Association of physical activity with fractures in kidney transplant recipients: A Korean nationwide cohort study.

Kidney transplant recipients are at high risk for fractures, primarily due to post-transplant bone disease. This retrospective cohort study analyzed data from the Korean National Health Insurance Service, including 10 083 kidney transplant recipients examined from 2009 to 2017. We assessed fracture incidence, emphasizing vertebral and hip fractures, and the association of physical activity and traditional risk factors with fracture risk. Kidney transplant recipients were categorized into three groups according to physical activity levels: non-activity, metabolic equivalent of task (MET) 1-499, and MET ≥500. Physical activity was associated with a decreased risk of all types of fractures: any (MET 1-499: adjusted hazard ratio (aHR) .75; 95% confidence interval (CI) .62-.92, MET ≥500: aHR .84; 95% CI .70-1.00), vertebral (MET 1-499: aHR .69; 95% CI .49-.98, MET ≥500: aHR .67; 95% CI .49-.91), and hip (MET 1-499: aHR .43; 95% CI .23-.81) fractures. Additionally, older age, female sex, and diabetes were associated with an increased fracture risk. The assessment of physical activity and traditional risk factors could improve fracture risk prediction. Our findings emphasize the need for further research to establish optimal physical activity recommendations for fracture prevention in kidney transplant recipients.

Role of quorum sensing and quorum quenching in anaerobic digestion: A scoping review.

Anaerobic digestion (AD) is a biological process that employs anaerobic microorganisms to degrade organic material, yielding biogas and biofertilizers. Understanding quorum sensing (QS) signaling in mixed microbial systems provides valuable insights into microbial behavior and functions. This review aims to examine recent studies on the roles of QS and QQ in the AD processes. A QS signal molecule, N-acyl homoserine lactone (AHL), induce the production of extraceluller polymers, promoting biofilm formation and bacterial aggregation, thereby the efficiency of AD process. QS-assisted granule formation fosters syntrophy between acetogens and methanogens, leading to increased organic removal and methane production. Specific AHLs were shown to be correlated with the abundance of hydrolytic bacteria and acidogens, further benefiting methane production. QQ was shown to effectively control membrane fouling in anaerobic membrane bioreactors, yet its impact on methane productivity remains unclear. This review shed lights on the existing literature gaps regarding the mechanisms of QS and QQ in AD systems, which will play a vital role in advancing AD applications in the future.

Characterization of the structural determinants of the ubiquitin-dependent proteasomal degradation of human hepatic tryptophan 2,3-dioxygenase.

Human hepatic tryptophan 2,3-dioxygenase (hTDO) is a homotetrameric hemoprotein. It is one of the most rapidly degraded liver proteins with a half-life (t1/2) of ∼2.3 h, relative to an average t1/2 of ∼2-3 days for total liver protein. The molecular mechanism underlying the poor longevity of hTDO remains elusive. Previously, we showed that hTDO could be recognized and ubiquitinated by two E3 ubiquitin (Ub) ligases, gp78/AMFR and CHIP, and subsequently degraded via Ub-dependent proteasomal degradation pathway. Additionally, we identified 15 ubiquitination K-sites and demonstrated that Trp-binding to an exosite impeded its proteolytic degradation. Here, we further established autophagic-lysosomal degradation as an alternative back-up pathway for cellular hTDO degradation. In addition, with protein kinases A and C, we identified 13 phosphorylated Ser/Thr (pS/pT) sites. Mapping these pS/pT sites on the hTDO surface revealed their propinquity to acidic Asp/Glu (D/E) residues engendering negatively charged DEpSpT clusters vicinal to the ubiquitination K-sites over the entire protein surface. Through site-directed mutagenesis of positively charged patches of gp78, previously documented to interact with the DEpSpT clusters in other target proteins, we uncovered the likely role of the DEpSpT clusters in the molecular recognition of hTDO by gp78 and plausibly other E3 Ub-ligases. Furthermore, cycloheximide-chase analyses revealed the critical structural relevance of the disordered N- and C-termini not only in the Ub-ligase recognition, but also in the proteasome engagement. Together, the surface DEpSpT clusters and the N- and C-termini constitute an intrinsic bipartite degron for hTDO physiological turnover.

