Clinical significance of urinary inflammatory biomarkers in patients with IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis, although the definitive markers are unknown. We aimed to investigate the clinical significance of urinary cytokines in patients with IgAN. METHODS: From 2009 to 2018, the patients were divided into three groups: IgAN (n = 191), disease control (n = 53), and normal control (n = 76). We used a multiplex enzyme-linked immunosorbent assay to measure 16 selected urinary inflammatory cytokines, evaluated the correlation between clinical and pathological features following regression analysis on progression. RESULTS: The IgAN group exhibited significantly different levels of urinary cytokines compared to the normal control and disease control groups. Urinary levels of B-cell-activating factor, vascular endothelial growth factor receptor-2, monocyte chemoattractant protein-1, C-X-C motif chemokine 10, C-X-C motif ligand 16, epidermal growth factor (EGF), endocan, endostatin, growth/differentiation factor-15 (GDF-15), interleukin-6 (IL-6), mannose-binding lectin, transferrin receptor, and kidney injury molecule-1 were significantly correlated with both the estimated glomerular filtration rate and urine protein-creatinine ratio. In a multivariate Cox regression analysis, urinary EGF (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.17-0.95, P = 0.04), GDF-15 (HR 2.45, 95% CI 1.01-5.94, P = 0.048), and IL-6 (HR 3.02, 95% CI 1.05-8.64, P = 0.04) were associated with progression in IgAN. CONCLUSIONS: Urinary inflammatory biomarkers may serve as alternative predictive biomarkers in patients with IgAN. Further studies are needed to elucidate the physiological mechanisms and confirm the results.

Urine Exosomal bkv-miR-B1-5p and BK Virus Nephropathy in Kidney Transplant Recipients.

BACKGROUND: Urine exosomal bkv-miR-B1-5p is associated with BK virus (BKV) nephropathy (BKVN); however, its posttransplantation changes and predictability for BKVN have not been determined in kidney transplant recipients (KTRs). METHODS: Urine exosomal bkv-miR-B1-5p and urine and plasma BKV DNA were measured at 2 weeks and 3, 6, and 12 months posttransplant in 83 KTRs stratified into biopsy-proven or presumptive BKVN, BKV viruria, and no evidence of BKV reactivation. Joint model, multivariable Cox model and receiver operating characteristic curve (ROC) were used to investigate the association of each assay with the following events: a composite of biopsy-proven or presumptive BKVN, and biopsy-proven BKVN. RESULTS: Urine exosomal bkv-miR-B1-5p and urine and plasma BKV DNA showed similar posttransplant time-course changes. Joint models incorporating serial values demonstrated significant associations of all assays with the events, and Cox analyses using single time point values at 2 weeks posttransplant showed that only urine exosomal bkv-miR-B1-5p was significantly associated with the events, although it did not outperform urine BKV DNA in ROC analyses. CONCLUSIONS: Urine exosomal bkv-miR-B1-5p was associated with BKVN as were urine and plasma BKV DNA loads on serial follow-up, and might have potential as a predictive marker for BKVN during the early posttransplant period. CLINICAL TRIALS REGISTRATION: Clinical Research Information Service (https://cris.nih.go.kr/cris/), KCT0001010.

How obesity and metabolic syndrome affect cardiovascular events, progression to kidney failure and all-cause mortality in chronic kidney disease.

BACKGROUND: Obesity and metabolic syndrome (MetS) are prevalent among chronic kidney disease (CKD) patients. However, it is unclear whether obesity without MetS is associated with a higher risk of adverse clinical outcomes in CKD patients. METHODS: We searched the National Health Insurance Service database of Korea for patients who underwent national health screenings in 2009-2011 and identified 59 725 CKD patients. Obesity was defined as a body mass index ≥25 kg/m2. MetS was defined as the presence of ≥3 metabolic risks. RESULTS: The cumulative event rate of cardiovascular events, progression to end-stage kidney disease (ESKD), and all-cause mortality was the lowest among obese patients without MetS (all P < 0.001). In multivariable analysis, obese (versus non-obese) patients without MetS were not at increased risks of cardiovascular events (adjusted hazard ratio [HR] 1.02; 95% confidence interval 0.94-1.11) or progression to ESKD (0.92; 0.77-1.09). Their risk of all-cause mortality was significantly decreased (0.82; 0.75-0.90). These findings were consistently observed in overweight, obese, and morbidly obese patients without MetS. Moreover, despite a linear increase in HR for each additional metabolic abnormality in both obese and non-obese patients, the slope of HR increase for cardiovascular events was significantly slower in obese patients (P for interaction = 0.038). CONCLUSIONS: Obesity without MetS did not increase the risk of cardiovascular complications or progression to ESKD. The healthy effect of obesity on all-cause mortality risk and its weakening effect on the association between metabolic hazards and cardiovascular risk should be considered in CKD patients.

