ScRNA-Seq Analyses Define the Role of GATA3 in iNKT Cell Effector Lineage Differentiation.

While the transcription factor GATA-3 is well-established for its crucial role in T cell development, its specific influence on invariant natural killer T (iNKT) cells remains relatively unexplored. Using flow cytometry and single-cell transcriptomic analysis, we demonstrated that GATA-3 deficiency in mice leads to the absence of iNKT2 and iNKT17 cell subsets, as well as an altered distribution of iNKT1 cells. Thymic iNKT cells lacking GATA-3 exhibited diminished expression of PLZF and T-bet, key transcription factors involved in iNKT cell differentiation, and reduced production of Th2, Th17, and cytotoxic effector molecules. Single-cell transcriptomics revealed a comprehensive absence of iNKT17 cells, a substantial reduction in iNKT2 cells, and an increase in iNKT1 cells in GATA-3-deficient thymi. Differential expression analysis highlighted the regulatory role of GATA-3 in T cell activation signaling and altered expression of genes critical for iNKT cell differentiation, such as Icos, Cd127, Eomes, and Zbtb16. Notably, restoration of Icos, but not Cd127, expression could rescue iNKT cell development in GATA-3-deficient mice. In conclusion, our study demonstrates the pivotal role of GATA-3 in orchestrating iNKT cell effector lineage differentiation through the regulation of T cell activation pathways and Icos expression, providing insights into the molecular mechanisms governing iNKT cell development and function.

Exploring nontraditional cardiorenal advantages of SGLT-2 inhibitors and GLP-1 receptor agonists.

This commentary provides an analysis of the study by Fu et al. in Kidney International, which employs 3 administrative databases to investigate the hyperkalemia protective effects of sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors. It emphasizes the methodological approach, notably the use of a fixed-effect model to aggregate pairwise comparisons from 3 data sets. In addition, we explored the broader cardiorenal and potential nonrenal benefits of these drug classes, underscoring the imperative for continued research in this domain.

Effect assessment of traditional Chinese medicine, Guilu Erxian Jiao, in patients with osteoporosis: A case-control study of the Chang gung memorial hospital.

BACKGROUND: Osteoporosis is a chronic skeletal disease characterized by low bone mass and increased risk of fracture. In Taiwan, Guilu Erxian Jiao (GEJ) is the commonly used formula of Chinese herbal medicines for patients with osteoporosis. However, the effect of GEJ on subsequent fractures in the long term is unclear. This is the first long-term case-control study of the effects of GEJ on the rates of fracture in patients with osteoporosis. METHODS: We collected data from January 1, 2000 to December 31, 2019 from the Chang Gung Research Database. We interpreted from the reports of DXA to confirm whether the patients met the criteria for osteoporosis (T score ≤ -2.5). Eighty-five patients were enrolled in the GEJ group. After two propensity score matchings, 425 patients were identified as the non-GEJ group. We assessed four outcomes to confirm the effects of GEJ in patients with osteoporosis, including the change in the T-score, new occurrences of fractures, cumulative rate of fracture, and how many doses of GEJ need to be administered to effectively reduce fractures RESULTS: There was no significant difference in either the improvement in the T score or the 5-year overall fracture (p = 0.335) between these two groups. At the fracture-prone sites, the fracture in lumbar vertebrae was less in the GEJ group (p = 0.034). A total of 600 GEJ pills are required to effectively reduce the incidence of fractures (p value= 0.0039). CONCLUSIONS: Patients who take at least 600 GEJ pills would have a decreased fracture risk at fracture-prone sites.

Blocking pathogenic Leptospira invasion with aptamer molecules targeting outer membrane LipL32 protein.

