Liver Disease-Associated Glomerulopathies.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infect a significant number of individuals globally and their extra-hepatic manifestations, including glomerular disease, are well established. Additionally, liver disease-associated IgA nephropathy is the leading cause of secondary IgA nephropathy with disease course varying from asymptomatic urinary abnormalities to progressive kidney injury. Herein we provide an updated review on the epidemiology, pathogenesis, clinical manifestations, and treatment of HBV- and HCV-related glomerulonephritis as well as IgA nephropathy in patients with liver disease. The most common HBV-related glomerulonephritis is membranous nephropathy, although membranoproliferative glomerulonephritis and podocytopathies have been described. The best described HCV-related glomerulonephritis is cryoglobulinemic glomerulonephritis occurring in about 30% of patients with mixed cryoglobulinemic vasculitis. The mainstay of treatment for HBV-GN and HCV-GN is antiviral therapy, with significant improvement in outcomes since the emergence of the direct-acting antivirals. However, cases with severe pathology and/or a more aggressive disease trajectory can be offered a course of immunosuppression, commonly anti-CD20 therapy, particularly in the case of cryoglobulinemic glomerulonephritis.

Microbial lipopeptides: their pharmaceutical and biotechnological potential, applications, and way forward.

As lead molecules, cyclic lipopeptides with antibacterial, antifungal, and antiviral properties have garnered a lot of attention in recent years. Because of their potential, cyclic lipopeptides have earned recognition as a significant class of antimicrobial compounds with applications in pharmacology and biotechnology. These lipopeptides, often with biosurfactant properties, are amphiphilic, consisting of a hydrophilic moiety, like a carboxyl group, peptide backbone, or carbohydrates, and a hydrophobic moiety, mostly a fatty acid. Besides, several lipopeptides also have cationic groups that play an important role in biological activities. Antimicrobial lipopeptides can be considered as possible substitutes for antibiotics that are conventional to address the current drug-resistant issues as pharmaceutical industries modify the parent antibiotic molecules to render them more effective against antibiotic-resistant bacteria and fungi, leading to the development of more resistant microbial strains. Bacillus species produce lipopeptides, which are secondary metabolites that are amphiphilic and are typically synthesized by non-ribosomal peptide synthetases (NRPSs). They have been identified as potential biocontrol agents as they exhibit a broad spectrum of antimicrobial activity. A further benefit of lipopeptides is that they can be produced and purified biotechnologically or biochemically in a sustainable manner using readily available, affordable, renewable sources without harming the environment. In this review, we discuss the biochemical and functional characterization of antifungal lipopeptides, as well as their various modes of action, method of production and purification (in brief), and potential applications as novel antibiotic agents.

AI Can Improve the Economics of Blindness Prevention in Canada.

Diabetic retinopathy is a leading cause of vision loss in Canada and creates significant economic and social burden on patients. Diabetic retinopathy is largely a preventable complication of diabetes mellitus. Yet, hundreds of thousands of Canadians continue to be at risk and thousands go on to develop vision loss and disability. Blindness has a significant impact on the Canadian economy, on families and the quality of life of affected individuals. This paper provides an economic analysis on two potential interventions for preventing blindness and concludes that use of AI to identify high-risk individuals could significantly decrease the costs of identifying, recalling, and screening patients at risk of vision loss, while achieving similar results as a full-fledged screening and recall program. We propose that minimal data interoperability between optometrists and family physicians combined with artificial intelligence to identify and screen those at highest risk of vision loss can lower the costs and increase the feasibility of screening and treating large numbers of patients at risk of going blind in Canada.

Kidney Dysfunction in the Setting of Liver Failure: Core Curriculum 2024.

