Risk of Kidney Failure in Patients With Cancer: A South Korean Population-Based Cohort Study.

RATIONALE & OBJECTIVE: Reduced kidney function is associated with an increased risk of cancer; however, it is unclear if cancer increases the risk of kidney failure with replacement therapy (KFRT). We assessed the risk of KFRT among patients with various types of cancer collectively and with specific types of cancer. STUDY DESIGN: Retrospective population-based cohort study. SETTING & PARTICIPANTS: A total of 2,473,095 participants with (n = 824,365) or without (n = 1,648,730) cancer registered in the Korean National Health Insurance Service database. PREDICTORS: Cancer and cancer subtypes defined using International Classification of Diseases, 10th Revision, Clinical Modification, codes. OUTCOMES: Primary outcome was KFRT defined as the initiation of hemodialysis or peritoneal dialysis or kidney transplantation. ANALYTICAL APPROACH: For each patient with cancer, 2 controls matched for age, sex, estimated glomerular filtration rate, diabetes, and hypertension were included. To address the competing risk of death, a competing risk survival analysis was conducted using the Fine and Gray method. RESULTS: Occurrence of KFRT was higher in patients with cancer than in controls without cancer (incidence rates of 1.07 vs 0.51 cases per 1,000 person-years). Competing risk analysis showed that cancer was significantly associated with an increased risk of KFRT after adjusting for other potential predictors (adjusted hazard ratio, 2.29 [95% CI, 2.20-2.39]). Multiple myeloma, leukemia, lymphoma, and kidney, ovarian, and liver cancer were most significantly associated with an increased KFRT risk, with multiple myeloma conferring the highest risk across age and sex groups. All subgroups of patients with cancer (based on age, sex, smoking, alcohol, exercise, obesity, and comorbid conditions) exhibited a higher risk of KFRT. LIMITATIONS: Causal association between cancer and kidney outcomes could not be confirmed. CONCLUSIONS: Patients with cancer, particularly those with multiple myeloma, exhibited an increased risk of KFRT after accounting for the competing risk of death.

Inflammation-sensing catalase-mimicking nanozymes alleviate acute kidney injury via reversing local oxidative stress.

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 Mn3O4 (dMn3O4) nanoparticles inside ROS-sensitive nanomicelles (PTC), resulting in an ROS-sensitive nanozyme (PTC-M). Hydrophobic dMn3O4 nanoparticles were loaded inside PTC micelles to prevent premature release during circulation and act as a therapeutic agent by ROS-responsive release of loaded dMn3O4 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.

Chronic and acute stress monitoring by electrophysiological signals from adrenal gland.

We present electrophysiological (EP) signals correlated with cellular cell activities in the adrenal cortex and medulla using an adrenal gland implantable flexible EP probe. With such a probe, we could observe the EP signals from the adrenal cortex and medulla in response to various stress stimuli, such as enhanced hormone activity with adrenocorticotropic hormone, a biomarker for chronic stress response, and an actual stress environment, like a forced swimming test. This technique could be useful to continuously monitor the elevation of cortisol level, a useful indicator of chronic stress that potentially causes various diseases.

CG200745, a Novel HDAC Inhibitor, Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome.

Histone deacetylases have been a target of therapy for organ fibrosis. Here, we report the protective effect of CG200745 (CG), a novel histone deacetylase inhibitor, on tubulointerstitial fibrosis in Col4a3-/- mice, a murine model of Alport syndrome. Morphological analyses revealed CG treatment markedly alleviated kidney fibrosis in Col4a3-/- mice at the age of 7 weeks. CG prevented the activation of transforming growth factor ß (TGFß) and its downstream SMAD signaling in the kidney of Col4a3-/- mice. As critical upstream regulators of TGFß signaling, immunoblotting of whole kidney lysate of Col4a3-/- mice reveled that intra-renal renin-angiotensin system (RAS) was activated with concurrent upregulation of inflammation and apoptosis, which were effectively suppressed by CG treatment. CG suppressed both activation of RAS and up-regulation of TGFß signals in angiotensin II-stimulated HK-2 cells, a human kidney proximal tubular epithelial cell line. CG inhibited activation of TGFß-driven signals and fibrosis in NRK-49F cells, a rat kidney fibroblast cell line, under angiotensin II-rich conditions. Collectively, CG was found to be effective both in proximal tubular epithelial cells by inhibiting local RAS and TGFß signaling activation, as well as in fibroblasts by blocking their transition to myofibroblasts, attenuating renal fibrosis in a murine model of Alport syndrome.

