Low-solute hyponatremia in a kidney transplant recipient.

BACKGROUND AND AIMS: Electrolyte and acid-base disturbances are common in kidney transplant recipients, but there are few reports of low-solute hyponatremia or beer potomania in this population. We report herein a case of low-solute hyponatremia in a kidney transplant recipient with impaired graft function, highlighting key issues in diagnosis and management of low-solute hyponatremia, as well as exploring the pathophysiology of hyponatremia after kidney transplantation. CASE PRESENTATION: A 51-year-old man who had received a cadaveric renal transplant 18 years before presented with symptomatic hyponatremia and seizure. Workup for an underlying intracranial pathology was negative, and subsequent biochemical workup suggested low-solute hyponatremia with potomania, arising from dietary modifications taken by the patient while self-isolating during the COVID-19 pandemic. Correction of hyponatremia was successful with conservative management with close monitoring. CONCLUSION: This case illustrates key points in the diagnosis and management of low-solute hyponatremia and highlights the pathophysiology of hyponatremia after kidney transplantation.

Epidemiology and Outcomes of Hypernatraemia in Patients with COVID-19-A Territory-Wide Study in Hong Kong.

BACKGROUND: Dysnatraemias are commonly reported in COVID-19. However, the clinical epidemiology of hypernatraemia and its impact on clinical outcomes in relation to different variants of SARS-CoV-2, especially the prevailing Omicron variant, remain unclear. METHODS: This was a territory-wide retrospective study to investigate the clinical epidemiology and outcomes of COVID-19 patients with hypernatraemia at presentation during the period from 1 January 2020 to 31 March 2022. The primary outcome was 30-day mortality. Key secondary outcomes included rates of hospitalization and ICU admission, and costs of hospitalization. RESULTS: In this study, 53,415 adult COVID-19 patients were included for analysis. Hypernatraemia was observed in 2688 (5.0%) patients at presentation, of which most cases (99.2%) occurred during the local "5th wave" dominated by the Omicron BA.2 variant. Risk factors for hypernatraemia at presentation included age, institutionalization, congestive heart failure, dementia, higher SARS-CoV-2 Ct value, white cell count, C-reactive protein and lower eGFR and albumin levels (p < 0.001 for all). Patients with hypernatraemia showed significantly higher 30-day mortality (32.0% vs. 5.7%, p < 0.001) and longer lengths of stay (12.9 ± 10.9 vs. 11.5 ± 12.1 days, p < 0.001) compared with those with normonatraemia. Multivariate analysis revealed hypernatraemia at presentation as an independent predictor for 30-day mortality (aHR 1.32, 95% CI 1.14-1.53, p < 0.001) and prolonged hospital stays (OR 1.55, 95% CI 1.17-2.05, p = 0.002). CONCLUSIONS: Hypernatraemia is common among COVID-19 patients, especially among institutionalized older adults with cognitive impairment and other comorbidities during large-scale outbreaks during the Omicron era. Hypernatraemia is associated with unfavourable outcomes and increased healthcare utilization.

Immunopathogenesis of Immune Checkpoint Inhibitor Induced Myocarditis: Insights from Experimental Models and Treatment Implications.

Despite the extraordinary success of immune checkpoint inhibitors (ICIs) in cancer treatment, their use is associated with a high incidence of immune-related adverse events (IRAEs), resulting from therapy-related autoimmunity against various target organs. ICI-induced myocarditis is one of the most severe forms of IRAE, which is associated with risk of hemodynamic compromise and mortality. Despite increasing recognition and prompt treatment by clinicians, there remain significant gaps in knowledge regarding the pathophysiology, diagnosis and treatment of ICI-induced myocarditis. As the newly emerged disease entity is relatively rare, it is challenging for researchers to perform studies involving patients at scale. Alternatively, mouse models have been developed to facilitate research understanding of the pathogenesis of ICI-induced myocarditis and drug discovery. Transgenic mice with immune checkpoint genes knocked out allow induction of myocarditis in a highly reproducible manner. On the other hand, it has not been possible to induce ICI-induced myocarditis in wild type mice by injecting ICIs monotherapy alone. Additional interventions such as combinational ICI, tumor inoculation, cardiac sarcomere immunization, or cardiac irradiation are necessary to mimic the underlying pathophysiology in human cancer patients and to induce ICI-induced myocarditis successfully. This review focuses on the immunopathogenesis of ICI-induced myocarditis, drawing insights from human studies and animal models, and discusses the potential implications for treatment.

The role of the complement system in primary membranous nephropathy: A narrative review in the era of new therapeutic targets.

