Reassessment of Relevance and Predictive Value of Parameters Indicating Early Graft Dysfunction in Liver Transplantation: AST Is a Weak, but Bilirubin and INR Strong Predictors of Mortality

Introduction: Early graft dysfunction (EAD) complicates liver transplantation (LT). The aim of this analysis was to discriminate between the weight of each variable as for its predictive value toward patient and graft survival.Methods: We reviewed all LT performed at the Medical University of Innsbruck between 2007 and 2018. EAD was recorded when one of the following criteria was present: (i) aspartate aminotransferase (AST) levels >2,000 IU/L within the first 7 days, (ii) bilirubin levels ≥10mg/dL or (iii) international normalized ratio (INR) ≥1.6 on postoperative day 7.Results: Of 616 LT, 30.7% developed EAD. Patient survival did not differ significantly (P = 0.092; log rank-test = 2.87), graft survival was significantly higher in non-EAD patients (P = 0.008; log rank-test = 7.13). Bilirubin and INR on postoperative day 7 were identified as strong mortality predictors (Bilirubin HR = 1.71 [1.34, 2.16]; INR HR = 2.69 [0.51, 14.31]), in contrast to AST (HR = 0.91 [0.75, 1.10]). Similar results were achieved for graft loss estimation. A comparison with the Model for Early Allograft Function (MEAF) and the Liver Graft Assessment Following Transplantation (L-GrAFT) score identified a superior discrimination potential but lower specificity.Conclusion: Contrarily to AST, bilirubin and INR have strong predictive capacity for patient and graft survival. This fits well with the understanding, that bile duct injury and deprivation of synthetic function rather than hepatocyte injury are key factors in LT.

Value of Plasmatic Villin-1 in the prediction of early graft dysfunction in kidney transplant recipients among Egyptian population

Background One of the main complications of kidney transplantation is delayed graft function (DGF). There has been enormous growing research interest in the potential for the rapidly expanding fields of medical technology to generate new biomarkers with the aim of early prediction of DGF and modifying its therapy accordingly. Villin-1 has been detected in urine of patients with AKI. Additionally, it is redistributed during AKI from the brush borders of the proximal tubular cells toward the basolateral membrane which positions villin-1 closer to the renal vasculature and suggests that it could be released in the blood as well, so can be as a novel biomarker for DGF. Methods Of 70 patients with end-stage renal disease with one or more risk factor for developing delayed graft function attending renal transplantation preparation clinics in ASUSH, IMC and NILE Badrawi hospital in Egypt from May 2016 to July 2019, 41 patients were eligible and assigned into two groups according to the correlation with the serum creatinine levels in the first two days post-transplantation after signed informed consent for participation in our study into group 1 (DGF group) and group 2 (NGF group). We measured the presence of villin-1 by ELISA technique (quantitative) in comparison to serum creatinine levels in plasma at the time of declamping (zero level), 1st, 3rd, 5th, 7th, 12th, 24th, 48th, 72th 96th, 120th hour post declamping, also samples from normal population and chronic kidney disease stage V patients have been collected to establish reference range guide for plasmatic villin-1 in both groups. Results Statistically significant differences were noted in the comparison between both groups as regard the plasmatic villin-1 levels at the same measurement points in both groups, also plasmatic villin-1 started to rise above its reference range in the ESRD patients at the 5th hour post declamping while its peak was at the 7th hour in the DGF group’s recipients then started to decrease after that but didn’t settle down between the reference range guide during the regular follow up of its level till the 120th hour post declamping. the reference range guide was from 0.08 and 0.35 ng\ml in males and from 0.055 to 0.35 ng\ml in females in normal population while from 0.38 and 1.4 ng\ml in males and from 0.28 to 1.1 ng\ml in females in the ESRD patients. Conclusions Plasmatic villin-1 is a promising novel biomarker for detection of early graft dysfunction in kidney transplant. Due to restrictions of the study design these observations need further confirmation by prospective studies.

Prognostic role of levels of extracellular histones H3 for diagnosis of early dysfunction of transplant after hepatic transplantation