Individuals with liver disease are susceptible to pathophysiological derangements that lead to kidney dysfunction. Patients with advanced cirrhosis and acute liver failure (ALF) are at risk of developing acute kidney injury (AKI). Hepatorenal syndrome type 1 (HRS-1, also called HRS-AKI) constitutes a form of AKI unique to the state of cirrhosis and portal hypertension. Although HRS-1 is a condition primarily characterized by marked renal vasoconstriction and kidney hypoperfusion, other pathogenic processes, such as acute tubular injury and renal vein congestion, can overlap and further complicate the course of HRS-1. ALF can lead to AKI through mechanisms that involve systemic inflammation, direct drug toxicity, or bile acid-induced tubulopathy. In addition, the growing prevalence of nonalcoholic steatohepatitis is changing the spectrum of chronic kidney disease in cirrhosis. In this installment of AJKD's Core Curriculum in Nephrology, we explore the underpinnings of how cirrhosis, ALF, acute cholestasis, and post-liver transplantation can be associated with various forms of acute, subacute, or chronic kidney diseases. We navigate through the recommended therapies for each condition, including supportive care, pharmacological interventions, kidney replacement therapy, and organ transplantation. Finally, key acid-base and electrolyte disorders associated with hepatobiliary disease are also summarized.

Prevalence and Overlap of Cardiac, Renal, and Metabolic Conditions in US Adults, 1999-2020.

Importance: Individually, cardiac, renal, and metabolic (CRM) conditions are common and leading causes of death, disability, and health care-associated costs. However, the frequency with which CRM conditions coexist has not been comprehensively characterized to date. Objective: To examine the prevalence and overlap of CRM conditions among US adults currently and over time. Design, Setting, and Participants: To establish prevalence of CRM conditions, nationally representative, serial cross-sectional data included in the January 2015 through March 2020 National Health and Nutrition Examination Survey (NHANES) were evaluated in this cohort study. To assess temporal trends in CRM overlap, NHANES data between 1999-2002 and 2015-2020 were compared. Data on 11 607 nonpregnant US adults (≥20 years) were included. Data analysis occurred between November 10, 2020, and November 23, 2022. Main Outcomes and Measures: Proportion of participants with CRM conditions, overall and stratified by age, defined as cardiovascular disease (CVD), chronic kidney disease (CKD), type 2 diabetes (T2D), or all 3. Results: From 2015 through March 2020, of 11 607 US adults included in the analysis (mean [SE] age, 48.5 [0.4] years; 51.0% women), 26.3% had at least 1 CRM condition, 8.0% had at least 2 CRM conditions, and 1.5% had 3 CRM conditions. Overall, CKD plus T2D was the most common CRM dyad (3.2%), followed by CVD plus T2D (1.7%) and CVD plus CKD (1.6%). Participants with higher CRM comorbidity burden were more likely to be older and male. Among participants aged 65 years or older, 33.6% had 1 CRM condition, 17.1% had 2 CRM conditions, and 5.0% had 3 CRM conditions. Within this subset, CKD plus T2D (7.3%) was most common, followed by CVD plus CKD (6.0%) and CVD plus T2D (3.8%). The CRM comorbidity burden was disproportionately high among participants reporting non-Hispanic Black race or ethnicity, unemployment, low socioeconomic status, and no high school degree. Among participants with 3 CRM conditions, nearly one-third (30.5%) did not report statin use, and only 4.8% and 3.0% used glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, respectively. Between 1999 and 2020, the proportion of US adults with multiple CRM conditions increased significantly (from 5.3% to 8.0%; P < .001 for trend), as did the proportion having all 3 CRM conditions (0.7% to 1.5%; P < .001 for trend). Conclusions and Relevance: This cohort study found that CRM multimorbidity is increasingly common and undertreated among US adults, highlighting the importance of collaborative and comprehensive management strategies.

Factors contributing to the adverse drug reactions associated with the dipeptidyl peptidase-4 (DPP-4) inhibitors: A scoping review.

