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Background There is a paucity of epidemiological data regarding pesticide intoxication-associated acute kidney injury (AKI). Therefore, the aim of this study was to identify the epidemiological features, risk factors, and adverse outcomes of AKI in this population. Methods The data used in this multi-center, hospitalized population-based, retrospective study were retrieved from electronic medical records. AKI was defined as an acute increase in serum creatinine according to the criteria of Kidney Disease: Improving Global Outcomes. The Charlson Comorbidity Index was used to evaluate the burden of in-hospital mortality. Results Of 3,371 adult patients in 11 hospitals, 398 (11.8%) were diagnosed with AKI (grade 1, 218 [6.5%]; grade 2, 89 [2.6%]; grade 3, 91 [2.7%]). Herbicide intoxication was associated with the highest incidence of AKI (53.5%) and higher grades of AKI. After multivariable adjustment, pesticide categories and moderate or severe renal disease were independently associated with AKI. As compared with the referred category, insecticide and herbicide intoxications were associated with a 1.3-fold (95% CI 1.688–3.245) and 3.8-fold (95% CI 3.537–6.586) greater risk of AKI. Regardless of the pesticide category, AKI was independently associated with in-hospital mortality, with odds ratios of 3.433 (95% CI 1.436–8.203) for insecticides, 2.153 (95% CI 1.377–3.367) for herbicides, and 4.524 (95% CI 1.230–16.632) for unclassified or other pesticides. Conclusion AKI is common in pesticide intoxication and associated with an increased in-hospital mortality. Herbicides pose the greatest risks of AKI and death.

Aim To develop a model for predicting renal recovery in cardiac surgery patients with acute kidney injury (AKI) requiring renal replacement therapy (RRT). Methods Data from a prospective randomized controlled trial, conducted in a tertiary hospital to compare the survival effect of two dosages of hemofiltration for continuous RRT in cardiac surgery patients between March 20, 2012 and August 9, 2015, were used to develop the model. The outcome was renal recovery defined as alive and dialysis-free 90 days after RRT initiation. Multivariate logistic regression with a stepwise backward selection of variables based on Akaike Information Criterion was applied to develop the model, which was internally validated using bootstrapping. Model discrimination, calibration, and clinical value were assessed using the concordance index (C-Index), calibration plots, and decision curve analysis, respectively. Results Totally, 211 patients with AKI requiring RRT (66.8% male) with median age of 57 years were included. The incidence of renal recovery was 33.2% (n = 70). The model included six variables: body mass index stratification, baseline estimated glomerular filtration rate, hypertension, sepsis, mean arterial pressure, and mechanical ventilation. The C-Index for this model was 0.807 (95%CI, 0.744-0.870). After correction by the bootstrap, the C-Index was 0.780 (95%CI, 0.720-0.845). The calibration plots indicated good consistency between actual observations and model prediction of renal recovery. Decision curve analysis demonstrated the model was clinical usefulness. Conclusion We developed and validated a model to predict the chance of renal recovery in cardiac surgery patients with AKI requiring RRT. This article is protected by copyright. All rights reserved.

Background Diabetic kidney diseases (DKD) were the leading cause of End-stage renal diseases worldwide. Albuminuria was a target for treatment in DKD and decreasing albuminuria was particularly important for improving its prognosis. However, there is still a lack of specific treatment for DKD. Methods We conducted a prospective, crossover, open-label study to investigate the effect of amiloride in patients with DKD. Safety and efficacy were assessed by monitoring urine protein creatinine ratio(uPCR), urinary albumin creatinine ratio (uACR), blood pressure, weight, serum sodium, serum potassium, cholesterol, triglyceride, uric acid, serum soluble urokinase-type plasminogen activator receptor (suPAR) and urinary suPAR. Ten subjects were enrolled in the trial. Results In this prospective, crossover, open-label design, amiloride could induce a significant decrease of uACR in DKD. The decrease of serum and urinary suPAR in the amiloride/hydrochlorothiazide (HCTZ) group was also significant compared with those patients using HCTZ as the control group. Correlation analysis showed that the levels of urinary suPAR were positively associated with uPCR and uACR. No significant difference in blood pressure, weight, serum sodium, serum potassium, cholesterol, triglyceride, uric acid was seen between the amiloride/HCTZ group and the control group. Conclusion In summary, among patients with DKD, amiloride could decrease albuminuria without severe side effects, which was accompanied by the significant decline of urinary suPAR.