Acute Kidney Injury: Biomarker-Guided Diagnosis and Management.

Acute kidney injury (AKI) is a common clinical syndrome that is characterized by abnormal renal function and structure. The Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference in 2019 reviewed the stages of AKI and the definitions of AKI-related terminologies, and discussed the advances in the last decade. Along with serum creatinine level and urine output, more accurate novel biomarkers for predicting AKI are being applied for the early detection of renal dysfunction. A literature search was conducted in PubMed, Scopus, Medline, and ClinicalTrials.gov using the terms AKI and biomarker, combined with diagnosis, management, or prognosis. Because of the large volume of data (160 articles) published between 2005 and 2022, representative literature was chosen. A number of studies have demonstrated that new biomarkers are more sensitive in detecting AKI in certain populations than serum creatinine and urine output according to the recommendations from the Acute Disease Quality Initiative Consensus Conference. To be specific, there is a persistently unresolved need for earlier detection of patients with AKI before AKI progresses to a need for renal replacement therapy. Biomarker-guided management may help to identify a high-risk group of patients in progression to severe AKI, and decide the initiation time to renal replacement therapy and optimal follow-up period. However, limitations such as biased data to certain studied populations and absence of cutoff values need to be solved for worldwide clinical use of biomarkers in the future. Here, we provide a comprehensive review of biomarker-based AKI diagnosis and management and highlight recent developments.

Urinary chemokine C-X-C motif ligand 16 and endostatin as predictors of tubulointerstitial fibrosis in patients with advanced diabetic kidney disease.

BACKGROUND: Interstitial fibrosis and tubular atrophy (IFTA) is a well-recognized risk factor for poor renal outcome in patients with diabetic kidney disease (DKD). However, a noninvasive biomarker for IFTA is currently lacking. The purpose of this study was to identify urinary markers of IFTA and to determine their clinical relevance as predictors of renal prognosis. METHODS: Seventy patients with biopsy-proven isolated DKD were enrolled in this study. We measured multiple urinary inflammatory cytokines and chemokines by multiplex enzyme-linked immunosorbent assay in these patients and evaluated their association with various pathologic features and renal outcomes. RESULTS: Patients enrolled in this study exhibited advanced DKD at the time of renal biopsy, characterized by moderate to severe renal dysfunction [mean estimated glomerular filtration rate (eGFR) 36.1 mL/min/1.73 m2] and heavy proteinuria (mean urinary protein:creatinine ratio 7.8 g/g creatinine). Clinicopathologic analysis revealed that higher IFTA scores were associated with worse baseline eGFR (P < 0.001) and poor renal outcome (P = 0.002), whereas glomerular injury scores were not. Among measured urinary inflammatory markers, C-X-C motif ligand 16 (CXCL16) and endostatin showed strong correlations with IFTA scores (P = 0.001 and P < 0.001, respectively), and patients with higher levels of urinary CXCL16 and/or endostatin experienced significantly rapid renal progression compared with other patients (P < 0.001). Finally, increased urinary CXCL16 and endostatin were independent risk factors for poor renal outcome after multivariate adjustments (95% confidence interval 1.070-3.455, P = 0.029). CONCLUSIONS: Urinary CXCL16 and endostatin could reflect the degree of IFTA and serve as biomarkers of renal outcome in patients with advanced DKD.

Associations between Cell-Free Mitochondrial DNA and Inflammation, and Their Clinical Implications for Patients on Hemodialysis: A Prospective Multicenter Cohort Study.