BACKGROUND AND AIM: Adverse drug reactions are one of the contributors to increased hospital admission and length of hospital stay. Among the various antidiabetic agents prescribed, dipeptidyl peptidase-4 (DPP-4) inhibitors have gained wide recognition and shown more persistence than other novel hypoglycemic agents. We performed a scoping review to identify the risk factors contributing to the adverse drug reactions with DPP-4 inhibitors. METHODOLOGY: We followed Preferred Reporting Items for Scoping Review (PRISMA-ScR) Guidelines for reporting the findings. Data sources such as PubMed/MEDLINE, Scopus, Embase, and Cochrane were assessed. We included studies that reported the risk factors contributing to the DPP-4 inhibitor-associated adverse drug reactions. The Joanna Briggs Institute (JBI) critical appraisal checklist was used to assess the methodological quality of the studies. RESULTS: Of the 6406 studies retrieved, 11 studies met our inclusion criteria. Of these 11 studies, seven were post-marketing surveillance studies, one nested case-control study, one comparator cohort study, one food and drug administration (FDA) adverse event reporting system (FAERS)-based observational study, and one questionnaire-based cross-sectional survey study. A total of eight factors were identified that contributed to the DPP-4 inhibitor-associated adverse drug reactions. CONCLUSION: The included studies suggested age >65 years, females, grade 4 and 5 renal impairment, concomitant drugs, disease and drug therapy duration, liver disease, non-smokers, and non-hypertension as risk factors. Further studies should be conducted to provide insight into these risk factors so that the appropriate use of DPP-4 inhibitors in the diabetic population can be encouraged to improve the health-related quality of life. PROSPERO REGISTRATION: CRD42022308764.

Clinical and economic outcomes in patients with chronic obstructive pulmonary disease initiating maintenance therapy with tiotropium bromide/olodaterol or fluticasone furoate/umeclidinium/vilanterol.

BACKGROUND: Clinical practice guidelines recommend dual long-acting muscarinic antagonists (LAMAs)/long-acting ß2agonists (LABAs) as maintenance therapy in patients with chronic obstructive pulmonary disease (COPD) and dyspnea or exercise intolerance. Escalation to triple therapy (TT) (LAMA/LABA/inhaled corticosteroid) is conditionally recommended for patients with continued exacerbations on dual LAMA/LABA therapy. Despite this guidance, TT use is widespread across COPD severities, which could impact clinical and economic outcomes. OBJECTIVE: To compare COPD exacerbations, pneumonia events, and disease-related and all-cause health care resource utilization and costs (in 2020 US dollars) in patients initiating fixed-dose combinations of either LAMA/LABA (tiotropium/olodaterol [TIO + OLO]) or TT (fluticasone furoate/umeclidinium/vilanterol [FF + UMEC + VI]). METHODS: This retrospective observational study of administrative claims included patients with COPD aged 40 years or older initiating TIO + OLO or FF + UMEC + VI from June 2015 to November 2019. TIO + OLO and FF + UMEC + VI cohorts in the overall and maintenance-naive populations were 1:1 propensity score matched on baseline demographics, comorbidities, COPD medications, health care resource utilization, and costs. Multivariable regression compared clinical and economic outcomes up to 12 months in FF + UMEC + VI vs TIO + OLO postmatched cohorts. RESULTS: After matching, there were 5,658 and 3,025 pairs in the overall and maintenance-naive populations, respectively. In the overall population, the risk of any (moderate or severe) exacerbation was 7% lower in FF + UMEC + VI vs TIO + OLO initiators (adjusted hazard ratio [aHR] = 0.93; 95% CI = 0.86-1.0; P = 0.047). There was no difference in the adjusted risk of any exacerbation in the maintenance-naive population (aHR = 0.99; 95% CI = 0.88-1.10). Pneumonia risk was not statistically different between cohorts in the overall (aHR = 1.12; 95% CI = 0.98-1.27) and maintenance-naive (aHR = 1.13; 95% CI = 0.95-1.36) populations. COPD- and/or pneumonia-related adjusted total annualized costs (95% CI) were significantly greater for FF + UMEC + VI vs TIO + OLO in the overall ($17,633 [16,661-18,604] vs $14,558 [13,709-15,407]; P < 0.001; differences [% of relative increase] = $3,075 [21.1%]) and maintenancenaive ($19,032 [17,466-20,598] vs $15,004 [13,786-16,223]; P < 0.001; $4,028 [26.8%]) populations, with significantly higher pharmacy costs with FF + UMEC + VI (overall: $6,567 [6,503-6,632] vs $4,729 [4,676-4,783]; P < 0.001; $1,838 [38.9%]; maintenance-naive: $6,642 [6,560-6,724] vs $4,750 [4,676-4,825]; P < 0.001; $1,892 [39.8%]). CONCLUSIONS: A lower risk of exacerbation was observed with FF + UMEC + VI vs TIO + OLO in the overall population but not among the maintenance-naive population. Patients with COPD initiating TIO + OLO had lower annualized costs than FF + UMEC + VI initiators in the overall and maintenance-naive populations. Thus, in the maintenance-naive population, initiation with dual LAMA/LABA therapy per practice guidelines can improve real-world economic outcomes. Study registration number: ClinicalTrials.gov (identifier: NCT05127304). DISCLOSURES: The study was funded by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI). To ensure independent interpretation of clinical study results and enable authors to fulfill their role and obligations under the ICMJE criteria, BIPI grants all external authors access to relevant clinical study data. In adherence with the BIPI Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript in a peer-reviewed journal, regulatory activities are complete and other criteria are met. Dr Sethi has received honoraria/fees for consulting/speaking from Astra-Zeneca, BIPI, and GlaxoSmithKline. He has received consulting fees for serving on data safety monitoring boards from Nuvaira and Pulmotect. He has received consulting fees from Apellis and Aerogen. His institution has received research funds for his participation in clinical trials from Regeneron and AstraZeneca. Ms Palli was an employee of BIPI at the time the study was conducted. Drs Clark and Shaikh are employees of BIPI. Ms Buysman and Mr Sargent are employees and Dr Bengtson was an employee of Optum, which was contracted by BIPI to conduct this study. Dr Ferguson reports grants and personal fees from Boehringer Ingelheim during the conduct of the study; grants from Novartis, Altavant, and Knopp; grants and personal fees from AstraZeneca, Verona, Theravance, Teva, and GlaxoSmithKline; and personal fees from Galderma, Orpheris, Dev.Pro, Syneos, and Ionis outside the submitted work. He was a paid consultant for BIPI for this study. The authors received no direct compensation related to the development of the manuscript. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