Maintenance of the critical care system during the pandemic in non-COVID-19 patients requiring continuous renal replacement therapy: a single center experience.

BACKGROUND: During the COVID-19 pandemic, maintenance of essential healthcare systems became very challenging. We describe the triage system of our institute, and assess the quality of care provided to critically ill non-COVID-19 patients requiring continuous renal replacement therapy (CRRT) during the pandemic. METHODS: We introduced an emergency triage pathway early in the pandemic. We retrospectively reviewed the medical records of patients who received CRRT in our hospital from January 2016 to March 2021. We excluded end-stage kidney disease patients on maintenance dialysis. Patients were stratified as medical and surgical patients. The time from hospital arrival to intensive care unit (ICU) admission, the time from hospital arrival to intervention/operation, and the in-hospital mortality rate were compared before (January 2016 to December 2019) and during (January 2021 to March 2021) the pandemic. RESULTS: The mean number of critically ill patients who received CRRT annually in the surgical department significantly decreased during the pandemic in (2016-2019: 76.5 ± 3.1; 2020: 56; p < 0.010). Age, sex, and the severity of disease at admission did not change, whereas the proportions of medical patients with diabetes (before: 44.4%; after: 56.5; p < 0.005) and cancer (before: 19.4%; after: 32.3%; p < 0.001) increased during the pandemic. The time from hospital arrival to ICU admission and the time from hospital arrival to intervention/operation did not change. During the pandemic, 59.6% of surgical patients received interventions/operations within 6 hours of hospital arrival. In Cox's proportional hazard modeling, the hazard ratio associated with the pandemic was 1.002 (0.778-1.292) for medical patients and 1.178 (0.783-1.772) for surgical patients. CONCLUSION: Our triage system maintained the care required by critically ill non-COVID-19 patients undergoing CRRT at our institution.

Induction via Functional Protein Stabilization of Hepatic Cytochromes P450 upon gp78/Autocrine Motility Factor Receptor (AMFR) Ubiquitin E3-Ligase Genetic Ablation in Mice: Therapeutic and Toxicological Relevance.

The hepatic endoplasmic reticulum (ER)-anchored monotopic proteins, cytochromes P450 (P450s), are enzymes that metabolize endobiotics (physiologically active steroids and fatty acids), as well as xenobiotics including therapeutic/chemotherapeutic drugs, nutrients, carcinogens, and toxins. Alterations of hepatic P450 content through synthesis, inactivation, or proteolytic turnover influence their metabolic function. P450 proteolytic turnover occurs via ER-associated degradation (ERAD) involving ubiquitin (Ub)-dependent proteasomal degradation (UPD) as a major pathway. UPD critically involves P450 protein ubiquitination by E2/E3 Ub-ligase complexes. We have previously identified the ER-polytopic gp78/AMFR (autocrine motility factor receptor) as a relevant E3 in CYP3A4, CYP3A23, and CYP2E1 UPD. We now document that liver-conditional genetic ablation of gp78/AMFR in male mice disrupts P450 ERAD, resulting in statistically significant stabilization of Cyp2a5 and Cyp2c, in addition to that of Cyp3a and Cyp2e1. More importantly, we establish that such stabilization is of the functionally active P450 proteins, leading to corresponding statistically significant enhancement of their drug-metabolizing capacities. Our findings, with clinically relevant therapeutic drugs (nicotine, coumarin, chlorzoxazone, and acetaminophen) and the prodrug (tamoxifen) as P450 substrates, reveal that P450 ERAD disruption could influence therapeutic drug response and/or toxicity, warranting serious consideration as a potential source of clinically relevant drug-drug interactions (DDIs). Because gp78/AMFR is not only an E3 Ub-ligase, but also a cell-surface prometastatic oncogene that is upregulated in various malignant cancers, our finding that hepatic gp78/AMFR knockout can enhance P450-dependent bioactivation of relevant cancer chemotherapeutic prodrugs is of therapeutic relevance and noteworthy in prospective drug design and development. SIGNIFICANCE STATEMENT: The cell-surface and ER transmembrane protein gp78/AMFR, a receptor for the prometastatic autocrine motility factor (AMF), as well as an E3 ubiquitin-ligase involved in the ER-associated degradation (ERAD) of not only the tumor metastatic suppressor KAI1 but also of hepatic cytochromes P450, is upregulated in various human cancers, enhancing their invasiveness, metastatic potential, and poor prognosis. Liver-specific gp78/AMFR genetic ablation results in functional protein stabilization of several hepatic P450s and consequently enhanced drug and prodrug metabolism, a feature that could be therapeutically exploited in the bioactivation of chemotherapeutic prodrugs through design and development of novel short-term gp78/AMFR chemical inhibitors.

