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The side effects of cisplatin, a widely used chemotherapeutic agent, include nephrotoxicity. Previous studies have reported that cisplatin induces ferroptosis and lipid peroxide accumulation. Ferroptosis, a type of regulated cell death, is characterized by iron-dependent lipid peroxidation. Although previous studies have examined the regulation of ferroptosis in acute kidney injury (AKI), the regulatory mechanism of ferroptosis has not been elucidated. Here, the ability of activated farnesoid X receptor (FXR) to attenuate cisplatin-induced AKI through the regulation of ferroptosis was examined. FXR deficiency exhibited more ferroptosis responses, such as increase in lipid peroxidation, iron content and heme oxygenase 1 protein, and a decrease in glutathione/glutathione disulfide ratio and glutathione peroxidase 4 levels in HK2 cells and mice. Increased blood urea nitrogen, serum creatinine, and ferroptotic responses in the cisplatin-induced AKI mouse model were mitigated upon treatment with the FXR agonist GW4064 but were exacerbated in FXR knockout mice. RNA sequencing analysis revealed that ferroptosis-associated genes were novel targets of FXR. FXR agonist upregulated the expression of lipid and glutathione metabolism-related genes and downregulated cell death-related genes. Additionally, chromatin immunoprecipitation assays, using mice renal tissues, revealed that agonist-activated FXR could bind to its known target genes (Slc51a, Slc51b, Osgin1, and Mafg) and ferroptosis-related genes (Aifm2, Ggt6, and Gsta4). Furthermore, activated FXR-dependent MAFG, a transcriptional repressor, could bind to Hmox1, Nqo1, and Tf in the renal tissues of FXR agonist-treated mice. These findings indicate that activated FXR regulates the transcription of ferroptosis-related genes and protects against cisplatin-induced AKI., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The reactive oxygen species (ROS) and inflammation, a critical contributor to tissue damage, is well-known to be associated with various disease. The kidney is susceptible to hypoxia and vulnerable to ROS. Thus, the vicious cycle between oxidative stress and renal hypoxia critically contributes to the progression of chronic kidney disease and finally, end-stage renal disease. Thus, delivering therapeutic agents to the ROS-rich inflammation site and releasing the therapeutic agents is a feasible solution., Results: We developed a longer-circulating, inflammation-sensing, ROS-scavenging versatile nanoplatform by stably loading catalase-mimicking 1-dodecanethiol stabilized Mn 3 O 4 (dMn 3 O 4 ) nanoparticles inside ROS-sensitive nanomicelles (PTC), resulting in an ROS-sensitive nanozyme (PTC-M). Hydrophobic dMn 3 O 4 nanoparticles were loaded inside PTC micelles to prevent premature release during circulation and act as a therapeutic agent by ROS-responsive release of loaded dMn 3 O 4 once it reached the inflammation site., Conclusions: The findings of our study demonstrated the successful attenuation of inflammation and apoptosis in the IRI mice kidneys, suggesting that PTC-M nanozyme could possess promising potential in AKI therapy. This study paves the way for high-performance ROS depletion in treating various inflammation-related diseases., (© 2022. The Author(s).)

