Graft-versus-host disease after liver transplantation is associated with bone marrow failure, hemophagocytosis, and DNMT3A mutations.

Graft-versus-host disease after liver transplantation (LT-GVHD) is rare, frequently fatal, and associated with bone marrow failure (BMF), cytopenias, and hyperferritinemia. Given hyperferritinemia and cytopenias are present in hemophagocytic lymphohistiocytosis (HLH), and somatic mutations in hematopoietic cells are associated with hyperinflammatory responses (clonal hematopoiesis of indeterminate potential, CHIP), we identified the frequency of hemophagocytosis and CHIP mutations in LT-GVHD. We reviewed bone marrow aspirates and biopsies, quantified blood/marrow chimerism, and performed next-generation sequencing (NGS) with a targeted panel of genes relevant to myeloid malignancies, CHIP, and BMF. In all, 12 marrows were reviewed from 9 LT-GVHD patients. In all, 10 aspirates were evaluable for hemophagocytosis; 7 had adequate DNA for NGS. NGS was also performed on marrow from an LT cohort (n = 6) without GVHD. Nine of 10 aspirates in LT-GVHD patients showed increased hemophagocytosis. Five (71%) of 7 with LT-GVHD had DNMT3A mutations; only 1 of 6 in the non-GVHD LT cohort demonstrated DNMT3A mutation (p = .04). Only 1 LT-GVHD patient survived. BMF with HLH features was associated with poor hematopoietic recovery, and DNMT3A mutations were over-represented, in LT-GVHD patients. Identification of HLH features may guide prognosis and therapeutics. Further studies are needed to clarify the origin and impact of CHIP mutations on the hyperinflammatory state.

Optimal Timing of Administration of Direct-acting Antivirals for Patients With Hepatitis C-associated Hepatocellular Carcinoma Undergoing Liver Transplantation.

OBJECTIVE: To investigate the optimal timing of direct acting antiviral (DAA) administration in patients with hepatitis C-associated hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). SUMMARY OF BACKGROUND DATA: In patients with hepatitis C (HCV) associated HCC undergoing LT, the optimal timing of direct-acting antivirals (DAA) administration to achieve sustained virologic response (SVR) and improved oncologic outcomes remains a topic of much debate. METHODS: The United States HCC LT Consortium (2015-2019) was reviewed for patients with primary HCV-associated HCC who underwent LT and received DAA therapy at 20 institutions. Primary outcomes were SVR and HCC recurrence-free survival (RFS). RESULTS: Of 857 patients, 725 were within Milan criteria. SVR was associated with improved 5-year RFS (92% vs 77%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 92%, and 82%, and 5-year RFS of 93%, 94%, and 87%, respectively. Among 427 HCV treatment-naïve patients (no previous interferon therapy), patients who achieved SVR with DAAs had improved 5-year RFS (93% vs 76%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 93%, and 78% (P < 0.01) and 5-year RFS of 93%, 100%, and 83% (P = 0.01). CONCLUSIONS: The optimal timing of DAA therapy appears to be 0 to 3 months after LT for HCV-associated HCC, given increased rates of SVR and improved RFS. Delayed administration after transplant should be avoided. A prospective randomized controlled trial is warranted to validate these results.

Cytomegalovirus serologic matching in deceased donor kidney allocation optimizes high- and low-risk (D+R- and D-R-) profiles and does not adversely affect transplant rates.

Cytomegalovirus (CMV) is a major cause of infection-related morbidity and mortality in kidney transplantation. The most significant risk for developing CMV infection after transplant depends upon donor (D) and recipient (R) CMV serostatus. In 2012, our Organ Procurement Organization (OPO) began a novel pretransplant CMV prevention strategy via matching deceased kidney donors and recipients by CMV serostatus. Prior to the matching protocol, our distribution of seropositive and seronegative donors and recipients was similar to the United States at large. After the matching protocol, high-risk D+R- were reduced from 18.5% to 2.9%, whereas low-risk D-R- were increased from 13.5% to 24%. There was no adverse effect on transplant rates and no differential effect on waiting times for R+ vs R- after the protocol was implemented. This protocol could be implemented on a regional or national level to optimize low and high-risk CMV seroprofiles and potentially improve CMV-related outcomes in kidney transplantation.