Systemic lupus erythematosus is a risk factor for atrial fibrillation: a nationwide, population-based study.

OBJECTIVES: Cardiac involvement is present in more than half of the patients with systemic lupus erythematosus (SLE). However, large-scale studies on the prevalence of atrial fibrillation (AF) in this disease do not exist. We aimed to investigate the incidence and clinical significance of AF in SLE. METHODS: Patients with SLE (n=21,143; mean age, 41.8±13.13 years; female, 90.38%) without previous AF were selected from the Korean National Health Insurance Service National Sample Cohort database between 2008 and 2014. Age-and sex-matched controls (n=105,715) were randomly sampled in a 5:1 ratio from the population of individuals without SLE from the same database. Both cohorts were followed-up for incidental AF and death until 2015. RESULTS: AF was newly detected in 481 (2.27%) patients with SLE and 619 (0.59%) controls (incidence: 3.692 and 0.941 per 1000 person-years, respectively). After multivariate adjustment, SLE was found to be a risk factor for developing AF [hazard ratio (HR), 2.84; 95% confidence interval (CI), 2.50-3.23]. On subgroup analysis, younger (age <40) patients showed a higher incidence of AF. SLE patients with incidental AF had a higher mortality rate compared with patients without SLE with AF (HR, 2.35; 95% CI 1.73-3.20) and those with SLE without AF (HR, 3.53; 95% CI 2.84-4.39) after adjustment. CONCLUSIONS: SLE was an independent risk factor for AF development, especially in younger patients without previous AF, stressing the importance of cardiac assessment in this population. Development of AF in patients with SLE was associated with increased mortality.

Obstructive sleep apnea as a risk factor for incident end stage renal disease: a nationwide population-based cohort study from Korea.

BACKGROUND: Obstructive sleep apnea (OSA) is known to be associated with metabolic dysregulation and incident cardiovascular diseases. However, its association with end-stage renal disease (ESRD) has not been clarified. This study aimed to evaluate longitudinally whether OSA is an independent risk factor for ESRD. METHODS: This retrospective nationwide population-based cohort study included data on 67,359 patients with OSA and 336,795 age-, sex- and years of the enrollment-matched controls without OSA obtained from the Korean National Health Insurance Service database from 2009 to 2014. The study population was followed up from baseline to the date of ESRD diagnosis or until 2016. A Cox proportional-hazards model with multivariable adjustment was used to evaluate the association between OSA and incident ESRD. RESULTS: A significantly higher incident ESRD risk (adjusted hazard ratio: 1.29, 95% confidence interval 1.02-1.62) was observed for patients older than 40 years with OSA than for matched controls, when adjusted for age, sex, income status, smoking, alcohol consumption, body mass index, diabetes, hypertension, dyslipidemia, estimated glomerular filtration rate, and proteinuria. The OSA group remained predictive of higher risk of ESRD incidence in subgroups of age ≥ 65 years, female sex, hypertension, dyslipidemia, proteinuria, and chronic kidney disease. CONCLUSION: OSA was associated with a higher risk of incident ESRD. Understanding the association between OSA and ESRD might provide further insights to establish national health care policy.

Partial nephrogenic diabetes insipidus associated with Castleman's disease.

BACKGROUND: Nephrogenic diabetes insipidus (DI) secondary to a urinary tract obstruction is a rare condition. Herein, we report a case of partial nephrogenic DI due to obstructive uropathy in a patient with Castleman's disease. CASE PRESENTATION: A 78-year-old man underwent computed tomography (CT) at his local hospital because of persistent edema of the leg and polyuria (both lasting approximately 2 months); retroperitoneal fibrosis was detected on the CT scan. An abdominal CT scan showed bilateral hydronephrosis, and a surgical biopsy of the para-aortic lymph node revealed Castleman's disease. To resolve the hydronephrosis, a double J stent was inserted; however, his polyuria continued. As his serum osmolality (311 mOsm/kg) was greater than 300 mOsm/kg, and his serum sodium level was 149 mEq/L, a water deprivation test was not performed. On a vasopressin challenge test, his urine was not sufficiently concentrated to the expected range, indicating partial nephrogenic DI. He was treated with hydrochlorothiazide (25 mg/day), and his urine output gradually decreased to within the normal range. The patient recovered uneventfully and underwent treatment for Castleman's disease. CONCLUSION: To the best of our knowledge, this is the first case of partial nephrogenic DI due to obstructive uropathy associated with Castleman's disease.

Olmesartan Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome by Suppressing Tubular Expression of TGFß.

Despite the wide use of angiotensin II receptor blockers in the treatment of Alport syndrome (AS), the mechanism as to how angiotensin II receptor blockers prevent interstitial fibrosis remains unclear. Here, we report that treatment of olmesartan effectively targets the feedback loop between the renin-angiotensin system (RAS) and transforming growth factor ß (TGFß) signals in tubular epithelial cells and preserves renal angiotensin-converting enzyme 2 (ACE2) expression in the kidney of Col4a3-/- mice, a murine model of experimental AS. Morphology analyses revealed amelioration of kidney fibrosis in Col4a3-/- mice by olmesartan treatment. Upregulation of TGFß and activation of its downstream in Col4a3-/- mice were attenuated by olmesartan in Col4a3-/- mice. Intriguingly, TGFß expression was preferentially upregulated in damaged tubular epithelial cells in Col4a3-/- mice. Concurrent upregulation of TNFα-converting enzyme and downregulation of ACE2 suggested RAS activation in Col4a3-/- mice, which was prevented by olmesartan. Mechanistically, olmesartan suppressed TGFß-induced RAS activation in tubular epithelial cells in vitro. Collectively, we concluded that olmesartan effectively suppresses the progression of tubulointerstitial fibrosis in AS by interrupting RAS-TGFß feedback loop to counterbalance intrarenal RAS activation.

Renoprotective Effect of the Histone Deacetylase Inhibitor CG200745 in DOCA-Salt Hypertensive Rats.

The novel histone deacetylase inhibitor CG200745 was initially developed to treat various hematological and solid cancers. We investigated the molecular mechanisms associated with the renoprotective effects of CG200745 using deoxycorticosterone acetate (DOCA)-salt hypertensive (DSH) rats. DOCA strips (200 mg/kg) were implanted into rats one week after unilateral nephrectomy. Two weeks after DOCA implantation, DSH rats were randomly divided into two groups that received either physiological saline or CG200745 (5 mg/kg/day) for another two weeks. The extent of glomerulosclerosis and tubulointerstitial fibrosis was determined by Masson's trichrome staining. The renal expression of fibrosis and inflammatory markers was detected by semiquantitative immunoblotting, a polymerase chain reaction, and immunohistochemistry. Pathological signs such as glomerulosclerosis, tubulointerstitial fibrosis, increased systolic blood pressure, decreased creatinine clearance, and increased albumin-to-creatinine ratios in DSH rats were alleviated by CG200745 treatment compared to those manifestations in positive control animals. Furthermore, this treatment counteracted the increased expression of αSMA, TGF-ß1, and Bax, and the decreased expression of Bcl-2 in the kidneys of DSH rats. It also attenuated the increase in the number of apoptotic cells in DSH rats. Thus, CG200745 can effectively prevent the progression of renal injury in DSH rats by exerting anti-inflammatory, anti-fibrotic, and anti-apoptotic effects.

