Approximately 1 million cases of leptospirosis, an emerging infectious zoonotic disease, are reported each year. Pathogenic
species express leucine-rich repeat (LRR) proteins that are rarely ...expressed in non-pathogenic
species. The LRR domain-containing protein family is vital for the virulence of pathogenic
species. In this study, the biological mechanisms of an essential LRR domain protein from pathogenic
were examined. The effects of
and recombinant LRR20 (rLRR20) on the expression levels of factors involved in signal transduction were examined using microarray, quantitative real-time polymerase chain reaction, and western blotting. The secreted biomarkers were measured using an enzyme-linked immunosorbent assay. rLRR20 colocalized with E-cadherin on the cell surface and activated the downstream transcription factor β-catenin, which subsequently promoted the expression of MMP7, a kidney injury biomarker. Additionally, MMP7 inhibitors were used to demonstrate that the secreted MMP7 degrades surface E-cadherin. This feedback inhibition mechanism downregulated surface E-cadherin expression and inhibited the colonization of Leptospira. The degradation of surface E-cadherin activated the NF-κB signal transduction pathway. Leptospirosis-associated acute kidney injury is associated with the secretion of NGAL, a downstream upregulated biomarker of the NF-κB signal transduction pathway. A working model was proposed to illustrate the crosstalk between E-cadherin/β-catenin and NF-κB signal transduction pathways during
infection. Thus, rLRR20 of Leptospira induces kidney injury in host cells and inhibits the adhesion and invasion of
through the upregulation of MMP7 and NGAL.
Allopurinol, a common drug for treating hyperuricemia, is associated with cutaneous adverse drug reactions ranging from mild maculopapular exanthema to life-threatening severe cutaneous adverse ...reactions, including drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. We have previously reported that HLA-B*58:01 is strongly associated with allopurinol-induced severe cutaneous adverse reactions in Han Chinese, but the associations of the HLA-B*58:01 genotype in an allopurinol-induced hypersensitivity phenotype remain unclear. To investigate the comprehensive associations of HLA-B*58:01, we enrolled 146 patients with allopurinol-induced cutaneous adverse drug reactions (severe cutaneous adverse reactions, n = 106; maculopapular exanthema, n = 40) and 285 allopurinol-tolerant control subjects. Among these allopurinol-induced cutaneous adverse drug reactions, HLA-B*58:01 was strongly associated with severe cutaneous adverse reactions (odds ratio OR = 44.0; 95% confidence interval = 21.5–90.3; P = 2.6 × 10-41), and the association was correlated with disease severity (OR = 44.0 for severe cutaneous adverse reactions, OR = 8.5 for maculopapular exanthema). The gene dosage effect of HLA-B*58:01 also influenced the development of allopurinol-induced cutaneous adverse drug reactions (OR = 15.25 for HLA-B*58:01 heterozygotes and OR = 72.45 for homozygotes). Furthermore, coexistence of HLA-B*58:01 and renal impairment increased the risk and predictive accuracy of allopurinol-induced cutaneous adverse drug reactions (heterozygous HLA-B*58:01 and normal renal function: OR = 15.25, specificity = 82%; homozygous HLA-B*58:01 and severe renal impairment: OR = 1269.45, specificity = 100%). This HLA-B*58:01 correlation study suggests that patients with coexisting HLA-B*58:01 and renal impairment (especially estimated glomerular filtration rate < 30ml/minute/1.73 m2) should be cautious and avoid using allopurinol.
Autosomal dominant polycystic kidney disease (ADPKD) is a common kidney disease caused by mutations in PKD1 or PKD2. Metformin reduces cyst growth in mouse models of PKD1. However, metformin has not ...been studied in animal models of PKD2, and the cellular mechanism underlying its effectiveness is not entirely clear. This study investigated the effects of metformin on cyst formation in a zebrafish model of polycystin-2 deficiency resulting from morpholino knockdown of pkd2. We added metformin (2.5 to 20 mM) to the embryo media between 4 and 48 hours post fertilisation and observed pronephric cyst formation by using the wt1b promoter-driven GFP signal in Tg(wt1b:GFP) pkd2 morphants. Metformin inhibited pronephric cyst formation by 42-61% compared with the untreated controls. Metformin also reduced the number of proliferating cells in the pronephric ducts, the degree of dorsal body curvature, and the infiltration of leukocytes surrounding the pronephros. Moreover, metformin treatment increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and enhanced autophagy in the pronephros. Our data suggest that metformin reduces cyst formation through activation of the AMPK pathway and modulation of defective cellular events such as proliferation and autophagy. These results also imply that metformin could have therapeutic potential for ADPKD treatment.