Human liver cytochrome P450 3A4 ubiquitination: molecular recognition by UBC7-gp78 autocrine motility factor receptor and UbcH5a-CHIP-Hsc70-Hsp40 E2-E3 ubiquitin ligase complexes.

CYP3A4 is an abundant and catalytically dominant human liver endoplasmic reticulum-anchored cytochrome P450 enzyme engaged in the biotransformation of endo- and xenobiotics, including >50% of clinically relevant drugs. Alterations of CYP3A4 protein turnover can influence clinically relevant drug metabolism and bioavailability and drug-drug interactions. This CYP3A4 turnover involves endoplasmic reticulum-associated degradation via the ubiquitin (Ub)-dependent 26 S proteasomal system that relies on two highly complementary E2 Ub-conjugating-E3 Ub-ligase (UBC7-gp78 and UbcH5a-C terminus of Hsc70-interacting protein (CHIP)-Hsc70-Hsp40) complexes, as well as protein kinases (PK) A and C. We have documented that CYP3A4 Ser/Thr phosphorylation (Ser(P)/Thr(P)) by PKA and/or PKC accelerates/enhances its Lys ubiquitination by either of these E2-E3 systems. Intriguingly, CYP3A4 Ser(P)/Thr(P) and ubiquitinated Lys residues reside within the cytosol-accessible surface loop and/or conformationally assembled acidic Asp/Glu clusters, leading us to propose that such post-translational Ser/Thr protein phosphorylation primes CYP3A4 for ubiquitination. Herein, this possibility was examined through various complementary approaches, including site-directed mutagenesis, chemical cross-linking, peptide mapping, and LC-MS/MS analyses. Our findings reveal that such CYP3A4 Asp/Glu/Ser(P)/Thr(P) surface clusters are indeed important for its intermolecular electrostatic interactions with each of these E2-E3 subcomponents. By imparting additional negative charge to these Asp/Glu clusters, such Ser/Thr phosphorylation would generate P450 phosphodegrons for molecular recognition by the E2-E3 complexes, thereby controlling the timing of CYP3A4 ubiquitination and endoplasmic reticulum-associated degradation. Although the importance of phosphodegrons in the CHIP targeting of its substrates is known, to our knowledge this is the first example of phosphodegron involvement in gp78-substrate recruitment, an important step in CYP3A4 proteasomal degradation.

Hepatic cytochromes P450: structural degrons and barcodes, posttranslational modifications and cellular adapters in the ERAD-endgame.