Abstract: Data on the overall epidemiology and temporal trends of end-stage renal disease (ESRD) requiring hemodialysis in Korea are scarce. We aimed to estimate the prevalence and incidence of ESRD requiring hemodialysis in Korea between 2002 and 2017.Using the National Health Insurance Service database, we analyzed data from the entire Korean population between 2002 and 2017. Hemodialysis patients were identified using rare incurable disease codes (V001) or prescription of medical fee codes of hemodialysis (O7020 and O7021). We only included patients who had been maintained on hemodialysis for more than 90 days from the date of dialysis initiation, to exclude patients who required short-term dialysis for acute kidney injury, conversion to peritoneal dialysis, or kidney transplantation.During the 16-year follow-up, the number of hemodialysis patients in Korea has steadily increased from 11,215 in 2002 to 67,486 in 2017. The mean age of these patients has gradually increased from 55.57 ± 13.31 years in 2002 to 62.13 ± 13.23 years in 2017. In 2017, the crude prevalence rate of hemodialysis was 1303.4 per million population. Overall, the number of men tended to be somewhat higher than that of women, and the proportion of men increased slightly from 55.56% in 2002 to 58.45% in 2017. The proportion of diabetic patients increased rapidly from 23.84% to 47.84%, and the percentage of dyslipidemic patients rose from 18.9% to 86.7%. The number of incident hemodialysis patients increased significantly from 4406 in 2003 to 12,134 in 2014, and then decreased to 8090 in 2017. In the incident cases of hemodialysis, the observed increase in the proportion of male patients and in diabetes and dyslipidemia were similar to that of prevalent patients. The more recent era of hemodialysis initiation, the better 5-year survival rates were observed.The prevalence and incidence of hemodialysis in Korea gradually increased between 2002 and 2017. The proportion of men, and patients with diabetes and dyslipidemia requiring hemodialysis also increased continuously. The survival rate of hemodialysis patients was gradually improving. These findings may serve as a reference for future epidemiological studies on hemodialysis in Korea., Competing Interests: The authors have no conflict of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Autophagy is important for cells to break down and recycle cellular proteins, remove damaged organelles, and especially, for recovery from acute kidney injury (AKI). Despite research on the role and cellular mechanism of autophagy in AKI, the role of autophagy in the progression to chronic kidney disease (CKD) remains poorly understood. Here, using farnesoid X receptor (FXR) knockout (KO) mice, we determined whether FXR prevents the progression of AKI to CKD after renal ischemic-reperfusion (such as I/R) injury through the regulation of renal autophagy and apoptosis. FXR regulated genes that participate in renal autophagy under feeding and fasting conditions, such as hepatic autophagy, and the activation of FXR by agonists, such as GW4064 and INT-747, attenuated the increased autophagy and apoptosis of hypoxia-induced human renal proximal tubule epithelial (HK2) cells. The expression levels of autophagy-related and apoptosis-related proteins in FXR KO mice were increased compared with those in wild-type (WT) mice. We also showed that the increase in reactive oxidative species (ROS) in hypoxia-treated HK2 cells was attenuated by treatment with FXR agonist or by FXR overexpression, and that the level of ROS was elevated in FXR-deficient cells and mice. At 28 days after I/R injury, the autophagy levels were still elevated in FXR KO mice, and the expression levels of fibrosis-related proteins and ROS deposits were higher than those in WT mice. In conclusion, the regulation of renal autophagy and apoptosis by FXR may be a therapeutic target for the early stages of kidney damage, and the progression of AKI to CKD.

Angiotensin-[1-7] (Ang-[1-7]) antagonize the actions of the renin-angiotensin-system via the Mas receptor and thereby exert renoprotective effects. Murine recombinant angiotensin-converting enzyme (ACE)2 was reported to show renoprotective effects in an experimental Alport syndrome model; however, the protective effect of direct administration of Ang-[1-7] is unknown. Here, we used Col4a3 -/- mice as a model of Alport syndrome, which were treated with saline or Ang- [1-7]; saline-treated wild-type mice were used as a control group. The mice were continuously infused with saline or Ang-[1-7] (25 μg/kg/h) using osmotic mini-pumps. Col4a3 -/- mice showed increased α-smooth muscle actin (SMA), collagen, and fibronectin expression levels, which were attenuated by Ang-[1-7] treatment. Moreover, Ang-[1-7] alleviated activation of transforming growth factor-β/Smad signaling, and attenuated the protein expression of ED-1 and heme oxygenase-1, indicating reduction of renal inflammation. Ang-[1-7] treatment further reduced the expression levels of inflammatory cytokines and adhesion molecules and attenuated apoptosis in human kidney cells. Finally, Ang-[1-7] downregulated TNF-α converting enzyme and upregulated ACE2 expression. Thus, treatment with Ang-[1-7] altered the ACE2-Ang-[1-7]-Mas receptor axis in the kidneys of Col4a3 -/- mice to attenuate the nephropathy progression of Alport syndrome.