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome are severe drug-induced cutaneous adverse reactions with high mortality. Acute kidney injury (AKI) was a ...common complication in an SJS/TEN group and noted as an independent risk factor for mortality in patients with SJS/TEN. To determine whether AKI staging can predict the outcome of patients with SJS/TEN, we compared the discriminative power of an AKI KDIGO staging system with that of SCROTEN, APACHE II, APACHE III, and SOFA.
We retrospectively analyzed the data of 75 patients who were diagnosed with SJS, TEN, or SJS/TEN overlap syndrome at a tertiary care university hospital between January 1, 2011 and December 31, 2014. The baseline characteristics, biochemical analysis data, medication use, and outcomes of the patients were assessed, and the discriminative ability for predicting mortality was determined for each prognostic model.
Of the 75 patients, 23 (30.7%) had AKI, of whom 13 (56.5%) died during the index admission. Of the prognostic risk models analyzed, the KDIGO staging system showed similar discriminative ability in predicting in-hospital mortality as did the other models. In addition, combining KDIGO with other scoring systems yielded significantly more accurate risk prediction for in-hospital mortality compared with the other individual scores alone, as measured by net reclassification index. The patients with KDIGO stages 2 and 3 exhibited a significantly lower 1-year survival rate than did those with KDIGO stages 0 and 1.
AKI KDIGO staging has good discriminative ability and is easy to utilize for predicting mortality.
Tuberculous peritonitis (TBP) is a rare but fatal complication in patients on peritoneal dialysis (PD). In this study, we aimed to determine the demographic features, clinical features, laboratory ...parameters, and clinical outcomes of PD patients with TBP and to clarify possible risk factors for mortality.
We retrospectively reviewed 2084 PD patients from January 1985 to December 2019. The diagnosis of TBP was established by positive peritoneal fluid culture for Mycobacterium tuberculosis.
18 patients were diagnosed with TBP. The incidence was 2.029 episodes per 1000 patient-years. The most common symptom was fever (94.4%), followed by cloudy effluent (83.3%) and abdominal pain (83.3%). The average peritoneal dialysis effluent (PDE) white blood cell (WBC) count was 172.7 cells/μL. Nine patients (50%) had WBC counts lower than 100 cells/μL and 13 patients (72.2%) had neutrophilic predominant WBC counts. Acid fast stain (AFS) was positive in 7 patients (38.9%). Only 2 patients (11.1%) continued with PD after TB infection, while 10 patients (55.6%) changed to hemodialysis. Seven patients (38.9%) died within 1 year. Significant differences were observed in sex (p = 0.040), the presence of diabetes mellitus (p = 0.024), and PD catheter removal (p < 0.001) between TBP patients with and without mortality. However, none of them was a significant factor for 1-year mortality in multivariate Cox regression model.
Physicians should pay attention to the unusual presentations of peritonitis, especially if symptoms include fever or an initial low PDE WBC count. Catheter removal is not mandatory if early diagnosis and appropriate therapy are available.