This study aimed to develop aptamers targeting LipL32, a most abundant lipoprotein in pathogenic Leptospira, to hinder bacterial invasion. The objectives were to identify high-affinity aptamers through SELEX and evaluate their specificity and inhibitory effects. SELEX was employed to generate LipL32 aptamers (L32APs) over 15 rounds of selection. L32APs' binding affinity and specificity for pathogenic Leptospira were assessed. Their ability to inhibit LipL32-ECM interaction and Leptospira invasion was investigated. Animal studies were conducted to evaluate the impact of L32AP treatment on survival rates, Leptospira colonization, and kidney damage. Three L32APs with strong binding affinity were identified. They selectively detected pathogenic Leptospira, sparing non-pathogenic strains. L32APs inhibited LipL32-ECM interaction and Leptospira invasion. In animal studies, L32AP administration significantly improved survival rates, reduced Leptospira colonies, and mitigated kidney damage compared to infection alone. This pioneering research developed functional aptamers targeting pathogenic Leptospira. The identified L32APs exhibited high affinity, pathogen selectivity, and inhibition of invasion and ECM interaction. L32AP treatment showed promising results, enhancing survival rates and reducing Leptospira colonization and kidney damage. These findings demonstrate the potential of aptamers to impede pathogenic Leptospira invasion and aid in recovery from Leptospira-induced kidney injury (190 words).

Gut flora metagenomic analysis coupled with metabolic and deep immune profiling in chronic kidney disease.

BACKGROUND: Perturbation of gut microbiota has been linked to chronic kidney disease (CKD), which was correlated with a sophisticated milieu of metabolic and immune dysregulation. METHODS: To clarify the underlying host-microbe interaction in CKD, we performed multi-omics measurements, including systems-level gut microbiome, targeted serum metabolome and deep immunotyping, in a cohort of patients and non-CKD controls. RESULTS: Our analyses on functional profiles of the gut microbiome showed a decrease in the diversity and abundance of carbohydrate-active enzyme (CAZyme) genes but an increase in the abundance of antibiotic resistance, nitrogen cycling enzyme and virulence factor genes in CKD. Moreover, models generated using measurements of serum metabolites (amino acids, bile acids and short-chain fatty acids) or immunotypes were predictive of renal impairment but less so than many of the functional profiles derived from gut microbiota, with the CAZyme genes being the top-performing model to accurately predict the early stage of diseases. In addition, co-occurrence analyses revealed coordinated host-microbe relationships in CKD. Specifically, the highest fractions of significant correlations were identified with circulating metabolites by several taxonomic and functional profiles of gut microbiome, while immunotype features were moderately associated with the abundance of microbiome-encoded metabolic pathways and serum levels of amino acids (e.g. B cell cluster tryptophan and B cell cluster tryptophan metabolism). CONCLUSION: Overall, our multi-omics integration revealed several signatures of systems-level gut microbiome in robust associations with host-microbe co-metabolites and renal function, which may have aetiological and diagnostic implications in CKD.

Interferon-alpha and MxA inhibit BK polyomavirus replication by interaction with polyomavirus large T antigen.

INTRODUCTION: BK Polyomavirus (BKPyV) infection is a common complication in kidney transplant recipients and can result in poor outcome and graft failure. Currently, there is no known effective antiviral agent. This study investigated the possible antiviral effects of Interferon alpha (IFNα) and its induced protein, MxA, against BKPyV. METHODS: In vitro cell culture experiments were conducted using human primary renal proximal tubular epithelial cells (HRPTECs). We also did animal studies using Balb/c mice with unilateral kidney ischemic reperfusion injury. RESULTS: Our results demonstrated that IFNα effectively inhibited BKPyV in vitro and murine polyomavirus in animal models. Additionally, IFNα and MxA were found to suppress BKPyV TAg and VP1 production. Silencing MxA attenuated the antiviral efficacy of IFNα.We observed that MxA interacted with BKPyV TAg, causing it to remain in the cytosol and preventing its nuclear translocation. To determine MxA's essential domain for its antiviral activities, different mutant MxA constructs were generated. The MxA mutant K83A retained its interaction with BKPyV TAg, and its antiviral effects were intact. The MxA T103A mutant, on the other hand, abolished GTPase activity and lost its protein-protein interaction with BKPyV TAg, and lost its antiviral effect. CONCLUSION: IFNα and its downstream protein, MxA, have potent antiviral properties against BKPyV. Furthermore, our findings indicate that the interaction between MxA and BKVPyV TAg plays a crucial role in determining the anti-BKPyV effects of MxA.

Clinical outcomes between elderly ESKD patients under peritoneal dialysis and hemodialysis: a national cohort study.