The endoplasmic reticulum (ER)-anchored hepatic cytochromes P450 (P450s) are enzymes that metabolize endo- and xenobiotics i.e. drugs, carcinogens, toxins, natural and chemical products. These agents modulate liver P450 content through increased synthesis or reduction via inactivation and/or proteolytic degradation, resulting in clinically significant drug-drug interactions. P450 proteolytic degradation occurs via ER-associated degradation (ERAD) involving either of two distinct routes: Ubiquitin (Ub)-dependent 26S proteasomal degradation (ERAD/UPD) or autophagic lysosomal degradation (ERAD/ALD). CYP3A4, the major human liver/intestinal P450, and the fast-turnover CYP2E1 species are degraded via ERAD/UPD entailing multisite protein phosphorylation and subsequent ubiquitination by gp78 and CHIP E3 Ub-ligases. We are gaining insight into the nature of the structural determinants involved in CYP3A4 and CYP2E1 molecular recognition in ERAD/UPD [i.e. K48-linked polyUb chains and linear and/or "conformational" phosphodegrons consisting either of consecutive sequences on surface loops and/or disordered regions, or structurally-assembled surface clusters of negatively charged acidic (Asp/Glu) and phosphorylated (Ser/Thr) residues, within or vicinal to which, Lys-residues are targeted for ubiquitination]. Structural inspection of select human liver P450s reveals that such linear or conformational phosphodegrons may indeed be a common P450-ERAD/UPD feature. By contrast, although many P450s such as the slow-turnover CYP2E1 species and rat liver CYP2B1 and CYP2C11 are degraded via ERAD/ALD, little is known about the mechanism of their ALD-targeting. On the basis of our current knowledge of ALD-substrate targeting, we propose a tripartite conjunction of K63-linked Ub-chains, P450 structural "LIR" motifs and selective cellular "cargo receptors" as plausible P450-ALD determinants.

Hepatic cytochrome P450 ubiquitination: conformational phosphodegrons for E2/E3 recognition?

Hepatic endoplasmic reticulum (ER) integral cytochromes P450 (P450s) are monooxygenases engaged in the biotransformation and elimination of endo- as well as xenobiotics. Of the human liver P450s, CYP3A4 is the major and most dominant catalyst responsible for the biotransformation of over 50% of clinically prescribed drugs. CYP2E1 metabolizes smaller molecular weight compounds (EtOH), carcinogens, environmental toxins, and endobiotics, and is justly implicated in various toxigenic/pathogenic mechanisms of human disease. Both P450s are notorious for their potential to generate pathogenic reactive oxygen species (ROS) during futile oxidative cycling and/or oxidative uncoupling. Such ROS not only oxidatively damage the P450 catalytic cage, but on their escape into the cytosol, also the P450 outer surface and any surrounding cell organelles. Given their ER-monotopic topology coupled with this high potential to acquire oxidative lesions in their cytosolic (C) domain, not surprisingly these P450 proteins exhibit shorter lifespans and are excellent prototype substrates of ER-associated degradation ("ERAD-C") pathway. Indeed, we have shown that both CYP3A4 and CYP2E1 incur ERAD-C, during which they are first phosphorylated by protein kinases A and C, which greatly enhance/accelerate their ubiquitination by UBC7/gp78 and UbcH5a/CHIP/Hsp70/Hsp40 E2/E3 ubiquitin ligase complexes. Such P450 phosphorylation occurs on Ser/Thr residues within linear sequences as well as spatially clustered acidic (Asp/Glu) residues. We propose that such S/T phosphorylation within these clusters creates negatively charged patches or conformational phosphodegrons for interaction with positively charged E2/E3 domains. Such P450 S/T phosphorylation we posit serves as a molecular switch to turn on its ubiquitination and ERAD-C.

Enhancement of biomethane recovery from batch anaerobic digestion by exogenously adding an N-acyl homoserine lactone cocktail.

Biomethane recovered through anaerobic digestion (AD) is a renewable, sustainable, and cost-effective alternative energy source that has the potential to help address rising energy demands. Efficient bioconversion during AD depends on the symbiotic relationship between hydrolytic bacteria and methanogenic archaea. Interactions between microorganisms occur in every biological system via a phenomenon known as quorum sensing (QS), in which signaling molecules are simultaneously transmitted and detected as a mode of cell-to-cell communication. However, there's still a lack of understanding on how QS works in the AD system, where diverse bacteria and archaea interact in a complex manner. In this study, different concentrations (0.5 and 5 µM) of signaling molecules in the form of an N-acyl homoserine lactone cocktail (C6-, C8-, C10-, and 3-oxo-C6-HSL) were prepared and introduced into anaerobic batch reactors to clearly assess how QS affects AD systems. It was observed that the methane yield increased with the addition of AHLs: a 5 µM AHL cocktail improved the methane yield (341.9 mL/g-COD) compared to the control without AHLs addition (285.9 mL/g-COD). Meanwhile, evidence of improved microbial growth and cell aggregation was noticed in AHLs-supplemented systems. Our findings also show that exogenously adding AHLs alters the microbial community structure by increasing the overall bacterial and archaeal population counts while favoring the growth of the methanogenic archaea group, which is essential in biomethane synthesis.