Background The study aimed to construct a clinical model based on preoperative data for predicting acute kidney injury (AKI) following cardiac surgery in patients with normal renal function. Methods A total of 22,348 consecutive patients with normal renal function undergoing cardiac surgery were enrolled. Among them, 15,701 were randomly selected for the training group and the remaining for the validation group. To develop a model visualized as a nomogram for predicting AKI, logistic regression was performed with variables selected using least absolute shrinkage and selection operator regression. The discrimination, calibration, and clinical value of the model were evaluated. Results The incidence of AKI was 25.2% in the training group. The new model consisted of nine preoperative variables, including age, male gender, left ventricular ejection fraction, hypertension, hemoglobin, uric acid, hypomagnesemia, and oral renin-angiotensin system inhibitor and non-steroidal anti-inflammatory drug within 1 week before surgery. The model had a good performance in the validation group. The discrimination was good with an area under the receiver operating characteristic curve of 0.740 (95% confidence interval, 0.726–0.753). The calibration plot indicated excellent agreement between the model prediction and actual observations. Decision curve analysis also showed that the model was clinically useful. Conclusions The new model was constructed based on nine easily available preoperative clinical data characteristics for predicting AKI following cardiac surgery in patients with normal kidney function, which may help treatment decision-making, and rational utilization of medical resources.

Histone deacetylase 6 (HDAC6) is the specific subtype of HDACs which preferentially located in the cytoplasm, and is crucial in insulin signalling. However, the role of HDAC6 in type 2 diabetic nephropathy (DN) remains undefined. In current study, we observed that HDAC6 was markedly activated in the kidneys of type 2 diabetic patients and db/db mice with albuminuria, along with the advanced glycation end products (AGE)‐treated podocytes. Selective inhibition of HDAC6 activity protected kidneys from hyperglycaemia in db/db mice. Notably, overexpressing HDAC6 inhibited autophagy and promoted motility aside from the apoptosis of podocytes exposed to AGE. We further determined that HDAC6 regulated the autophagy partially by decreasing the acetylation of α‐tubulin at the residue of lysine 40. In contrast, we confirmed that there was no interaction of HDAC6 with α‐tubulin at the sites of lysine 112 and lysine 352. Consistently, inhibiting HDAC6 by siRNA or the selective inhibitor, tubacin, restored the autophagy level and motility of podocytes and rescued podocytes from AGE stimulation. We provide strong evidence of an unexpected role of HDAC6 in the cascade that modulates podocytes autophagy and motility, enlightening that HDAC6 may be a promising therapeutic target for DN treatment.

Posttraumatic stress disorder is a mental disorder with a known cause, yet effective behavioral and pharmacotherapies remain elusive for many afflicted patients. Propranolol is suggested to be effective as a fear-reducing agent when paired with behavioral therapy soon after trauma when psychological stress is high, possibly dampening or preventing the later development of posttraumatic stress disorder. In our previous study, we found propranolol efficaciously reduced fear retention induced by reactivation via β-adrenergic receptors in lateral amygdala. However, it is unclear which subtypes of β-adrenergic receptors dominate the function of adrenergic activation in lateral amygdala. In this study, we investigated the action of β1-adrenergic receptor antagonist-metoprolol and β2-adrenergic receptor antagonist-butoxamine on the retention of conditioned fear memory and synaptic adaptation in the lateral amygdala of rats. We found metoprolol not butoxamine attenuated the reactivation-induced strengthening of fear retention and restored the impaired long-term depression in lateral amygdala. Intra-amygdala infusion of metoprolol not butoxamine attenuated reactivation-induced enhancement of fear retention. Our results suggest that β1-adrenergic receptor antagonist-metoprolol may be more suitable for the treatment of posttraumatic stress disorder.

Autophagy is an important renal-protective mechanism in septic acute kidney injury (AKI). Receptor interacting protein kinase 3 (RIP3) has been implicated in the renal tubular injury and renal dysfunction during septic AKI. Here we investigated the role and mechanism of RIP3 on autophagy in septic AKI. We showed an activation of RIP3, accompanied by an accumulation of the autophagosome marker LC3II and the autophagic substrate p62, in the kidneys of lipopolysaccharide (LPS)-induced septic AKI mice and LPS-treated cultured renal proximal tubular epithelial cells (PTECs). The lysosome inhibitor did not further increase the levels of LCII or p62 in LPS-treated PTECs. Moreover, inhibition of RIP3 attenuated the aberrant accumulation of LC3II and p62 under LPS treatment in vivo and in vitro. By utilizing mCherry-GFP-LC3 autophagy reporter mice in vivo and PTECs overexpression mRFP-GFP-LC3 in vitro, we observed that inhibition of RIP3 restored the formation of autolysosomes and eliminated the accumulated autophagosomes under LPS treatment. These results indicated that RIP3 impaired autophagic degradation, contributing to the accumulation of autophagosomes. Mechanistically, the nuclear translocation of transcription factor EB (TFEB), a master regulator of the lysosome and autophagy pathway, was inhibited in LPS-induced mice and LPS-treated PTECs. Inhibition of RIP3 restored the nuclear translocation of TFEB in vivo and in vitro. Co-immunoprecipitation further showed an interaction of RIP3 and TFEB in LPS-treated PTECs. Also, the expression of LAMP1 and cathepsin B, two potential target genes of TFEB involved in lysosome function, were decreased under LPS treatment in vivo and in vitro, and this decrease was rescued by inhibiting RIP3. Finally, overexpression of TFEB restored the autophagic degradation in LPS-treated PTECs. Together, the present study has identified a pivotal role of RIP3 in suppressing autophagic degradation through impeding the TFEB-lysosome pathway in septic AKI, providing potential therapeutic targets for the prevention and treatment of septic AKI.