With ageing populations, new elderly end-stage kidney disease (ESKD) cases rise. Unlike younger patients, elderly ESKD patients are less likely to undergo kidney transplant, and therefore the decision of receiving peritoneal dialysis (PD) and hemodialysis (HD) is more crucial. A total of 36,852 patients, aged more than 65, who were newly diagnosed with ESKD and initiated renal replacement therapy between 2013 and 2019 were identified. These patients were categorized into two groups: the PD group and the HD group according to their long-term renal replacement treatment. After propensity score matching, the PD group (n = 1628) displayed a lower incidence of major adverse cardiac and cerebrovascular events (MACCE) (10.09% vs. 13.03%, hazard ratio (HR): 0.74, 95% confidence interval (CI): 0.66-0.83), malignancy (1.23% vs. 2.14%, HR: 0.55, 95% CI: 0.40-0.76), and MACCE-associated mortality (1.35% vs. 2.25%, HR: 0.62, 95% CI: 0.46-0.84) compared to the HD group (n = 6512). However, the PD group demonstrated a higher rate of infection (34.09% vs. 24.14%, HR: 1.28, 95% CI: 1.20-1.37). The risks of all-cause mortality and infection-associated mortality were not different. This study may provide valuable clinical information to assist elderly ESKD patients to choose HD or PD as their renal replacement therapy.

Immunosenescence, gut dysbiosis, and chronic kidney disease: Interplay and implications for clinical management.

Immunosenescence refers to the immune system changes observed in individuals over 50 years old, characterized by diminished immune response and chronic inflammation. Recent investigations have highlighted similar immune alterations in patients with reduced kidney function. The immune system and kidney function have been found to be closely interconnected. Studies have shown that as kidney function declines, both innate and adaptive immunity are affected. Chronic kidney disease (CKD) patients exhibit decreased levels of naive and regular T cells, as well as naive and memory B cells, while memory T cell counts increase. Furthermore, research suggests that CKD and end-stage kidney disease (ESKD) patients experience early thymic dysfunction and heightened homeostatic proliferation of naive T cells. In addition to reduced thymic T cell production, CKD patients display shorter telomeres in both CD4+ and CD8+ T cells. Declining kidney function induces uremic conditions, which alter the intestinal metabolic environment and promote pathogen overgrowth while reducing diversity. This dysbiosis-driven imbalance in the gut microbiota can result in elevated production of uremic toxins, which, in turn, enter the systemic circulation due to compromised gut barrier function under uremic conditions. The accumulation of gut-derived uremic toxins exacerbates local and systemic kidney inflammation. Immune-mediated kidney damage occurs due to the activation of immune cells in the intestine as a consequence of dysbiosis, leading to the production of cytokines and soluble urokinase-type plasminogen activator receptor (suPAR), thereby contributing to kidney inflammation. In this review, we delve into the fundamental mechanisms of immunosenescence in CKD, encompassing alterations in adaptive immunity, gut dysbiosis, and an overview of the clinical findings pertaining to immunosenescence.

Potential therapeutic targets beyond cytokines and Janus kinases for autoimmune arthritis.

Synovial inflammation and destruction of articular cartilage and bone are hallmarks of autoimmune arthritis. Although current efforts to inhibit proinflammatory cytokines (biologics) or block Janus kinases (JAK) appear to be promising in many patients with autoimmune arthritis, adequate disease control is still lacking in a significant proportion of autoimmune arthritis patients. The possible adverse events from taking biologics and JAK inhibitors, such as infection, remain a major concern. Recent advances showing the effects of a loss of balance between regulatory T cells and T helper-17 cells as well as how the imbalance between osteoblastic and osteoclastic activities of bone cells exaggerates joint inflammation, bony destruction and systemic osteoporosis highlight an interesting area to explore in the search for better therapeutics. The recognition of the heterogenicity of synovial fibroblasts in osteoclastogenesis and their crosstalk with immune and bone cells provides an opportunity for identifying novel therapeutic targets for autoimmune arthritis. In this commentary, we comprehensively review the current knowledge regarding the interactions among heterogenic synovial fibroblasts, bone cells and immune cells and how they contribute to the immunopathogenesis of autoimmune arthritis, as well as the search for novel therapeutic targets not targeted by current biologics and JAK inhibitors.