Leptospirosis is an overlooked zoonotic disease caused by pathogenic Leptospira depended on virulence of Leptospira and the host-pathogen interaction. Kidney is the major organ infected by Leptospira ...which causes tubulointerstitial nephritis. Leptospira outer membrane contains several virulence factors and an outer membrane protein A (OmpA) like protein (Loa22) is essential for virulence. Pull-down assays suggested that Loa22 was a potential Toll-Like Receptor 2 (TLR2) binding candidates from pathogenic Leptospira. Confocal microscopy was employed to observe the co-localization of TLR2 and Loa22-LPGN (Leptospira peptidoglycan) complexes. Atomic force microscopy (AFM), side-directed mutagenesis, and enzyme-linked immunosorbent assay (ELISA) were performed to investigate the affinity between rLoa22, LPGN, and TLR2. Real time PCR was applied to measure the cytokines expression. Downstream signal transduction components were verified by western blot to evaluate the gene regulations. Mutation of two Loa22 key residues (Asp
and Arg
) attenuated the affinities for LPGN. rLoa22-LPGN complexes were observed to co-localize with TLR2 and provoked inflammatory responses including CXCL8/IL8, hCCL2/MCP-1, and hTNF-α. Affinity studies suggested that Loa22-LPGN complexes elevated the affinity to TLR2 as compared to Loa22 protein. Downstream signals from TLR2 including p38, ERK, and JNK were regulated under rLoa22-LPGN complexes treatments. This study identified LPGN mediates interactions between Loa22 and TLR2 and induces downstream signals to trigger inflammatory responses. rLoa22-LPGN-TLR2 complexes reveal a novel binding mechanism for the innate immune system.
The aberrant activation of the purinergic signaling pathway has been shown to promote cyst growth and fluid secretion in autosomal dominant polycystic kidney disease (ADPKD). Suramin is an ...anti-parasitic drug that has strong anti-purinergic properties. Whether suramin could have a therapeutic effect on ADPKD has not been fully investigated. We examined the effect of suramin on cyst progression in a Pkd1 microRNAs transgenic mouse model that presented stable Pkd1 knockdown and moderate disease progression. The Pkd1-deficient mice were treated with suramin (60 mg/kg) by intraperitoneal injection twice a week from postnatal days 35 to 90. Kidney-to-body weight ratios, cyst indices, and blood urea nitrogen (BUN) levels were measured. Cell proliferation and macrophage infiltration were determined by immunohistochemistry. The suramin-treated group had significantly lower renal cyst densities, cell proliferation, and macrophage infiltration compared with saline-treated controls. Suramin significantly inhibited ERK phosphorylation and the expression of Il1b, Il6, Nlrp3, Tgfb, Fn1, P2rx7, and P2ry2 mRNAs in the kidneys. However, BUN levels remained high despite the reduction in cyst growth. Furthermore, plasma cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) levels were significantly higher in the suramin-treated group compared with the control group. Periodic acid-Schiff staining revealed degenerative changes and epithelial cell vacuolation in the non-cystic renal tubules, which indicated phospholipidosis following suramin treatment. These results suggest that suramin may reduce renal cyst growth and inflammation, but the associated tubular cell injuries could limit its therapeutic potential. Other purinergic receptor antagonists with less nephrotoxicity may deserve further investigation for the treatment of ADPKD.
Abstract
Context
Fenofibrate provides limited cardiovascular (CV) benefits in the general population; however, little is known about its benefit among advanced chronic kidney disease (CKD) patients.
...Objective
This study compared outcomes among advanced CKD patients treated with fenofibrate, statins, a combination of both, and none of these.
Methods
This national cohort study was based on Taiwan’s National Health Insurance Research Database. Patients younger than 20 years with advanced CKD were identified and further divided into 4 groups according to treatment. The inverse probability of treatment weighting was used to balance baseline characteristics. Patients received fenofibrate, statins, a combination of fenofibrate and statins, or none of these in the 3 months preceding the advanced CKD date. Main outcome measures included all-cause mortality, CV death, and incidence of permanent dialysis.
Results
The fenofibrate and statin groups exhibited a lower risk of CV death (fenofibrate vs nonuser: hazard ratio HR: 0.84; 95% CI, 0.75-0.94; statins vs nonuser: HR: 0.94; 95% CI, 0.90-0.97) compared with the nonuser group. The fenofibrate group further exhibited the lowest incidence of permanent dialysis (fenofibrate vs nonuser: subdistribution HR SHR: 0.78; 95% CI, 0.77-0.80; statins vs fenofibrate: SHR: 1.27; 95% CI, 1.26-1.29; combination vs fenofibrate: SHR: 1.15; 95% CI, 1.13-1.17). Furthermore, the combined administration of fenofibrate and high-intensity statins exhibited a lower risk of major adverse cardiac and cerebrovascular events.