BACKGROUND: Cell-free mitochondrial DNA (cf-mtDNA) has recently been in the spotlight as an endogenously produced danger molecule that can potentially elicit inflammation. However, its clinical and prognostic implications are uncertain in patients undergoing hemodialysis. METHODS: We examined the association of baseline cf-mtDNA categorized as tertiles with health-related quality of life (HRQOL), inflammatory cytokines, and mortality in a multicenter prospective cohort of 334 patients on hemodialysis. To better understand cf-mtDNA-mediated inflammation, we measured cytokine production after in vitro stimulation of bone marrow-derived macrophages (BMDMs) with mtDNA. RESULTS: The higher cf-mtDNA tertile had a longer dialysis vintage, a greater comorbidity burden, and increased levels of inflammatory markers, including high-sensitivity-C-reactive protein, tumor necrosis factor-alpha, CXCL16, and osteoprotegerin. In particular, mtDNA augmented inflammatory cytokine release from BMDMs by lipopolysaccharide, the levels of which are reported to be increased in hemodialysis patients. Although the patients with higher levels of cf-mtDNA generally had lower (poorer) scores for HRQOL, cf-mtDNA was not associated with all-cause mortality in hemodialysis patients. CONCLUSION: cf-mtDNA was correlated with poor clinical status and modestly associated with impaired quality of life in patients on hemodialysis. In proinflammatory milieu in end-stage renal disease, these associations may be attributed to the boosting effects of cf-mtDNA on inflammation.

Clinical significance of urinary tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in immunoglobulin A nephropathy
.

AIMS: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been implicated as a mediator of chronic inflammatory processes. Recently, it was reported that TWEAK may play an important role in the pathogenesis of kidney damage. In the present study, we investigated the role of TWEAK in immunoglobulin A nephropathy (IgAN). MATERIALS AND METHODS: The levels of serum TWEAK (sTWEAK) and urinary TWEAK (uTWEAK) in 45 patients with IgAN and 15 healthy subjects were measured. We analyzed the correlations of uTWEAK level with clinical and pathological parameters in patients with IgAN. We then divided the patients into two groups according to uTWEAK level and investigated 5-year chronic kidney disease (CKD) progression. RESULTS: The level of uTWEAK was significantly higher in patients with IgAN than in healthy controls (p < 0.001). sTWEAK level showed no significant difference between the two groups (p = 0.225). The level of uTWEAK correlated significantly with serum albumin (p < 0.001), urine protein excretion (p < 0.001), and histological classification (p < 0.016) in patients with IgAN. uTWEAK was significantly increased even in patients with IgAN who had lower proteinuria. There was a significant association between uTWEAK level and CKD progression (p = 0.049). CONCLUSION: Although uTWEAK is not a superior biomarker compared to proteinuria, it has a significant correlation with IgAN patients and seems to be useful in determining disease progression.

Renal dysfunction is associated with decline of cognitive function in community-dwelling older adults: Korean frailty and aging cohort study.

BACKGROUND: Cognitive decline is common in older adults. Similarly, the prevalence of renal dysfunction is also increased in the elderly population. We conducted this study to clarify the relationship between renal dysfunction and decline of cognitive function in community-dwelling elderly population. METHODS: A cross-sectional analysis was performed using data from the Korean Frailty and Aging Cohort Study, a nationwide cohort study. Total 2847 (1333 men, 1514 women) eligible participants were enrolled for this study. The estimated glomerular filtration rate (eGFR, mL/min/1.73m2) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Global cognitive function was assessed with the Mini-mental State Examination-Korean version. Other domains of cognitive function were tested with the Consortium to Establish a Registry for Alzheimer's disease and the Frontal Assessment Battery. RESULTS: The mean age of all participants was 76.0 ± 3.9 years and eGFR (all in mL/min/1.73 m2) was 77.5 ± 14.3. And the mean eGFR was 91.7 ± 3.2 in quartile 1, 84.9 ± 1.8 in quartile 2, 76.1 ± 3.7 in quartile 3, and 57.2 ± 10.8 in quartile 4. In baseline characteristics, participants with lower eGFR tend to have lower cognitive function scores than participant with higher eGFR. In linear regression analysis, eGFR was correlated with the word list memory (ß = 0.53, P = 0.005), word list recall (ß = 0.86, P < 0.001), and word list recognition (ß = 0.43, P = 0.030) after adjustment of confounding variables. Moreover, after multivariate adjustment the association with cognitive impairment in quartile 2 was stronger (adjusted OR: 1.535, 95% CI: 1.111-2.120, P = 0.009), and the ORs of cognitive impairment were 1.501 (95% CI: 1.084-2.079, P = 0.014) in quartile 3 and 1.423 (95% CI: 1.022-1.983, P = 0.037) in quartile 4. CONCLUSION: In older adults, the immediate, recent memory, and recognition domains were significantly related to renal function. Also, the mild renal dysfunction was independently associated with impairment of global cognitive function. These results suggest that the early stages of renal dysfunction could be an effective target to prevent worsening of cognitive impairment. Therefore, regular monitoring and early detection of mild renal dysfunction in elderly population might be needed.