Leptospirosis kidney disease: Evolution from acute to chronic kidney disease.

Leptospirosis is a neglected bacterial disease caused by leptospiral infection that carries a substantial mortality risk in severe cases. Research has shown that acute, chronic, and asymptomatic leptospiral infections are closely linked to acute and chronic kidney disease (CKD) and renal fibrosis. Leptospires affect renal function by infiltrating kidney cells via the renal tubules and interstitium and surviving in the kidney by circumventing the immune system. The most well-known pathogenic molecular mechanism of renal tubular damage caused by leptospiral infection is the direct binding of the bacterial outer membrane protein LipL32 to toll-like receptor-2 expressed in renal tubular epithelial cells (TECs) to induce intracellular inflammatory signaling pathways. These pathways include the production of tumor necrosis factor (TNF)-α and nuclear factor kappa activation, resulting in acute and chronic leptospirosis-related kidney injury. Few studies have investigated the relationship between acute and chronic renal diseases and leptospirosis and further evidence is necessary. In this review, we intend to discuss the roles of acute kidney injury (AKI) to/on CKD in leptospirosis. This study reviews the molecular pathways underlying the pathogenesis of leptospirosis kidney disease, which will assist in concentrating on potential future research directions.

Transcriptome landscape reveals the chronic inflammatory response in kidneys affected by the combinatory effect of leptospirosis and nephrotoxic injury.

Leptospirosis can cause chronic kidney damage, putting patients at risk of additional kidney injury due to other factors that can lead to renal failure. To understand the combined effect, the transcriptome profiles of kidneys of mice with adenine-induced and chronically Leptospira-infected kidneys were analysed. Chronic inflammation and T-helper 17 immune responses were activated and a high-level expression of Indoleamine 2,3-dioxygenase 1 protein was found. The results indicate that the combination may predispose patients to chronic inflammation, kidney function disruption, and symptoms seen in progressive chronic kidney disease (CKD). Furthermore, immunometabolic regulation may contribute to renal injury caused by chronic leptospirosis with secondary nephrotoxic injury. This study identified several significantly disrupted genes that could serve as potential targets for the diagnosis or treatment of CKD. Our work provides insight into the combined effect of leptospirosis and secondary kidney damage and the molecular basis for rapid progression of CKD.

Pioglitazone reduces cardiovascular events and dementia but increases bone fracture in elderly patients with type 2 diabetes mellitus: a national cohort study.

The prevalence of type 2 diabetes (T2DM) in elderly people has expanded rapidly. Considering cognitive impairment and being prone to hypoglycemia of the elder, the pros and cons of oral hypoglycemic agents (OHA) should be reassessed in this population. Pioglitazone might be appropriate for elderly DM patients because of its insulin-sensitizing effect and low risk of hypoglycemia. By using Taiwan's National Health Insurance Research Database, 191,937 types 2 diabetes patients aged ≥65 years under treatment between 2005 and 2013 were identified and further divided into two groups according to whether they received pioglitazone (pioglitazone group) or other OHAs (non-pioglitazone group) in the 3 months preceding their first outpatient visit date after 65 years of age, with a diagnosis of T2DM. Propensity score stabilization weight (PSSW) was used to balance the baseline characteristics. In results, the pioglitazone group (n = 17,388) exhibited a lower rate (per person-years) of major advanced cardiovascular events MACCE (2.76% vs. 3.03%, hazard ratio [HR]: 0.91, 95% confidence interval [CI]: 0.87-0.95), new- diagnosis dementia (1.32% vs. 1.46%, HR: 0.91, 95% CI: 0.84-0.98) but a higher rate of new-diagnosis bone fractures (5.37% vs. 4.47%, HR: 1.24, 95% CI: 1.19-1.28) than the non-pioglitazone group (n = 174,549). In conclusion, using pioglitazone may reduce the risks of MACCE and dementia but increases the probability of bone fractures in the elderly DM population.

Deep immune profiling of patients with renal impairment unveils distinct immunotypes associated with disease severity.