G-protein-coupled receptor 40 (GPR40) has an anti-apoptotic effect in pancreatic β-cells. However, its role in renal tubular cell apoptosis remains unclear. To explore the role of GPR40 in renal tubular apoptosis, a two-week unilateral ureteral obstruction (UUO) mouse model was used. The protein expression of GPR40 was decreased, while the Bax/Bcl-2 protein expression ratio, the expression of tumor necrosis factor (TNF)-α mRNA, and angiotensin II type 1 receptor (AT1R) protein were increased in mice with UUO. In vitro, pretreatment of rat proximal tubular (NRK52E) cells with GW9508, a GPR40 agonist, attenuated the decreased cell viability, increased the Bax/Bcl-2 protein expression ratio, increased protein expression of cleaved caspase-3 and activated the nuclear translocation of nuclear factor-κB (NF-κB) p65 subunit induced by TNF-α treatment. TNF-α treatment significantly increased the expression of AT1R protein and the generation of reactive oxygen species (ROS), whereas GW9508 treatment markedly reversed these effects. Pretreatment with GW1100, a GPR40 antagonist, or silencing of GPR40 in NRK52E cells promoted the increased expression of the cleaved caspase-3 protein by TNF-α treatment. Our results demonstrate that decreased expression of GPR40 is associated with apoptosis via TNF-α and AT1R in the ureteral obstructed kidney. The activation of GPR40 attenuates TNF-α-induced apoptosis by inhibiting AT1R expression and ROS generation through regulation of the NF-κB signaling pathway.

Background/aims: There is a paucity of literature that investigates a biomarker associated with successful renal recovery following continuous renal replacement therapy (CRRT). Our study aimed to identify potential renal biomarkers or clinical indicators that could predict the successful weaning from CRRT., Methods: We conducted a prospective, observational study of 110 patients who had received CRRT and were weaned after renal recovery. Patients were considered to have successfully weaned from CRRT once there was no need for renal replacement therapy (RRT) for at least 14 days. For patients who had to restart dialysis within 14 days were considered unsuccessful., Results: Of the 110 patients evaluated, 89 (80.9%) were successfully weaned from CRRT. These patients had lower serum cystatin C (CysC) levels and higher urine output than the group that restarted RRT at the time of CRRT cessation. However, the levels of serum creatinine and neutrophil gelatinase-associated lipocalin were not significantly lower in the successful group compared to the restart-RRT group. A multivariable logistic regression showed that serum CysC was an independent predictor for the successful weaning from CRRT. Furthermore, in a multivariable Cox proportional hazards analysis, the group that was successfully weaned from CRRT had a lower in-hospital mortality compared to the restarted RRT group., Conclusion: Serum CysC, at the time of CRRT cessation, is an independent predictor of the successful weaning from CRRT in critically ill patients with acute kidney injury., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Rationale: Povidone-iodine is a broad-spectrum antiseptic applied topically to treat wounds and prevent their infection. There have been several case reports of acute kidney injury (AKI) in burn patients after povidone-iodine irrigation and in patients receiving the substance as a sclerotherapy agent for management of lymphocele after renal transplantation. However, biopsy-confirmed AKI after ingestion of povidone-iodine has not previously been described., Patient Concerns: A 47-year-old man who had apparently ingested povidone-iodine solution and presented with nausea, vomiting, and reduced urine output. Laboratory data revealed blood urea nitrogen of 124 mg/dL, serum creatinine of 6.3 mg/dL, impaired liver function, and leukocytosis. Urine iodine/creatinine ratio was markedly elevated., Diagnoses: Acute tubular necrosis and interstitial nephritis secondary to povidone-iodine ingestion., Interventions: The patient was admitted to the intensive care unit and underwent continuous venovenous hemodiafiltration. Kidney biopsy showed acute tubular necrosis and interstitial nephritis. Unstained sections showed tan objects in the tubular lumina that were suspected to be povidone-iodine casts. Corticosteroid therapy (1 mg/kg/day) was started after kidney biopsy., Outcomes: Renal function recovered after hemodialysis and corticosteroid medication, but not completely., Lessons: We have reported the first case of biopsy-confirmed AKI accompanied by increased urine iodine concentration following povidone-iodine ingestion.

Acute kidney injury (AKI) is common after gastric surgery for gastric cancer and associated with adverse outcomes. However, the impact of transient or persistent AKI on clinical outcomes after gastric surgery for gastric cancer has not been described. We performed a retrospective study of 4,886 patients with normal renal function who underwent partial or total gastrectomy for gastric cancer between June 2002 and December 2012. AKI patients were classified as transient and persistent AKI based on the return of serum creatinine to the level indicating no AKI within 7 days. Our outcomes included occurrence of new-onset chronic kidney disease (CKD) and mortality 1 year after gastric surgery. AKI occurred in 638 (13.1%) after gastric surgery. Transient AKI was documented in 574 (90%). Use of diuretics and contrast agents was a common risk factor for persistent and transient AKI. Length of intensive care unit (ICU) and hospital stay, and ICU admission rate were higher in patients with transient AKI than in those without AKI. Although patients with persistent AKI had a higher new-onset CKD 1 year after gastric surgery after adjusting for multiple covariates, transient AKI was not associated with new-onset CKD. The 1-year mortality rates were significantly higher in patients with transient and persistent AKI. Not only persistent AKI but transient AKI is associated with increased risk of hospital complications and a significantly higher risk of long-term mortality than patients without AKI after gastric surgery. Moreover, persistent AKI, but not transient AKI, is associated with CKD progression at 1 year., Competing Interests: The authors have declared that no competing interests exist.

Background: The use of herbal medicine may be a risk factor for the development of kidney injury, as it has been reported to cause various renal syndromes. Dioscorea quinqueloba is a medicinal herb that is used as an alternative therapy for cardiovascular disease and various medical conditions., Case Presentation: A 52-year-old man was admitted with complaints of skin rash and burning sensation. He had ingested a raw extract of D. quinqueloba as a traditional remedy. Laboratory tests revealed the following values: absolute eosinophil count, 900/mm(3); serum creatinine level, 2.7 mg/dL; and blood urea nitrogen, 33.0 mg/dL. The immunoglobulin E level was markedly increased at 1320.0 IU/mL. Urinalysis revealed a fractional excretion of sodium of 3.77%, protein 1+, and blood 3+. Histological examination of the renal biopsy specimen showed a diffusely edematous interstitium with infiltrates composed of eosinophils, lymphocytes, and neutrophils., Conclusion: Here, we present the first reported case of biopsy-proven acute interstitial nephritis following ingestion of D. quinqueloba associated with skin rash, eosinophilia, and increased plasma immunoglobulin E level.

The farnesoid X receptor (FXR) is mainly expressed in liver, intestine and kidney. We investigated whether 6-ethyl chenodeoxycholic acid (6ECDCA), a semisynthetic derivative of chenodeoxycholic aicd (CDCA, an FXR ligand), protects against kidney injury and modulates small heterodimer partner (SHP) in cisplatin-induced kidney injury. Cisplatin inhibited SHP protein expression in the kidney of cisplatin-treated mice and human proximal tubular (HK2) cells; this effect was counteracted by FXR ligand. Hematoxylin and eosin staining revealed the presence of tubular casts, obstructions and dilatations in cisplatin-induced kidney injury, which was attenuated by FXR ligand. FXR ligand also attenuated protein expression of transforming growth factor-β1 (TGF-β1), Smad signaling, and the epithelial-to-mesenchymal transition process, inflammatory markers and cytokines, and apoptotic markers in cisplatin-treated mice. Cisplatin induced NF-κB activation in HK2 cell; this effect was attenuated by pretreatment with FXR ligand. In SHP knockdown by small interfering RNA, cisplatin-induced activation of TGF-β1, p-JNK and Bax/Bcl-2 ratio was not attenuated, while SHP overexpression and FXR ligand inhibited expression of these proteins in cisplatin-pretreated HK2 cells. In conclusion, FXR ligand, 6ECDCA prevents cisplatin-induced kidney injury, the underlying mechanism of which may be associated with anti-fibrotic, anti-inflammatory, and anti-apoptotic effects through SHP induction.