Epidemiology, risk factors, and clinical impact of early post-transplant infection in older kidney transplant recipients: the Korean organ transplantation registry study.

BACKGROUND: As in younger recipients, post-transplant infection is a frequent and devastating complication after kidney transplantation (KT) in older recipients. However, few studies have analyzed characteristics of post-transplant infection in older kidney recipients. In this study of a nation-wide cohort of older kidney recipients, we investigated the current epidemiology, risk factors, and clinical impacts of early post-transplant infection, which was defined as infectious complications requiring hospitalization within the first 6 months after KT. METHODS: Three thousand seven hundred thirty-eight kidney recipients registered in the Korean Organ Transplantation Registry between 2014 and 2017 were enrolled. Recipients were divided into two groups, younger (n = 3081) and older (n = 657), with a cutoff age of 60 years. We observed characteristics of early post-transplant infection, and investigated risk factors for the development of infection. We also analyzed the association of early post-transplant infection with clinical outcomes including cardiac events, rejection, graft loss, and all-cause mortality. RESULTS: The incidence of early post-transplant infection was more frequent in older recipients (16.9% in younger group and 22.7% in older group). Bacteria were the most common causative pathogens of early post-transplant infection, and the most frequent site of infection was the urinary tract in both older and younger recipients. Older recipients experienced more mycobacterial infections, co-infections, and multiple site infections compared with younger recipients. In older recipients, female sex (HR 1.398, 95% CI 1.199-1.631), older donor age (HR 1.010, 95% CI 1.004-1.016), longer hospitalization after KT (HR 1.010, 95% CI 1.006-1.014), and experience of acute rejection (HR 2.907, 95% CI 2.471-3.419) were independent risk factors for the development of early post-transplant infection. Experiencing infection significantly increases the incidence of rejection, graft loss, and all-cause mortality. CONCLUSION: Our results illustrate current trends, risk factors, and clinical impacts of early post-transplant infection after KT in older recipients. Considering the poor outcomes associated with early post-transplant infection, careful screening of recipients at high risk for infection and monitoring of recipients who experience infection are advised. In addition, since older recipients exhibit different clinical characteristics than younger recipients, further studies are needed to establish effective strategies for treating older recipients.

Gait speed and handgrip strength as predictors of all-cause mortality and cardiovascular events in hemodialysis patients.

BACKGROUND: Low physical performance in patients undergoing maintenance hemodialysis is associated with a high mortality rate. We investigated the clinical relevance of gait speed and handgrip strength, the two most commonly used methods of assessing physical performance. METHODS: We obtained data regarding gait speed and handgrip strength from 277 hemodialysis patients and evaluated their relationships with baseline parameters, mental health, plasma inflammatory markers, and major adverse clinical outcomes. Low physical performance was defined by the recommendations suggested by the Asian Working Group on Sarcopenia. RESULTS: The prevalence of low gait speed and handgrip strength was 28.2 and 44.8%, respectively. Old age, low serum albumin levels, high comorbidity index score, and impaired cognitive functions were associated with low physical performance. Patients with isolated low gait speed exhibited a general trend for worse quality of life than those with isolated low handgrip strength. Gait speed and handgrip strength showed very weak correlations with different determining factors (older age, the presence of diabetes, and lower serum albumin level for low gait speed, and lower body mass index and the presence of previous cardiovascular events for low handgrip strength). Patients with low gait speed and handgrip strength had elevated levels of plasma endocan and matrix metalloproteinase-7 and the highest risks for all-cause mortality and cardiovascular events among the groups (adjusted hazard ratio of 2.72, p = 0.024). Elderly patients with low gait speed and handgrip strength were at the highest risk for poor clinical outcomes. CONCLUSION: Gait speed and handgrip strength reflected distinctive aspects of patient characteristics and the use of both factors improved the prediction of adverse clinical outcomes in hemodialysis patients. Gait speed seems to be a better indicator of poor patient outcomes than is handgrip strength.