Primary membranous nephropathy (MN) is an important cause of nephrotic syndrome and chronic kidney disease (CKD) in the adult population. Although the discovery of different autoantibodies against glomerular/podocytic antigens have highlighted the role of B cells in the pathogenesis of MN, suboptimal response or even resistance to B cell-directed therapies occurs, suggesting that other pathophysiological mechanisms are involved in mediating podocyte injury. The complement system plays an important role in the innate immune response to infection, and dysregulation of the complement system has been observed in various kidney diseases. There is compelling evidence of complement cascade activation in primary MN, with the mannose-binding lectin (MBL) and alternative pathways particularly implicated. With appropriate validation, assays of complements and associated activation products could hold promise as adjunctive tools for non-invasive disease monitoring and prognostication. While there is growing interest to target the complement system in MN, there is concern regarding the risk of infection due to encapsulated organisms and high treatment costs, highlighting the need for clinical trials to identify patients most likely to benefit from complement-directed therapies.

Circular RNAs in Acute Kidney Injury: Roles in Pathophysiology and Implications for Clinical Management.

Acute kidney injury (AKI) is a common clinical condition, results in patient morbidity and mortality, and incurs considerable health care costs. Sepsis, ischaemia-reperfusion injury (IRI) and drug nephrotoxicity are the leading causes. Mounting evidence suggests that perturbations in circular RNAs (circRNAs) are observed in AKI of various aetiologies, and have pathogenic significance. Aberrant circRNA expressions can cause altered intracellular signalling, exaggerated oxidative stress, increased cellular apoptosis, excess inflammation, and tissue injury in AKI due to sepsis or IRI. While circRNAs are dysregulated in drug-induced AKI, their roles in pathogenesis are less well-characterised. CircRNAs also show potential for clinical application in diagnosis, prognostication, monitoring, and treatment. Prospective observational studies are needed to investigate the role of circRNAs in the clinical management of AKI, with special focus on the safety of therapeutic interventions targeting circRNAs and the avoidance of untoward off-target effects.

Long-Term Results of Triple Immunosuppression With Tacrolimus Added to Mycophenolate and Corticosteroids in the Treatment of Lupus Nephritis.

Introduction: Addition of a calcineurin inhibitor (CNI) to corticosteroids and mycophenolate increased the renal response rate in lupus nephritis (LN) because of proteinuria reduction, but there is little long-term efficacy and safety data on this triple immunosuppressive regimen. Methods: This is a cohort study of patients with class III/IV/V LN whose proteinuria persisted despite initial standard therapy with mycophenolate mofetil (MMF) and prednisolone (PRED), in whom tacrolimus (TAC) was added (target 12-hour trough TAC plasma levels of 4-6 µg/l). Results: A total of 22 patients with LN treated with triple immunosuppression were included, with follow-up of 61.1 ± 28.1 months. Achieved trough levels of TAC and mycophenolic acid (MPA) were 3.8 to 5.7 µg/l and 1.3 to 2.1 mg/l respectively. Significant proteinuria reduction occurred after 6 months and was sustained up to 5 years. Complete response (CR) and partial response (PR) rates at 12, 24, and 36 months was 59.1%, 72.7%, and 77.3% respectively. The slope of estimated glomerular filtration rate (eGFR) over time did not change after TAC was added. A total of 7 patients (31.8%) showed progressive chronic kidney disease (CKD). Two patients reached end-stage kidney disease during follow-up. Renal survival rate at -, 3, and 5 years was 100.0%, 95.0%, and 88.7% respectively. Two patients (9.1%) had renal relapse after 8.5 ± 0.7 months. A total of 5 patients (22.7%) showed worsening of hypertension, and 3 (13.6%) had worsened hyperlipidemia. Other key adverse events included infection (n = 16, 1 in 7 patient-years) and gastrointestinal upset (n = 6). Conclusion: Triple immunosuppression with the addition of TAC to mycophenolate and PRED resulted in further proteinuria reduction and sustained disease quiescence in patients with LN whose proteinuria did not respond optimally to standard therapy.

Epidemiology and outcomes of hyponatremia in patients with COVID-19-A territory-wide study in Hong Kong.

Background: Hyponatremia is common in COVID-19, but its epidemiology and impact on clinical outcomes in relation to different variants, especially the Omicron variant, requires further clarification. Methods: This was a territory-wide retrospective study to investigate the epidemiology and outcomes of COVID-19 patients with hyponatremia from January 1, 2020 to March 31, 2022 in Hong Kong. The primary outcome was 30-day mortality of patients with COVID-19 and hyponatremia at presentation. Secondary outcomes included rate of hospitalization, intensive care unit (ICU) hospitalization, overall duration of hospitalization, and duration of ICU hospitalization. Results: A total of 53,415 COVID-19 patients were included for analysis, of which 14,545 (27.2%) had hyponatremia at presentation. 9813 (67.5%), 2821 (19.4%), and 1911 (13.1%) had mild (130 to <135 mmol/L), moderate (125 to <130 mmol/L), and severe hyponatremia (<125 mmol/L) at presentation respectively. Age, male sex, diabetes, active malignancy, white cell count, serum creatinine, hypoalbuminemia, C-reactive protein, and viral loads were independent predictors for hyponatremia in COVID-19 patients (P < 0.001, for all). Hyponatremic patients had increased 30-day mortality (9.7 vs. 5.7%, P < 0.001), prolonged hospitalization (11.9 ± 15.1 days vs. 11.5 ± 12.1 days, P < 0.001), and more ICU admissions (7.0% vs. 3.3%, P < 0.001). Patients diagnosed during the "fifth wave" Omicron BA.2 outbreak had 2.29-fold risk (95% CI 2.02-2.59, P < 0.001) of presenting with hyponatremia compared to other waves. Conclusion: Hyponatremia is common among COVID-19 patients, and may serve as a prognostic indicator for unfavorable outcomes and increased healthcare utilization in the evolving COVID-19 outbreak.

B Cells in Primary Membranous Nephropathy: Escape from Immune Tolerance and Implications for Patient Management.

Membranous nephropathy (MN) is an important cause of nephrotic syndrome and chronic kidney disease (CKD) in adults. The pathogenic significance of B cells in MN is increasingly recognized, especially following the discovery of various autoantibodies that target specific podocytic antigens and the promising treatment responses seen with B cell depleting therapies. The presence of autoreactive B cells and autoantibodies that bind to antigens on podocyte surfaces are characteristic features of MN, and are the result of breaches in central and peripheral tolerance of B lymphocytes. These perturbations in B cell tolerance include altered B lymphocyte subsets, dysregulation of genes that govern immunoglobulin production, aberrant somatic hypermutation and co-stimulatory signalling, abnormal expression of B cell-related cytokines, and increased B cell infiltrates and organized tertiary lymphoid structures within the kidneys. An understanding of the role of B cell tolerance and homeostasis may have important implications for patient management in MN, as conventional immunosuppressive treatments and novel B cell-targeted therapies show distinct effects on proliferation, differentiation and reconstitution in different B cell subsets. Circulating B lymphocytes and related cytokines may serve as potential biomarkers for treatment selection, monitoring of therapeutic response and prediction of disease relapse. These recent advances in the understanding of B cell tolerance in MN have provided greater insight into its immunopathogenesis and potential novel strategies for disease monitoring and treatment.

Brimonidine Eye Drops Causing Encephalopathy in a Patient With Advanced Chronic Kidney Disease.

Brimonidine eye drops are frequently prescribed for the treatment of glaucoma and ocular hypertension in adults. Systemic toxicities including neurological side effects have been reported with its use, especially in the paediatric population. In this report, we present a case of encephalopathy secondary to the use of brimonidine eye drops in a patient with underlying advanced chronic kidney disease, who recovered promptly after drug cessation. Herein, we also review the pharmacokinetics of eye drops leading to their systemic side effects, especially in the context of renal impairment. We also explore the possibility of extracorporeal treatment, such as by haemodialysis, for the treatment of these manifestations. This case demonstrates the need to clarify a patient's drug history and stop offending medications early on in a patient with delirium, while treatments such as antidotes or extracorporeal treatment are being considered.

MicroRNAs in Lupus Nephritis-Role in Disease Pathogenesis and Clinical Applications.

MicroRNAs (miRs) are non-coding small RNAs that act as epigenetic modulators to regulate the protein levels of target mRNAs without modifying the genetic sequences. The role of miRs in the pathogenesis of lupus nephritis (LN) is increasingly recognized and highly complex. Altered levels of different miRs are observed in the blood, urine and kidney tissues of murine LN models and LN patients. Accumulating evidence suggests that these miRs can modulate immune cells and various key inflammatory pathways, and their perturbations contribute to the aberrant immune response in LN. The dysregulation of miRs in different resident renal cells and urinary exosomes can also lead to abnormal renal cell proliferation, inflammation and kidney fibrosis in LN. While miRs may hold promise in various clinical applications in LN patients, there are still many potential limitations and safety concerns for their use. Further studies are worthwhile to examine the clinical utility of miRs in the diagnosis, disease activity monitoring, prognostication and treatment of LN.