De novo thrombotic microangiopathy in two kidney transplant recipients from the same deceased donor: A case series.

Thrombotic microangiopathy (TMA) is a recognized and serious complication of renal transplantation. Atypical hemolytic uremic syndrome (aHUS), a subset of TMA, occurs in the setting of dysregulation of the alternative complement pathway and can cause disease in native kidneys as well as recurrence in allografts. De novo TMA represents a classification of TMA post-transplant in the absence of clinical or histopathological evidence of TMA or aHUS in the native kidney. De novo TMA is a more heterogeneous syndrome than aHUS and the pathogenesis and risk factors for de novo TMA are poorly understood. The association between calcineurin inhibitors (CNI) and de novo TMA is controversial. Anti-complement blockade therapy with eculizumab is effective in some cases, but more studies are needed to identify appropriate candidates for therapy. We present two cases of de novo TMA occurring immediately in recipients from the same deceased donor and provoking the question of whether deceased donor-related factors could represent risks for developing de novo TMA.

The efficacy and safety of direct oral anticoagulants in patients with chronic renal insufficiency: A review of the literature.

Direct oral anticoagulants (DOACs) have been shown to be superior to vitamin K antagonists (VKAs) in regards to safety and efficacy in numerous clinical trials and are now the preferred oral anticoagulant by multiple professional societies. However, patients with significant levels of organ dysfunction were excluded from all major clinical trials, leaving the clinical benefit in these subsets uncertain. Patients with chronic kidney disease (CKD) specifically often require anticoagulation for acute or long-term indications such as venous thromboembolism, atrial fibrillation, or mechanical heart valves. The efficacy and safety of anticoagulation in patients with renal failure is less certain, however, particularly with DOACs which have altered pharmacokinetics in patients with renal failure and limited observational data on their use in this population. In this review, we compile the most up to date data on the DOAC use in patients with CKD. DOAC use in patients with ESRD and advanced CKD is increasing despite the presence of a clear benefit, and with the potential for increased risk of bleeding compared to warfarin. Apixaban has the greatest amount of outcomes research supporting its use over warfarin in this patient population; however, further research on DOAC safety and efficacy in those with advanced CKD is still needed.

Sulfonamide desensitization in solid organ transplant recipients: A protocol-driven approach during the index transplant hospitalization.

Trimethoprim-sulfamethoxazole (TMP-SMX) is the first-line agent for Pneumocystis jiroveci pneumonia (PJP) prophylaxis for solid organ transplant (SOT) recipients because of its efficacy for this indication, extended antimicrobial coverage, and favorable cost. Reported sulfonamide allergy is not uncommon and often results in TMP-SMX avoidance. Desensitization offers an efficacious and cost-effective alternative to TMP-SMX avoidance. Herein, we reviewed our experience with desensitization during the index transplant hospitalization among 52 SOT recipients with history of a non-anaphylactic sulfonamide allergy. Of those enrolled in the desensitization protocol, 92% (48/52) completed the protocol, with nearly 80% (41/52) still on TMP-SMX at 3 months without adverse reaction. Eleven patients discontinued TMP-SMX (7 for allergic reactions and 4 for non-allergic reasons) and switched to pentamidine. A cost savings of $575 per desensitization was calculated based on annual wholesale drug prices, for a total savings of $23 575. Additionally, the protocol did not delay discharge in any patient nor was it associated with any severe allergic reactions. These findings suggest TMP-SMX desensitization is safe and effective in SOT recipients with a history of non-anaphylactic, non-life-threatening sulfonamide hypersensitivity.