Real-world impact of empagliflozin on total cost of care in adults with type 2 diabetes: Results from an outcomes-based agreement.

BACKGROUND: Value-based health care is expanding through payment models such as outcomes-based agreements between manufacturers and payers. OBJECTIVE: To describe the total-cost-of-care outcomes of an outcomes-based agreement evaluating the real-world impact of empagliflozin vs other type 2 diabetes mellitus (T2DM) drugs among all patients with T2DM, with and without cardiovascular disease (within and beyond the requirement of the agreement). METHODS: In this prospective real-world analysis, members from the health plan of an integrated health care delivery system from the commercial and Medicare Advantage lines of business, who qualify under the confines of the contract, were included for analysis. Thus, members aged 18 years and older who were continuously enrolled in the identification (January 1, 2018, to December 31, 2018) and measurement periods (≤1 year post-index) with a T2DM diagnosis were retained. Patients using empagliflozin and empagliflozin-combination drugs constituted the empagliflozin group; those using all other antihyperglycemics, the nonempagliflozin group. Patients with type 1 diabetes, or those using metformin or insulin monotherapy, at index were excluded. Eligible members were followed for up to the earliest occurrence of disenrollment date, discontinuation (60-day medication fill gap allowed) of empagliflozin (or nonempagliflozin containing) medication, or the end of the measurement period. We compared, using Student's t-test and summary statistics (for reporting the outcomes agreement) and a propensity-matched difference-in-difference model (for the followup evaluation beyond the requirement of the agreement), the mean all-cause total cost of care (pharmacy plus medical) per patient per month (PPPM) between the 2 groups, including a subgroup of members with a baseline cardiovascular disease diagnosis. RESULTS: There were 4,577 (3,069 and 1,508 in the commercial and Medicare) and 33,712 (15,571 and 18,141 in the commercial and Medicare) in the empagliflozin and nonempagliflozin groups, respectively. The difference in mean total cost PPPM was $75 lower for empagliflozin vs nonempagliflozin groups, driven mainly by lower medical costs in the empagliflozin group (-$465 PPPM). However, the difference was not statistically significant in the propensity score-matched model. CONCLUSIONS: Although empagliflozin had higher pharmacy costs, the total cost of care for patients with T2DM and with established cardiovascular disease were comparable to the group of patients with all other T2DM, driven mainly by lower medical costs. DISCLOSURES: The authors report no conflicts of interest beyond being employees of the 2 organizations involved in this outcomes-based agreement. Ms. Palli is a former employee of Boehringer Ingelheim Pharmaceuticals, Inc., who was affiliated at the time of study conduct.