Background: Chronic kidney disease (CKD) is pathologically correlated with a sophisticated milieu of innate and adaptive immune dysregulation, but the underlying immunological disturbances remain poorly understood. Methods: To address this, we comprehensively interrogated cellular and soluble elements of the immune system by using high-dimensional flow cytometry to analyze peripheral blood mononuclear cells and performing cytokine/chemokine profiling of serum samples, respectively, in a cohort of 69 patients and 19 non-CKD controls. Results: Altered serum levels of several cytokines/chemokines were identified, among which concentrations of stem cell factor (SCF) were found to be elevated with the progression of CKD and inversely correlated with estimated glomerular filtration rate (eGFR). Deep immunophenotyping analyses reveal a global change in immune modulation associated with CKD severity. Specifically, a decrease in the subsets of CD56dim natural killer (NK) cells (KLRG-1+CD38+CD64+CD15+CD197+) and monocytes (KLRG-1+CD38+PD-1+) was detected in severe CKD compared with controls and mild CKD. In addition, comparisons between mild and severe CKD demonstrated a loss of a mature B cell population (PD-1+CD197+IgD+HLA-DR+) in the advanced stages of disease. Further, we identified immunophenotypic markers to discriminate mild CKD from the controls, among which the portion of CD38+ monocytes was of particular value in early diagnosis. Conclusions: Our data unveil severity-specific immunological signatures perturbed in CKD patients.

Leptospirosis: A Potential Culprit for Chronic Kidney Disease of Uncertain Etiology.

PURPOSE: Chronic kidney disease of uncertain etiology (CKDu) is an environmental nephropathy in which the etiological factors are yet uncertain. Leptospirosis, a spirochetal infection that is common among agricultural communities, has been identified as a potential etiology for CKDu beyond environmental nephropathy. Although CKDu is a chronic kidney disease, in endemic regions, an increasing number of cases are reported with features suggestive of acute interstitial nephritis without any known reason (AINu), with or without background CKD. The study hypothesizes that exposure to pathogenic leptospires is one of the causative factors for the occurrence of AINu. METHOD: This study was carried out using 59 clinically diagnosed AINu patients, 72 healthy controls from CKDu endemic region (endemic controls [ECs]), and 71 healthy controls from CKDu non-endemic region (non-endemic controls [NECs]). RESULTS: The seroprevalence of 18.6, 6.9, and 7.0% was observed in the AIN (or AINu), EC, and NEC groups, respectively, from the rapid IgM test. Among 19 serovars tested, the highest seroprevalence was observed at 72.9, 38.9, and 21.1% in the AIN (AINu), EC, and NEC groups, respectively, by microscopic agglutination test (MAT), particularly for serovar Leptospira santarosai serovar Shermani. This emphasizes the presence of infection in AINu patients, and this also suggests that Leptospira exposure might play an important role in AINu. CONCLUSION: These data suggest that exposure to Leptospira infection could be one of the possible causative factors for the occurrence of AINu, which may lead to CKDu in Sri Lanka.

Hungry bone syndrome after parathyroid surgery.

INTRODUCTION: Data on the incidence rates of hungry bone syndrome after parathyroidectomy in patients on dialysis are inconsistent, as the published rates vary from 15.8% to 92.9%. METHODS: Between 2009 and 2019, 120 hemodialysis patients underwent parathyroidectomy for secondary hyperparathyroidism at the Chang Gung Memorial Hospital. The patients were stratified into two groups based on the presence (n = 100) or absence (n = 20) of hungry bone syndrome after parathyroidectomy. FINDINGS: Subtotal parathyroidectomy was the most common surgery performed (76.7%), followed by total parathyroidectomy with autoimplantation (23.3%). Pathological examination revealed parathyroid hyperplasia. Hungry bone syndrome developed within 0.3 ± 0.3 months and lasted for 11.1 ± 14.7 months. After surgery, compared with patients without hungry bone syndrome, patients with hungry bone syndrome had lower levels of nadir corrected calcium (P < 0.001), as well as lower nadir (P < 0.001) and peak (P < 0.001) intact parathyroid hormone levels. During 59.3 ± 44.0 months of follow-up, persistence and recurrence of hyperparathyroidism occurred in 25 (20.8%) and 30 (25.0%) patients, respectively. Furthermore, patients with hungry bone syndrome had a lower rate of persistent hyperparathyroidism than those without hungry bone syndrome (P < 0.001). Four patients (3.3%) underwent a second parathyroidectomy. Patients with hungry bone syndrome received fewer second parathyroidectomies than those without hungry bone syndrome (P < 0.001). Finally, a multivariate logistic regression model revealed that the preoperative blood ferritin level was a negative predictor of the development of hungry bone syndrome (P = 0.038). DISCUSSION: Hungry bone syndrome is common (83.3%) after parathyroidectomy for secondary hyperparathyroidism in patients undergoing hemodialysis, and this complication should be monitored and managed appropriately.