Background: Postoperative acute kidney injury (AKI), a serious surgical complication, is common after cardiac surgery; however, reports on AKI after noncardiac surgery are limited. We sought to determine the incidence and predictive factors of AKI after gastric surgery for gastric cancer and its effects on the clinical outcomes., Methods: We conducted a retrospective study of 4718 patients with normal renal function who underwent partial or total gastrectomy for gastric cancer between June 2002 and December 2011. Postoperative AKI was defined by serum creatinine change, as per the Kidney Disease Improving Global Outcomes guideline., Results: Of the 4718 patients, 679 (14.4%) developed AKI. Length of hospital stay, intensive care unit admission rates, and in-hospital mortality rate (3.5% versus 0.2%) were significantly higher in patients with AKI than in those without. AKI was also associated with requirement of renal replacement therapy. Multivariate analysis revealed that male gender; hypertension; chronic obstructive pulmonary disease; hypoalbuminemia (<4 g/dl); use of diuretics, vasopressors, and contrast agents; and packed red blood cell transfusion were independent predictors for AKI after gastric surgery. Postoperative AKI and vasopressor use entailed a high risk of 3-month mortality after multiple adjustments., Conclusions: AKI was common after gastric surgery for gastric cancer and associated with adverse outcomes. We identified several factors associated with postoperative AKI; recognition of these predictive factors may help reduce the incidence of AKI after gastric surgery. Furthermore, postoperative AKI in patients with gastric cancer is an important risk factor for short-term mortality.

Background: Hospital-acquired anemia (HAA) is common in patients with acute myocardial infarction (AMI) and is an independent indicator of long-term mortality in these patients. However, limited information exists regarding the development and prognostic impact of HAA associated with acute kidney injury (AKI) and chronic kidney disease (CKD) in AMI patients., Methods and Results: We retrospectively analyzed 2,289 patients with AMI, and excluded those with anemia at admission. The study population included 1,368 patients, of whom 800 (58.5%) developed HAA. Age, Hgb level at admission, Length of hospital stay, documented in-hospital bleeding and use of glycoprotein IIb/IIIa inhibitor, presence of CKD and occurrence of AKI were significantly associated with the development of HAA. HAA was significantly associated with higher 3-year mortality (4.8% and 11.4% for non-HAA and HAA patients, respectively; P < 0.001). After adjustment for multivariable confounders, the risk for long-term mortality was increased in HAA patients with AKI and/or CKD but not in HAA patients without AKI and/or CKD, compared to non-HAA patients (HAA patients without AKI and CKD, hazard ratio [HR]: 1.34, 95% confidence interval [CI]: 0.70-2.56; HAA patients with either AKI or CKD, HR: 2.80, 95% CI: 1.37-5.73; HAA patients with AKI and CKD, HR: 3.25, 95% CI: 1.28-8.24; compared with the non-HAA group)., Conclusion: AKI and CKD were strongly associated with the development of HAA in AMI patients. HAA, when accompanied by AKI or CKD, is an independent risk predictor for long-term mortality in AMI patients.

Purpose: The aim of this study was to investigate clinical characteristics and risk factors of acute kidney injury (AKI) in patients with sepsis and septic shock. Additionally, we explored whether the severity of AKI affects on the clinical outcomes., Materials and Methods: Data were collected retrospectively in a single center. Among 5680 patients who visited emergency department from January to December 2010, 992 patients with sepsis and septic shock were enrolled. Patients were divided into two groups, patients who developed AKI or not, to compare the baseline characteristics, and laboratory and physiologic data. Patients with AKI were subdivided according to its stages for survival analysis., Results: AKI was developed in 57.7% of patients. Multivariable logistic regression analysis revealed that development of septic AKI was associated with older age, pre-existing chronic kidney disease, use of angiotensin converting enzyme inhibitor or angiotensin receptor blocker, presence of shock, positive blood culture results, and low white blood cell and platelet counts. Hospital mortality was higher in AKI group. Crude Kaplan-Meier survival curves demonstrated reduced 30-day survival rate was significantly associated with the severity of acute kidney injury., Conclusion: The development of septic AKI was associated with poor clinical outcomes. Furthermore, the severity of AKI was associated with increased mortality.

