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.

The essential role of the ERK activation in large T antigen of BK polyomavirus regulated cell migration.

Recent studies have suggested that BK polyomavirus (BKPyV) may be associated with the development of urothelial carcinoma. In Merkel cell carcinoma, TAg and tAg are the major viral proteins of Merkel cell polyomavirus with oncogenic potential. In this study, we aimed to distinguish the role of TAg and tAg in cell migration. Our result demonstrated that ERK was phosphorylated in human renal tubular cells expressing its TAg and tAg after BKPyV infection. Treatment with the ERK inhibitor U0126 suppressed BKPyV gene expression and reduced BKPyV replication. Both TAg and tAg induced cell migration via ERK-dependent signaling. Furthermore, the expression of TAg and tAg had a significant regulatory effect on focal adhesion molecules in renal proximal tubular cells, which strongly suggests that alterations in the focal adhesion complexes are critically involved in TAg and tAg-induced cell migration. Gelatin zymography profiling revealed that TAg regulates the expression and activity of MMP-2 and MMP-9, but not tAg. Interestingly, TAg regulates the expression and activity of MMP-9 through ERK signaling, whereas MMP-2 is regulated through an ERK-independent pathway. Unbalanced ERK pathway activity is frequently observed in many cancers, while MMP proteins are usually overexpressed in aggressive tumors. These findings support the view that BKPyV is an oncogenic virus.

Experiences of oncology healthcare personnel in international medical service quality: a phenomenological study.

BACKGROUND: With the globalization of medical services on the rise, Asia has ascended to a destination of choice for its high-quality medical services at very reasonable rates. Monitoring the quality of the international medical industry is vital to maintain service demand. The experiences of healthcare personnel (HCP) involved in international medical services (IMS) regarding the provision of services to international cancer patients have not yet been discussed. This study aimed to explore oncology HCP experiences of IMS quality in caring for international cancer patients in Taiwan. METHODS: Descriptive phenomenological method and were analyzed through Colaizzi's seven-step approach. In this study, 19 respondents were collected data by using in-depth semi-structured interviews. An average interview lasted approximately 45 min. RESULTS: Four major themes were identified from the interviews: patient selection, psycho-oncology care, predicaments, and promoting suggestions. Additionally, thirteen subthemes emerged, including necessary selection of patients, reasons for unwillingness to enroll international patients, helpless patients, emotional distress, care with warmth, insufficient manpower, an unfair reward mechanism, poor hardware equipment, the predicaments of oncology care, various publicity strategies, one-on-one service model, design of a designated area, and reasonable benefit distribution. CONCLUSIONS: This study explored oncology HCP experiences of IMS quality in caring for international cancer patients, with implications for hospitals in developing high-quality IMS. Due to the fact that IMS is a global trend, HCPs, administrators, and policy-makers are advised to improve the quality of IMS in the oncology department, which has been the least studied field in IMS quality.

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.

Use of fibrates is not associated with reduced risks of mortality or cardiovascular events among ESRD patients: A national cohort study.

Background: Although a recent study reported that fibrates are associated with a low risk of cardiovascular (CV) death and can postpone the need for long-term hemodialysis in patients with advanced chronic kidney disease (CKD), little is known regarding whether the CV protective effects of fibrates extend to patients with end-stage renal disease (ESRD). The present study compared CV outcomes and mortality among patients with ESRD treated with fibrates, statins, neither, or their combination. Methods: This cohort study extracted data from Taiwan's National Health Insurance Research Database (NHIRD). Adult patients with ESRD and hyperlipidemia were identified and categorized into four groups (fibrate, statin, combination, and non-user groups) according to their use of different lipid-lowering therapies within 3 months prior to the commencement of permanent dialysis. Inverse probability of treatment weighting was used to balance the baseline characteristics of the groups. The follow-up outcomes were all-cause mortality, CV death, and major adverse cardiac and cerebrovascular events (MACCEs). Results: Compared with the non-user and statin groups, the fibrate group did not exhibit significantly lower risks of all-cause mortality [fibrate vs. non-user: hazard ratio (HR), 0.97; 95% confidence interval (CI), 0.92-1.03; statin vs. fibrate: HR, 0.95; 95% CI, 0.90-1.01], CV death (fibrate vs. non-user: HR, 0.97; 95% CI, 0.90-1.05; statin vs. fibrate: HR, 0.97; 95% CI, 0.90-1.06), and MACCEs (fibrate vs. non-user: HR, 1.03; 95% CI, 0.96-1.10; statin vs. fibrate: HR, 0.94; 95% CI, 0.87-1.004). The combination of fibrates and statins (specifically moderate- to high-potency statins) did not result in lower risks of all-cause mortality, CV death, or MACCEs compared with statins alone. Conclusion: In patients with ESRD, the use of fibrates might be not associated with reduced mortality or CV risks, regardless of whether they are used alone or in combination with statins.