The role of the pharmacist in the management of kidney transplant recipients.

Pharmacists may play a key role on the multidisciplinary transplant team. This article describes the development and current status of pharmacists in the management of transplant recipients in the United States. Traditionally, pharmacists played an important support role in transplant medicine. This role has been expanded to include direct patient care for the avoidance, detection, and/or treatment of side effects from the polypharmacy necessary in the management of these complex patients. Pharmacists provide pre- and post-transplant education to transplant recipients to enhance adherence to complicated medical regimens and thereby reduce readmission to hospital and unscheduled, costly visits to urgent care centers and/or hospital emergency departments.

Tacrolimus exposure in the real world: an analysis from the Mycophenolic acid Observational REnal transplant study.

Tacrolimus exposure and renal function data to 36 months post-transplant were analyzed from the prospective, observational Mycophenolic acid Observational REnal transplant (MORE) registry in which de novo kidney transplant patients were managed according to local practice. Tacrolimus trough (C0 ) concentration at month 12 was stratified as low (<6 ng/mL), moderate (6-8 ng/mL), or high (>8 ng/mL) in 724 patients. Estimated glomerular filtration rate (eGFR) was stratified as low (<60 mL/min/1.73 m(2) ) or high (≥60 mL/min/1.73 m(2) ). High tacrolimus C0 (>8 ng/mL) was observed in 47.7%, 34.1%, 26.8%, and 26.7% of patients at baseline and months 12, 24, and 36, respectively. Biopsy-proven acute rejection was similar to month 36 regardless of tacrolimus C0 category at month 12. Tacrolimus C0 >8 ng/mL vs. <6 ng/mL at month 12 was predictive of low eGFR at month 24 (p = 0.023) with a nonsignificant trend at month 36 (p = 0.085). Infections (p < 0.013) and BK virus infection (p < 0.001) were most frequent in the low tacrolimus C0 cohort. Neutropenia was most frequent in the high tacrolimus C0 category (p = 0.010). In conclusion, over a quarter of patients were exposed to high tacrolimus C0 to 36 months post-transplant. Tacrolimus exposure did not affect rejection risk, but tacrolimus C0 >8 ng/mL at month 12 was predictive of subsequent low eGFR compared to C0 <6 ng/mL.

A single dose of a non-steroidal anti-inflammatory drug (NSAID) prevents severe pain after ureteric stent removal: a prospective, randomised, double-blind, placebo-controlled trial.

OBJECTIVES: To determine the incidence of severe pain after ureteric stent removal. To evaluate the efficacy of a single dose of a non-steroidal anti-inflammatory drug (NSAID) in preventing this complication. PATIENTS AND METHODS: A prospective, randomised, double-blind, placebo-controlled trial was performed at our institution. Adults with an indwelling ureteric stent after ureteroscopy were randomised to receive either a single dose of placebo or an NSAID (rofecoxib 50 mg) before ureteric stent removal. Pain was measured using a visual analogue scale (VAS) just before and 24 h after stent removal Pain medication use after ureteric stent removal was measured using morphine equivalents. RESULTS: In all, 22 patients were enrolled and randomised into the study before ending the study after interim analysis showed significant decrease in pain level in the NSAID group. The most common indication for ureteroscopy was urolithiasis (14 patients). The proportion of patients with severe pain (VAS score of ≥7) during the 24 h after ureteric stent removal was six of 11 (55%) in the placebo group and it was zero of 10 in the NSAID group (P < 0.01). There were no complications related to the use of rofecoxib. CONCLUSIONS: We found a 55% incidence of severe pain after ureteric stent removal. A single dose of a NSAID before stent removal prevents severe pain after ureteric stent removal.

Evaluation of potential interactions between mycophenolic acid derivatives and proton pump inhibitors.