Purpose: This study aimed to compare the incidence and clinical significance of transient versus persistent acute kidney injury (AKI) on acute ST elevation myocardial infarction (STEMI)., Materials and Methods: The study was a retrospective cohort of 855 patients with STEMI. AKI was defined as an increase of ≥0.3 mg/dL in creatinine level at any point during hospital stay. The study population was classified into 5 groups: 1) patients without AKI; 2) patients with mild AKI that was resolved by discharge (creatinine change less than 0.5mg/dL compared with admission creatinine during hospital stay, transient mild AKI); 3) patients with mild AKI that did not resolve by discharge (persistent mild AKI); 4) patients with moderate/severe AKI that was resolved by discharge (creatinine change more than 0.5 mg/dL compared with admission creatinine, transient moderate/severe AKI); 5) patients with moderate/ severe AKI that did not resolve by discharge (persistent moderate/severe AKI). We investigated 1-year all-cause mortality after hospital discharge for the primary outcome of the study. The relation between AKI and 1-year mortality after STEMI was analyzed., Results: AKI occurred in 74 (8.7%) patients during hospital stay. Adjusted hazard ratio for mortality was 3.139 (95% CI 0.764 to 12.897, p=0.113) in patients with transient, mild AKI, and 8.885 (95% CI 2.710 to 29.128, p<0.001) in patients with transient, moderate/severe AKI compared to patients without AKI. Persistent moderate/severe AKI was also independent predictor of 1 year mortality (hazard ratio, 5.885; 95% CI 1.079 to 32.101, p=0.041)., Conclusion: Transient and persistent moderate/severe AKI during acute myocardial infarction is strongly related to 1-year all cause mortality after STEMI.

Background/aims: Continuous renal replacement therapy (CRRT) has been widely used for treating critically ill patients with acute kidney injury (AKI). Whether CRRT is better than intermittent hemodialysis for the treatment of AKI remains controversial. We sought to identify the clinical features that can predict survival for the patients who are treated with CRRT., Methods: We analyzed the data of 125 patients who received CRRT between 2005 and 2007. We identified the demographic variables, the underlying diagnoses, the duration of CRRT, the mean arterial blood pressure (ABP) and the Simplified Acute Physiology Score (SAPS) II. The classification/staging system for acute kidney injury (AKI) was applied to all the patients, who were then divided into stage 1-3 subgroups., Results: The average age of the patients was 61.414.3 years and the mortality rate was 60% (75 of 125 patients). The survivors had a significantly higher mean ABP and a higher mean serum bicarbonate level, which were measured the day after CRRT, than the nonsurvivors (86.723.7 vs. 69.224.6 mm Hg, respectively, 21.43.5 vs. 16.45.4 mmol/L, respectively,; p<0.05 for each). The stage 3 AKI patients showed the worst parameters for the SAPS II score and the serum levels of creatinine and blood urea nitrogen. The mortality rate was higher for the stage 3 subgroup than the other groups (70.5%, p<0.05)., Conclusions: The patients with AKI and who require CRRT continue to have a high mortality rate. A higher mean ABP and a higher serum bicarbonate level measured the day after CRRT may predict a more favorable prognosis. The staging system for AKI can improve the ability to predict the outcomes of CRRT patients.

Background Incident hemodialysis patients have the highest mortality in the first several months after starting dialysis. This study evaluated the in-hospital mortality rate after hemodialysis initiation, as well as related risk factors. Methods We examined in-hospital mortality and related factors in 2,692 patients starting incident hemodialysis. The study population included patients with acute kidney injury, acute exacerbation of chronic kidney disease, and chronic kidney disease. To determine the parameters associated with in-hospital mortality, patients who died in hospital (nonsurvivors) were compared with those who survived (survivors). Risk factors for in-hospital mortality were determined using logistic regression analysis. Results Among all patients, 451 (16.8%) died during hospitalization. The highest risk factor for in-hospital mortality was cardiopulmonary resuscitation, followed by pneumonia, arrhythmia, hematologic malignancy, and acute kidney injury after bleeding. Albumin was not a risk factor for in-hospital mortality, whereas C-reactive protein was a risk factor. The use of vancomycin, inotropes, and a ventilator was associated with mortality, whereas elective hemodialysis with chronic kidney disease and statin use were associated with survival. The use of continuous renal replacement therapy was not associated with in-hospital mortality. Conclusion Incident hemodialysis patients had high in-hospital mortality. Cardiopulmonary resuscitation, infections such as pneumonia, and the use of inotropes and a ventilator was strong risk factors for in-hospital mortality. However, elective hemodialysis for chronic kidney disease was associated with survival. [ABSTRACT FROM AUTHOR]