Tumor necrosis factor α-converting enzyme inhibitor attenuates lipopolysaccharide-induced reactive oxygen species and mitogen-activated protein kinase expression in human renal proximal tubule epithelial cells.

Tumor necrosis factor-α (TNFα) and the angiotensin system are involved in inflammatory diseases and may contribute to acute kidney injury. We investigated the mechanisms by which TNFα-converting enzyme (TACE) contributes to lipopolysaccharide (LPS)-induced renal inflammation and the effect of TACE inhibitor treatment on LPS-induced cellular injury in human renal proximal tubule epithelial (HK-2) cells. Mice were treated with LPS (10 mg/kg, i.p.) and HK-2 cells were cultured with or without LPS (10 µg/ml) in the presence or absence of a type 1 TACE inhibitor (1 µM) or type 2 TACE inhibitor (10 µM). LPS treatment induced increased serum creatinine, TNFα, and urinary neutrophil gelatinase-associated lipocalin. Angiotensin II type 1 receptor, mitogen activated protein kinase (MAPK), and TACE increased, while angiotensin-converting enzyme-2 (ACE2) expression decreased in LPS-induced acute kidney injury and LPS-treated HK-2 cells. LPS induced reactive oxygen species and the down-regulation of ACE2, and these responses were prevented by TACE inhibitors in HK-2 cells. TACE inhibitors increased cell viability in LPS-treated HK-2 cells and attenuated oxidative stress and inflammatory cytokines. Our findings indicate that LPS activates renin angiotensin system components via the activation of TACE. Furthermore, inhibitors of TACE are potential therapeutic agents for kidney injury.

Role of APE1/Ref-1 in hydrogen peroxide-induced apoptosis in human renal HK-2 cells.

BACKGROUND: Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multipotent protein that plays essential roles in cellular responses to oxidative stress. METHODS: To examine the role of APE1/Ref-1 in ischemia-reperfusion (I/R) injuries and hydrogen peroxide (H2O2)-induced renal tubular apoptosis, we studied male C57BL6 mice and human proximal tubular epithelial (HK-2) cells treated with H2O2 at different concentrations. The colocalization of APE1/Ref-1 in the proximal tubule, distal tubule, thick ascending limb, and collecting duct was observed with confocal microscopy. The overexpression of APE1/Ref-1 with knockdown cell lines using an APE1/Ref-1-specific DNA or small interfering RNA (siRNA) was used for the apoptosis assay. The promotor activity of nuclear factor kappa B (NF-κB) was assessed and electrophoretic mobility shift assay was conducted. RESULTS: APE1/Ref-1 was predominantly localized to the renal tubule nucleus. In renal I/R injuries, the levels of APE1/Ref-1 protein were increased compared with those in kidneys subjected to sham operations. The overexpression of APE1/Ref-1 in HK-2 cells enhanced the Bax/Bcl-2 ratio as a marker of apoptosis. Conversely, the suppression of APE1/Ref-1 expression by siRNA in 1-mM H2O2-treated HK-2 cells decreased the Bax/Bcl-2 ratio, the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, p38, c-Jun N-terminal kinase (JNK) 1/2, and NF-κB. In HK-2 cells, the promoter activity of NF-κB increased following H2O2 exposure, and this effect was further enhanced by APE1/Ref-1 transfection. CONCLUSION: The inhibition of APE1/Ref-1 with siRNA attenuated H2O2-induced apoptosis through the modulation of mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 and the nuclear activation of NF-κB and proapoptotic factors.

A Case of Recurrent Renal Infarction Following Transient Resolution: Evidence From Serial Computed Tomography.

