Browsing by Author "Kubal, Chandrashekhar A."
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Item Admission Factor V Predicts Transplant-Free Survival in Acute Liver Failure(Springer, 2021) Patidar, Kavish R.; Davis, Brian C.; Slaven, James E.; Ghabril, Marwan S.; Kubal, Chandrashekhar A.; Lee, William M.; Stravitz, Richard T.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthBackground and aims: Traditional laboratory markers are insensitive in distinguishing between patients with acute liver failure (ALF) who will require urgent liver transplantation (LT) from those who will recover spontaneously, particularly within 24 h of presentation. Coagulation factor-V (FV) may improve the accuracy of outcome prediction in ALF due to its predominant synthesis in the liver and short half-life in plasma. Methods: Patients enrolled in the ALF Study Group Registry from a single site had FV determined within 24 h of presentation (Derivation-Cohort). Area under the receiver operating characteristic curves (AUROC) dichotomized by ALF etiology [acetaminophen (APAP) or non-APAP] were constructed to evaluate the diagnostic performance of FV for transplant-free-survival (TFS). Multivariate logistic regression modeling was performed using FV and other clinical variables to predict TFS. Accuracy of FV and multivariable model were performed in a Validation-Cohort from a different site. Results: 90-patients (56% with APAP) were included in the Derivation-Cohort. Median FV was significantly higher in TFS versus those who died/LT (31% vs. 15%, respectively; p = 0.001). When dichotomized by etiology, AUROC for FV was 0.77 for APAP (cutoff, sensitivity, specificity 10.5%, 79%, 69%, respectively) and 0.77 for non-APAP (22%, 85%, 67%, respectively). When the optimal cutoffs for FV in the Derivation-Cohort were applied to the Validation-Cohort (N = 51; 59% with APAP), AUROC for FV was 0.75 for APAP (sensitivity/specificity 81/44) and 0.95 for non-APAP (sensitivity/specificity 90/73). In multivariate analyses, AUROC for FV model was 0.86 in the Derivation-Cohort and 0.90 in the Validation-Cohort. Conclusion: Admission FV may improve selection of patients who are likely to improve without LT.Item CAD-LT score effectively predicts risk of significant coronary artery disease in liver transplant candidates(Elsevier, 2021-07) Rachwan, Rayan Jo; Kutkut, Issa; Timsina, Lava R.; Chaaya, Rody G. Bou; El-Am, Edward A.; Sabra, Mohammad; Mshelbwala, Fakilahyel S.; Rahal, Mahmoud A.; Lacerda, Marco A.; Kubal, Chandrashekhar A.; Fridell, Jonathan A.; Ghabril, Marwan S.; Bourdillon, Patrick D.; Mangus, Richard S.; Surgery, School of MedicineBackground & Aims Patients with cirrhosis and significant coronary artery disease (CAD) are at risk of peri-liver transplantation (LT) cardiac events. The coronary artery disease in liver transplantation (CAD-LT) score and algorithm aim to predict the risk of significant CAD in LT candidates and guide pre-LT cardiac evaluation. Methods Patients who underwent pre-LT evaluation at Indiana University (2010-2019) were studied retrospectively. Stress echocardiography (SE) and cardiac catheterization (CATH) reports were reviewed. CATH was performed for predefined CAD risk factors, irrespective of normal SE. Significant CAD was defined as CAD requiring percutaneous or surgical intervention. A multivariate regression model was constructed to assess risk factors. Receiver-operating curve analysis was used to compute a point-based risk score and a stratified testing algorithm. Results A total of 1,771 pre-LT patients underwent cardiac evaluation, including results from 1,634 SE and 1,266 CATH assessments. Risk-adjusted predictors of significant CAD at CATH were older age (adjusted odds ratio 1.05; 95% CI 1.03–1.08), male sex (1.69; 1.16–2.50), diabetes (1.57; 1.12–2.22), hypertension (1.61; 1.14–2.28), tobacco use (pack years) (1.01; 1.00–1.02), family history of CAD (1.63; 1.16–2.28), and personal history of CAD (6.55; 4.33–9.90). The CAD-LT score stratified significant CAD risk as low (≤2%), intermediate (3% to 9%), and high (≥10%). Among patients who underwent CATH, a risk-based testing algorithm (low: no testing; intermediate: non-invasive testing vs. CATH; high: CATH) would have identified 97% of all significant CAD and potentially avoided unnecessary testing (669 SE [57%] and 561 CATH [44%]). Conclusions The CAD-LT score and algorithm (available at www.cad-lt.com) effectively stratify pre-LT risk for significant CAD. This may guide more targeted testing of candidates with fewer tests and faster time to waitlist. Lay summary The coronary artery disease in liver transplantation (CAD-LT) score and algorithm effectively stratify patients based on their risk of significant coronary artery disease. The CAD-LT algorithm can be used to guide a more targeted cardiac evaluation prior to liver transplantation.Item Challenges