Hypertension is one of the most common complications of chronic kidney disease (CKD). Some research has indicated that changes in large artery function especially caused by thromboxane A2 (TXA2) may be a novel factor acting to induce hypertension in CKD. We studied the 5/6 nephrectomy rat model and measured serum levels of creatinine (Cr), calcium (Ca), phosphorus (P), TXA2-stable metabolites (thromboxane B2, TXB2), and caudal artery pressure after nephrectomy. The tension variations in thoracic aortas were measured after stimulating by vasoconstrictor/vasodilator using the cumulative concentration administration method and then tested the expression of TXA2 receptors in the thoracic aortas through western blots. The CKD rats developed uremia, electrolyte imbalances，and hypertension. They also exhibited a significant increase in TXB2 concentration. The aortic rings of CKD rats showed an increased contraction response to U46619 (a TXA2 analogue) and the expression of TXA2 receptors also enhanced. In the meanwhile, the diastolic function decreased in the CKD group. Our results demonstrate that the impairment of artery contractile function caused by the increase of TXA2 receptors on the wall of aortic rings may be involved in hypertension in CKD rats.

Mitochondrial damage in renal tubular epithelial cells (RTECs) is a hallmark of endotoxin-induced acute kidney injury (AKI). Forkhead box O1 (FOXO1) is responsible for regulating mitochondrial function and is involved in several kidney diseases. Here, we investigated the effect of FOXO1 on endotoxin-induced AKI and the related mechanism. In vivo, FOXO1 downregulation in mouse RTECs and mitochondrial damage were found in endotoxin-induced AKI. Overexpression of FOXO1 by kidney focal adeno-associated virus (AAV) delivery improved renal function and reduced mitochondrial damage. Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1-α), a master regulator of mitochondrial biogenesis and function, was reduced in endotoxin-induced AKI, but the reduction was reversed by FOXO1 overexpression. In vitro, exposure to LPS led to a decline in HK-2 cell viability, mitochondrial fragmentation, and mitochondrial superoxide accumulation, as well as downregulation of FOXO1, PGC1-α, and mitochondrial complex I/V. Moreover, overexpression of FOXO1 in HK-2 cells increased HK-2 cell viability and PGC1-α expression, and it alleviated the mitochondrial injury and superoxide accumulation induced by LPS. Meanwhile, inhibition of FOXO1 in HK-2 cells by siRNA treatment decreased PGC1-α expression and HK-2 cell viability. Chromatin immunoprecipitation assays and PCR analysis confirmed that FOXO1 bound to the PGC1-α promoter in HK-2 cells. In conclusion, downregulation of FOXO1 in RTECs mediated endotoxin-induced AKI and mitochondrial damage. Overexpression of FOXO1 could improve renal injury and mitochondrial dysfunction, and this effect occurred at least in part as a result of PGC1-α signaling. FOXO1 might be a potential target for the prevention and treatment of endotoxin-induced AKI.

BACKGROUND: AKI is characterized by abrupt and reversible kidney dysfunction, and incomplete recovery leads to chronic kidney injury. Previous studies by us and others have indicated that macrophage infiltration and polarization play key roles in recovery from AKI. The role in AKI recovery played by IFN regulatory factor 4 (IRF4), a mediator of polarization of macrophages to the M2 phenotype, is unclear. METHODS: We used mice with myeloid or macrophage cell–specific deletion of Irf4 (MΦ Irf4 (−/−)) to evaluate Irf4’s role in renal macrophage polarization and development of fibrosis after severe AKI. RESULTS: Surprisingly, although macrophage Irf4 deletion had a minimal effect on early renal functional recovery from AKI, it resulted in decreased renal fibrosis 4 weeks after severe AKI, in association with less-activated macrophages. Macrophage Irf4 deletion also protected against renal fibrosis in unilateral ureteral obstruction. Bone marrow–derived monocytes (BMDMs) from MΦ Irf4 (−/−) mice had diminished chemotactic responses to macrophage chemoattractants, with decreased activation of AKT and PI3 kinase and increased PTEN expression. PI3K and AKT inhibitors markedly decreased chemotaxis in wild-type BMDMs, and in a cultured macrophage cell line. There was significant inhibition of homing of labeled Irf4 (−/−) BMDMs to postischemic kidneys. Renal macrophage infiltration in response to AKI was markedly decreased in MΦ Irf4 (−/−) mice or in wild-type mice with inhibition of AKT activity. CONCLUSIONS: Deletion of Irf4 from myeloid cells protected against development of tubulointerstitial fibrosis after severe ischemic renal injury in mice, due primarily to inhibition of AKT-mediated monocyte recruitment to the injured kidney and reduced activation and subsequent polarization into a profibrotic M2 phenotype.