Refractoriness of Hyperkalemia and Hyperphosphatemia in Dialysis-Dependent AKI Associated with COVID-19.

Background: Persistent hyperkalemia (hyperK) and hyperphosphatemia (hyperP) despite renal replacement therapy (RRT) was anecdotally reported in COVID-19 and acute kidney injury (AKI) requiring RRT (CoV-AKI-RRT). However, observation bias could have accounted for the reports. Thus, we systematically examined the rate and severity of hyperK and hyperP in patients with CoV-AKI-RRT in comparison with the pre-COVID-19 era. Methods: We identified patients with CoV-AKI-RRT treated with sustained low-efficiency dialysis (SLED) for ≥2 days in March-April 2020. As pre-COVID-19 control, we included patients with AKI treated with SLED in December 2019. We examined the rates of hyperK (serum potassium [sK] ≥5.5 mEq/L), severe hyperK (sK ≥6.5 mEq/L), hyperP (serum phosphate [sP] ≥4.5 mg/dl), and moderate or severe hyperP (sP ≥7-10 and >10 mg/dl, respectively) as %SLED-days with an event. Results: Along the duration of SLED, the incidence of hyperK was greater in CoV-AKI-RRT (n=64; mean 19%±2% versus 14%±3% SLED-days, P=0.002) compared with control (n=60). The proportion of patients with one or more event of severe hyperK was greater in CoV-AKI (33% versus 7%, P<0.001). The incidence of hyperP was similar between groups (mean 56%±4% versus 53%±5% SLED-days, P=0.49). However, the proportion of patients with one or more event of moderate and severe hyperP was greater in CoV-AKI-RRT (86% versus 60%, P=0.001, and 50% versus 18%, P<0.001, respectively). Among those with CoV-AKI-RRT, sK and sP correlated with lactate dehydrogenase (LDH; r=0.31, P=0.04, and r=0.31, P=0.04, respectively), whereas hyperP also correlated with shorter SLED runs (hours/run; r=-0.27, P=0.05). Conclusions: Refractory hyperK and hyperP were more frequent in CoV-AKI-RRT compared with the pre-COVID-19 era. Because of the correlation of sK and sP with higher LDH and sP with shorter SLED runs, intracellular ion release from cell injury due to cytokine storm and RRT interruptions may account for the findings.

A Rare Case of Stage IV Mixed Neuroendocrine Small Cell and Adenosquamous Cell Carcinoma of the Gallbladder.

Gallbladder (GB) carcinoma is the fifth most common type of gastrointestinal cancer. Although a majority of these cancers are found to be adenocarcinomas, we present a rare case in which the GB carcinoma was found to have mixed histology with both small cell neuroendocrine carcinoma and adenosquamous cell carcinoma.

Two PerPLEXing Cases of Hashimoto's Encephalopathy Unresponsive to Steroid and Intravenous Immunoglobulin Therapy.

Hashimoto's encephalopathy is a nebulous entity over which much controversy exists. Often referred to as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), it describes a myriad of neurological sequelae that typically are observed to occur in patients with the presence of thyroid antibodies. We aim to raise clinical awareness of this seldom diagnosed entity as a potential etiology for altered mental status in patients who present with supporting clinical features and elevated thyroid antibodies. While steroid responsiveness is deemed a typical presenting feature of this medical condition, our cases aim to describe two cases that required escalation of therapy to intravenous immunoglobulins, and ultimately, plasmapheresis therapy for improvement in their clinical status. Our patients had a dramatic improvement in their mentation within three to four sessions of plasmapheresis, improving rapidly toward their baseline. Such a dramatic improvement, coupled with the corresponding reduction in their thyroid antibody titer supports the diagnosis of Hashimoto's encephalopathy and highlights the importance of having a low clinical threshold for the diagnosis of this entity in patients who, despite extensive evaluation, reveal no apparent cause for their altered mental status.