Objective. The aim of this study was to determine the prognostic role of extracellular histones in the diagnosis of early graft dysfunction after liver transplantation.. Materials and methods. The 93 recipients undergoing LDLT were enrolled in this prospective study. Blood samples of patients were collected on postoperative day 1 and histone levels in the plasma samples were measured with Total Histone H3 sandwich ELISA kits. 19 (20.4%) subjects had early graft dysfunction (EAD) which was diagnosed on postoperative day 7 according to Ol-thoff’s criteria, based on liver function tests and coagulation profiles. Other 74 (79.6%) recipients did not have EGD. Results. Levels of circulating histones were depressed in patients with EGD (0,808±0.026, 95% (CI) 0.752-0.864) than in patients without EGD (0.820±0.017, 95% (CI) 0.786-0.854) (P=0.727). These differences were not significant. The sources of histones in the circulation are not etiologies specific and levels of total histone H 3 after 24 h of operation had not stronger predictive value with AUC 0.477 (95 % CI 0.329 to 0.625) for liver dysfunction. The AUC value of the total bilirubin (AUC 0.685, 95 % CI 0.546 to 0.825) in predicting early graft dysfunction outperformed other LFTs and was less than CRP (AUC 0.705, CI 0.573 to 0.838). The optimal cutoff value of total bilirubin obtained from the analysis of ROC curves was 4,5 and surpassed all other parameters with a sensitivity of 94.4% and a specificity of 40.7% respectively for prognoses of EGD (P=0.012). The univariate analysis determined that postoperative neutrophils level and CRP were identified as independent risk factors for early graft dysfunction. Neutrophils had a higher predictive value for liver dysfunction than any other parameter within 24 h (Odds ratio (OR) 16.3; 95% CI: 1.7-156.3, P = 0.016). Conclusion. Collectively, extracellular histone H3 levels were depressed, total bilirubin and CRP levels were elevated in patients with EGD, which can be used as early predictors for liver tissue damage and early allograft dysfunction in patients after liver transplantation.

Evaluation of Early Renal Allograft Dysfunction from Living Donors among Egyptian Patients (Histopathological and Immunohistochemical Study)

BACKGROUND: Early renal graft dysfunction is a major problem in the early post-transplantation period and is considered a major cause of graft loss. Clinical diagnosis based on the clinical criteria alone is unreliable; therefore, biopsy remains the gold standard to differentiate between rejection and non-rejection causes. AIM: This study was designed to identify and differentiate between causes of early graft dysfunction during the first post-transplantation month and to correlate between histological lesions and immunohistochemistry (IHC) for accurate diagnosis and a better outcome. MATERIALS AND METHODS: A total of 163 renal allograft biopsies, performed in the first post-transplantation month over 6 years, were included in the study. New sections were prepared from the paraffin blocks and stained with conventional stains. Additional sections were prepared and treated by complement fragment 4d (C4d) and cluster differentiation 3 (CD3) antibodies for IHC evaluation. RESULTS: All the studied cases were from living donors. The mean patient age was 39 years with predominant males. The clinical indication for most biopsies (94.5%) was impaired graft function. Acute rejection (AR) was the main diagnostic category observed in (98/163, 60.1%); out of which, T cell-mediated rejection (TCMR) was observed in (62/98, 63.2%). Drug toxicity was suspected in (53/163, 32.5%), acute tubular injury (ATI) not otherwise specified (nos) in (21/163, 12.9%), and other lesions including thrombotic microangiopathy were observed in the remaining biopsies. The most common cause of graft dysfunction in the 1st and 2nd weeks was AR representing. A significant correlation was seen between mild glomerulitis (g1) and mild peritubular capillaritis (PTC) 1, on the one side, and negative C4d staining, on the other side. No significant correlation was seen between moderate glomerulitis (g2) and moderate ptc2 at one side and positive C4d staining at the other side reflecting the poor association between the microvascular inflammation (“g” and “ptc” scores) and C4d positivity (r = 0.2). Missed mild tubulitis (t1) was found in a single case and missed moderate tubulitis (t2) was found in a single case detected by CD3 IHC. CONCLUSION: AR and drug toxicity account for the majority of early graft dysfunction, however, other pathological lesions, per se or coincide with them may be the cause. The significance of g2 per se as a marker for diagnosis of antibody-mediated rejection requires further study. Considering C4d score 1 (by IHC) positive; also requires further study with follow-up.

Renal Transplant Pathology: Demographic Features and Histopathological Analysis of the Causes of Graft Dysfunction

Background. Renal transplant has emerged as a preferred treatment modality in cases of end-stage renal disease; however, a small percentage of cases suffer from graft dysfunction. Aim. To evaluate the renal transplant biopsies and analyze the various causes of graft dysfunction. Materials and Methods. 163 renal transplant biopsies, reported between 2014 and 2019 and who fulfilled the inclusion criteria, were evaluated with respect to demographics, clinical, histological, and immunohistochemical features. Results. Of 163 patients, 26 (16%) were females and 137 (84%) were males with a mean age of 34 ± 7 years. 53 (32.5%) cases were of rejection (ABMR and TCMR), 1 (0.6%) was borderline, 15 were of IFTA, and rest of 94 cases (57.7%) belonged to the others category. SCr (serum creatinine) in cases of rejection was 3.85 ± 0.55 mg/dl. Causes of early graft dysfunction included active ABMR (7.1 ± 4.7 months), acute TCMR (5.5 months), and acute tubular necrosis (after 6 ± 2.2 months of transplant) while the causes of late rejection were CNIT and IFTA (34 ± 4.7 and 35 ± 7.8 months, respectively). Conclusion. Renal graft dysfunction still remains a concerning area for both clinicians and patients. Biopsy remains the gold standard for diagnosing the exact cause of graft dysfunction and in planning further management.