Rhabdomyolysis-Induced AKI Was Ameliorated in NLRP3 KO Mice via Alleviation of Mitochondrial Lipid Peroxidation in Renal Tubular Cells.

INTRODUCTION: A recent study showed that early renal tubular injury is ameliorated in Nod-like receptor pyrin domain-containing protein 3 (NLRP3) KO mice with rhabdomyolysis-induced acute kidney injury (RIAKI). However, the precise mechanism has not been determined. Therefore, we investigated the role of NLRP3 in renal tubular cells in RIAKI. METHODS: Glycerol-mediated RIAKI was induced in NLRP3 KO and wild-type (WT) mice. The mice were euthanized 24 h after glycerol injection, and both kidneys and plasma were collected. HKC-8 cells were treated with ferrous myoglobin to mimic a rhabdomyolytic environment. RESULTS: Glycerol injection led to increase serum creatinine, aspartate aminotransferase (AST), and renal kidney injury molecule-1 (KIM-1) level; renal tubular necrosis; and apoptosis. Renal injury was attenuated in NLRP3 KO mice, while muscle damage and renal neutrophil recruitment did not differ between NLRP3 KO mice and WT mice. Following glycerin injection, increases in cleaved caspase-3, poly (ADP-ribose) polymerase (PARP), and a decrease in the glutathione peroxidase 4 (GPX-4) level were observed in the kidneys of mice with RIAKI, and these changes were alleviated in the kidneys of NLRP3 KO mice. NLRP3 was upregulated, and cell viability was suppressed in HKC-8 cells treated with ferrous myoglobin. Myoglobin-induced apoptosis and lipid peroxidation were significantly decreased in siNLRP3-treated HKC-8 cells compared to ferrous myoglobin-treated HKC-8 cells. Myoglobin reduced the mitochondrial membrane potential and increased mitochondrial fission and reactive oxygen species (ROS) and lipid peroxidation levels, which were restored to normal levels in NLRP3-depleted HKC-8 cells. CONCLUSIONS: NLRP3 depletion ameliorated renal tubular injury in a murine glycerol-induced acute kidney injury (AKI) model. A lack of NLRP3 improved tubular cell viability via attenuation of myoglobin-induced mitochondrial injury and lipid peroxidation, which might be the critical factor in protecting the kidney.

Sex-related differences in the intratubular renin-angiotensin system in two-kidney, one-clip hypertensive rats.

The intratubular renin-angiotensin system (RAS) is thought to play an essential role in hypertensive renal disease, but information regarding sex-related differences in this system is limited. The present study investigated sex differences in the intratubular RAS in two-kidney, one-clip (2K1C) rats. A 2.5-mm clip was placed on the left renal artery of Sprague-Dawley rats, and rats were euthanized 3 or 5 wk after the operation. Systolic blood pressure increased in 2K1C rats in both sexes but was significantly higher in male rats than in female rats, and an antihypertensive effect was not observed in 2K1C ovariectomized (OVX) female rats. Compared with male 2K1C rats, intratubular angiotensin-converting enzyme (ACE) and ANG II were repressed, and intratubular ACE2, angiotensin (1-7), and Mas receptor were increased in both kidneys in female 2K1C rats 5 wk after surgery. Comparison with male and female rats and intratubular mRNA levels of ACE and ANG II type 1 receptor were augmented in OVX female rats, regardless of the clipping surgery 3 wk postoperation. ANG II type 2 receptor was upregulated in female rats with or without OVX; thus, the ANG II type 1-to-type 2 receptor ratio was higher in male rats than in female rats. In conclusion, female rats were protected from hypertensive renal and cardiac injury after renal artery clipping. An increase in the intratubular nonclassic RAS [ACE2/angiotensin (1-7)/Mas receptor] and a decrease in the ANG II type 1-to-type 2 receptor ratio could limit the adverse effects of the classic RAS during renovascular hypertension in female rats, and estrogen is suggested to play a primary role in the regulation of intratubular RAS components.

