Variants in autophagy genes MTMR12 and FAM134A are putative modifiers of the hepatic phenotype in α1-antitrypsin deficiency.

BACKGROUND AND AIMS: In the classical form of α1-antitrypsin deficiency, a misfolded variant α1-antitrypsin Z accumulates in the endoplasmic reticulum of liver cells and causes liver cell injury by gain-of-function proteotoxicity in a sub-group of affected homozygotes but relatively little is known about putative modifiers. Here, we carried out genomic sequencing in a uniquely affected family with an index case of liver failure and 2 homozygous siblings with minimal or no liver disease. Their sequences were compared to sequences in well-characterized cohorts of homozygotes with or without liver disease, and then candidate sequence variants were tested for changes in the kinetics of α1-antitrypsin variant Z degradation in iPS-derived hepatocyte-like cells derived from the affected siblings themselves. APPROACH AND RESULTS: Specific variants in autophagy genes MTMR12 and FAM134A could each accelerate the degradation of α1-antitrypsin variant Z in cells from the index patient, but both MTMR12 and FAM134A variants were needed to slow the degradation of α1-antitrypsin variant Z in cells from a protected sib, indicating that inheritance of both variants is needed to mediate the pathogenic effects of hepatic proteotoxicity at the cellular level. Analysis of homozygote cohorts showed that multiple patient-specific variants in proteostasis genes are likely to explain liver disease susceptibility at the population level. CONCLUSIONS: These results validate the concept that genetic variation in autophagy function can determine susceptibility to liver disease in α1-antitrypsin deficiency and provide evidence that polygenic mechanisms and multiple patient-specific variants are likely needed for proteotoxic pathology.

A Retrospective Analysis of COVID-19-infected Patients with Acute Hepatitis who Develop Acute Liver Failure in a Safety Net Hospital.

OBJECTIVE: In early 2019, a new coronavirus called SARS-CoV-2 emerged and changed the course of civilization. Our study aims to analyze the association between acute liver failure (ALF) and mortality in patients infected with COVID-19. A retrospective analysis of 864 COVID-19-infected patients admitted to Nassau University Medical Center in New York was performed. DESIGN: ALF is identified by acute liver injury (elevations in liver enzymes), hepatic encephalopathy and an international normalised ratio greater than or equal to 1.5. These parameters were analysed via daily blood work and clinical assessment. Multivariate logistic regression model predicting mortality and controlling for confounders such as age, coronary artery disease, intubation, hypertension, diabetes mellitus and acute kidney injury were used to determine the association of ALF with mortality. RESULTS: A total of 624 patients, out of the initial 864, met the inclusion criteria-having acute hepatitis and COVID-19 infection. Of those 624, 43 (6.9%) patients developed ALF during the course of their hospitalisation and their mortality rate was 74.4%. The majority of patients with ALF were male (60.6%). The logistic model predicting death and controlling for confounders shows COVID-19 patients with ALF had a nearly four-fold higher odds of death in comparison to those without ALF (p=0.0063). CONCLUSIONS: Findings from this study suggest that there is a significant association between mortality and the presence of ALF in patients infected with COVID-19. Further investigation into patients with COVID-19 and ALF can lead to enhanced treatment regimens and risk stratification tools, which can ultimately improve mortality rates during these arduous times.

Complicated Traumatic Nerve Injury Treated with Tendon Transfers in a Patient with Myotonic Dystrophy: First Case Report.

CASE: We report a right-handed 37-year-old woman, with myotonic dystrophy type 1 (MD1), presenting with a posterior interosseus nerve injury because of a penetrating trauma in the right forearm. The tendon transfer technique was chosen based on tendon response and functionality of the arms during the surgery. The patient has been able return to her daily life activities with proper fine and gross motor control. CONCLUSION: Despite tendon transfer surgery being a common technique for radial nerve palsy reconstruction, its use has not been extensively described in the literature in patients with muscular dystrophies such as MD1.