Tumor necrosis factor-alpha blockade suppresses BK polyomavirus replication.

PURPOSE: BK Polyomavirus (BKPyV) infection manifests as renal inflammation and can cause kidney damage. Tumor necrosis factor-α (TNF-α) is increased in renal inflammation and injury. The aim of this study was to investigate the effect of TNF-α blockade on BKPyV infection. METHODS: Urine specimens from 22 patients with BKPyV-associated nephropathy (BKPyVN) and 35 non-BKPyVN kidney transplant recipients were analyzed. RESULTS: We demonstrated increased urinary levels of TNF-α and its receptors, TNFR1 and TNFR2, in BKPyVN patients. Treating BKPyV-infected human proximal tubular cells (HRPTECs) with TNF-α stimulated the expression of large T antigen and viral capsid protein-1 mRNA and proteins and BKPyV promoter activity. Knockdown of TNFR1 or TNFR2 expression caused a reduction in TNF-α-stimulated viral replication. NF-κB activation induced by overexpression of constitutively active IKK2 significantly increased viral replication and the activity of the BKPyV promoter containing an NF-κB binding site. The addition of a NF-κB inhibitor on BKPyV-infected cells suppressed viral replication. Blockade of TNF-α functionality by etanercept reduced BKPyV-stimulated expression of TNF-α, interleukin-1ß (IL-1ß), IL-6 and IL-8 and suppressed TNF-α-stimulated viral replication. In cultured HRPTECs and THP-1 cells, BKPyV infection led to increased expression of TNF-α, interleukin-1 ß (IL-1ß), IL-6 and TNFR1 and TNFR2 but the stimulated magnitude was far less than that induced by poly(I:C). This may suggest that BKPyV-mediated autocrine effect is not a major source of TNFα. CONCLUSION: TNF-α stimulates BKPyV replication and inhibition of its signal cascade or functionality attenuates its stimulatory effect. Our study provides a therapeutic anti-BKPyV target.

Functional characterization of the MyD88 homologs in Strongylocentrotus purpuratus.

Toll-like receptor signaling is an evolutionarily conserved pathway to induce the expression of immune mediators in response to encounters with pathogens. MyD88 is a central adapter connecting the intracellular domain of the receptors to downstream kinases. Here, we conducted a comprehensive assessment of the MyD88 family in an echinoderm, Strongylocentrotus purpuratus. Of five SpMyD88s only two closely related proteins, SpMyD88A and SpMyD88B, are functional in mammalian cell lines as their overexpression facilitates the activation of the downstream transcription factor NF-κB. This requires the presence of the endogenous mammalian MyD88s, and domain swapping indicated that the death domains of S. purpuratus MyD88 are unable to efficiently connect to the respective domains of the vertebrate IRAK kinases. This suggests that the interaction surfaces between the signaling mediators in this conserved signaling pathway are not as conserved as previously thought but were likely shaped and evolved by pathogenic selection over evolutionary timescales.

Contribution of genetic variants associated with primary immunodeficiencies to childhood-onset systemic lupus erythematous.