Association between Plasma Levels of Growth Differentiation Factor-15 and Renal Function in the Elderly: Korean Frailty and Aging Cohort Study.

BACKGROUND/AIMS: Growth differentiation factor-15 (GDF-15) expression has been reported to increase in response to tissue damage and has recently emerged as a useful biomarker for various diseases. Although emerging evidence supports the clinicopathological value of GDF-15 in renal impairment, few studies have analyzed it in the elderly. Thus, we conducted a cross-sectional study to investigate the association of plasma GDF-15 with renal function and the presence of chronic kidney disease (CKD) in community-dwelling elderly. MATERIALS: The present study was based on the baseline data of the Korean Frailty and Aging Cohort Study (KFACS), a nationwide cohort study that began in 2016. Of the 1,559 participants assessed in the first year, 443 with available plasma GDF-15 data were enrolled in this study. We investigated the association of plasma GDF-15 levels with clinical and biochemical parameters. The study population was divided into two groups according to renal function (CKD and non-CKD groups) to investigate whether GDF-15 can determine the presence of renal dysfunction in the elderly. Plasma GDF-15 was measured by enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: In a simple regression analysis, the levels of plasma GDF-15 were negatively correlated with estimated glomerular filtration rate (eGFR; r = -0.383, p < 0.001). In multiple linear regression analysis, GDF-15 levels were still significantly correlated with eGFR, even after adjusting for other parameters (r = -0.259, p < 0.001). Plasma GDF-15 levels were significantly higher in the elderly with CKD than in those without CKD (2,364.025 ± 1,052.23 ng/L and 1,451.23 ± 835.79 ng/L, respectively; p < 0.001). The optimal cut-off value of plasma GDF-15 for detecting the presence of CKD was 1,699.4 ng/L (76.5% sensitivity and 76.0% specificity), as determined by the receiver operating characteristic curve. The area under the curve was 0.793 ± 0.033 (95% CI 0.729-0.857, p < 0.001). CONCLUSION: Plasma GDF-15 levels were negatively associated with eGFR and were significantly increased in the elderly with CKD. Our results suggested that plasma GDF-15 might be a useful marker for discriminating renal impairment in the elderly. Further large and prospective outcome studies of extended duration are needed.

Itraconazole Attenuates Peritoneal Fibrosis Through Its Effect on the Sonic Hedgehog Signaling Pathway in Mice.

BACKGROUND: Peritoneal fibrosis is a devastating complication of peritoneal dialysis. However, its precise mechanism is unclear, and specific treatments have not yet been established. Recent evidence suggests that the sonic hedgehog (SHH) signaling pathway is involved in tissue fibrogenesis. Drugs that inhibit this pathway are emerging in the field of anti-fibrosis therapy. Itraconazole, an anti-fungal agent, was also recently recognized as an inhibitor of the SHH signaling pathway. In this study, we used a mouse model to investigate whether the SHH signaling pathway is involved in the development of peritoneal fibrosis and the effects of itraconazole on peritoneal fibrosis. METHODS: Peritoneal fibrosis was induced by intraperitoneal (IP) injection of 0.1% chlorhexidine gluconate (CG) solution every other day for 4 weeks, with or without itraconazole treatment (20 mg/kg, IP injection on a daily basis). Male C57BL/6 mice were divided into 4 groups: saline group, saline plus itraconazole group, CG group, and CG plus itraconazole group. Isotonic saline was administered intraperitoneally to the control group. The peritoneal tissues were evaluated for histological changes, expression of fibrosis markers, and the main components of the SHH signaling pathway. RESULTS: Peritoneal thickening was evident in the CG group and was significantly decreased by itraconazole administration (80.4 ± 7.7 vs. 28.2 ± 3.8 µm, p < 0.001). The expression of the following SHH signaling pathway components was upregulated in the CG group and suppressed by itraconazole treatment: SHH, patched, smoothened, and glioma-associated oncogene transcription factor 1. The IP injection of CG solution increased the expression of fibrosis markers such as α-smooth muscle actin and transforming growth factor-ß1 in the peritoneal tissues. Itraconazole treatment significantly decreased the expression of these markers. CONCLUSION: Our study provides the first evidence that the SHH signaling pathway may be implicated in peritoneal fibrosis. It also demonstrates that itraconazole treatment has protective effects on peritoneal fibrosis through the regulation of the SHH signaling pathway. These findings suggest that blockage of the SHH signaling pathway is a potential therapeutic strategy for peritoneal fibrosis.