with Intestine and Multivisceral Re-Transplantation: Importance of Timing of Re-Transplantation and Optimal Immunosuppression(Springer, 2018-02-06) Kubal, Chandrashekhar A.; Pennington, Catherine; Fridell, Jonathan; Ekser, Burcin; Muhaylov, Plamen; Mangus, Richard; Surgery, School of MedicineBACKGROUND Patients undergoing re-transplantation often receive high doses of immunosuppression, which may lead to an immunocompromised status of the recipient. This study investigates the outcomes after intestine/multivisceral re-transplantation. MATERIAL AND METHODS Clinical outcomes of 23 patients undergoing 24 re-transplantations at a single intestine transplant center were reviewed. Bone marrow suppression was used as a surrogate marker of immunocompromised status, and was defined as platelet count <50 k/mm3 and absolute lymphocyte count <200/mm³. RESULTS All re-transplants except one were liver inclusive. Fifteen of 23 patients died at a median time of 12 months (range 0.2-75) after re-transplantation. Of the 15 deaths, nine (60%) resulted from complications associated with a compromised host immune status: graft versus host disease (GVHD) affecting bone marrow (three cases), persistent viral infection (three cases), post-transplant lymphoproliferative disorder (PTLD (one case), metastatic cancer (one case), multi-drug resistant polymicrobial sepsis (one case). Four deaths (27%) resulted from severe rejection. Non-survivors were more likely to have received alemtuzumab, and had higher incidence of bone marrow suppression. In addition to immunocompromised status and rejection, the use of alemtuzumab was associated with mortality after intestinal/multivisceral re-transplantation. CONCLUSIONS High mortality was associated with intestine/multivisceral re-transplantation. To improve clinical outcomes of intestine and multivisceral transplantation, it is important to allow reconstitution of host immunity. Longer interval between the two transplantations, and strategies such as allograft specific immunosuppression, may spare the host from the devastating effects of potent immunosuppression currently used.Item Comparison of Artificial Intelligence and Eyeball Method in the Detection of Fatty Liver Disease(2023-07-26) Catron, Evan J.; Passarelli, Robert P.; Danielle, Wilmes; Wei, Barry; Le, Thi M.U.; Li, Ping; Zhang, Wenjun; Lin, Jingmei; Melcher, Mark L.; Mihaylov, Plamen V.; Kubal, Chandrashekhar A.; Mangus, Robert S.; Ekser, BurcinBackground: Quantification of liver fat content relies on visual microscopic inspection of liver biopsies by pathologists. Their percent macrosteatosis (%MaS) estimation is vital in determining donor liver transplantability; however, the eyeball method may vary between observers. Overestimations of %MaS can potentially lead to the discard of viable donor livers. We hypothesize that artificial intelligence (AI) could be helpful in providing a more objective and accurate measurement of %MaS. Methods: Literature review identified HALO (image analysis) and U-Net (deep-learning) as high-accuracy AI programs capable of calculating %MaS in liver biopsies. We compared (i) an experienced pathologist’s and (ii) a transplant surgeon’s eyeball %MaS estimations from de-novo liver transplant (LT) biopsy samples taken 2h post-reperfusion to (iii) the HALO-calculated %MaS (Fig.1). 250 patients had undergone LT at Indiana University between 2020-2021, and 211 had sufficient data for inclusion. Each biopsy was digitized into 5 random non-overlapping tiles at 20x magnification (a total of 1,055 images). We used HALO software for analysis and set the minimum vacuole area to 10μm² to avoid the inclusion of microsteatosis. Microsteatosis was excluded by the pathologist and the surgeon by the eyeball method using the same 1,055 images. Each %MaS estimation was compared with early allograft dysfunction (EAD). EAD is defined by the presence of at least one of the following: INR >1.6 on postoperative day (POD) 7, total bilirubin >10mg/dL on POD7, or AST/ALT >2000IU/L within the first 7 days following LT. Results: Of 211 LTs, 42 (19.9%) had EAD. The mean %MaS estimation of pathologist and transplant surgeon were 6.3% (SD: 11.9%) and 3.2% (SD: 6.4%), respectively. HALO yielded a significantly lower mean %MaS of 2.6% (SD: 2.6%) than the pathologist’s eyeball method (p<0.001). The mean %MaS calculated by HALO was higher in EAD patients than in non-EAD (p=0.032), but this difference did not reach statistical significance in the pathologist’s estimation (p=0.069). Conclusions: Although mean %MaS measurements from all parties were mild (<10%), human eyeball estimations of %MaS were significantly higher than HALO’s %MaS. The HALO-calculated %MaS differed significantly between the EAD and non-EAD LTs which might suggest a possible correlation between the AI’s steatosis analysis and EAD outcomes. However, pathologic variables