Complete Genome Sequence of Ralstonia solanacearum Strain Bs715, a Member of Biovar 4 and a Strong Pathogen of Bacterial Wilt on Solanum lycopersicum.

Ralstonia solanacearum is a notorious pathogen of bacterial wilt on Solanum lycopersicum. Most isolates from diseased tomato tissues are biovar 3, and their genomes are publicly available; however, information on biovar 4 strains is limited. Here, the complete genome sequence of R. solanacearum Bs715, a biovar 4 strain, is presented.

Complete Genome Sequence of Ralstonia solanacearum WR-1, a Virulent Strain on Solanum lycopersicum.

Ralstonia solanacearum is a bacterial wilt pathogen of Solanum lycopersicum. Its pathogenicity is the result of coevolution during continuous interaction with its host plants under given biotic and abiotic environments. To elucidate clues for pathogenicity of our WR-1 strain, its genome sequence was analyzed.

Complete Genome Sequence of Ralstonia pseudosolanacearum Strain Sw698, Isolated from Solanum lycopersicum.

Ralstonia pseudosolanacearum is a member of the Ralstonia solanacearum species complex (RSSC), which is composed of three species and diverse subspecific groups. Some strains cause bacterial wilt in Solanum lycopersicum; others are beneficial for their hosts. Herein, we present the complete genome sequence of an RSSC strain, Sw698, beneficial for S. lycopersicum growth.

Regulation of mouse steroidogenesis by WHISTLE and JMJD1C through histone methylation balance.

The dynamic exchange of histone lysine methylation status by histone methyltransferases and demethylases has been previously implicated as an important factor in chromatin structure and transcriptional regulation. Using immunoaffinity TAP analysis, we purified the WHISTLE-interacting protein complexes, which include the heat shock protein HSP90α and the jumonji C-domain harboring the histone demethylase JMJD1C. In this study, we demonstrate that JMJD1C specifically demethylates histone H3K9 mono- and di-methylation, and mediates transcriptional activation. We also provide evidence suggesting that both WHISTLE and JMJD1C performs functions in the development of mouse testes by regulating the expression of the steroidogenesis marker, p450c17, via SF-1-mediated transcription. Furthermore, we demonstrate that WHISTLE is recruited to the p450c17 promoter via SF-1 and represses the transcription of prepubertal stages of steroidogenesis, after which JMJD1C replaces WHISTLE and activates the expression of target genes via SF-1-mediated interactions. Our results demonstrate that the histone methylation balance mediated by HMTase WHISTLE and demethylase JMJD1C perform a transcriptional regulatory function in mouse testis development.

Efficacy of a Tibia Counter Rotator System for the Treatment of Internal Tibial Torsion in Children.

Internal tibial torsion is more common in the Asian population than in Western populations. Generally, surgery should be considered for the treatment of severe internal tibial torsion. As an alternative approach, the usefulness of a tibia counter rotator (TCR), a corrective orthosis based on the theory of the tibia torsional transformer, has been demonstrated, but the evidence is limited. In the present study, the efficacy and safety of TCR treatment were investigated in pediatric patients with internal tibial torsion. The subjects were 124 pediatric patients with internal tibial torsion who were between 3 and 15 years of age and had no underlying diseases. The severity of tibial intorsion was evaluated by the tibial transmalleolar angle (TMA). A TMA less than 5° was defined as internal tibial torsion, and less than −20° was defined as severe in this study. The median duration of TCR use was 11 (9, 12) (median (IQR: interquartile range)) months, and the treatment completion rate was 94.4% (117/124). The TMA at 12 months from the start of treatment in patients who completed treatment was 5° (0°, 10°) on the right (n = 66) (p < 0.01 vs. pretreatment) and 0° (−5°, 8°) on the left (n = 71) (p < 0.01 vs. pretreatment). The tibial torsional transformer used in this study is effective in the initial treatment of mild to severe internal tibial torsion, with no adverse effects. Although internal tibial torsion is generally expected to resolve spontaneously, TCR treatment may be an effective alternative to surgical therapy in the Asian pediatric population.