Reducing the Complexity of Model-Based MRI Reconstructions via Sparsification.

Model-based reconstruction methods have emerged as a powerful alternative to classical Fourier-based MRI techniques, largely because of their ability to explicitly model (and therefore, potentially overcome) moderate field inhomogeneities, streamline reconstruction from non-Cartesian sampling, and even allow for the use of custom designed non-Fourier encoding methods. Their application in such scenarios, however, often comes with a substantial increase in computational cost, owing to the fact that the corresponding forward model in such settings no longer possesses a direct Fourier Transform based implementation. This paper introduces an algorithmic framework designed to reduce the computational burden associated with model-based MRI reconstruction tasks. The key innovation is the strategic sparsification of the corresponding forward operators for these models, giving rise to approximations of the forward models (and their adjoints) that admit low computational complexity application. This enables overall a reduced computational complexity application of popular iterative first-order reconstruction methods for these reconstruction tasks. Computational results obtained on both synthetic and experimental data illustrate the viability and efficiency of the approach.

Cellular Immunity to Predict the Risk of Cytomegalovirus Infection in Kidney Transplantation: A Prospective, Interventional, Multicenter Clinical Trial.

BACKGROUND: Improving cytomegalovirus (CMV) immune-risk stratification in kidney transplantation is highly needed to establish guided preventive strategies. METHODS: This prospective, interventional, multicenter clinical trial assessed the value of monitoring pretransplant CMV-specific cell-mediated immunity (CMI) using an interferon-γ release assay to predict CMV infection in kidney transplantation. One hundred sixty donor/recipient CMV-seropositive (D+/R+) patients, stratified by their baseline CMV (immediate-early protein 1)-specific CMI risk, were randomized to receive either preemptive or 3-month antiviral prophylaxis. Also, 15-day posttransplant CMI risk stratification and CMI specific to the 65 kDa phosphoprotein (pp65) CMV antigen were investigated. Immunosuppression consisted of basiliximab, tacrolimus, mycophenolate mofetil, and corticosteroids in 80% of patients, whereas 20% received thymoglobulin induction therapy. RESULTS: Patients at high risk for CMV based on pretransplant CMI developed significantly higher CMV infection rates than those deemed to be at low risk with both preemptive (73.3% vs 44.4%; odds ratio [OR], 3.44 [95% confidence interval {CI}, 1.30-9.08]) and prophylaxis (33.3% vs 4.1%; OR, 11.75 [95% CI, 2.31-59.71]) approaches. The predictive capacity for CMV-specific CMI was only found in basiliximab-treated patients for both preemptive and prophylaxis therapy. Fifteen-day CMI risk stratification better predicted CMV infection (81.3% vs 9.1%; OR, 43.33 [95% CI, 7.89-237.96]). CONCLUSIONS: Pretransplant CMV-specific CMI identifies D+/R+ kidney recipients at high risk of developing CMV infection if not receiving T-cell-depleting antibodies. Monitoring CMV-specific CMI soon after transplantation further defines the CMV infection prediction risk. Monitoring CMV-specific CMI may guide decision making regarding the type of CMV preventive strategy in kidney transplantation. CLINICAL TRIALS REGISTRATION: NCT02550639.

Mineral metabolism disorders, vertebral fractures and aortic calcifications in stable kidney transplant recipients: The role of gender (EMITRAL study).