Background Idiopathic membranous nephropathy (IMN) is frequently coexisted with diabetes mellitus (DM). Few researches investigate clinical outcomes in IMN patients coexisting diabetes mellitus (DM), including remission rates, renal survival and complications. Concurrent DM also pose therapeutic challenges to IMN patients due to the influence of glucocorticoids and immunosuppressant on metabolic disorders. We performed this study to investigate the impact of DM on clinical outcomes in IMN and the influence of therapeutic regime on metabolic parameters in diabetic IMN patients. Methods Two hundred and six adult hospitalized patients diagnosed with biopsy-proven IMN were retrospectively studied, including 42 patients coexisted with DM. Clinical outcomes including remission rates, renal outcome and complications were compared between groups. Impact of cyclophosphamide and ciclosporin on metabolism and complications were analyzed in IMN patients coexisting DM. Results IMN patients coexisted with DM were presented with advanced age, lower level of eGFR and hemoglobin. Patients coexisted with DM experienced worse renal function deterioration and higher incidence of infection. COX regression analysis showed that DM was an independent risk factor for renal function deterioration in IMN patients. There was no significant difference in remission rates and incidence of venous thromboembolism between two groups. Further exploration on the impact of therapeutic regimens on complications and metabolism showed that cyclophosphamide and ciclosporin had no significant difference in incidence of complications including infection and venous thromboembolism, and posed comparable influences on blood glucose, uric acid and blood lipids in IMN patients coexisted with DM. Conclusion Coexisting DM was an independent risk factor for renal function deterioration in IMN patients but did not influence the remission of proteinuria. Glucocorticoids in combination with cyclophosphamide or ciclosporine had similar impact on complications and metabolic index including blood glucose, uric acid and blood lipids in IMN patients coexisted with DM.

Background Metabolic syndrome (MS) and diabetes mellitus (DM) are risk factors for cardiovascular diseases in general population. However, there was a paucity of studies investigating their impact in primary glomerular diseases (PGD). Hypothesis MS and concomitant DM are associated with higher risk of cardiovascular comorbidity in PGD. Methods In a retrospective observational design, we analyzed 3622 hospitalized adult PGD patients and compared the prevalence of cardiovascular comorbidity in non‐MS, MS with and without DM. Risk factors for cardiovascular comorbidity were identified using univariate and multivariate logistic regression. Results Among 3622 PGD patients, 308 (8.5%) cases accompanied with MS, including 180 (5.0%) patients with DM and 128 (3.5%) without DM. One hundred and sixty four (4.5%) cases coexisted with cardiovascular comorbidity. Patients with MS and concomitant DM exhibited a higher prevalence of cardiovascular comorbidity than those without MS stratified by estimated glomerular filtration rate and pathological types. Logistic regression showed that MS and concomitant DM (OR: 2.496, 95% CI: 1.600‐3.894, P

Emotional memory deficit is a well-known complication in early Parkinson's disease. However, its molecular mechanism is still not well known. To address this issue, we examined the cue-related fear-conditioning task and long-term potentiation (LTP) of the thalamus to the lateral amygdala in rats treated with low doses of reserpine (Res). We found that low-dose Res treatment impaired emotional memory and LTP. We also found that exogenous upregulation of norepinephrine (NE) ameliorated the impairment of LTP by facilitating β-adrenergic receptors. Finally, acute treatment with NE or desipramine rescued the impaired emotional memory induced by a low-dose of Res. These results imply a pivotal role for NE in synaptic plasticity and associative fear memory in rats treated with low doses of Res and suggest that desipramine is a potential candidate for treating Parkinson's disease-related emotional memory deficit.

Aim Phospholipase A2 receptor (PLA2R) is a target antigen for idiopathic membranous nephropathy (IMN). However, the association between renal PLA2R antigen and disease prognosis had not been fully investigated. In addition, there was a paucity of studies investigating the difference of therapeutic effects between cyclophosphamide and cyclosporine A in PLA2R‐associated IMN. Methods This retrospective cohort study recruited 300 eligible patients diagnosed with biopsy‐proven IMN between September 2015 and July 2018 in Guangdong Provincial People's Hospital. The remission of proteinuria was compared between PLA2R‐associated and non‐PLA2R‐associated IMN. The difference of therapeutic effects between cyclophosphamide and cyclosporine A were also investigated in PLA2R‐associated IMN. Results The positive rate of renal PLA2R antigen in recruited IMN patients was 82.3%. Non‐PLA2R‐associated IMN patients had a higher probability to achieve remission than PLA2R‐associated IMN patients (Log–rank test, P = .013). Multivariate COX analysis showed that renal PLA2R antigen was an independent risk factor for not achieving remission in IMN patients (Hazard Ratio: 1.619; 95% confidence interval: 1.133 to 2.313; P = .008). In PLA2R‐associated IMN, patients receiving cyclophosphamide had a higher probability to achieve remission compared with those receiving cyclosporine A (Log–rank test, P = .018) while there was no difference in renal survival. Multivariate COX regression analysis showed that compared with cyclosporine A, patients receiving cyclophosphamide had a higher probability to achieve remission. Conclusion Phospholipase A2 receptor ‐associated IMN patients had a lower probability to achieve remission compared with non‐PLA2R‐associated IMN. Compared with cyclosporine A, cyclophosphamide exerted better therapeutic effects in remission of proteinuria and may be the preferred immunosuppressant for PLA2R‐associated IMN. SUMMARY AT A GLANCE This article highlighted the prognostic value of intra‐renal phospholipase A2 receptor deposition in idiopathic membranous nephropathy (IMN). Renal phospholipase A2 receptor (PLA2R)‐associated IMN patients had a lower probability to achieve remission compared with non‐PLA2R‐associated IMN.