Worsening or improving hypoalbuminemia during continuous renal replacement therapy is predictive of patient outcome: a single-center retrospective study.

BACKGROUND: Hypoalbuminemia at the initiation of continuous renal replacement therapy (CRRT) is a risk factor for poor patient outcomes. However, it is unknown whether the patterns of changes in serum albumin levels during CRRT can be used to predict patient outcomes. METHODS: This retrospective study analyzed data that had been consecutively collected from January 2016 to December 2020 at the Third Affiliated Hospital. We included patients with acute kidney injury who received CRRT for ≥ 72 h. We divided the patients into four groups based on their serum albumin levels (albumin ≥ 3.0 g/dL or < 3.0 g/dL) at the initiation and termination of CRRT. RESULTS: The 793 patients in this study were categorized into the following albumin groups: persistently low, 299 patients (37.7%); increasing, 85 patients (10.4%); decreasing, 195 patients (24.6%); and persistently high, 214 patients (27.1%). In-hospital mortality rates were highest in the persistently low and decreasing groups, followed by the increasing and persistently high groups. The hazard ratio for in-hospital mortality was 0.481 (0.340-0.680) in the increasing group compared to the persistently low group; it was 1.911 (1.394-2.620) in the decreasing group compared to the persistently high group. The length of ICU stay was 3.55 days longer in the persistently low group than in the persistently high group. CONCLUSIONS: Serum albumin levels changed during CRRT, and monitoring of patterns of change in serum albumin levels is useful for predicting in-hospital mortality and the length of ICU stay.

Liver cytochrome P450 3A ubiquitination in vivo by gp78/autocrine motility factor receptor and C terminus of Hsp70-interacting protein (CHIP) E3 ubiquitin ligases: physiological and pharmacological relevance.

CYP3A4 is a dominant human liver cytochrome P450 enzyme engaged in the metabolism and disposition of >50% of clinically relevant drugs and held responsible for many adverse drug-drug interactions. CYP3A4 and its mammalian liver CYP3A orthologs are endoplasmic reticulum (ER)-anchored monotopic proteins that undergo ubiquitin (Ub)-dependent proteasomal degradation (UPD) in an ER-associated degradation (ERAD) process. These integral ER proteins are ubiquitinated in vivo, and in vitro studies have identified the ER-integral gp78 and the cytosolic co-chaperone, CHIP (C terminus of Hsp70-interacting protein), as the relevant E3 Ub-ligases, along with their cognate E2 Ub-conjugating enzymes UBC7 and UbcH5a, respectively. Using lentiviral shRNA templates targeted against each of these Ub-ligases, we now document that both E3s are indeed physiologically involved in CYP3A ERAD/UPD in cultured rat hepatocytes. Accordingly, specific RNAi resulted in ≈80% knockdown of each hepatic Ub-ligase, with a corresponding ≈2.5-fold CYP3A stabilization. Surprisingly, however, such stabilization resulted in increased levels of functionally active CYP3A, thereby challenging the previous notion that E3 recognition and subsequent ERAD of CYP3A proteins required ab initio their structural and/or functional inactivation. Furthermore, coexpression in HepG2 cells of both CYP3A4 and gp78, but not its functionally inactive RING-finger mutant, resulted in enhanced CYP3A4 loss greater than that in corresponding cells expressing only CYP3A4. Stabilization of a functionally active CYP3A after RNAi knockdown of either of the E3s, coupled with the increased CYP3A4 loss on gp78 or CHIP coexpression, suggests that ERAD-associated E3 Ub-ligases can influence clinically relevant drug metabolism by effectively regulating the physiological CYP3A content and consequently its function.

Bone-added osteotome technique versus lateral approach for sinus floor elevation: a comparative radiographic study.