OBJECTIVE: To evaluate the incidence of gastrointestinal (GI) complications in solid organ transplant (SOT) recipients, impact of the complications on transplant outcomes, and the potential interactions between mycophenolic acid (MPA) derivatives and proton pump inhibitors (PPIs). DATA SOURCES: An unrestricted literature search (1980-January 2012) was performed with MEDLINE and EMBASE using the following key words: drug-drug interaction, enteric-coated mycophenolic acid, GI complications, mycophenolate mofetil, solid organ transplant, and proton pump inhibitor, including individual agents within the class. Abstracts from scientific meetings were also evaluated. Additionally, reference citations from identified publications were reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language, original research articles and review articles were evaluated if they focused on any of the topics identified in the search or included substantial content addressing GI complications in SOT recipients or drug interactions. DATA SYNTHESIS: GI complications are frequent among SOT recipients, with some studies showing prevalence rates as high as 70%. Transplant outcomes among renal transplant recipients are significantly impacted by GI complications, especially in patients requiring immunosuppressant dosage reductions or premature discontinuation. To this end, PPI use among patients receiving transplants is common. Recent data demonstrate that PPIs significantly reduce the overall exposure to MPA after oral administration of mycophenolate mofetil. Similar studies show this interaction does not exist between PPIs and enteric-coated mycophenolic acid (EC-MPA). Unfortunately, most of the available data evaluating this interaction are pharmacokinetic analyses that do not investigate the clinical impact of this interaction. CONCLUSIONS: A significant interaction exists between PPIs and mycophenolate mofetil secondary to reduced dissolution of mycophenolate mofetil in higher pH environments. EC-MPA is not absorbed in the stomach; therefore, low intragastric acidity does not impact EC-MPA and bioavailability is maintained with this formulation during PPI coadministration. The clinical impact of this interaction is unknown, yet one can theorize that reduced exposure to MPA in SOT recipients can increase the risk of allograft rejection and/or failure.

The Clinical and Economic Benefit of CMV Matching in Kidney Transplant: A Decision Analysis.

BACKGROUND: The development of cytomegalovirus (CMV) infection after kidney transplant remains a significant cause of posttransplant morbidity, graft loss, and mortality. Despite appropriate antiviral therapy, recipients without previous CMV exposure can currently be allocated a kidney from a donor with previous CMV infection (D+R-) that carries the greatest risk of posttransplant CMV infection and associated complications. Preferential placement of CMV D- organs in negative recipients (R-) has been shown to reduce the risk of viral infection and associated complications. METHODS: To assess the long-term survival and economic benefits of allocation policy reforms, a decision-analytic model was constructed to compare receipt of CMV D- with CMV D+ organ in CMV R- recipients using data from transplant registry, Medicare claims, and pharmaceutical costs. RESULTS: For CMV R- patients, receipt of a CMV D- organ was associated with greater average survival (14.3 versus 12.6 y), superior quality-adjusted life years (12.6 versus 9.8), and lower costs ($529 512 versus $542 963). One-way sensitivity analysis demonstrated a survival advantage for patients waiting as long as 30 mo for a CMV D- kidney. CONCLUSIONS: Altering national allocation policy to preferentially offer CMV D- organs to CMV R- recipients could improve survival and lower costs after transplant if appropriately implemented.

A quantitative approach to drug dosing in chronic kidney disease.

Chronic kidney disease (CKD) is increasing at an alarming rate. Medication prescribing in this growing population is especially difficult. Many pharmacological agents or their metabolites are eliminated unchanged through the kidney. Drug dosing in CKD is challenging as most patients have a number of comorbid conditions. Patients with CKD take pharmacological agents with potential for drug interactions. Most patients also have alterations to the normal functioning of a number of different organs or systems (e.g. heart, liver, gastrointestinal system) which affect pharmacokinetics of commonly used drugs in CKD. Pharmacokinetic behaviors of most drugs are highly variable in patients with CKD. In addition, pharmacological management of patients with CKD is imprecise and requires estimating renal function, applying clinical judgment and, if available, therapeutic drug monitoring to provide adequate pharmacotherapeutic concentrations to optimize pharmacodynamic response while minimizing toxicities. For drugs that are removed through the renal system unchanged, a dosing modification should be considered according to patient- and drug-specific factors. Renal replacement therapy and dialysis remove pharmacologic agents extensively, and thus a replacement dose is needed to avoid therapeutic failure. By applying a quantitative approach, health care providers can improve pharmacotherapeutic outcomes while reducing adverse drug reactions.

Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry.

BACKGROUND: Candidemia remains a major cause of morbidity and mortality in the health care setting, and the epidemiology of Candida infection is changing. METHODS: Clinical data from patients with candidemia were extracted from the Prospective Antifungal Therapy (PATH) Alliance database, a comprehensive registry that collects information regarding invasive fungal infections. A total of 2019 patients, enrolled from 1 July 2004 through 5 March 2008, were identified. Data regarding the candidemia episode were analyzed, including the specific fungal species and patient survival at 12 weeks after diagnosis. RESULTS: The incidence of candidemia caused by non-Candida albicans Candida species (54.4%) was higher than the incidence of candidemia caused by C. albicans (45.6%). The overall, crude 12-week mortality rate was 35.2%. Patients with Candida parapsilosis candidemia had the lowest mortality rate (23.7%; P<.001) and were less likely to be neutropenic (5.1%; P<.001) and to receive corticosteroids (33.5%; P<.001) or other immunosuppressive drugs (7.9%; P=.002), compared with patients infected with other Candida species. Candida krusei candidemia was most commonly associated with prior use of antifungal agents (70.6%; P<.001), hematologic malignancy (52.9%; P<.001) or stem cell transplantation (17.7%; P<.001), neutropenia (45.1%; P<.001), and corticosteroid treatment (60.8%; P<.001). Patients with C. krusei candidemia had the highest crude 12-week mortality in this series (52.9%; P<.001). Fluconazole was the most commonly administered antimicrobial, followed by the echinocandins, and amphotericin B products were infrequently administered. CONCLUSIONS: The epidemiology and choice of therapy for candidemia are rapidly changing. Additional study is warranted to differentiate host factors and differences in virulence among Candida species and to determine the best therapeutic regimen.

Presentation of the PATH Alliance registry for prospective data collection and analysis of the epidemiology, therapy, and outcomes of invasive fungal infections.

Randomized clinical trials for patients with invasive fungal infections (IFIs) are often limited or precluded, necessitating alternate sources of information. The Prospective Antifungal Therapy Alliance (PATH Alliance) is a registry that collects data on patients with IFIs at medical centers in North America. Patients with a diagnosis of proven or probable IFI are enrolled and followed prospectively for 12 weeks. Using a Web-based electronic data capture and reporting system, the registry collects anonymous data to address end points in epidemiology, diagnosis, treatment, and outcome of IFIs. As of October 2006, 1892 IFIs were observed in 1710 patients enrolled at 22 sites. The most commonly encountered IFIs were caused by Candida spp. (73.0%), presenting predominantly as candidemia, followed by Aspergillus spp. (14.8%). A small number of IFIs with uncommon and emerging moulds were observed. Culture remains the main diagnostic tool for most IFIs (91.8%). Antifungal agent choice depended on the fungal species isolated, with fluconazole being the most frequently administered agent (58.2%). The overall crude 12-week mortality, excluding the patients lost to follow-up, was 43.9%. PATH Alliance is a network of medical institutions gathering significant information about IFIs in North America. Significant trends and treatment practices concerning yeasts and moulds were observed. As enrollment continues, additional data will be analyzed and published, which will provide valuable information concerning the epidemiology, therapy, and outcomes of IFIs.

Detecting unstable periodic orbits in chaotic time series using synchronization.