Ischemia-reperfusion (I/R)-induced acute kidney injury (I/R-AKI) favors mitochondrial permeability transition pore (mPTP) opening and subsequent cell death. Cyclophilin D (CypD) is an essential component of the mPTP, and recent findings have implicated the p53-CypD complex in cell death. To evaluate the role of p53-CypD after I/R-AKI, we tested the hypothesis that the p53-CypD complex mediates renal tubular cell apoptosis in I/R-AKI via mPTP opening. Expression of p53 and cleaved caspase-3 was significantly increased in rats subjected to I/R-AKI compared with normal controls and sham-operated controls. The underlying mechanisms were determined using an in vitro model of ATP depletion. Inhibition of mPTP opening using the CypD inhibitor cyclosporin A or siRNA for p53 in ATP-depleted HK-2 cells prevented mitochondrial membrane depolarization and reduced apoptosis. Furthermore, p53 bound to CypD in ATP-depleted HK-2 cells. These results suggest that the p53-CypD complex mediates renal tubular cell apoptosis in I/R-AKI via mPTP opening.

Renal tubular epithelial cell apoptosis is an important pathological mechanism of septic acute kidney injury (AKI). Endotoxin, also known as lipopolysaccharide (LPS), has a key role in septic AKI and can directly induce tubular epithelial cell apoptosis. The upregulation of receptor‑interacting protein kinase 3 (RIPK3) in tubular epithelial cells has been reported in septic AKI, with RIPK3 mediating apoptosis in several cell types. In the present study, the effect of RIPK3 on endotoxin‑induced AKI was investigated in mouse tubular epithelial cell apoptosis in vitro and in vivo. It was found that the expression of RIPK3 was markedly increased in endotoxin‑induced AKI. Endotoxin‑induced AKI and tubular epithelial cell apoptosis could be attenuated by GSK'872, a RIPK3 inhibitor. LPS stimulation also upregulated RIPK3 expression in tubular epithelial cells in a time‑dependent manner. Both RIPK3 inhibitor and small interfering RNA (siRNA) targeting RIPK3 reduced LPS‑induced tubular epithelial cell apoptosis in vitro. The expression of the proapoptotic protein Bax was induced by LPS and reversed by GSK'872 or RIPK3‑siRNA. The present study revealed that RIPK3 mediated renal tubular cell apoptosis in endotoxin‑induced AKI. RIPK3 may be a potential target for the prevention of renal tubular cell apoptosis in endotoxin‑induced AKI.

Background Two-dimensional speckle-tracking echocardiography (2D-STE) enables objective assessment of left atrial (LA) deformation through the analysis of myocardial strain, which can be measured by different speckle-tracking software. The aim of this study was to compare the consistency of 3 different commercially available software, which include vendor-specific software for measuring left ventricle (VSSLV), vendor-independent software packages for measuring LV strain (VISLV) and vendor-independent software packages for measuring LA strain (VISLA). Methods Sixty-four subjects (mean age: 44 ± 16 years, 50% males) underwent conventional echocardiograms using a GE Vivid 9 (GE Ultrasound, Horten, Norway) cardiac ultrasound system. Standard apical 4 and 2 chamber views of the left atrium were obtained in each subject with a frame-rate range of 40–71 frames/s. LA strain during the contraction phase (Sct), conduit phase (Scd), reservoir phase (Sr = Sct + Scd) were analyzed by 2 independent observers and 3 different software. Results Sct, Scd, Sr were, respectively, − 11.26 ± 2.45%, − 16.77 ± 7.06%, and 28.03 ± 7.58% with VSSLV, − 14.77 ± 3.59%, − 23.17 ± 10.33%, and 38.23 ± 10.99% with VISLV, and − 14.80 ± 3.88%, − 23.94 ± 10.48%, and 38.73 ± 11.56% when VISLA was used. A comparison of strain measurements between VSSLV and VIS (VISLV and VISLA) showed VIS had significantly smaller mean differences and narrower limits of agreement. Similar results were observed in the coefficient of variation (CV) for measurements between VSSLV and VIS (VISLV and VISLA). Comparison of the intra-class correlation coefficients (ICCs) indicated that measurement reliability was weaker with VSSLV (ICC 0.9). For intra-observer ICCs, VISLA > VSSLV = VISLV. For inter-observer ICCs, VSSLV > VISLA > VISLV. Conclusions Software measurement results of LA strain vary considerably. We recommended not measuring LA strain across vendor platforms. Electronic supplementary material The online version of this article (10.1186/s12947-019-0158-y) contains supplementary material, which is available to authorized users.