Although renal infarction (RI) is not a rare disease, its outcomes have not been well-documented. Furthermore, transient resolution and recurrence of RI have not been captured through imaging. We report a case of idiopathic RI that recurred within a short period following transient resolution, as demonstrated by serial computed tomography (CT). A 53-year-old man diagnosed with RI was transferred to the emergency room. An abdominal CT scan at the local hospital revealed a segmental wedge-shaped perfusion defect in the left kidney and a focal thrombotic filling defect in the anterior segmental branch of the left renal artery. Since his left flank pain improved, another CT scan was performed again 6 hours after the initial CT scan. A repeat CT scan showed that the thrombus in the renal artery remained, but the perfusion defect had spontaneously resolved. We initiated anticoagulant therapy using unfractionated heparin. On the sixth day of hospitalization, the left flank pain recurred, prompting another CT scan. The follow-up CT scan confirmed that RI had recurred in the same area as before. We continued anticoagulant therapy and switched to warfarin. After treatment, his symptoms improved, and he was discharged. RI can recur at any time, even after it has spontaneously resolved, as evidenced by our case. Therefore, it is crucial to closely monitor patients who experience resolution of RI for any recurrence of symptoms, and repeat radiological evaluation should be performed even within a short period.

Obesity is associated with incident chronic kidney disease in individuals with normal renal function.

Background/Aims: Obesity has known to be a modifiable risk factor associated with worse outcomes in chronic kidney disease (CKD), but few studies have examined the impact of obesity on CKD incidence in the general population. The purpose of this study was to investigate the role of body mass index (BMI) and waist-to-hip ratio (WHR) as predictors of incident CKD and to evaluate the impact of weight reduction on CKD prevention. Methods: A total of 2,711 participants from a community-based cohort with normal renal function were prospectively analyzed. Among participants with obesity, we analyzed the change in WHR to evaluate the association of obesity reduction with CKD development. Results: During a mean follow-up of 11.03 ± 4.22 years, incident CKD occurred in 190 (7.0%) participants. In the fully adjusted multivariable Cox proportional hazard models, the risk of incident CKD increased with higher BMI (hazard ratio, 1.06; 95% confidence interval, 1.00-1.11; p = 0.033) and higher WHR (hazard ratio, 1.33; 95% confidence interval, 1.07-1.66; p = 0.009). In the Kaplan-Meier analysis, cumulative adverse renal events were significantly more common in the maintained obesity group than in the reduced obesity group (p = 0.001). Conclusions: Both higher BMI and WHR were associated with development of CKD, but the magnitude of the effect of WHR was higher than that of BMI. Moreover, reducing obesity would be beneficial for renal prognosis.

Early single session of hyperbaric oxygen therapy mitigates renal apoptosis in lipopolysaccharides-induced endotoxemia in rats.

Background: Sepsis-associated acute kidney injury (SA-AKI) is a prominent sepsis complication, often resulting in adverse clinical outcomes. Hyperbaric oxygen therapy (HBOT), known for its anti-inflammatory characteristics, antioxidant effects, and ability to deliver high oxygen tension to hypo-perfused tissues, offers potential benefits for SA-AKI. This study investigated whether HBOT improved renal injury in sepsis and elucidated its underlying mechanisms. Methods: A lipopolysaccharide (LPS)-induced endotoxemia model was established using 8-week-old C57BL/6 mice. Thirty minutes post-LPS administration, a group of mice underwent HBOT at a 2.5 atmospheric pressure absolute with 100% oxygen for 60 minutes. After 24 hours, all mice were euthanized for measurements. Results: Our results demonstrated that HBOT effectively mitigated renal tubular cell apoptosis. Additionally, HBOT significantly reduced phosphorylated p53 proteins and cytochrome C levels, suggesting that HBOT may attenuate renal apoptosis by impeding p53 activation and cytochrome C release. Notably, HBOT preserved manganese-dependent levels of superoxide dismutase, an antioxidant enzyme, compared to the LPS group. Furthermore, transforming growth factor beta (TGF-ß)/Smad4 and alpha smooth muscle actin expressions were significantly reduced in the LPS + HBOT group. Conclusion: An early single session of HBOT exhibited renoprotective effects in LPS-induced endotoxemia mice models by suppressing p53 activation and cytochrome C levels to mitigate apoptosis. The observed TGF-ß decrease, downstream Smad expression reduction, and antioxidant capacity preservation following HBOT may contribute to these effects.