PURPOSE: The aim of this study was to evaluate and compare the radiographic results of bone-added osteotome sinus floor elevation (BAOSFE) and lateral approach sinus floor elevation techniques. METHODS: The 43 patients who had undergone implant procedure with either BAOSFE or lateral approach method on their maxillary molar edentulous area were included. Their dental records were confirmative and the radiographic-changes using orthopantomographs were consistently checked up during 2 years after the procedure (immediately after procedure and 6 months, 12 months, and 24 months after implant placement). RESULTS: The radiographic evaluation after 2 years of implantation with sinus elevation showed the significant amount of bone formation (6.75 mm for BAOSFE and 11.36 mm for lateral approach method). Largest amount of grafted height loss occurred during the first 6 months (62.8% of total amount of bone loss), but the resorption was minimal (1.35 mm for BAOSFE and 1.36 mm for lateral approach method) for overall 24 months. CONCLUSION: Long-term stability of graft height was achieved using both BAOSFE and lateral approach sinus floor elevation. Overall, graft height decreased gradually during 2 years after procedures, but the changes were minimal.

Pembrolizumab-induced focal segmental glomerulosclerosis: A case report.

RATIONALE: Focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder that leads to end-stage kidney disease. Pembrolizumab, an immune checkpoint inhibitor, is an anti-programmed death 1 (PD-1) immunoglobulin G4 antibody approved for the treatment of advanced melanoma and can cause various renal immune-related adverse events (AEs), including acute kidney injury. Several cases of anti PD-1 therapy-induced glomerulonephritis have been reported so far, but FSGS has seldom been reported. PATIENT CONCERNS: 46-year old woman presented to our hospital with generalized edema. DIAGNOSES: Laboratory examination revealed features of nephrotic syndrome, and kidney biopsy confirmed FSGS. After other etiological factors of secondary FSGS were ruled out, she was diagnosed with FSGS caused by pembrolizumab. INTERVENTIONS: She did not resume treatment with pembrolizumab and was treated with irbesartan and furosemide according to the American Society of Clinical Oncology Practice guidelines. OUTCOMES: After 2 months, the features of nephrotic syndrome resolved. LESSONS: This case provides valuable insight into the etiology of FSGS that can occur as a renal immune-related AE of PD-1 inhibitor therapy. Therefore, patients should undergo evaluation for renal function and urinalysis at baseline and after treatment. If patients treated with PD-1 inhibitors present with renal injury and/or unexplained proteinuria >1 g/day, we would recommend a kidney biopsy to determine the underlying cause and establish an appropriate therapeutic plan.

Immunoglobulin A nephropathy in a patient with neurofibromatosis type 1: A case report and literature review.

RATIONALE: Neurofibromatosis type 1 (NF-1) is an autosomal-dominant neurocutaneous disorder that affects the skin, bones, and nervous system. The most common manifestation of kidney involvement is renal artery stenosis; glomerulonephritis is extremely rare. In this case report, we present a patient with NF-1 and immunoglobulin A nephropathy (IgAN). PATIENT CONCERNS: A 51-year-old Korean man previously diagnosed with NF-1 presented with persistent proteinuria and hematuria identified during a routine medical check-up. He had no history of hypertension or diabetes, and denied a history of alcohol use or smoking. DIAGNOSIS: The contrast-enhanced computed tomography scan revealed normal-sized kidneys and no evidence of renal artery stenosis. On the day of the kidney biopsy, laboratory tests showed a serum creatinine level of 1.1 mg/dL, urine protein/creatinine ratio of 1.3 g/g, and urine red blood cell count of >10 to 15/HPF. The kidney biopsy sample revealed IgAN grade III, according to Lee glomerular grading system. INTERVENTION: The patient was advised to take 4 mg of perindopril. OUTCOME: Three months after the treatment, the urine protein/creatinine ratio decreased to 0.6 g/g, with no change in the serum creatinine level (1.03 mg/dL). LESSONS: A genetic link between NF-1 and IgAN or other glomerular diseases is not established. However, activation of the mTOR pathway may explain this association.

Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications.

The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance. P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover. Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies, we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance. We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury, or viral hepatitis; (ii) discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates; and (iii) detail the pathophysiological consequences of disrupted P450 ERAD, contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions.