Alterations in exhausted and classical memory B cells in lupus nephritis - Relationship with disease relapse.

INTRODUCTION: B cell exhaustion is a functional abnormality of B lymphocytes observed in chronic infections and shows association with autoreactivity. The role of exhausted and classical memory B cells in maintaining disease stability of lupus nephritis (LN) remains unclear. METHODS: We measured classical memory (CD19+CD21+CD27+), exhausted B cells (CD19+CD21-CD27-), and related cytokines in LN patients with multiple relapses (MR) (n = 15) and no relapse (NR) (n = 15) during disease remission. The expression of inhibitory/adhesion molecules, cell proliferation and calcium mobilization in classical memory and exhausted B cells were also assessed. RESULTS: The MR group had higher proportion of circulating exhausted and classical memory B cells compared to the NR group and healthy controls (HC) (p all <0.05 for MR vs. NR or HC). Blood levels of IL-6, BAFF, IL-21, CD62L, CXCR3 and Siglec-6 were all higher in the MR group (p < 0.05, for all). Exhausted B cells from the MR group showed higher FcRL4, CD22, CD85j and CD183 but lower CD62L expression than NR and HC groups. Exhausted B cells from MR patients exhibited reduced proliferation compared to NR patients and HC, while classical memory B cell proliferation in MR group was higher than the other two groups. Exhausted B cells from both MR and NR patients showed impaired calcium mobilization. CONCLUSION: Alterations in exhausted and classical memory B cells are related to disease relapse in LN. These findings may help devise new strategies for monitoring disease activity and preventing relapse in LN.

Palliative care in kidney transplant recipients with graft failure.

Kidney transplantation is the best renal replacement therapy for patients with end stage kidney disease. It provides longer patient survival and better quality of life than dialysis. The clinical course after kidney transplantation could be complex and variable. Patients may develop various complications or even kidney graft failure. Symptom burden related to uraemia in patients with graft failure, and the side-effects of immunosuppression, cause psychological distress and adversely affect the quality of life of patients. Treatment decisions in patients with graft failure can be challenging to patients and their caregivers. Renal palliative care is an emerging field, but its adoption remains relatively low among kidney transplant recipients with progressive graft failure. In this context, timely consideration and referral for palliative care can improve symptom burden, reduce stress in patients and their caregivers, and facilitate treatment goal setting and advanced care planning. Common barriers to bring palliative care to suitable patients include: (I) misconception in patients, caregivers and healthcare providers that palliative care means abandonment of life sustaining treatment; (II) over-optimistic prognostic assessment and over-aggressive management approach; (III) insufficient awareness and training in palliative care of healthcare professionals; (IV) inadequate access to and insufficient resources in palliative care. Enhanced training and awareness, and further studies, would be needed to optimize the decision process and delineate the benefit of palliative care, and to guide evidence-based practice in the transplant population.

Impact of renal function variability on long-term prognosis in ischemic stroke patients with atrial fibrillation.

Background: Although renal dysfunction is associated with adverse clinical outcomes in patients with atrial fibrillation (AF) following stroke, the impact of renal function variability is unclear. Aim: This study aimed to assess the association between renal function variability and various adverse clinical outcomes in patients with transient ischemic attack (TIA)/ischemic stroke and atrial fibrillation (AF). Methods: We conducted a population-based study and retrospectively identified patients hospitalized with a diagnosis of TIA/ischemic stroke and AF during 2016-2020 using the Clinical Data Analysis and Reporting System of Hong Kong. Serial serum creatinine tested upon the onset of TIA/ischemic stroke and during their subsequent follow-up was collected. Renal function variability was calculated using the coefficient of variation of the estimated glomerular filtration rate (eGFR). Clinical endpoints that occurred during the study period were captured and included ischemic stroke/systemic embolism, intracerebral hemorrhage (ICH), total bleeding, major adverse cardiovascular events (MACE), cardiovascular, non-cardiovascular, and all-cause mortality. Competing risk regression and Cox proportional hazard regression models were used to assess the associations of renal function variability with the outcomes of interest. Results: A total of 3,809 patients (mean age 80 ± 10 years, 43% men) who satisfied the inclusion and exclusion criteria were followed up for a mean of 2.5 ± 1.5 years (9,523 patient-years). The mean eGFR was 66 ± 22 mL/min/1.73 m2 at baseline, and the median number of renal function tests per patient during the follow-up period was 20 (interquartile range 11-35). After accounting for potential confounders, a greater eGFR variability was associated with increased risks of recurrent ischemic stroke/systemic embolism [fully adjusted subdistribution hazard ratio 1.11, 95% confidence interval (CI) 1.03-1.20], ICH (1.17, 1.01-1.36), total bleeding (1.13, 1.06-1.21), MACE (1.22, 1.15-1.30), cardiovascular (1.49, 1.32-1.69), non-cardiovascular (1.43, 1.35-1.52), and all-cause mortality (fully adjusted hazard ratio 1.44, 1.39-1.50). Conclusion: Visit-to-visit renal function variability is independently associated with adverse clinical outcomes in TIA/ischemic stroke patients with AF. Further large-scale studies are needed to validate our results.

Immunogenicity and Safety of the Three-Dose COVID-19 Vaccine Regimen in Patients Receiving Renal Replacement Therapy: A Systematic Review and Meta-Analysis.

Background: A three-dose regimen is the current standard for COVID-19 vaccination, but systematic data on immunogenicity and safety in chronic kidney disease patients remains limited. Objectives: We conducted a meta-analysis on the immunogenicity and safety of three-dose COVID-19 vaccination in patients on renal replacement therapy (RRT). Methods: Systematic literature search in four electronic databases yielded twenty eligible studies (2,117 patients, 94% of whom received mRNA vaccines) for meta-analysis. Results: The overall seropositivity rate of anti-SARS-CoV-2 was 74.2% (95% CI: 65.0-83.4%) after three-dose COVID-19 vaccination. The seropositivity rate of anti-SARS-CoV-2 in kidney transplant recipients (KTRs) was 64.6% (95% CI: 58.7-70.5%), and 43.5% (95% CI: 38.5-48.6%) of non-responders after second dose became seropositive after third dose. The seropositivity rate of anti-SARS-CoV-2 was 92.9% (95% CI: 89.5-96.2%) in dialysis patients, and 64.6% (95% CI: 46.8-82.3%) of non-responders after second dose became seropositive after third dose. In KTRs, each year increase in transplant vintage was associated with 35.6% increase in anti-SARS-CoV-2 seropositivity (95% CI: 15.9-55.4%, p = 0.01). There were no serious adverse events attributed to vaccination in KTRs, and the commonest local and systemic adverse events were injection site pain and fatigue, respectively. Conclusion: Three-dose COVID-19 vaccination regimen in patients on RRT is associated with reduced immunogenicity, especially in KTRs. There are no adverse events associated with third-dose COVID-19 vaccine in KTRs.

Risk of acute kidney injury in critically-ill patients with COVID-19 compared with seasonal influenza: a retrospective cohort study.

Background: The SARS-CoV-2 virus can bind to angiotensin-converting enzyme 2 receptors on host renal cells and may cause acute kidney injury (AKI). The comparative risks of AKI in patients severely ill with COVID-19 and influenza A have not been examined. Methods: This is a retrospective cohort study including patients with positive PCR results for SARS-CoV-2 or influenza A virus admitted to the intensive care units (ICUs) of 15 public hospitals in Hong Kong between 1st January 2013 and 30th April 2023. Patients who were already on chronic dialysis or had missing values in the confounder model were excluded. Data were retrieved from Hong Kong Hospital Authority's electronic healthcare records. The primary outcome was incident AKI during ICU stay. Secondary outcomes included acute kidney disease (AKD) and hospital mortality. All analyses were examined in multivariable regression adjusting for potential confounders (age, sex, baseline eGFR, PaO2/FiO2 ratio, baseline comorbidities, APACHE IV predicted risk of death, Charlson Comorbidity Index, emergent hospital admission, admission from elderly home, reason for ICU admission, presence of bacterial co-infections, use of medications [including vasopressors, antiviral medications, steroids and nephrotoxic antibiotics], as well as anaemia and leucocytosis). Patients were matched in a 1:1 ratio using a propensity score generated based on the full confounder model. The analyses were repeated using inverse probability weighting and in propensity-score matched cohorts. Findings: A total of 5495 ICU patients were identified. After excluding 1093 (19.9%) patients who met the exclusion criteria and 74 (1.3%) patients who had one or more missing values in the logistic regression model, a total of 4328 patients were included in the final analysis, with 2787 (64.4%) patients who tested positive for SARS-CoV-2 reverse transcription (RT)-PCR and 1541 (35.6%) patients who tested positive for influenza A virus RT-PCR. The comorbidity burden was greater in patients with COVID-19 (Charlson Comorbidity Index 3 [2-4] vs. 3 [1-4]), but the median APACHE IV predicted risk of death was significantly lower (0.19 [0.08-0.38] vs. 0.25 [0.11-0.52]). A total of 1053 (37.8%) patients with COVID-19 and 828 (53.7%) patients with influenza A developed AKI of any stage during ICU stay. In adjusted analysis, the risk of AKI was significantly lower in patients with COVID-19 compared with influenza A (adjusted odds ratio 0.51, 95% confidence interval 0.42-0.61, P < 0.0001]. The risk of stage 3 AKI and AKD were also significantly lower in patients with COVID-19. These results remained robust in multiple pre-planned sensitivity analyses including inverse probability weighting and propensity score matching. Interpretation: Our results suggest that the risk of AKI in patients severely ill with COVID-19 was lower than in patients with influenza A. The burden of concurrent organ failure complicating respiratory viral infections, such as the higher disease-attributable risk of AKI associated with influenza, should be clarified. Funding: An unrestricted philanthropic donation from Mr and Mrs Laurence Tse, The Wai Im Charitable Foundation, Chan Sui Kau Family Benefits and Charitable Foundation, So Ka Wing and Lee Sau Ying Charitable Foundation, Mr & Mrs Tam Wing Fun Edmund Renal Research Fund, the Theme-Based Research Scheme of the Research Grants Council, Hong Kong Special Administrative Region, The Government of the Hong Kong Special Administrative Region; Programme of Enhancing Laboratory Surveillance and Investigation of Emerging Infectious Diseases and Antimicrobial Resistance for the Department of Health of the Hong Kong Special Administrative Region Government; Emergency COVID-19 Project, Major Projects on Public Security, National Key Research and Development Program; Emergency Collaborative Project of Guangzhou Laboratory; the National Key Research and Development Program of China; Sanming Project of Medicine in Shenzhen China; and the High Level-Hospital Program, Health Commission of Guangdong Province, China.

Cardiovascular risk factors and complications in patients with systemic lupus erythematosus with and without nephritis: a systematic review and meta-analysis.

INTRODUCTION: It remains unclear how the presence of renal involvement will affect the cardiovascular (CV) risk factors and complications in patients with SLE. METHODS: We conducted a systematic review and meta-analysis using PubMed, EMBASE, MEDLINE and Scopus to identify studies published between 1947 and 2022 that evaluate the CV risk factors and complications in patients with SLE with or without lupus nephritis (LN). RESULTS: 58 studies were evaluated, with 22 two-arm studies (n=8675) included in two-arm meta-analysis and 45 studies (n=385 315) included in proportional meta-analysis. Patients with SLE with LN showed significantly higher risk of hypertension (HT) (OR=4.93, 95% CI=3.17 to 7.65, p<0.00001, I2=56%), hyperlipidaemia (OR=11.03, 95% CI=4.20 to 28.95, p<0.00001, I2=0%) and diabetes mellitus (DM) (OR=1.88, 95% CI=1.09 to 3.25, p=0.02, I2=32%) compared with those without LN. Patients with LN showed numerically higher prevalence of myocardial infarction (OR=1.35, 95% CI=0.53 to 3.45, p=0.52, I2=78%) and cerebrovascular accident (OR=1.64, 95% CI=0.79 to 3.39, p=0.27, I2=23%) than general patients with SLE. The incidence rates of CV mortality are also increased in patients with SLE with LN compared with those without LN (11.7/1000 patient-years vs 3.6/1000 patient-years). CONCLUSION: Patients with SLE with LN show increased risk of CV risk factors including DM, HT and hyperlipidaemia. Early identification and optimal control of these CV risk factors may reduce the risk of CV disease and other non-CV complications. PROSPERO REGISTRATION NUMBER: CRD42022314682.

Consensus statement on the management of hyperkalaemia-An Asia-Pacific perspective.

Hyperkalaemia is an electrolyte imbalance that impairs muscle function and myocardial excitability, and can potentially lead to fatal arrhythmias and sudden cardiac death. The prevalence of hyperkalaemia is estimated to be 6%-7% worldwide and 7%-10% in Asia. Hyperkalaemia frequently affects patients with chronic kidney disease, heart failure, and diabetes mellitus, particularly those receiving treatment with renin-angiotensin-aldosterone system (RAAS) inhibitors. Both hyperkalaemia and interruption of RAAS inhibitor therapy are associated with increased risks for cardiovascular events, hospitalisations, and death, highlighting a clinical dilemma in high-risk patients. Conventional potassium-binding resins are widely used for the treatment of hyperkalaemia; however, caveats such as the unpalatable taste and the risk of gastrointestinal side effects limit their chronic use. Recent evidence suggests that, with a rapid onset of action and improved gastrointestinal tolerability, novel oral potassium binders (e.g., patiromer and sodium zirconium cyclosilicate) are alternative treatment options for both acute and chronic hyperkalaemia. To optimise the care for patients with hyperkalaemia in the Asia-Pacific region, a multidisciplinary expert panel was convened to review published literature, share clinical experiences, and ultimately formulate 25 consensus statements, covering three clinical areas: (i) risk factors of hyperkalaemia and risk stratification in susceptible patients; (ii) prevention of hyperkalaemia for at-risk individuals; and (iii) correction of hyperkalaemia for at-risk individuals with cardiorenal disease. These statements were expected to serve as useful guidance in the management of hyperkalaemia for health care providers in the region.

Hospitalized acute exacerbation in chronic obstructive pulmonary disease - impact on long-term renal outcomes.

INTRODUCTION: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a common and preventable event in patients with chronic obstructive pulmonary disease (COPD). Data regarding the impact of AECOPD on short- and long-term renal outcomes are lacking. METHODS: We included all COPD patients who were followed at Queen Mary Hospital (QMH) in year 2015 and reviewed their clinical/renal outcomes in subsequent five years. Relationships between AECOPD and adverse renal outcomes were evaluated. RESULTS: 371 COPD patients were included. 169 patients had hospitalized AECOPD in past one year (HAE group) while 202 patients did not (non-HAE group). 285 patients (76.8%) had renal progression/death and 102 (27.5%) patients developed acute kidney injury (AKI). HAE group showed a more rapid eGFR decline than non-HAE group (-4.64 mL/min/1.73m2/year vs. -2.40 mL/min/1.73m2/year, p = 0.025). HAE group had significantly higher risk for renal progression/death at 5 years [adjusted OR (aOR) 2.380 (95% CI = 1.144-4.954), p = 0.020]. The frequency of hospitalized AECOPD in past 3 years, any AECOPD in past 3 years, hospitalized AECOPD in past 3 years were also predictive of renal progression/death at 5 years [aOR were 1.176 (95% CI = 1.038- 1.331), 2.998 (95% CI = 1.438-6.250) and 2.887 (95% CI = 1.409-5.917) respectively; p = 0.011, 0.003 and 0.004]. HAE group also showed significantly higher risk of AKI [adjusted HR (aHR) 2.430; 95% CI = 1.306-4.519, p = 0.005]. CONCLUSIONS: AECOPD, in particular HAE, was associated with increased risk of renal progression/death and AKI. Prevention of AECOPD, especially HAE, may potentially improve short- and long-term renal outcomes in COPD patients.

Renal relapse in children and adolescents with childhood-onset lupus nephritis: a 20-year study.

OBJECTIVES: There is little data on renal relapse in childhood-onset LN (cLN). We investigate the incidence, predictive factors and outcomes related to renal relapse. METHODS: We conducted a retrospective cohort study of all cLN diagnosed at ≤18 years between 2001-2021 to investigate the incidence and outcomes related to renal relapse. RESULTS: Ninety-five Chinese cLN patients (91% proliferative LN) were included. Induction immunosuppression was prednisolone and CYC [n = 36 (38%)] or MMF [n = 33 (35%)]. Maintenance immunosuppression was prednisolone and MMF [n = 53 (54%)] or AZA [n = 29 (31%)]. The rates of complete remission/partial remission (CR/PR) at 12 months were 78.9%/7.4%. Seventy renal relapses occurred in 39 patients over a follow-up of 10.2 years (s.d. 5.9) (0.07 episode/patient-year). Relapse-free survival was 94.7, 86.0, 80.1, 71.2, 68.3, 50.3 and 44.5% at 1, 2, 3, 4, 5, 10 and 20 years, respectively. Multivariate analysis showed that LN diagnosis <13.1 years [adjusted hazard ratio (HRadj) 2.59 995% CI 1.27, 5.29), P = 0.01], AZA maintenance [HRadj 2.20 (95% CI 1.01, 4.79), P = 0.05], PR [HRadj 3.9 (95% CI 1.03, 9.19), P = 0.01] and non-remission [HRadj 3.08 (95% CI 1.35, 11.3), P = 0.04] at 12 months were predictive of renal relapse. Renal relapse was significantly associated with advanced chronic kidney disease (stages 3-5) and end-stage kidney disease (17.9% vs 1.8%, P < 0.01). Furthermore, patients with renal relapse showed an increased incidence of infections (30.8% vs 10.7%, P = 0.02), osteopenia (38.5% vs 17.9%, P = 0.04) and hypertension (30.8% vs 7.1%, P < 0.01). CONCLUSION: Renal relapse is common among cLN, especially among young patients, and is associated with an increased incidence of morbidity and mortality. Attaining CR and the use of MMF appear to decrease the incidence of renal relapse.

ABO-adjusted cPRA metric for kidney allocation in an Asian-predominant population.

Recent studies showed that ABO-adjusted calculated panel reactive antibody (ABO-cPRA) may better reflect the histocompatibility level in a multi-ethnic population, but such data in Asians is not available. We developed an ABO-adjusted cPRA metric on a cohort of waitlist kidney transplant patients (n = 647, 99% Chinese) in Hong Kong, based on HLA alleles and ABO frequencies of local donors. The concordance between the web-based ABO-cPRA calculator and the impact on kidney allocation were evaluated. The blood group distribution for A, B, O and AB among waitlist kidney candidates were 26.2%, 27.5%, 40.1%, and 6.1%, and their chances of encountering incompatible blood group donors were 32.6%, 32.4%, 57.6%, and 0%, respectively. There is poor agreement between web-based ABO-cPRA calculator and our locally developed metrics. Over 90% of patients showed an increase in cPRA after ABO adjustment, most notably in those with cPRA between 70% and 79%. Blood group O patients had a much greater increase in cPRA scores after adjustment while patients of blood group A and B had similar increment. 10.6% of non-AB blood group waitlist patients had ABO-cPRA elevated to ≥80%. A local ABO-adjusted cPRA metric is required for Asian populations and may improve equity in kidney distribution for patients with disadvantageous blood groups. The result from the current study potentially helps other countries/localities in establishing their own unified ABO-cPRA metrics and predict the impact on kidney allocation.

Electric impedance tomography enables portable and non-invasive approach to screen and monitor chronic kidney disease.

Chronic kidney disease (CKD) is an escalating global health concern, and non-invasive means for early CKD detection is eagerly awaited. Here, we explore the potential of using home-based frequency-difference electrical impedance tomography (fdEIT) to evaluate CKD based on bio-conductivity characteristics. We performed bio-conductivity measurement in vivo paired with standard estimated glomerular filtration rate (eGFR) measurements on a N=126 CKD patients by EIT and traditional blood and urine tests, respectively. We developed an EIT processing pipeline that extracts the kidney regions from EIT images. We further developed a regression model and a CKD classification scheme. Our results showed a significant correlation between EIT-features and eGFR, and the classification scheme shows sensitivity and specificity of 76.2% and 74.6% respectively considering stages 1 and 2 CKD versus stages 3, 4 and 5 CKD. These results suggest the feasibility of EIT to be used as a portable, self-administrated and home-based approach for CKD early diagnostic screening and longitudinal monitoring.Clinical Relevance-The results presented here demonstrates a cost-effective, home-based and self-administrative screening process on chronic kidney disease patients, thereby enhancing the quality and area of possible application of telemedicine. By achieving this, the process presented here can relieve the burden of public health system.

A retrospective cohort study on the clinical outcomes of patients admitted to intensive care units with dysnatremia.

With evolving patient characteristics and patterns of ICU utilization, the impact of dysnatremias on patient outcomes and healthcare costs in the present era have not been well studied. Patients ≥ 18 years admitted to the ICUs in public hospitals in Hong Kong between January 2010 and June 2022 and had at least one serum sodium measurement obtained within 24 h prior to or following ICU admission were stratified into normonatremic (135-145 mmol/L), hyponatremic (< 135 mmol/L) and hypernatremic (> 145 mmol/L) groups. A total of 162,026 patients were included-9098 (5.6%), 40,533 (25.0%) and 112,395 (69.4%) patients were hypernatremic, hyponatremic and normonatremic at the time of ICU admission, respectively. The odds of patients with hypernatremia and hyponatremia dying in the ICU were 27% and 14% higher (aOR 1.27, 95% CI 1.19-1.36 and aOR 1.14, 95% CI 1.08-1.19, respectively; P < 0.001 for both), and 52% and 21% higher for dying in the hospital (aOR 1.52, 95% CI 1.43-1.62 and aOR 1.21, 95% CI 1.17-1.26, respectively; P < 0.001 for both] compared with those with normonatremia. Patients with dysnatremia also had longer ICU length of stay (LOS), hospital LOS, and higher healthcare costs than the normonatremic group. Dysnatremias at ICU admission were associated with increased ICU and in-hospital mortality and overall healthcare burden.

Humoral and cellular immunity against different SARS-CoV-2 variants in patients with chronic kidney disease.

Chronic kidney disease (CKD) patients are at higher risk of severe COVID-19. Humoral and cellular immunity from prior infection or vaccination are important for protection, but the neutralizing antibody (nAb) response against SARS-CoV-2 variants is impaired. We investigated the variant-specific nAb and T cell immunity among CKD patients. Adult CKD patients were recruited between August and October 2022. nAb against the SARS-CoV-2 (ancestral strains and four Omicron sublineages) and T cell response were measured using the live virus neutralization assay and interferon-gamma release assay (IGRA). The correlation between nAb/T-cell response and subsequent infection after recruitment were also determined. Among the 88 recruited patients, 95.5% had prior infection or had completed the primary vaccine series. However, only 77.3% had detectable nAb against at least one SARS-CoV-2 strains, 59.1% tested positive in IGRA, and 52.3% had detectable nAb and tested positive in the IGRA. The nAb geometic mean titers (GMTs) against XBB.1, BA.5 and BA.2.3.20 were significantly lower than those against BA.2 and ancestral strain. Prior SARS-CoV-2 infection was associated with elevated nAb and T cell response. More kidney transplant recipients (KTRs) showed absent nAb and T cell response (36.8% vs. 10.1%), despite a higher prevalence of vaccine booster in this population (94.7% vs. 50.7%). Lower levels of nAb titer and T cell response were significantly associated with subsequent infection. A considerable proportion of CKD patients, especially KTRs, showed absence of humoral and cellular protective immunity against SARS-CoV-2. Strategies to improve immunogenicity in this population are urgently needed.

Rethinking Palliative Care in Psychiatry.

This Viewpoint describes specific issues related to severe mental illnesses for palliative care.

Risk and Factors associated with disease manifestations in systemic lupus erythematosus - lupus nephritis (RIFLE-LN): a ten-year risk prediction strategy derived from a cohort of 1652 patients.

Objectives: Lupus nephritis (LN) remains one of the most severe manifestations in patients with systemic lupus erythematosus (SLE). Onset and overall LN risk among SLE patients remains considerably difficult to predict. Utilizing a territory-wide longitudinal cohort of over 10 years serial follow-up data, we developed and validated a risk stratification strategy to predict LN risk among Chinese SLE patients - Risk and Factors associated with disease manifestations in systemic Lupus Erythematosus - Lupus Nephritis (RIFLE-LN). Methods: Demographic and longitudinal data including autoantibody profiles, clinical manifestations, major organ involvement, LN biopsy results and outcomes were documented. Association analysis was performed to identify factors associated with LN. Regression modelling was used to develop a prediction model for 10-year risk of LN and thereafter validated. Results: A total of 1652 patients were recruited: 1382 patients were assigned for training and validation of the RIFLE-LN model; while 270 were assigned for testing. The median follow-up duration was 21 years. In the training and validation cohort, 845 (61%) of SLE patients developed LN. Cox regression and log rank test showed significant positive association between male sex, age of SLE onset and anti-dsDNA positivity. These factors were thereafter used to develop RIFLE-LN. The algorithm was tested in 270 independent patients and showed good performance (AUC = 0·70). Conclusion: By using male sex, anti-dsDNA positivity, age of SLE onset and SLE duration; RIFLE-LN can predict LN among Chinese SLE patients with good performance. We advocate its potential utility in guiding clinical management and disease monitoring. Further validation studies in independent cohorts are required.