An alternative approach of detecting unstable periodic orbits in chaotic time series is proposed using synchronization techniques. A master-slave synchronization scheme is developed, in which the chaotic system drives a system of harmonic oscillators through a proper coupling condition. The proposed scheme is designed so that the power of the coupling signal exhibits notches that drop to zero once the system approaches an unstable orbit yielding an explicit indication of the presence of a periodic motion. The results shows that the proposed approach is particularly suitable in practical situations, where the time series is short and noisy, or it is obtained from high-dimensional chaotic systems.

Hepatitis C infection increases the risk of new-onset diabetes after transplantation in liver allograft recipients.

BACKGROUND: Recent evidence suggests that new-onset diabetes after transplant (NODAT) adversely affects orthotopic liver transplant (OLTX) patient and graft survival. The objective of this study is to evaluate the effect of hepatitis C infection on the natural history of NODAT. METHODS: A retrospective review of 492 OLTX recipients at a single center was conducted from January 1993 to January 2003. Patients were followed for a minimum of 12 months (range 12 months-10 years). The study population consisted of 444 OLTX recipients who were either HCV positive (n = 206) or HCV negative (n = 238). NODAT was defined by the need for antidiabetic medication for at least 7 days starting anytime after OLTX. Statistical analysis was performed by using the Student t test, Kaplan-Meier survival, and chi-square tests. RESULTS: The overall incidence of NODAT was 33% (146/444). There was a significant difference in the development of NODAT between the HCV-positive group (82/206, 40%) and the HCV-negative group (64/238, 27%) (P < .001). Other independent risk factors for development of NODAT were male gender and age >50 years. CONCLUSION: Hepatitis C infection contributes to the development of diabetes mellitus in OLTX recipients. The mechanisms behind HCV infection and associated NODAT in HCV-positive OLTX recipients warrant further investigation.

Controlling chaos using a system of harmonic oscillators.

An effective method of controlling chaos is proposed. The control mechanism of the proposed method can be interpreted as the synchronization of a chaotic system with a system of harmonic oscillators. It is a practically noninvasive method that does not change the solution of dynamical systems, but stabilizes their periodic behavior by applying only small perturbations. The proposed method has fairly simple structure that suggests a clear stabilizing mechanism, and allows a straightforward evaluation of stability properties. This control scheme can be implemented experimentally even if the dynamical system is not analytically known. The efficiency of the proposed method is demonstrated through numerical simulation as well as experimental implementation.

High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure.

HYPOTHESIS: The use of potentially hepatotoxic herbal and dietary supplements is highly prevalent in the fulminant hepatic failure (FHF) patient population at our institution, and this subgroup of patients has a worse prognosis. DESIGN: Retrospective case series. Settings An adult tertiary care university hospital and a Veterans Affairs hospital in Oregon. PATIENTS: All patients referred to the liver transplantation service for FHF from January 2001 through October 2002 (N = 20). We defined FHF as onset of encephalopathy within 8 weeks of onset of jaundice in the absence of preexisting liver disease. All patients underwent investigation for potential causes of liver injury. Potentially hepatotoxic supplements were defined as those with previously published reports of hepatic injury related to their use. RESULTS: Ten patients (50%) were recent or active users of potentially hepatotoxic supplements or herbs; 10 had no history of supplement use. In the supplement group, 7 patients (35%) had no other identified cause for hepatic failure. Six patients in the supplement group and 2 patients in the nonsupplement group underwent orthotopic liver transplantation. Five patients in each group died. There were no significant differences in transplantation rate (P =.07) or survival (P>.99) between groups. Supplement use alone accounted for the most cases of FHF during this period, exceeding acetaminophen toxicity and viral hepatitis. CONCLUSIONS: Herbal and dietary supplements were potential hepatotoxins in a high proportion of patients with FHF at our institution. Enhanced public awareness of the potential hepatotoxicity of these commonly used agents and increased regulatory oversight of their use is strongly urged.