Association between albuminuria and retinal microvascular parameters measured with swept-source optical coherence tomography angiography in patients with diabetic retinopathy.

PURPOSE: To evaluate the relationship between urine albumin excretion (UAE) and retinal microvascular parameters assessed using swept-source optical coherence tomography angiography (SS-OCTA) in patients with diabetic retinopathy (DR). METHODS: This retrospective cross-sectional study included 180 patients with diabetes and 50 age-matched controls. Patients with diabetes were grouped according to the five-stage DR severity, combined with the presence of albuminuria. All subjects underwent 12×12mm2 field SS-OCTA. The foveal avascular zone metrics, vessel density, and capillary nonperfusion area (NPA) were quantified using a semi-automatic software algorithm on three different rectangular fields (3×3 mm2, 6×6 mm2, and 10×10 mm2). The correlations between albuminuria and the four OCTA parameters were analyzed. RESULTS: A total of 105 subjects had normal UAE, and 75 subjects had albuminuria. Of the 102 subjects whose DR severity was higher than mild non-proliferative DR (NPDR), capillary NPA on the 3×3 mm2, 6×6 mm2, and 10×10 mm2 fields was significantly larger in the albuminuria group. None of the OCTA parameters were significantly different between the two groups in subjects with mild NPDR or without DR. Multiple logistic regression analysis showed that an increase in NPA in the 6×6 mm2 and 10×10 mm2 fields was a significant risk factor for the presence of albuminuria (odds ratio = 1.92 and 1.35). CONCLUSION: An increase in capillary NPA was independently associated with albuminuria in patients with clinically significant DR levels. SS-OCTA imaging can be a useful marker for the early detection of diabetic nephropathy.

Association of the Intensive Blood Pressure Target and Cardiovascular Outcomes in the Population With Chronic Kidney Disease: A Retrospective Study in Korea.

BACKGROUND: Recently, the target systolic blood pressure (BP) <120 mm Hg was suggested in the population with chronic kidney disease. We aimed to determine the applicability of intensified BP and to assess the incidence of cardiovascular disease (CVD) in the population with chronic kidney disease. METHODS AND RESULTS: Participants who were >20 years old and had estimated glomerular filtration rate 15 to 60 mL/min per 1.73 m2 during 2009 to 2011 were included from the database of Korean National Health Insurance Service and were followed up to 2018. Participants were categorized by BP as <120/80 mm Hg; 120 to 129/<80 mm Hg; 130 to 139/80 to 89 mm Hg; ≥140/90 mm Hg. The primary outcome was CVD risk and the secondary outcomes were all-cause mortality and progression to end-stage renal disease followed by subgroup analysis. Among the 45 263 adults with chronic kidney disease, 5196 CVD events were noted. In Cox regression analysis, higher BP was associated with a higher risk for CVD (hazard ratio [HR], 1.15 [95% CI, 1.12-1.19]; P for trend <0.001), end-stage renal disease (HR, 1.29 [95% CI, 1.22-1.37]; P for trend <0.001), and all-cause mortality (HR, 1.09 [95% CI, 1.06-1.13]; P for trend <0.001) than BP <120/80 mm Hg. In subgroup analysis, the association between BP and CVD showed a different trend in participants taking antihypertensives compared with those not using antihypertensive drugs. When comparing BP-treated individuals to untreated individuals, a significant interaction in the association between BP categories and end-stage renal disease was observed. CONCLUSIONS: The new intensive BP target proposed by 2021 Kidney Disease: Improving Global Outcomes should be applied to patients with chronic kidney disease in a personalized and advisory manner.

Fasting blood glucose and the risk of all-cause mortality in patients with diabetes mellitus undergoing hemodialysis.