GADD45A and GADD45B as Novel Biomarkers Associated with Chromatin Regulators in Renal Ischemia-Reperfusion Injury.

Chromatin regulators (CRs) are essential upstream regulatory factors of epigenetic modification. The role of CRs in the pathogenesis of renal ischemia-reperfusion injury (IRI) remains unclear. We analyzed a bioinformatic analysis on the differentially expressed chromatin regulator genes in renal IRI patients using data from public domains. The hub CRs identified were used to develop a risk prediction model for renal IRI, and their expressions were also validated using Western blot, qRT-PCR, and immunohistochemistry in a murine renal IRI model. We also examined the relationships between hub CRs and infiltrating immune cells in renal IRI and used network analysis to explore drugs that target hub CRs and their relevant downstream microRNAs. The results of machine learning methods showed that five genes (DUSP1, GADD45A, GADD45B, GADD45G, HSPA1A) were upregulated in renal IRI, with key roles in the cell cycle, p38 MAPK signaling pathway, p53 signaling pathway, FoxO signaling pathway, and NF-κB signaling pathway. Two genes from the network, GADD45A and GADD45B (growth arrest and DNA damage-inducible protein 45 alpha and beta), were chosen for the renal IRI risk prediction model. They all showed good performance in the testing and validation cohorts. Mice with renal IRI showed significantly upregulated GADD45A and GADD45B expression within kidneys compared to sham-operated mice. GADD45A and GADD45B showed correlations with plasmacytoid dendritic cells (pDCs) in infiltrating immune cell analysis and enrichment in the MAPK pathway based on the weighted gene co-expression network analysis (WGCNA) method. Candidate drugs that target GADD45A and GADD45B include beta-escin, sertraline, primaquine, pimozide, and azacyclonol. The dysregulation of GADD45A and GADD45B is related to renal IRI and the infiltration of pDCs, and drugs that target GADD45A and GADD45B may have therapeutic potential for renal IRI.

Clinico-pathological correlations and outcomes of de novo glomerular diseases in patients after haematopoietic stem cell transplantation.

Background: Various glomerular pathologies have been reported in patients who have undergone haematopoietic stem cell transplantation (HSCT), but the data on clinico-pathological correlations and clinical outcome remain limited. Methods: We analysed the clinical and histopathological data of patients who had biopsy-proven de novo glomerular diseases after HSCT since 1999. Results: A total of 2204 patients underwent HSCT during the period 1999-2021, and 31 patients (1.4%) developed de novo glomerular diseases after a mean duration of 2.8 ± 2.7 years after HSCT. Fifteen of these patients (48.4%) had graft-versus-host-disease prior to or concomitant with renal abnormalities. Proteinuria and eGFR at the time of kidney biopsy were 4.1 ± 5.3 g/day and 50.8 ± 25.4 mL/min/1.73 m2, respectively. Kidney histopathologic diagnoses included thrombotic microangiopathy (TMA) (38.7%), membranous nephropathy (MN) (25.8%), mesangial proliferative glomerulonephritis (12.9%), minimal change disease (9.7%), focal segmental glomerulosclerosis (9.7%) and membranoproliferative glomerulonephritis (3.2%). Immunosuppressive treatment was given to patients who presented with nephrotic-range proteinuria and/or acute kidney injury, while renin-angiotensin-aldosterone blockade was given to all patients with proteinuria ≥1 g/day, with complete and partial response rates of 54.8% and 19.4%, respectively. One patient with TMA progressed to end-stage kidney disease after 24 weeks, and two patients, one with TMA and one with MN, (6.4%) progressed to chronic kidney disease (CKD) Stage ≥3. Kidney and patient survival rates were 96.6% and 83.5%, respectively, at 5 years. Conclusion: De novo glomerular diseases with diverse histopathologic manifestations affect 1.4% of patients after HSCT, and approximately 10% develop progressive CKD.