Ketoanalogues Supplemental Low Protein Diet Safely Decreases Short-Term Risk of Dialysis among CKD Stage 4 Patients.

Background: Rigid dietary controls and pill burden make a very-low protein (0.3−0.4 g/kg body weight per day), vegetarian diet supplemented with ketoanalogues of amino acids (sVLPD) hard to follow in the long-term. This study aimed to evaluate whether a ketoanalogue supplemental low-protein diet (sLPD) (0.6 g/kg body weight per day) could also reduce the risks of dialysis among CKD stage 4 patients. Methods: Patients aged >20 years with a diagnosis of stage 4 CKD who subsequently received ketosteril treatment, which is the most commonly used ketoanalogue of essential amino acids, between 2003 and 2018 were identified from the Chang Gung Research Database (CGRD). Then, these individuals were divided into two groups according to the continuation of ketosteril for more than three months or not. The primary outcome was ESKD requiring maintenance dialysis. Results: With one-year follow-up, the continuation group (n = 303) exhibited a significantly lower incidence of new-onset end-stage kidney disease (ESKD) requiring maintenance dialysis (6.8% vs. 10.4%, hazard ratio [HR]: 0.62, 95% confidence interval [CI]: 0.41−0.94) in comparison to the discontinuation group (n = 238). Conclusions: This study demonstrated that initiating sLPDs since CKD stage 4 may additionally reduce the short-term risks of commencing dialysis without increasing CV events, infections, or mortality.

Strategies for post-cardiac surgery acute kidney injury prevention: A network meta-analysis of randomized controlled trials.

Objects: Cardiac surgery is associated with acute kidney injury (AKI). However, the effects of various pharmacological and non-pharmacological strategies for AKI prevention have not been thoroughly investigated, and their effectiveness in preventing AKI-related adverse outcomes has not been systematically evaluated. Methods: Studies from PubMed, Embase, and Medline and registered trials from published through December 2021 that evaluated strategies for preventing post-cardiac surgery AKI were identified. The effectiveness of these strategies was assessed through a network meta-analysis (NMA). The secondary outcomes were prevention of dialysis-requiring AKI, mortality, intensive care unit (ICU) length of stay (LOS), and hospital LOS. The interventions were ranked using the P-score method. Confidence in the results of the NMA was assessed using the Confidence in NMA (CINeMA) framework. Results: A total of 161 trials (involving 46,619 participants) and 53 strategies were identified. Eight pharmacological strategies {natriuretic peptides [odds ratio (OR): 0.30, 95% confidence interval (CI): 0.19-0.47], nitroprusside [OR: 0.29, 95% CI: 0.12-0.68], fenoldopam [OR: 0.36, 95% CI: 0.17-0.76], tolvaptan [OR: 0.35, 95% CI: 0.14-0.90], N-acetyl cysteine with carvedilol [OR: 0.37, 95% CI: 0.16-0.85], dexmedetomidine [OR: 0.49, 95% CI: 0.32-0.76;], levosimendan [OR: 0.56, 95% CI: 0.37-0.84], and erythropoietin [OR: 0.62, 95% CI: 0.41-0.94]} and one non-pharmacological intervention (remote ischemic preconditioning, OR: 0.76, 95% CI: 0.63-0.92) were associated with a lower incidence of post-cardiac surgery AKI with moderate to low confidence. Among these nine strategies, five (fenoldopam, erythropoietin, natriuretic peptides, levosimendan, and remote ischemic preconditioning) were associated with a shorter ICU LOS, and two (natriuretic peptides [OR: 0.30, 95% CI: 0.15-0.60] and levosimendan [OR: 0.68, 95% CI: 0.49-0.95]) were associated with a lower incidence of dialysis-requiring AKI. Natriuretic peptides were also associated with a lower risk of mortality (OR: 0.50, 95% CI: 0.29-0.86). The results of a sensitivity analysis support the robustness and effectiveness of natriuretic peptides and dexmedetomidine. Conclusion: Nine potentially effective strategies were identified. Natriuretic peptide therapy was the most effective pharmacological strategy, and remote ischemic preconditioning was the only effective non-pharmacological strategy. Preventive strategies might also help prevent AKI-related adverse outcomes. Additional studies are required to explore the optimal dosages and protocols for potentially effective AKI prevention strategies.