other than %MaS (necrosis or cholestasis) should be included in future analyses to determine whether %MaS is the dominant parameter predicting EAD. AI is a promising tool to quantify liver steatosis and will help pathologists and transplant surgeons predict liver transplant viability.Item Computed tomography measures of nutrition in patients with end-stage liver disease provide a novel approach to characterize deficits(Elsevier, 2018) Bush, Weston J.; Davis, Jason P.; Maluccio, Mary A.; Kubal, Chandrashekhar A.; Salisbury, Jared B.; Mangus, Richard S.; Surgery, School of MedicineAim Patients with cirrhosis and end-stage liver disease (ESLD) develop severe nutrition deficits that impact on morbidity and mortality. Laboratory measures of nutrition fail to fully assess clinical deficits in muscle mass and fat stores. This study employs computed tomography imaging to assess muscle mass and subcutaneous and visceral fat stores in patients with ESLD. Methods This 1:1 case-control study design compares ESLD patients with healthy controls. Study patients were selected from a database of ESLD patients using a stratified method to assure a representative sample based on age, body mass index (BMI), gender, and model for end-stage liver disease score (MELD). Control patients were trauma patients with a low injury severity score (<10) who had a CT scan during evaluation. Cases and controls were matched for age +/- 5 years, gender, and BMI +/- 2. Results There were 90 subjects and 90 controls. ESLD patients had lower albumin levels (p<0.001), but similar total protein levels (p=0.72). ESLD patients had a deficit in muscle mass (-19%, p<0.001) and visceral fat (-13%, p<0.001), but similar subcutaneous fat (-1%, p=0.35). ESLD patients at highest risk for sarcopenia included those over age 60, BMI< 25.0, and female gender. We found degree of sarcopenia to be independent of MELD score. Conclusions These results support previous research demonstrating substantial nutrition deficits in ESLD patients that are not adequately measured by laboratory testing. Patients with ESLD have significant deficits of muscle and visceral fat stores, but a similar amount of subcutaneous fat.Item DELAYED KIDNEY TRANSPLANTATION AFTER 83 HOURS OF COLD ISCHEMIA TIME IN COMBINED LIVER-KIDNEY TRANSPLANT(Wolters Kluwer, 2019-02) Ekser, Burcin; Chen, Angela M.; Kubal, Chandrashekhar A.; Fridell, Jonathan A.; Mihaylov, Plamen; Goggins, William C.; Powelson, John A.; Surgery, School of MedicineItem Donation After Circulatory Arrest in Pancreas Transplantation: A Report of 10 Cases(Elsevier, 2017-12) Fridell, Jonathan A.; Mangus, Richard S.; Thomas, Christopher M.; Kubal, Chandrashekhar A.; Powelson, John A.; Surgery, School of MedicineIntroduction Transplantation of pancreas allografts procured from donation after circulatory death (DCD) remains uncommon. This study reviews a series of pancreas transplants at a single center to assess the donor and recipient characteristics for DCD pancreas transplant and to compare clinical outcomes. Methods DCD procurement was performed with a 5-minute wait time from pronouncement of death to first incision. In 2 patients, tissue plasminogen activator was infused as a thrombolytic during the donor flush. All kidney grafts were placed on pulsatile perfusion. Results There were 606 deceased donor pancreas transplants, 596 standard donors and 10 DCD donors. Of the 10 DCD transplants, 6 were simultaneous pancreas-kidney and 4 were pancreas transplant alone. The average time from incision to aortic cannulation was less than 3 minutes. The median total ischemia time for the DCD grafts was 5.4 hours, compared with 8.0 hours for standard donors (P = .15). Median length of hospital stay was 7 days for both groups, and there were no episode of acute cellular rejection in the first year post-transplant for the DCD group (4.2 % for standard group, P = .65). There was no difference in early or late graft survival, with 100% graft survival in the DCD group up to 1 year post-transplant. Ten-year Kaplan-Meier analysis shows similar graft survival for the 2 groups (P = .92). Conclusions These results support the routine use of carefully selected DCD pancreas donors. There were no differences in graft function, postoperative complications, and early and late graft survival.Item Excellent outcomes in combined liver-kidney transplantation: Impact of KDPI and delayed kidney transplantation(Wiley, 2017) Ekser, Burcin; Mangus, Richard S.; Kubal, Chandrashekhar A.; Powelson, John A.; Fridell, Jonathan A.; Goggins, William C.; Surgery, School of MedicineThe positive impact of delayed kidney transplantation (KT) on patient survival for combined liver-KT (CLKT) has already been demonstrated by our group. The purpose of this study is to identify whether the quality of the kidneys (based on KDPI) or the delayed approach KT contributes to improved patient survival. 