Systematic metabolomics study in the serum and urine of a mouse model of Fabry disease.

Background: Fabry disease (FD) is an X-linked lysosomal disorder caused by α-galactosidase A enzyme activity deficiency. Although glycosphingolipid analogs have been identified in the plasma or urine of patients with FD, there is a limited understanding of altered metabolomics profiles beyond the globotriaosylceramide accumulation in FD. Methods: Metabolomics study was performed for monitoring of biomarker and altered metabolism related with disease progression in serum and urine from male α-galactosidase A knockout mice and age-matched wild-type mice at 20 and 40 weeks. Profiling analysis for metabolites, including organic acids, amino acids, fatty acids, kynurenine pathway metabolites, and nucleosides in the serum and urine was performed using gas chromatography-tandem mass spectrometry and liquid chromatography-tandem mass spectrometry combined with star symbol patterns and partial least squares discriminant analysis (PLS-DA). Results: A total of 27 and 23 metabolites from the serum and urine of Fabry mice were distinguished from those of wild-type mice, respectively, based on p-value (<0.05) and variable importance in projection scores (>1.0) of PLS-DA. In the serum, metabolites of the glutathione, glutathione disulfide, citrulline, and kynurenine pathways that are related to oxidative stress, nitric oxide biosynthesis, and inflammation were increased, whereas those involved in pyruvate and tyrosine metabolism and the tricarboxylic acid cycle were altered in the 20- and 40-week-old urine of FD model mice. Conclusion: Altered metabolic signatures associated with disease progression by oxidative stress, inflammation, nitric oxide biosynthesis, and immune regulation in the early and late stages of FD.

Circulating osteoprotegerin as a cardiac biomarker for left ventricular diastolic dysfunction in patients with pre-dialysis chronic kidney disease: the KNOW-CKD study.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a major cause of mortality in patients with chronic kidney disease (CKD), and diagnosis is challenging. Moreover, no specific biomarker for HFpEF has been validated in patients with CKD. The present study aimed to investigate the association between serum osteoprotegerin (OPG) levels and the risk of left ventricular diastolic dysfunction (LVDD), a surrogate of HFpEF, in patients with pre-dialysis CKD. METHODS: A total of 2039 patients with CKD at stage 1 to pre-dialysis 5 were categorized into quartiles (Q1 to Q4) by serum OPG levels, and were cross-sectionally analyzed. The study outcome was LVDD, which was operationally defined as the ratio of early transmitral blood flow velocity to early diastolic velocity of the mitral annulus (E/e') > 14. RESULTS: In the analysis of baseline characteristics, higher serum OPG levels were clearly related to the risk factors of HFpEF. A scatter plot analysis revealed a moderate correlation between serum OPG levels and E/e' (R = 0.351, P < 0.001). Logistic regression analysis demonstrated that the risk of LVDD in Q3 (adjusted odds ratio 2.576, 95% confidence interval 1.279 to 5.188) and Q4 (adjusted odds ratio 3.536, 95% confidence interval 1.657 to 7.544) was significantly higher than that in Q1. CONCLUSIONS: Elevated serum OPG levels are associated with the risk of LVDD in patients with pre-dialysis CKD. The measurement of serum OPG levels may help the diagnosis of LVDD, which is an important echocardiographic feature of HFpEF.