Identifying survival protective factors for chronic dialysis patients with surgically confirmed acute mesenteric ischemia.

BACKGROUND: Mesenteric ischemia is significantly more common in end-stage kidney disease patients undergoing chronic dialysis than in the general population and is associated with high morbidity and mortality. However, reports on prognostic factors in this population are limited. AIM: To elucidate the in-hospital outcomes of acute mesenteric ischemia in chronic dialysis patients and to analyze protective factors for survival. METHODS: The case data of 426 chronic dialysis patients who were hospitalized in a tertiary medical center for acute mesenteric ischemia over a 14-year period were retrospectively reviewed. Of these cases, 103 were surgically confirmed, and the patients were enrolled in this study. A Cox regression analysis was used to evaluate the protective factors for survival. RESULTS: The in-hospital mortality rate among the 103 enrolled patients was 46.6%. Univariate analysis was performed to compare factors in survivors and nonsurvivors, with better in-hospital outcomes associated with a surgery delay (defined as the time from onset of signs and symptoms to operation) < 4.5 d, no shock, a higher potassium level on day 1 of hospitalization, no resection of the colon, and a total bowel resection length < 110 cm. After 1 wk of hospitalization, patients with lower white blood cell count and neutrophil counts, higher lymphocyte counts, and lower C-reactive protein levels had better in-hospital outcomes. Following multivariate adjustment, a higher potassium level on day 1 of hospitalization (HR 1.71, 95%CI 1.19 to 2.46; P = 0.004), a lower neutrophil count (HR 0.91, 95%CI 0.84 to 0.99; P = 0.037) at 1 wk after admission, resection not involving the colon (HR 2.70, 95%CI 1.05 to 7.14; P = 0.039), and a total bowel resection length < 110 cm (HR 4.55, 95%CI 1.43 to 14.29; P = 0.010) were significantly associated with survival. CONCLUSION: A surgery delay < 4.5 d, no shock, no resection of the colon, and a total bowel resection length < 110 cm predicted better outcomes in chronic dialysis patients with acute mesenteric ischemia.

Association of Low-Density Lipoprotein Cholesterol Levels During Statin Treatment With Cardiovascular and Renal Outcomes in Patients With Moderate Chronic Kidney Disease.

Background The benefit of low-density lipoprotein cholesterol (LDL-C) levels in chronic kidney disease populations remains unclear. This study evaluated the cardiovascular and renal outcomes in patients with stage 3 chronic kidney disease with different LDL-C levels during statin treatment. Methods and Results There were 8500 patients newly diagnosed as having stage 3 chronic kidney disease under statin treatment who were identified from the Chang Gung Research Database and divided into 3 groups according to their first LDL-C level after the index date: <70 mg/dL, 70 to 100 mg/dL, and >100 mg/dL. Inverse probability of treatment weighting was performed to balance baseline characteristics. Compared with the LDL-C ≥100 mg/dL group, the 70≤LDL-C<100 mg/dL group exhibited significantly lower risks of major adverse cardiac and cerebrovascular events (6.8% versus 8.8%; subdistribution hazard ratio [SHR], 0.76 [95% CI, 0.64-0.91]), intracerebral hemorrhage (0.23% versus 0.51%; SHR, 0.44 [95% CI, 0.25-0.77]), and new-onset end-stage renal disease requiring chronic dialysis (7.6% versus 9.1%; SHR, 0.82 [95% CI, 0.73-0.91]). By contrast, the LDL-C <70 mg/dL group exhibited a marginally lower risk of major adverse cardiac and cerebrovascular events (7.3% versus 8.8%; SHR, 0.82 [95% CI, 0.65-1.02]) and a significantly lower risk of new-onset end-stage renal disease requiring chronic dialysis (7.1% versus 9.1%; SHR, 0.76 [95% CI, 0.67-0.85]). Conclusions Among patients with stage 3 chronic kidney disease, statin users with 70≤LDL-C<100 mg/dL and with LDL-C <70 mg/dL had similar beneficial effect in the reduction of risks of major adverse cardiac and cerebrovascular events and new-onset end-stage renal disease compared with those with LDL-C >100 mg/dL. Moreover, the 70≤LDL-C<100 mg/dL group seemed to have a lowest risk of intracerebral hemorrhage, although the incidence was low.