130 CLKT were performed between 2002-2015; 69 with simultaneous KT (Group S) and 61 with delayed KT (Group D) (performed as a second operation with a mean cold ischemia time [CIT] of 50±15h). All patients were categorized according to the KDPI score; 1-33%, 34-66%, and 67-99%. Recipient and donor characteristics were comparable within Groups S and D. Transplant outcomes were comparable within Groups S and D, including liver and kidney CIT, warm ischemia time, and delayed graft function. Lower KDPI kidneys (<34%) were associated with increased patient survival in both groups. Combination of delayed KT and KDPI 1-33% resulted in 100% patient survival at 3-years. These results support that delayed KT in CLKT improves patient survival. The combination of delayed KT and low KDPI offers excellent patient survival up to 3-years. Improved outcomes in the delayed KT group including high KDPI kidneys supports expansion of the donor pool with the use of more ECD and DCD kidneys.Item Expanding the Donor Pool with Utilization of Extended Criteria DCD Livers(AASLD, 2019) Mihaylov, Plamen; Mangus, Richard; Ekser, Burcin; Cabrales, Arianna; Timsina, Lava; Fridell, Jonathan; Lacerda, Marco; Ghabril, Marwan; Nephew, Lauren; Chalasani, Naga; Kubal, Chandrashekhar A.; Pediatrics, School of MedicineUtilization of donation after circulatory death donor (DCD) livers for transplantation has remained cautious in the U.S. The aim of this study was to demonstrate the expansion of DCD liver transplant (LT) program with the use of extended criteria DCD livers. After institutional review board approval, 135 consecutive DCD LTs were retrospectively studied. ECD DCD livers were defined as those with one of the followings: 1) donor age >50 years, 2) donor BMI >35 kg/m2, 3) donor functional warm ischemia time (fWIT) >30 minutes, and 4) donor liver macrosteatosis >30%. An optimization protocol was introduced in July 2011 to improve outcomes of DCD LT, which included thrombolytic donor flush, and efforts to minimize ischemic times. The impact of this protocol on outcomes was evaluated in terms of graft loss, ischemic cholangiopathy (IC) and change in DCD LT volume. Of 135 consecutive DCD LT, 62 were ECD DCDs. 24 ECD DCD LT were performed before (Era I) and 38 after the institution of optimization protocol (Era II), accounting for an increase in the use of ECD DCD livers from 39% to 52%. Overall outcomes of ECD DCD LT improved in Era II, with a significantly lower incidence of IC (5% vs. 17% in Era I; P = 0.03) and better 1‐year graft survival (93% vs. 75% in Era I, P = 0.07). Survival outcomes for ECD DCD LT in Era II were comparable to matched deceased donor (DBD) LT. With the expansion of the DCD donor pool, the number of DCD LT performed at our center gradually increased in Era II to account for > 20% of the center's LT volume. In conclusion, with the optimization of perioperative conditions, ECD DCD livers can be successfully transplanted to expand the donor pool for LT.Item Human organ donor-derived vagus nerve biopsies allow for well-preserved ultrastructure and high-resolution mapping of myelinated and unmyelinated fibers(Springer Nature, 2021) Havton, Leif A.; Biscola, Natalia P.; Stern, Esther; Mihaylov, Plamen V.; Kubal, Chandrashekhar A.; Wo, John M.; Gupta, Anita; Baronowsky, Elizabeth; Ward, Matthew P.; Jaffey, Deborah M.; Powley, Terry L.; Surgery, School of MedicineThe vagus nerve provides motor, sensory, and autonomic innervation of multiple organs, and electrical vagus nerve stimulation (VNS) provides an adjunctive treatment option for e.g. medication-refractory epilepsy and treatment-resistant depression. The mechanisms of action for VNS are not known, and high-resolution anatomical mapping of the human vagus nerve is needed to better understand its functional organization. Electron microscopy (EM) is required for the detection of both myelinated and unmyelinated axons, but access to well-preserved human vagus nerves for ultrastructural studies is sparse. Intact human vagus nerve samples were procured intra-operatively from deceased organ donors, and tissues were immediately immersion fixed and processed for EM. Ultrastructural studies of cervical and sub-diaphragmatic vagus nerve segments showed excellent preservation of the lamellated wall of myelin sheaths, and the axolemma of myelinated and unmyelinated fibers were intact. Microtubules, neurofilaments, and mitochondria were readily identified in the axoplasm, and the ultrastructural integrity of Schwann cell nuclei, Remak bundles, and basal lamina was also well preserved. Digital segmentation of myelinated and unmyelinated axons allowed for determination of fiber size and myelination. We propose a novel source of human vagus nerve tissues for detailed ultrastructural studies and mapping to support efforts to refine neuromodulation strategies, including VNS.