Another Way to Break Hearts: Reverse Takotsubo Cardiomyopathy.

A 34-year-old female was found to be hypoxic shortly after intubation during elective eye surgery. The patient then went into ventricular fibrillation leading to cardiac arrest. Return of spontaneous circulation (ROSC) was achieved after several rounds of cardiopulmonary resuscitation with epinephrine. The patient was immediately taken for cardiac catherization which revealed angiographically normal coronary arteries. A computed tomography angiogram chest showed pulmonary embolism and unclear chronicity. Transthoracic echocardiogram (TTE) showed a reduced ejection fraction of 30%-35% with nearly akinetic basal walls, consistent with reverse Takotsubo cardiomyopathy. The patient was started on anticoagulation and was successfully extubated shortly afterward. Cardiac magnetic resonance imaging (MRI) one week later revealed a recovered left ventricular ejection fraction. Our case demonstrated variants of Takotsubo cardiomyopathy while highlighting the notion that cardiac function can be temporarily compromised by acute physiological stressors.

Flecainide-Induced Left Bundle Branch Block.

Flecainide is the first-line antiarrhythmic agent used in patients without structural heart disease. It is a class IC antiarrhythmic drug that inhibits inward sodium current through its dose-dependent blockade of voltage-gated calcium channels within the cardiac membrane. It has been shown to slow the conduction in the left bundle branch block. Unmonitored toxicity can cause ventricular dyssynchrony or fatal arrhythmia. We present a case in which flecainide use caused a new left bundle branch block (LBBB).

Ventriculitis Presenting as a Complication of Haemophilus Influenzae Mastoiditis and Meningitis.

Ventriculitis is a rare intracranial disease with potentially life-threatening consequences. Here, we present a case of acute mastoiditis that progressed to Haemophilus influenzae meningitis evolving to ventriculitis. This case was complicated by hydrocephalus that subsequently required the placement of a ventriculoperitoneal shunt. In patients presenting with mastoiditis, it is imperative to initiate early and appropriate treatment to prevent disease progression and devastating outcomes. We aim to increase recognition of potential complications and encourage childhood vaccination of Haemophilus influenzae.

Renal manifestations of hepatitis E among immunocompetent and solid organ transplant recipients.

Hepatitis E virus (HEV) infections are generally self-limited. Rare cases of hepatitis E induced fulminant liver failure requiring liver transplantation are reported in the literature. Even though HEV infection is generally encountered among developing countries, a recent uptrend is reported in developed countries. Consumption of unprocessed meat and zoonosis are considered to be the likely transmission modalities in developed countries. Renal involvement of HEV generally holds a benign and self-limited course. Although rare cases of cryoglobulinemia are reported in immunocompetent patients, glomerular manifestations of HEV infection are frequently encountered in immunocompromised and solid organ transplant recipients. The spectrum of renal manifestations of HEV infection include pre-renal failure, glomerular disorders, tubular and interstitial injury. Kidney biopsy is the gold standard diagnostic test that confirms the pattern of injury. Management predominantly includes conservative approach. Reduction of immunosuppressive medications and ribavirin (for 3-6 mo) is considered among patients with solid organ transplants. Here we review the clinical course, pathogenesis, renal manifestations, and management of HEV among immunocompetent and solid organ transplant recipients.

Enhancing Communication and Patient Care: The Reverse Stethoscope Technique.

Patients with hearing loss have increased difficulties while navigating communication, especially complex conversations that take place in healthcare settings. Patients with hearing disabilities may often find themselves in noisy reception areas or busy emergency departments where their confidentiality is compromised for the sake of communication, resulting in suboptimal care. The reverse stethoscope technique is a tool that healthcare professionals can use to enhance communications to optimize patient care and maintain confidentiality. We describe a case of an 83-year-old male with bilateral hearing loss whose hearing disability became a major obstacle in his access to healthcare in the inpatient setting. With the help of the reverse stethoscope technique, the patient was able to understand his hospital course, diagnosis, and treatment options and was able to actively participate in making an informed decision.