Integrated Metabolomic and Transcriptomic Analysis of Acute Kidney Injury Caused by Leptospira Infection.

Renal leptospirosis caused by leptospiral infection is characterised by tubulointerstitial nephritis and tubular dysfunction, resulting in acute and chronic kidney injury. Metabolomic and transcriptomic data from a murine model of Leptospira infection were analysed to determine whether metabolomic data from urine were associated with transcriptome changes relevant to kidney injury caused by Leptospira infection. Our findings revealed that 37 metabolites from the urine of L. interrogans-infected mice had significantly different concentrations than L. biflexa-infected and non-infected control mice. Of these, urinary L-carnitine and acetyl-L-carnitine levels were remarkably elevated in L. interrogans-infected mice. Using an integrated pathway analysis, we found that L-carnitine and acetyl-L-carnitine were involved in metabolic pathways such as fatty acid activation, the mitochondrial L-carnitine shuttle pathway, and triacylglycerol biosynthesis that were enriched in the renal tissues of the L. interrogans-infected mice. This study highlights that L-carnitine and acetyl-L-carnitine are implicated in leptospiral infection-induced kidney injury, suggesting their potential as metabolic modulators.

Therapeutic Potential of Exosomes Derived from Diabetic Adipose Stem Cells in Cutaneous Wound Healing of db/db Mice.

(1) Background: Diabetes impairs angiogenesis and wound healing. Paracrine secretion from adipose stem cells (ASCs) contains membrane-bound nano-vesicles called exosomes (ASC-Exo) but the functional role and therapeutic potential of diabetic ASC-Exo in wound healing are unknown. This study aims to investigate the in vivo mechanistic basis by which diabetic ASC-Exo enhance cutaneous wound healing in a diabetic mouse model. (2) Methods: Topically applied exosomes could efficiently target and preferentially accumulate in wound tissue, and the cellular origin, ASC or dermal fibroblast (DFb), has no influence on the biodistribution pattern of exosomes. In vivo, full-thickness wounds in diabetic mice were treated either with ASC-Exo, DFb-Exo, or phosphate-buffered saline (PBS) topically. ASC-Exo stimulated wound healing by dermal cell proliferation, keratinocyte proliferation, and angiogenesis compared with DFb-Exo and PBS-treated wounds. (3) Results: Diabetic ASC-Exo stimulated resident monocytes/macrophages to secrete more TGF-ß1 and activate the TGF-ß/Smad3 signaling pathway. Fibroblasts activated by TGF-ß1containing exosomes from ASCs initiate the production of TGF-ß1 protein in an autocrine fashion, which leads to more proliferation and activation of fibroblasts. TGF-ß1 is centrally involved in diabetic ASC-Exo mediated cellular crosstalk as an important early response to initiating wound regeneration. (4) Conclusions: The application of diabetic ASC-Exo informs the potential utility of a cell-free therapy in diabetic wound healing.

In-Hospital Outcomes and Recurrence of Infectious Spondylitis in Patients with and without Chronic Hemodialysis: A Nationwide Cohort Study.