Background Sex differences mediating predisposition to kidney injury are well known, with evidence indicating lower CKD incidence rates and slower decline in renal function in nondiabetic CKD for premenopausal women compared with men. However, signaling pathways involved have not been elucidated to date. The EGF receptor (EGFR) is widely expressed in the kidney in glomeruli and tubules, and persistent and dysregulated EGFR activation mediates progressive renal injury. Methods To investigate the sex differences in response to renal injury, we examined EGFR expression in mice, in human kidney tissue, and in cultured cell lines. Results In wild type mice, renal mRNA and protein EGFR levels were comparable in males and females at postnatal day 7 but were significantly lower in age-matched adult females than in adult males. Similar gender differences in renal EGFR expression were detected in normal adult human kidneys. In Dsk5 mutant mice with a gain-of-function allele that increases basal EGFR kinase activity, males had progressive glomerulopathy, albuminuria, loss of podocytes, and tubulointerstitial fibrosis, but female Dsk5 mice had minimal kidney injury. Oophorectomy had no effect on renal EGFR levels in female Dsk5 mice, while castration protected against the kidney injury in male Dsk5 mice, in association with a reduction in EGFR expression to levels seen in females. Conversely, testosterone increased EGFR expression and renal injury in female Dsk5 mice. Testosterone directly stimulated EGFR expression in cultured kidney cells. Conclusions These studies indicate that differential renal EGFR expression plays a role in the sex differences in susceptibility to progressive kidney injury that may be mediated at least in part by testosterone.

Podocyte depletion is a central pathological mechanism of diabetic nephropathy (DN). Hyperglycemia induced podocyte apoptosis, resulting in podocyte depletion. However, the crucial mechanism of hyperglycemia-induced podocyte apoptosis remains poorly understood. In this study, we evaluated the expression of septin 7, a GTP-binding protein, in glomerular podocytes of patients and mice with DN, and investigated the pro-apoptotic effect of septin 7 on high glucose (HG) induced podocyte apoptosis in vitro. We found septin 7 expression was markedly increased not only in glomerular podocytes of patients and db/db mice with DN but also in cultured podocytes with HG stimulation. Knocking down septin 7 with siRNA could attenuate HG induced podocytes apoptosis and excessive intracellular Ca2+ concentration. This study revealed septin7 may potentially play a proapoptotic role in podocyte under diabetic conditions and may provide a potential target for preventing podocyte apoptosis in DN.

BackgroundThe correlation between proteinuria and contrast-induced acute kidney injury (CI-AKI) in patients with cerebrovascular disease is still unknown.ObjectiveTo determine whether proteinuria is a risk factor for CI-AKI and death in patients with stroke undergoing cerebral angiography.MethodsData from 2015 patients with stroke undergoing cerebral angiography between January 2009 and December 2013 were retrospectively collected. Clinical parameters were obtained from the hospital's computerized database. All variables were analyzed by univariate analysis and multivariate logistic regression analysis.ResultsCI-AKI was seen in 85 patients (4.2%). After adjustment for potential confounding risk factors, patients with proteinuria had a fivefold higher risk of CI-AKI than patients without proteinuria (OR=5.74; 95% CI 2.23 to 14.83; p2, anemia, and a high National Institute of Health Stroke Scale score. Proteinuria did not increase in-hospital mortality (OR=1.25; 95% CI 0.49 to 3.17; p=0.639) but did increase 1-year mortality (HR=2.30, 95% CI 1.55 to 3.41, pConclusionsProteinuria is an independent risk factor for CI-AKI and 1-year mortality in patients with stroke undergoing cerebral angiography. More attention should be paid to the development of CI-AKI in patients with stroke with proteinuria.