Long-term outcomes with rituximab as add-on therapy in severe childhood-onset lupus nephritis.

BACKGROUND: Long-term data pertaining to rituximab as add-on therapy in childhood-onset lupus nephritis (cLN) is scarce. METHODS: A retrospective cohort study was conducted on all patients with proliferative cLN, diagnosed ≤ 18 years and between 2005 and 2021, who received rituximab for LN episodes that were life/organ threatening and/or treatment resistant to standard immunosuppression. RESULTS: Fourteen patients with cLN (female, n = 10) were included, with median follow-up period of 6.9 years. LN episodes (class III, n = 1; class IV, n = 11; class IV + V, n = 2) requiring rituximab occurred at 15.6 years (IQR 12.8-17.3), urine protein:creatinine ratio was 8.2 mg/mg (IQR 3.4-10.1) and eGFR was 28 mL/min/1.73 m2 (IQR 24-69) prior to rituximab treatment. Ten and four patients received rituximab at 1500 mg/m2 and 750 mg/m2, which were given at 46.5 days (IQR 19-69) after commencement of standard therapies. Treatment with rituximab resulted in improvements in proteinuria (ps < 0.001), eGFR (ps < 0.01) and serological parameters, including haemoglobin levels, complement 3 levels and anti-dsDNA antibodies, compared with baseline. Rates of complete/partial remission at 6-, 12- and 24-month post-rituximab were 28.6/42.8%, 64.2/21.4% and 69.2/15.3%. All three patients who required acute kidney replacement therapy became dialysis-free after rituximab. Relapse rate following rituximab was 0.11 episodes/patient-year. There was no lethal complication or severe infusion reaction. Hypogammaglobulinaemia was the most frequent complication (45%) but was mostly asymptomatic. Neutropenia and infections were observed in 20% and 25% of treatments. Upon last follow-up, three (21%) and two (14%) patients developed chronic kidney disease (stage 2, n = 2; stage 4; n = 1) and kidney failure, respectively. CONCLUSION: Add-on rituximab is an effective and safe rescue therapy for cLN patients with life-/organ-threatening manifestations or treatment-resistance. A higher resolution version of the Graphical abstract is available as Supplementary information.

Safety, Tolerability, and Pharmacokinetics of Benralizumab: A Phase 1, Randomized, Single-Blind Study of Healthy Chinese Participants.

Purpose: Biological therapies targeting eosinophils have been shown to be effective in treating patients with severe eosinophilic asthma. Benralizumab (Fasenra®, AstraZeneca) is a humanized monoclonal antibody binding to the alpha subunit of the interleukin-5 receptor, which rapidly depletes eosinophils via antibody-dependent cellular cytotoxicity. The aim of this Phase 1 study was to assess the safety, tolerability, and pharmacokinetics of benralizumab in healthy Chinese individuals. Materials and Methods: In this randomized, single-blind study (NCT03928262), healthy Chinese adult participants aged 18 to 45 years, weighing 50 to 100 kg, were randomized 1:1:1 to receive a single subcutaneous (SC) injection of benralizumab 10 mg, 30 mg, or 100 mg in the upper arms on Day 1. Safety was monitored throughout the study (up to Day 85), and blood samples were taken to determine serum benralizumab concentrations and for detection of anti-drug antibody. A non-compartmental analysis was conducted to estimate the pharmacokinetic parameters. Results: Thirty-six healthy participants were enrolled, 12 in each dose group (mean [SD] age 26 [6] years). Following a single SC injection of benralizumab, 13 adverse events were reported by 10 participants (28%), with one mild injection-site reaction assessed as related. The mean serum benralizumab concentrations increased in a dose proportional manner, followed by exponential decreases. The mean terminal half-lives were 15.1 days for the 10 mg dose, 14.4 days for the 30 mg dose, and 15.4 days for the 100 mg dose. All doses resulted in near-complete depletion of eosinophils on Day 2, which was maintained throughout the study to Day 85. Conclusion: A single SC injection of benralizumab was well tolerated by healthy Chinese participants, with no new or unexpected safety findings. The pharmacokinetics of benralizumab in Chinese participants was dose-proportional and consistent with those of non-Chinese participants observed in previous studies. Clinical Trial Registration: NCT03928262 (https://clinicaltrials.gov/ct2/show/NCT03928262).