Purpose: The incidence of bloodstream infection among end-stage kidney disease (ESKD) patients on chronic hemodialysis (HD) was 26-fold higher than population controls, causing higher morbidity and costs. The aim of this investigation was to clarify the prognostic factors, in-hospital outcomes and recurrence of infectious spondylitis of patients with and without chronic HD. Patients and Methods: This nationwide study analyzed 2592 patients who admitted for first-time infectious spondylitis between January 1, 2003, and December 31, 2015. Patients were classified into the chronic HD or the non-HD group. The logistic regression model and the general linear model were utilized to determine the impact of chronic HD on in-hospital mortality and recurrence. The Cox proportional hazard model was used to estimate the predictive factors of in-hospital mortality and recurrence. Results: Compared to the non-HD group, patients in the chronic HD group had a higher risk of respiratory failure, sepsis, in-hospital mortality, longer hospital stay, and higher medical spending. Chronic HD was an independent risk factor for in-hospital mortality (hazard ratio 2.21, 95% confidence interval 1.34-3.65, p=0.0019), but not for recurrence. Intravascular device implantation or revision was a prognosticator for the mortality of both groups and a predictor for recurrence of the non-HD group. Surgical treatment was associated with a decreased risk of recurrence, whereas treatment with CT-guided abscess drainage was associated with an increased risk of recurrence in both groups. Conclusion: Patients with infectious spondylitis who were receiving chronic HD had a higher in-hospital mortality compared to those without HD. Intravascular device implantations or revision within 6 months was a significant predictor of in-hospital mortality and disease recurrence. Surgical treatment of infectious spondylitis had a lower risk of recurrence than those with CT-guided abscess drainage in both patient groups.

Clinical and visual outcomes following endogenous endophthalmitis: 175 consecutive cases from a tertiary referral center in Taiwan.

BACKGROUND: To elucidate the linkage between organisms and visual outcome in cases of endogenous endophthalmitis. METHODS: Patients who presented with signs of endogenous endophthalmitis between January 2008 and December 2015 and underwent a vitreous tapping were enrolled. The patients' demographics and clinical findings were recorded. The outcomes include visual acuity and enucleation. RESULTS: A total of 175 consecutive patients with endogenous endophthalmitis were enrolled. Forty-four percent of the patients had a known distal focus of infection. The most common focus was liver abscess (24.6%), and the major intravitreal isolate was Klebsiella pneumoniae (34.4%). In this series, 51.4% of the intravitreal cultures were positive. The visual acuity of fungal ophthalmitis were better than in bacterial ophthalmitis. Multivariate logistic regression showed that Gram negative vitreous isolates, compared with the negative vitreous culture, were associated with higher risk of enucleation (Odds ratio [OR]: 10.424, 95% confidence interval [95% CI]: 3.019-35.995). The use of intravitreal antibiotics, compared non-users, was associated with a reduced risk of enucleation (OR:0.084, 95% CI: 0.026-0.268). Trans pars plana vitrectomy was not associated with risk of enucleation (OR: 0.307, 95% CI: 0.035-2.693). The post-treatment VA was positively correlated with the presenting VA (r = 0.718, p = 0.0001). CONCLUSION: Our study demonstrated that liver abscess is the most common source of endogenous endophthalmitis in Taiwan. The visual outcome is good when the presenting visual acuity is relatively well preserved and when the infecting organism is fungus. The use of intra-vitreal antibiotics reduces the risk of enucleation.

Prognostic Performance of Existing Scoring Systems among Critically Ill Patients Requiring Continuous Renal Replacement Therapy: An Observational Study.

BACKGROUND: Among critical patients, few studies have evaluated the discrimination of current illness scoring systems in predicting outcomes after continuous renal replacement therapy (CRRT) initiation. METHODS: Patients receiving CRRT in the ICU between 2005 and 2018 from the Chang Gung Research Database were extracted. All the components of the Acute Physiology Assessment and Chronic Health Evaluation (APACHE) III, Sequential Organ Failure Assessment (SOFA), qSOFA, and MOSAIC scoring systems on days 1, 3, and 7 of CRRT were recorded. Patients older than 80 years were identified and analyzed separately. RESULTS: We identified 3370 adult patients for analysis. The discrimination ability of the scoring systems was acceptable at day 7 after CRRT initiation, including SOFA (area under the receiver operating characteristic curve, 74.1% (95% confidence interval, 71.7-76.5%)), APACHEIII (74.7% (72.3-77.1%)), and MOSAIC (71.3% (68.8%-73.9%)). These systems were not ideal on days 1 and 3, and that of qSOFA was poor at any time point. The discrimination performance was slightly better among patients ≥80 years. CONCLUSIONS: APACHE III, MOSAIC, and SOFA can be intensivists and families' reference to make their decision of withdrawing or withholding CRRT after a short period of treatment, especially in adults ≥80 years old.

