared with 6% (4 of 64) without RTECs (sensitivity 79%, specificity 97%, positive predictive value 88%, negative predictive value 94%). No patient developed a urinary tract malignancy. RTECs are relatively common in urine cytology from transplant patients, but are rare in other urine specimens. Recognition is important as they can be mistaken for urothelial carcinoma or adenocarcinoma. There appears to be a strong association with later development of graft dysfunction. These cells are most likely evidence of renal tubular injury secondary to a variety of factors, including rejection.

The pathogenesis of acute allograft dysfunction in desensitized renal transplant recipients

Acute allograft rejection after HLA desensitization is common early post-transplant but the sequence of histopathologic changes leading to graft dysfunction has not been well defined. We evaluated the early pathogenesis and sequence of antibody-mediated graft damage of 35 desensitized living donor kidney recipients by studying the course of biopsies taken in the very early post-transplant period (<1 month). A total of 14 of the 35 patients met criteria for acute antibody-mediated rejection (AMR). In these patients, the chronologic sequence of pathologic changes was C4d peritubular capillary deposition, acute tubular injury, and peritubular capillaritis, followed by glomerulitis and interstitial inflammation. Classic AMR lesions occurred early, followed by mononuclear cellular infiltration, which comprised CD4 and CD8 T cells and monocytes. Development of graft dysfunction in most patients occurred concurrently with the emergence of graft cellular infiltration, rather than at the earlier time of antibody deposition as detected via C4d deposition. These data provide novel insight into the sequence of pathologic changes in patients with AMR post-transplant after HLA desensitization.

Inflammation after renal transplantation: Role in the development of graft dysfunction and potential therapies

Inflammation is the response of the body to various stimuli. Mediators of inflammation include complements, pro-coagulants, cytokines, and fibrinolytics. In renal transplantation (RT), immediately after a kidney is procured, ischemia then reperfusion (I-R) occurs, involving immunologic and non-immunologic mechanisms. Inflammation causes the generation of reactive oxygen species, lipid peroxidation, and simultaneous cell necrosis and apoptosis. The mediators of I-R injury include leukocytes, platelets, and pro-coagulants. Eventually, inflammation may cause extensive tissue destruction. Attenuation of the inflammatory process is achieved by use of an interleukin (IL)-6 antibody, zinc pretreatment, and in P-selectin knockouts. The relationship between inflammation and acute rejection (AR) is present before grafting. Pre-RT serum C-reactive protein, IL-2, and interferon (IFN)-γ concentrations before, and at 1 and 2 weeks after, RT are higher in patients who develop AR. Furthermore, renal IL-6 expression is fo...

Inflammation after renal transplantation: Role in the development of graft dysfunction and potential therapies

Inflammation is the response of the body to various stimuli. Mediators of inflammation include complements, pro-coagulants, cytokines, and fibrinolytics. In renal transplantation (RT), immediately after a kidney is procured, ischemia then reperfusion (I-R) occurs, involving immunologic and non-immunologic mechanisms. Inflammation causes the generation of reactive oxygen species, lipid peroxidation, and simultaneous cell necrosis and apoptosis. The mediators of I-R injury include leukocytes, platelets, and pro-coagulants. Eventually, inflammation may cause extensive tissue destruction. Attenuation of the inflammatory process is achieved by use of an interleukin (IL)-6 antibody, zinc pretreatment, and in P-selectin knockouts. The relationship between inflammation and acute rejection (AR) is present before grafting. Pre-RT serum C-reactive protein, IL-2, and interferon (IFN)-γ concentrations before, and at 1 and 2 weeks after, RT are higher in patients who develop AR. Furthermore, renal IL-6 expression is fourfold higher in patients with AR. Administration of Met-regulated on activation, normal T cell expressed and secreted (RANTES), a chemokine receptor antagonist, suppresses recruitment of inflammatory cells into rat renal allografts. In chronic allograft nephropathy (CAN), renal lesions are induced by repeated inflammation by Th1 and/or Th2-directed antibody endothelial damage. Pro-inflammatory and pro-fibrotic mediators (IL-1, IFN-γ, tumor growth factor-β, platelet-derived growth factor, endothelin, and angiotensin II) and chemokines (RANTES) play essential roles in the development of CAN. The use of a complement regulator reduces the prevalence of CAN by minimizing I-R. Also, retinoids, which are anti-inflammatory, reduce damage consistent with CAN. In summary, there is a complex relationship between the immune system and RT organ function. Immune factors contribute to the development of organ dysfunction.

Xanthine oxidoreductase and preservation injury in human liver transplantation.

Preservation injury is a major cause of primary graft dysfunction in liver transplantation (LT). Oxidative damage is considered to be the first event leading to graft damage. Xanthine oxidoreductase (XOR) and neutrophil activation, two sources of reactive oxygen species, could play a role in the development of graft dysfunction. We determined activities of XOR forms, polymorphonuclear elastase (PMN-E), aminotransferases, and hyaluronic acid in plasma of 20 patients undergoing LT. Samples were taken from the radial artery (RA) before the anhepatic phase; from the portal vein (PV) before reperfusion; from graft caval effluent (CE) at reperfusion; and from RA, PV, and the hepatic vein (HV) 10 and 90 min postreperfusion. The graft, but not recipient bowel, released XOR into blood (XOR in CE, median, 61.2 mU/g protein [range, 1.9-160.4 vs. undetectable in PV before reperfusion). Circulating XOR was transformed from dehydrogenase to reversible oxidase (XOrev) (XOrev-to-XOR ratio, 48.1% in CE and 65.1% in HV 90 min postreperfusion). Neutrophil activation was detected in the recipients before reperfusion, and in liver at early post-reperfusion (median PMN-E was 0.85 microg/g protein [range, 0.01-1.58] in RA before the anhepatic phase; 2.22 microg/g protein [range, 0.20-5.88] in PV prereperfu-sion; and 3.60 microg/g protein [range, 0.48-6.78] in HV 10 min postreperfusion). XOR, but none of the other markers, was higher in the CE of patients with moderate primary graft dysfunction than in those with slight primary graft dysfunction. XOR release and neutrophil activation are produced during LT, and they are potentially injurious mechanisms associated with this therapy.