Conclusion
For patients with advanced CKD, continuing fenofibrate may provide a protective effect on CV outcomes equal to that of statins, and it may further delay the need for permanent dialysis. The combination of fenofibrate and high-intensity statins may have additional benefits.
Phosphate level is often deranged during acute illness, regardless of the presence of kidney injury or not. A few studies described that hypophosphatemia may associated with outcome in patients ...admitted to the burn unit, but the literatures for hyperphosphatemia is limited. Our study aims to evaluate if hyperphosphatemia, one of the sign of severe tissue damage or kidney injury, will associate with mortality of patients with severe burns.
The study was a post hoc analysis of prospectively collected data from patients admitted to the burn unit between September 2006 and December 2011. Patients were stratified into normophosphatemic or hyperphosphatemic group by baseline plasma phosphate level. The primary endpoint is 90-day mortality.
Total 301 patients were included (hyperphosphatemia: n = 52; normophosphatemia: n = 249). The hyperphosphatemic group had lower Glasgow Coma Scale, mean arterial blood pressure, hemoglobin level, albumin, and higher TBSA of burns, APACHE II score, ABSI score, Acute kidney injury (AKI), and creatinine. The 90-day mortality was higher in the hyperphosphatemic group than in the normal group (53.8% vs 18.1%, P < .001) and this difference was still significant when adjusting for several confounding factors (hazard ratio, 2.05; 95% CI, 1.17-3.59). Multivariable Cox analysis showed risk factors of mortality included TBSA of burns, hyperphosphatemia, reduced urine output, and APACHE II score.
Our study found in addition to TBSA of burns and inhalation injury, baseline hyperphosphatemia in patients with severe burns is also associated with higher mortality.
Glucagon-like peptide-1 (GLP-1) receptor agonist use is associated with reduced mortality and improved cardiovascular outcomes in the general population with diabetes. Dipeptidyl peptidase-4 (DPP-4) ...inhibitors are commonly used antidiabetic agents for patients with advanced-stage chronic kidney disease (CKD). The association of these 2 drug classes with outcomes among patients with diabetes and advanced-stage CKD or end-stage kidney disease (ESKD) is not well understood.
To assess whether use of GLP-1 receptor agonists in a population with diabetes and advanced-stage CKD or ESKD is associated with better outcomes compared with use of DPP-4 inhibitors.
This retrospective cohort study used data on patients with type 2 diabetes and stage 5 CKD or ESKD obtained from the National Health Insurance Research Database of Taiwan. The study was conducted between January 1, 2012, and December 31, 2018. Data were analyzed from June 2020 to July 2021.
Treatment with GLP-1 receptor agonists compared with treatment with DPP-4 inhibitors.
All-cause mortality, sepsis- and infection-related mortality, and mortality related to major adverse cardiovascular and cerebrovascular events were compared between patients treated with GLP-1 receptor agonists and patients treated with DPP-4 inhibitors. Propensity score weighting was used to mitigate the imbalance among covariates between the groups.
Of 27 279 patients included in the study, 26 578 were in the DPP-4 inhibitor group (14 443 54.34% male; mean SD age, 65 13 years) and 701 in the GLP-1 receptor agonist group (346 49.36% male; mean SD age, 59 13 years). After weighting, the use of GLP-1 receptor agonists was associated with lower all-cause mortality (hazard ratio HR, 0.79; 95% CI, 0.63-0.98) and lower sepsis- and infection-related mortality (HR, 0.61; 95% CI, 0.40-0.91). Subgroup analysis demonstrated a lower risk of mortality associated with use of GLP-1 receptor agonists compared with DDP-4 inhibitors among patients with cerebrovascular disease (HR, 0.33; 95% CI, 0.12-0.86) than among those without cerebrovascular disease (HR, 0.89; 95% CI, 0.71-1.12) (P = .04 for interaction).
Treatment with GLP-1 receptor agonists was associated with lower all-cause mortality among patients with type 2 diabetes, advanced-stage CKD, and ESKD than was treatment with DPP-4 inhibitors. Additional well-designed, prospective studies are needed to confirm the potential benefit of GLP-1 receptor agonist treatment for patients with advanced CKD or ESKD.
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