Rapamycin attenuates PLA2R activation-mediated podocyte apoptosis via the PI3K/AKT/mTOR pathway.

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults without diabetes. Primary MN has been associated with circulating antibodies against native podocyte antigens, including phospholipase A2 receptor (PLA2R); however, precision therapy targeting the signaling cascade of PLA2R activation is lacking. Both PLA2R and the mammalian target of rapamycin (mTOR) exist in podocytes, but the interplay between these two proteins and their roles in MN warrants further exploration. This study aimed to investigate the crosstalk between PLA2R activation and mTOR signaling in a human podocyte cell line. We demonstrated that podocyte apoptosis was induced by Group IB secretory phospholipase A2 (sPLA2IB) in a concentration- and time-dependent manner via upregulation of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and mTOR, and inhibited by rapamycin or LY294002. Furthermore, aberrant activation of the PI3K/AKT/mTOR pathway triggers both extrinsic (caspase-8 and caspase-3) and intrinsic (Bcl-2-associated X protein [BAX], B-cell lymphoma 2 [BCL-2], cytochrome c, caspase-9, and caspase-3) apoptotic cascades in podocytes. The therapeutic implications of our findings are that strategies to reduce PLA2R activation and PI3K/AKT/mTOR pathway inhibition in PLA2R-activated podocytes help protect podocytes from apoptosis. The therapeutic potential of rapamycin shown in this study provides cellular evidence supporting the repurposing of rapamycin for MN treatment.

Supplemented Low-Protein Diet May Delay the Need for Preemptive Kidney Transplantation: A Nationwide Population-Based Cohort Study.

BACKGROUND: Although several studies suggest the benefit of a low-protein diet supplemented with amino acids and keto acids (sLPD) in delaying the initiation of hemodialysis, evidence on whether these nutritional approaches could delay the timing of preemptive transplantation is lacking. METHODS: Retrospective nationwide cohort study, from Taiwan's National Health Insurance Research Database. Patients having undergone a first preemptive kidney transplantation between 2001 and 2017 were identified and divided into two groups according to the presence of sLPD treatment or not. The primary outcome was the time between the diagnosis of advanced CKD and transplantation. Secondary outcomes were post-transplantation adverse events. RESULTS: A total of 245 patients who received their first preemptive kidney transplantation were identified from the nationwide database; 63 of them had been on an sLPD prior to transplantation (sLPD group). The duration between the day of advanced CKD diagnosis and the day of transplantation was significantly longer in the sLPD group compared with the non-sLPD group (median duration: 345 vs. 220 days, p = 0.001). The risk of post-transplantation adverse events did not differ between the two groups. CONCLUSIONS: Within the limits of its observational, retrospective design, this is the first study to suggest that nutritional management with sLPDs can safely delay the timing of preemptive kidney transplantation.

Does Statin Therapy Reduce the Risks of Mortality and Major Adverse Cardiac and Cerebrovascular Events in Young Adults with End-Stage Renal Disease? Population-Based Cohort Study.

Among hemodialysis patients aged more than 40 years old, previous large-scale studies showed statin treatment had no effect on reducing cardiovascular adverse events. However, young-adult-onset end-stage renal disease (ESRD) patients have different physicosocial factors compared to older ESRD patients. The benefit of statins in such a specific group has not been well evaluated. Through the use of Taiwan's National Health Insurance Research Database (NHIRD), young adult patients aged 20-40 with incident ESRD requiring permanent dialysis between 1 January 2003 and 31 December 2015 were identified. The enrollees were further divided into two groups depending on whether they received statin therapy for more than 90 days (statin group) or never received any statin (nonstatin group) in the first year after initiation of dialysis. Propensity score weighting (PSW) was used to balance the baseline characteristics between the two groups. After PSW, the statin group (n = 771) exhibited a higher rate of major adverse cardiac and cerebrovascular events (MACCEs) (2.65% vs. 1.44%, hazard ratio (HR): 1.87, 95% confidence interval (CI): 1.43-2.45), and acute myocardial infarction (1.51% vs. 0.30%, HR: 5.34, 95% CI: 3.40-8.39) compared to the nonstatin group (n = 1709). The risk of all-cause mortality, cardiovascular (CV) death. and stroke did not significantly differ between the two groups. Similar to older patients, this study demonstrated that statin therapy cannot offer any protective effects in reducing CV outcomes among young adult ESRD patients undergoing dialysis.