The Hakka are a sub-ethnicity with unique diet customs in South China. This study investigated hyperphosphatemia in hemodialysis patients in relation to the current Hakka dietary customs and explored health education patterns for hyperphosphatemia control. Two continuous cross-sectional surveys were conducted among the local patients on dialysis. After the first survey, the patients with hyperphosphatemia were semi-randomized into regular (group 1) and individual (group 2) education groups. Regular health education was conducted for both groups. In group 2, the awareness of health knowledge and dietary customs was investigated using a self-designed questionnaire. Based on the questionnaire, individual dietary guidance was given. The second survey was performed after 3 months. In the first survey, a high-phosphorus diet was found in all 46 patients with 43 (93.5%) diagnosed with hyperphosphatemia. In group 1 and group 2, 15 patients and 25 patients completed the two surveys, respectively. In group 1, no patient changed their dietary habits; however, in group 2, some patients did. The level of serum inorganic phosphorus in group 1 increased significantly. In group 2, the data remained stable; the awareness rate of chronic kidney disease-mineral and bone disorder (CKD-MBD) increased, and six patients with good compliance showed decreased serum inorganic phosphorus (p = 0.046). High-phosphorus dietary customs and low CKD-MBD knowledge awareness are important reasons for the difficulty in hyperphosphatemia control of patients on dialysis in the Hakka region. Individual health education led by medical staff might be helpful in hyperphosphatemia control, but the pattern still needs further exploration.

To investigate the impact of pre-operative uric acid on acute kidney injury (AKI) after cardiac surgery in elderly patients.Clinical data were collected from 936 elderly patients (age ≥ 60 years) undergoing cardiac surgery with cardiopulmonary bypass in Guangdong General Hospital between January 2005 and May 2011. The baseline serum creatinine was defined as the latest serum creatinine before surgery, and AKI was diagnosed according to RIFLE criteria. Patients were divided into three groups according to the sex-specific cutoff values of serum uric acid tertiles (group A: ≤ 384.65 µmol/L in men, and ≤ 354.00 µmol/L in women; group B:384.66-476.99 µmol/L in men and 354.01-437.96 µmol/L in women; group C: ≥ 477.00 µmol/L in men and ≥ 437.97 µmol/L in women). Multivariate logistic regression analysis was used to analyze the independent risk factors for AKI.Among 936 elderly patients, 576 cases (61.5%) developed AKI. Mean uric acid concentration was higher in AKI patients than in Non-AKI patients ( (436.6 ± 119.1) µmol/L vs. (398.0 ± 107.2) µmol/L, P0.001). The incidence of AKI was 56.1% (175/312) in group A, 56.3% (175/311) in group B, 72.2% (226/313) in group C (P0.001). Multiple logistic regression analysis showed that, after adjusted for age, gender, co-morbidities(hypertension, diabetes mellitus, cerebrovascular disease, chronic obstructive pulmonary disease), previous cardiac surgery, eGFR60 ml×min(-1) ×1.73 m(-2), heart function ≥ 3 (NYHA), positive urine protein, combination of coronary artery bypass grafting and valvular surgery, cardiopulmonary bypass operation time, aortic cross-clamping time, pre-operative angiotensin converting enzyme inhibitor or angiotensin II receptor blockers and lipid-lowering drugs use, early postoperative angiotensin converting enzyme inhibitor or angiotensin II receptor blockers, diuretics and digoxin use, post-operation central venous pressure, risk of post operative AKI was significantly higher in group C than in group A (OR:1.897, 95%CI: 1.270-2.833, P = 0.002).Pre-operative elevated uric acid is an independent risk factor of AKI after cardiac surgery in elderly patients.

Objective Acute kidney injury (AKI) in patients hospitalized for acute heart failure (AHF) is usually type 1 of the cardiorenal syndrome (CRS) and has been associated with increased morbidity and mortality. Early recognition of AKI is critical. This study was to determine if the new KDIGO criteria (Kidney Disease: Improving Global Outcomes) for identification and short-term prognosis of early CRS type 1 was superior to the previous RIFLE and AKIN criteria. Methods The association between AKI diagnosed by KDIGO but not by RIFLE or AKIN and in-hospital mortality was retrospectively evaluated in 1005 Chinese adult patients with AHF between July 2008 and May 2012. AKI was defined as RIFLE, AKIN and KDIGO criteria, respectively. Cox regression was used for multivariate analysis of in-hospital mortality. Results Within 7 days on admission, the incidence of CRS type 1 was 38.9% by KDIGO criteria, 34.7% by AKIN, and 32.1% by RIFLE. A total of 110 (10.9%) cases were additional diagnosed by KDIGO criteria but not by RIFLE or AKIN. 89.1% of them were in Stage 1 (AKIN) or Stage Risk (RIFLE). They accounted for 18.4% (25 cases) of the overall death. After adjustment, this proportion remained an independent risk factor for in-hospital mortality [odds ratios (OR)3.24, 95% confidence interval(95%CI) 1.97–5.35]. Kaplan-Meier curve showed AKI patients by RIFLE, AKIN, KDIGO and [K(+)R(−)+K(+)A(−)] had lower hospital survival than non-AKI patients (Log Rank P

Podocyte damage and loss together have an important role in the pathogenesis and progression of glomerulonephritis. Glomerulonephritis patients and healthy controls were enrolled in this study. Biochemical, clinical and experimental procedures included measurement of total urinary protein, renal biopsy and gene expression analysis of the receptor activator of NF-kappaB (RANK). The urinary mRNA levels of RANK were significantly higher in the glomerulonephritis group compared to the controls. The urinary RANK level of glomerular subtypes was correlated significantly with proteinuria. The calculated area of RANK mRNA levels under the curve was 0.61 for minimal change disease (MCD), 0.97 for membranous nephropathy (MN), 0.65 for IgA nephropathy (IgAN), 0.70 for lupus nephritis (LN) and 0.70 for focal segmental glomerulosclerosis (FSGS). The urinary mRNA of RANK might be used to differentiate histologic subtypes of glomerulonephritis, particularly between MCD and MN.

Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis with various histological and clinical phenotypes. N-acetylgalactosamine (GalNAc) exposure plays a pivotal role in the pathogenesis of IgAN. The aim of the current study is to investigate whether GalNAc exposure of serum IgA1 was associated with clinical and pathological manifestation of IgAN.Sera from 199 patients with biopsy proved IgAN were collected. Clinical and pathological manifestations were collected. Biotinylated Helix aspersa were used in ELISA to examine GalNAc exposure on IgA1 molecules. Patients were divided into two groups according to the GalNAc exposure rate less or more than 0.4.Age, gender, and serum creatinine were comparable between the two groups. Univariate analysis showed that significantly higher urinary protein excretion rate but less severe glomerular sclerosis and tubularinterstitial fibrosis were observed in the lower GalNAc exposure group. Multivariate regression analysis demonstrated that adjusted by age and gender, the GalNAc exposure rate more than 0.4 was a risk factor of glomerular sclerosis and tubularinterstitial fibrosis, OR*(95% CI) were 2.76 (1.19-6.37) and 2.49 (1.18-5.25), respectively.Immunoglobulin A nephropathy patients with lower proteinuria had higher GalNAc exposure rates. The GalNAc exposure rate more than 0.4 was a risk factor of severe chronic renal tissue change.

Hemodialysis patients are at an increased risk of cardiovascular (CV) morbidity and mortality. Pulmonary hypertension (PH) has been recently reported as a new entity and unrecognized threat in maintenance hemodialysis (MHD) patients, whether PH predicts CV mortality and events in this population remains unknown. The aim of the present study was to determine the value of PH in predicting CV mortality and events in a prospective cohort of MHD patients. We studied 278 MHD patients (98 with and 180 without PH) in Guangdong General Hospital Blood Purification Center, Guangzhou, China. All patients had been followed up for 2 years, and in survival analysis, we considered time to death or first cardiovascular event. The endpoints were all-cause mortality, CV mortality and CV events. PH was defined as systolic pulmonary artery pressure (SPAP) ≥ 35 mmHg as determined by Doppler echocardiographic evaluation. Of the 278 MHD patients, 53 (19.1 %) died as a result of all causes, 28 (10.1 %) died from CV events (52.8 % of causes of death), and 87 (31.3 %) had new-onset CV events. The survival curve showed that all-cause and CV mortality and new-onset CV events were higher in PH group than the non-PH group. In a multivariate Cox proportional hazard model, the adjusted HR for all-cause mortality, CV mortality and CV events was 1.85 [95 % confidence interval (CI) 1.03–3.34], 2.36 (95 % CI 1.05–5.31) and 2.27 (95 % CI 1.44–3.58), respectively. Our study showed that PH was an independent predictor of all-cause mortality and CV mortality and events in MHD patients. We suggest to evaluate SPAP in MHD patients in order to stratify risk of death and CV events.

Background Glomerulosclerosis correlates with reduction in podocyte number that occurs through mechanisms which include apoptosis. Podocyte injury or podocyte loss in the renal glomerulus has been proposed as the crucial mechanism in the development of glomerulosclerosis. However, the mechanism by which podocytes respond to injury is poorly understood. TNF and TNF receptor superfamilies are important in the pathogenesis of podocyte injury and apoptosis. The ligand of receptor activator of NF-kappaB (RANKL) and receptor activator of NF-kappaB (RANK) are members of the TNF and receptor superfamilies. We investigated whether RANK - RANKL is a receptor - ligand complex for podocytes responding to injury. Methodology/Principal Findings In this study, RANKL and RANK were examined in human podocyte diseases and a rat model of puromycin aminonucleoside nephrosis (PAN). Compared with controls, RANK and RANKL were increased in both human podocyte diseases and the rat PAN model; double immunofluorescence staining revealed that RANK protein expression was mainly attributed to podocytes. Immunoelectron microscopy showed that RANK was localized predominantly at the top of the foot process membrane and the cytoplasm of rat podocyte. In addition, RANK was upregulated in mouse podocytes in vitro after injury induced by puromycin aminonucleoside (PA). Knockdown of RANK expression by small interference RNA (siRNA) exacerbated podocyte apoptosis induced by PA. However, RANKL inhibited significantly the apoptosis of podocytes induced by PA. Conclusions/Significance These findings suggest the increase in RANK–RANKL expression is a response to podocyte injury, and RANK–RANKL may be a novel receptor–ligand complex for the survival response during podocyte injury.