BACKGROUND: A dysregulated immune response is a hallmark of autoimmune disorders. Evidence suggests that systemic autoimmune diseases and primary immunodeficiency disorders (PIDs) may be similar diseases with different clinical phenotypes. OBJECTIVE: This study aimed to investigate the burden of PID-associated genetic variants in patients with childhood-onset systemic lupus erythematosus (cSLE). METHODS: We enrolled 118 cSLE patients regularly followed at Chang Gung Memorial Hospital. Targeted next-generation sequencing identified PID genetic variants in patients versus 1475 unrelated healthy individuals, which were further filtered by allelic frequency and various functional scores. Customized immune assays tested the functions of the identified variants. RESULTS: On filtration, 36 patients (30.5%) harbored rare variants in PID-associated genes predicted to be damaging. One homozygous TREX1 (c.294dupA) mutation and 4 heterozygous variants with possible dominant PID traits, including BCL11B (c.G1040T), NFKB1 (c.T695G), and NFKB2 (c.G1210A, c.G1651A), were discovered. With recessive traits, variants were found across all PID types; one fifth involved phagocyte number or function defects. Predicted pathogenic PID variants were more predominant in those with a family history of lupus, regardless of infection susceptibility. Moreover, mutation loads were greater among cSLE patients than controls despite sex or age at disease onset. While greater mutation loads were observed among cSLE patients with peripubertal disease onset, no significant differences in sex or phenotype were noted among cSLE patients. CONCLUSION: cSLE is mostly not monogenic. Gene-specific analysis and mutation load investigations suggested that rare and predicted damaging variants in PID-related genes can potentially contribute to cSLE susceptibility.

The intragraft vascularized bone marrow induces secondary donor-specific mystacial pad allograft tolerance.

Introduction: Vascularized bone marrow (VBM) is essential in tolerance induction through chimerism. We hypothesized that the inclusion of VBM contributes to the induction of mystacial pad allotransplantation tolerance. Method: In this study, 19 VBM, nine mystacial pad, and six sequential VBM and mystacial pad allografts were transplanted from Brown Norway (BN) rats to Lewis (LEW) rats to test our hypothesis. The VBM recipients were divided into antilymphocyte serum (ALS) monotherapy group (two doses of ALS on day 3 pretransplantation and day 1 posttransplantation), immunosuppressant group [a week of 2 mg/kg/day tacrolimus (Tac) and 3 weeks of 3 mg/kg/day rapamycin (RPM)], and combined therapy group. The mystacial pad recipients were divided into VBM and non-VBM transplantation groups, and both groups were treated with an immunosuppression regimen that consists of ALS, Tac, and RPM. For the recipients of sequential VBM and mystacial pad allotransplantations, additional Tac was given 1 week after mystacial pad transplantation. Allograft survival, donor-specific tolerance, and chimerism level were evaluated. Results: With the administration of ALS and short-term Tac and RPM treatments, VBM recipients demonstrated long-term graft survival (>120 days) with persistent chimerism for 30 days. CD3+ T cells from tolerant rats showed donor-specific hyporesponsiveness and tolerance to donor skin grafts but not to third-party counterparts. Furthermore, mystacial pad graft recipients with VBM transplantation exhibited a higher allograft survival rate than those without VBM transplantation [median survival time (MST) >90 days vs. 70 days, p < 0.05]. Conclusion: This study demonstrated that VBM transplantation is an efficient strategy to induce and maintain donor-specific tolerance for an osseous-free allograft.

Long-Term Outcome of Leptospirosis Infection with Acute Kidney Injury.

Acute kidney injury (AKI) is associated with long-term mortality and morbidity outcomes. Severe leptospirosis usually results in AKI and multiple organ failure, but is associated with favorable short-term outcomes, if treatment is initiated early. However, information on long-term outcomes after leptospirosis-associated AKI is limited. The effects of leptospirosis on resulting chronic kidney disease (CKD), as well as mortality, were evaluated in this study. We studied 2145 patients with leptospirosis from the National Health Insurance Research Database over an 8-year follow-up period. Patient demographics and characteristics were analyzed for AKI and dialysis. The risk factors for renal outcomes were analyzed using multivariate logistic regression. In total, 443 (20.6%) patients had AKI. Among them, 77 (3.6%) patients received replacement therapy (AKI-RRT group). Long-term mortality was higher in the AKI-RRT group than in the AKI group and non-AKI group, based on a multivariate logistic regression model. Similarly, the incidence rate of CKD was highest in the AKI-RRT group, followed by the AKI and non-AKI groups. Leptospirosis, complicated with AKI, may play a critical role in the long-term outcomes, resulting in CKD. The severity of AKI determines the incidence of CKD. Additional prospective investigations for the early detection of AKI in leptospirosis are warranted.