Injection of hybrid 3D spheroids composed of podocytes, mesenchymal stem cells, and vascular endothelial cells into the renal cortex improves kidney function and replenishes glomerular podocytes.

Podocytes are highly differentiated epithelial cells that are crucial for maintaining the glomerular filtration barrier in the kidney. Podocyte injury followed by depletion is the major cause of pathological progression of kidney diseases. Although cell therapy has been considered a promising alternative approach to kidney transplantation for the treatment of kidney injury, the resultant therapeutic efficacy in terms of improved renal function is limited, possibly owing to significant loss of engrafted cells. Herein, hybrid three-dimensional (3D) cell spheroids composed of podocytes, mesenchymal stem cells, and vascular endothelial cells were designed to mimic the glomerular microenvironment and as a cell delivery vehicle to replenish the podocyte population by cell transplantation. After creating a native glomerulus-like condition, the expression of multiple genes encoding growth factors and basement membrane factors that are strongly associated with podocyte maturation and functionality was significantly enhanced. Our in vivo results demonstrated that intrarenal transplantation of podocytes in the form of hybrid 3D cell spheroids improved engraftment efficiency and replenished glomerular podocytes. Moreover, the proteinuria of the experimental mice with hypertensive nephropathy was effectively reduced. These data clearly demonstrated the potential of hybrid 3D cell spheroids for repairing injured kidneys.

A validation study comparing existing prediction models of acute kidney injury in patients with acute heart failure.

Acute kidney injury (AKI) is a common complication in acute heart failure (AHF) and is associated with prolonged hospitalization and increased mortality. The aim of this study was to externally validate existing prediction models of AKI in patients with AHF. Data for 10,364 patients hospitalized for acute heart failure between 2008 and 2018 were extracted from the Chang Gung Research Database and analysed. The primary outcome of interest was AKI, defined according to the KDIGO definition. The area under the receiver operating characteristic (AUC) curve was used to assess the discrimination performance of each prediction model. Five existing prediction models were externally validated, and the Forman risk score and the prediction model reported by Wang et al. showed the most favourable discrimination and calibration performance. The Forman risk score had AUCs for discriminating AKI, AKI stage 3, and dialysis within 7 days of 0.696, 0.829, and 0.817, respectively. The Wang et al. model had AUCs for discriminating AKI, AKI stage 3, and dialysis within 7 days of 0.73, 0.858, and 0.845, respectively. The Forman risk score and the Wang et al. prediction model are simple and accurate tools for predicting AKI in patients with AHF.

High Incidence and Early Onset of Urinary Tract Cancers in Patients with BK Polyomavirus Associated Nephropathy.

Over-immunosuppressed kidney transplant recipients are susceptible to malignancies and BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN). This study aimed to verify the association between BKPyV infection and urinary tract cancers (UTC). A total of 244 kidney transplant recipients were enrolled at Chang Gung Memorial Hospital from June 2000 to February 2020. Biopsy-proven BKPyVAN patients (n = 17) had worse kidney function (eGFR: 26 ± 13.7 vs. 47.8 ± 31.0 mL/min/1.73 m2). The 5-year allograft survival rates for patients with and without BKPyVAN were 67% and 93%, respectively (p = 0.0002), while the 10-year patient survival was not different between the two groups. BKPyVAN patients had a significantly higher incidence of UTC compared to the non-BKPyVAN group (29.4% vs. 6.6%). Kaplan-Meier analysis showed that the UTC-free survival rate was significantly lower in BKPyVAN patients, and the onset of UTC was significantly shorter in BKPyVAN patients (53.4 vs. 108.9 months). The multivariate logistic regression analysis demonstrated that age (RR = 1.062) and BKVAN (RR = 6.459) were the most significant risk factors for the development of UTC. Our study demonstrates that BKPyVAN patients have greater allograft losses, higher incidence, a lower cancer-free survival rate, and an earlier onset with a higher relative risk of developing UTC compared to non-BKPyVAN patients.