Background: Glycemic control is particularly important in hemodialysis (HD) patients with diabetes mellitus (DM). Although fasting blood glucose (FBG) level is an important indicator of glycemic control, a clear target for reducing mortality in HD patients with DM is lacking. Methods: A total of 26,162 maintenance HD patients with DM were recruited from the National Health Insurance Database of Korea between 2002 and 2018. We analyzed the association of FBG levels at the baseline health examination with the risk of all-cause and cause-specific mortality. Results: Patients with FBG 80100 mg/dL showed a higher survival rate compared with that of other FBG categories (p < 0.001). The risk of all-cause mortality increased with the increase in FBG levels, and adjusted hazard ratios (HRs) were 1.10 (95% confidence interval [CI], 1.04-1.17), 1.21 (95% CI, 1.13-1.29), 1.36 (95% CI, 1.26-1.46), and 1.61 (95% CI, 1.51-1.72) for patients with FBG 100-125, 125-150, 150-180, and ≥180 mg/dL, respectively. The HR for mortality was also significantly increased in patients with FBG < 80 mg/dL (adjusted HR, 1.14; 95% CI, 1.05-1.23). The analysis of cause-specific mortality also revealed a J-shaped curve between FBG levels and the risk of cardiovascular deaths. However, the risk of infection or malignancy-related deaths was not linearly increased as FBG levels increased. Conclusion: A J-shaped association was observed between FBG levels and the risk of all-cause mortality, with the lowest risk at FBG 80100 mg/dL in HD patients with DM.

Association between circulating ECM-associated molecules and cardiovascular outcomes in hemodialysis patients: a multicenter prospective cohort study.

Hemodialysis patients are susceptible to cardiovascular remodeling, which increases the risk of cardiovascular morbidity and mortality. Circulating extracellular matrix (ECM)-associated molecules increase during cardiovascular remodeling and can be potential biomarkers of adverse cardiovascular outcomes. However, their clinical significance in patients undergoing hemodialysis remain unclear. This study aimed to elucidate the association between circulating ECM-associated molecules and cardiovascular outcomes in patients undergoing hemodialysis. To this end, we measured levels of plasma matrix metalloproteinase (MMP)-2, MMP-9, tenascin-C, and thrombospondin-2 in 372 patients with hemodialysis. Plasma MMP-2 levels were significantly higher in patients with future cardiovascular events than in those without future cardiovascular events (P = 0.004). All measured molecules had significant correlations with amino-terminal pro-brain natriuretic peptide levels, but the correlation coefficient was the strongest for plasma MMP-2 (rho = 0.317, P < 0.001). High plasma MMP-2 levels were predictive of left ventricular (LV) diastolic dysfunction (adjusted odds ratio per a standard deviation increase = 1.48, 95% confidence interval [CI] = 1.05-2.08) and were independently associated with an increased risk of composite cardiovascular events (adjusted hazard ratio per a standard deviation increase = 1.30, 95% CI = 1.04-1.63). In conclusion, high plasma MMP-2 levels are associated with LV diastolic dysfunction and an increased risk of adverse cardiovascular outcomes in hemodialysis patients.

Circulatory endostatin level and risk of cardiovascular events in patients with end-stage renal disease on hemodialysis.

BACKGROUND: Endostatin is released during extracellular matrix remodeling and is involved in the development of vascular pathology and cardiovascular (CV) disease. However, the role of circulating endostatin as a biomarker of vascular calcification and CV events in patients undergoing hemodialysis (HD) remains unclear. METHODS: A total of 372 patients undergoing HD were prospectively recruited. Plasma endostatin levels were measured at baseline, and their associations with circulating mineral bone disease (MBD) biomarkers and abdominal aortic vascular calcification scores were analyzed. The primary endpoint was defined as a composite of CV and cardiac events. RESULTS: Plasma levels of patients in endostatin tertile 3 were significantly associated with low-density lipoprotein cholesterol levels and predialysis systolic blood pressure in multivariate analysis. However, endostatin levels did not correlate with circulating MBD biomarkers or vascular calcification scores. Patients in endostatin tertile 3 had a significantly higher cumulative event rate for the composite of CV events (p = 0.006). Endostatin tertile 3 was also associated with an increased cumulative rate of cardiac events (p = 0.04). In multivariate Cox regression analyses, endostatin tertile 3 was associated with a 4.37-fold risk for composite CV events and a 3.88-fold risk for cardiac events after adjusting for multiple variables. CONCLUSION: Higher circulating endostatin levels were independently associated with atherosclerotic risk factors but did not correlate with MBD markers or vascular calcification. Higher circulating endostatin levels were associated with a greater risk of composite CV events in patients undergoing HD, and endostatin is a biomarker that helps to determine the high risk of CV events.