BACKGROUND AND OBJECTIVES: The relationship between mineral metabolism disorders, bone fractures and vascular calcifications in kidney transplant recipients has not been established. METHOD: We performed a cross-sectional study in 727 stable recipients from 28 Spanish transplant clinics. Mineral metabolism parameters, the semi-quantification of vertebral fractures and abdominal aortic calcifications were determined centrally. RESULTS: Vitamin D deficiency (25OHD3<15ng/ml) was more common in female recipients at CKD-T stages I-III (29.6% vs 44.4%; p=0.003). The inverse and significant correlation between 25OHD3 and PTH was gender-specific and women exhibited a steeper slope than men (p=0.01). Vertebral fractures (VFx) with deformity grade ≥2 were observed in 15% of recipients. Factors related to VFx differed by gender; in males, age (OR 1.04; 95% CI 1.01-1.06) and CsA treatment (OR: 3.2; 95% CI: 1.6-6.3); in females, age (OR 1.07; 95% CI: 1.03-1.12) and PTH levels (OR per 100pg/ml increase: 1.27; 95% CI: 1.043-1.542). Abdominal aortic calcifications were common (67.2%) and related to classical risk factors but not to mineral metabolism parameters. CONCLUSIONS: Vitamin D deficiency is more common among female kidney transplant recipients at earlier CKD-T stages, and it contributes to secondary hyperparathyroidism. Prevalent vertebral fractures are only related to high serum PTH levels in female recipients.

New options and perspectives for proteinuria management after kidney transplantation.

Proteinuria has been strongly correlated with reduced function and graft survival in kidney-transplanted patients. Data regarding new strategies in proteinuria treatment and subsequent allograft survival are lacking. Similarities between chronic graft injury and chronic kidney disease (CKD) suggest that the same therapeutic antiproteinuric tools should be effective in kidney-transplanted patients. The classic strategies to decrease proteinuria such as blood pressure control, nicotine cessation, low-salt diet, and maintaining an ideal body weight seem to be not enough to achieve proteinuria control. Improvements in our understanding of the pathogenesis of CKD have led to the identification of several novel targets for proteinuria management. In this review, we discuss novel pharmacological approaches that aim to decrease proteinuria in CKD patients, including the use of direct renin inhibitors, vitamin D analogs, pentoxifylline, and endothelin receptor antagonists. We also discuss the promise of using antifibrotic agents to treat proteinuria. The identification of new biomarkers of CKD and its progression can help in the selection of the most effective treatment for decreasing proteinuria and maintaining kidney function.

Renal transplantation in patients with hepatitis C virus antibody. A long national experience.

Background. Renal transplantation is the best therapy for patients with hepatitis C virus (HCV) infection with end-stage renal disease. Patient and graft survival are lower in the long term compared with HCV-negative patients. The current study evaluated the results of renal transplantation in Spain in a long period (1990-2002), focusing on graft failure.Methods. Data on the Spanish Chronic Allograft Nephropathy Study Group including 4304 renal transplant recipients, 587 of them with HCV antibody, were used to estimate graft and patient survival at 4 years with multivariate Cox models.Results. Among recipients alive with graft function 1 year post-transplant, the 4-year graft survival was 92.8% in the whole group; this was significantly better in HCV-negative vs HCV-positive patients (94.4% vs 89.5%, P < 0.005). Notably, HCV patients showed more acute rejection, a higher degree of proteinuria accompanied by a diminution of renal function, more graft biopsies and lesions of de novo glomerulonephritis and transplant glomerulopathy. Serum creatinine and proteinuria at 1 year, acute rejection, HCV positivity and systolic blood pressure were independent risk factors for graft loss. Patient survival was 96.3% in the whole group, showing a significant difference between HCV-negative vs HCV-positive patients (96.6% vs 94.5%, P < 0.05). Serum creatinine and diastolic blood pressure at 1 year, HCV positivity and recipient age were independent risk factors for patient death.Conclusions. Renal transplantation is an effective therapy for HCV-positive patients with good survival but inferior than results obtained in HCV-negative patients in the short term. Notably, HCV-associated renal damage appears early with proteinuria, elevated serum creatinine showing chronic allograft nephropathy, transplant glomerulopathy and, less frequently, HCV-associated de novo glomerulonephritis. We suggest that HCV infection should be recognized as a true risk factor for graft failure, and preventive measures could include pre-transplant therapy with interferon.