Findings from the KNOW-CKD Study indicate that higher systolic blood pressure time in target range is associated with a lower risk of chronic kidney disease progression.

Time-in-target range (TTR) of systolic blood pressure (SBP) is determined by the proportion of time during which SBP remains within a defined optimal range. TTR has emerged as a useful metric for assessing SBP control over time. However, it is uncertain if SBP-TTR can predict the progression of chronic kidney disease (CKD). Here, we investigated the association between SBP-TTR during the first year of enrollment and CKD progression among 1758 participants from the KNOW-CKD (KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease). Baseline median estimated glomerular filtration rate (eGFR) was 51.7 ml/min per 1.73 m2. Participants were categorized into four SBP-TTR groups (0%, 1-50%, 51-99%, and 100%). The primary outcome was CKD progression defined as 50% or more decline in eGFR from baseline measurement or the initiation of kidney replacement therapy. During the follow-up period (9212 person-years over a median 5.4 years), the composite outcome occurred in 710 participants. In the multivariate cause-specific hazard model, a one-standard deviation increase in SBP-TTR was associated with an 11% lower risk of the composite outcome with hazard ratio, 0.89 (95% confidence interval, 0.82-0.97). Additionally, compared to patients with SBP-TTR 0%, the respective hazard ratios for those with SBP-TTR 1-50%, 51-99%, and 100% were 0.85 (0.68-1.07), 0.76 (0.60-0.96), and 0.72 (0.55-0.94), and the respective corresponding slopes of eGFR decline were -3.17 (-3.66 to -2.69), -3.02 (-3.35 to -2.68), -2.62 (-2.89 to - 2.36), and -2.33 (-2.62 to -2.04) ml/min/1.73 m2. Thus, higher SBP-TTR was associated with a decreased risk of CKD progression in patients with CKD.

Association between colchicine use and adverse cardiovascular events in patients with gout: a nationwide nested case-control study.

OBJECTIVE: The association between colchicine use and the primary prevention of atherosclerotic cardiovascular disease (ASCVD) remains unknown. This study aimed to explore the association between colchicine use and new development of ASCVD and ASCVD-related mortality in patients with incident gout. METHODS: This nested case-control study utilized the nation-wide claims database of the Korean National Health Insurance System. Patients without a history of ASCVD who developed incident gout and were newly started on allopurinol as first-line therapy between 2011 and 2016 were initially screened. Individuals who experienced ASCVD event or ASCVD-related mortality during the follow-up period were matched with four controls for age, sex, income, residential area, co-morbidities, and medications. The main exposure was colchicine use, assessed by 1) the cumulative defined daily doses (cDDDs) and 2) the cumulative duration. For secondary analyses, the risk of ASCVD events and ASCVD-related mortality were examined, separately. RESULTS: Overall, 9,346 patients with ASCVD event or ASCVD-related mortality were matched with 35 070 controls. The patient population was predominantly male. Compared with non-users, a curvilinear relationship between higher cDDDs of colchicine and the odds of ASCVD event was observed; the odds ratios (95% confidence interval) were were 1.09 (1.04-1.15) for <90 cDDDs, 1.20 (1.07-1.33) for 80-179 cDDDs, and 1.21 (1.09-1.35) for ≥180 cDDDs. This association was similarly observed for ASCVD events and ASCVD-related mortality, respectively. CONCLUSION: Colchicine use was associated with an increased risk of ASCVD in patients with newly diagnosed gout who did not have a prior history of ASCVD.

Non-alcoholic Fatty Liver Disease (NAFLD) and its association with kidney and cardiovascular outcomes in moderate to advanced chronic kidney disease.

Introduction Non-alcoholic fatty liver disease (NAFLD) has emerged as a potential indicator for cardio-metabolic risk. However, clinical implications of NAFLD in patients with chronic kidney disease (CKD) are still elusive. We investigated to explore the association between NAFLD and adverse clinical outcomes among patients with CKD. Methods In this national population-based retrospective cohort study, we analyzed 816,857 individuals who underwent National Health Insurance Service health examinations and had an eGFR of 15-59 mL/min/1.73 m2. The main predictor was the fatty liver index (FLI), a surrogate marker for NAFLD. The primary outcome was a composite cardiovascular or kidney events, which were examined combined or separately. Results During a median follow-up of 7.7 (IQR, 6.4-9.6) years, the composite outcome events occurred in 74,266 (9.1%) individuals. Among these, there were 55,525 (6.8%) cardiovascular events and 22,961 (2.8%) kidney events, respectively. Compared to FLI of <30, the HRs (95% CIs) for the composite outcome were 1.16 (1.14-1.18) and 1.30 (1.26-1.33) for the FLIs of 30-59 and ≥60, respectively. The corresponding HRs for cardiovascular events were 1.21 (95% CI, 1.18-1.23) and 1.36 (95% CI, 1.31-1.40), respectively. Furthermore, FLIs of 30-59 and ≥60 were associated with an 11% (HR, 1.11; 95% CI, 1.07-1.15) and 24% (HR, 1.24; 95% CI, 1.17-1.30) increased risk of kidney events, respectively. Conclusions NAFLD was associated with higher risk of adverse clinical outcomes in individuals with CKD. These findings suggest that NAFLD, as assessed by the FLI, can serve as a predictor of cardiovascular and kidney events in CKD population.

The 2021 KDIGO blood pressure target and the progression of chronic kidney disease: Findings from KNOW-CKD.

BACKGROUND: The 2021 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for the management of blood pressure (BP) in chronic kidney disease (CKD) recommends a target systolic BP of <120 mmHg as this target can provide cardiovascular benefits. However, it remains unclear whether implementing the new BP target could improve kidney outcomes. METHODS: The association between the 2021 KDIGO BP target and CKD progression was examined and compared with the 2012 KDIGO BP target among 1724 participants included in the KoreaN Cohort Study for Outcomes in Patients With CKD. The main exposure was the BP status categorized according to the 2012 or 2021 KDIGO guideline: (1) controlled within the 2021 target, (2) controlled within the 2012 target only, and (3) above both targets. The primary outcome was a composite kidney outcome of ≥50% decline in the estimated glomerular filtration rate from baseline or the initiation of kidney replacement therapy during the follow-up period. RESULTS: Composite kidney outcomes occurred in 650 (37.7%) participants during the 8078 person-years of follow-up (median, 4.9 years). The incidence rates of this outcome were 55, 66.5, and 116.4 per 1000 person-years in BP controlled within the 2021 and 2012 KDIGO targets, and BP above both targets, respectively. In the multivariable cause-specific hazard model, hazard ratios for the composite outcome were 0.76 (95% confidence interval (CI), 0.60-0.95) for BP controlled within the 2021 target and 1.36 (95% CI, 1.13-1.64) for BP above both targets, compared with BP controlled within 2012 target only. CONCLUSION: The newly lowered BP target by the 2021 KDIGO guideline was associated with improved kidney outcome compared with BP target by the 2012 KDIGO guideline.

Urinary chloride concentration and progression of chronic kidney disease: results from the KoreaN cohort study for Outcomes in patients With Chronic Kidney Disease.

BACKGROUND: Urinary chloride is regulated by kidney transport channels, and high urinary chloride concentration in the distal tubules can trigger tubuloglomerular feedback. However, little attention has been paid to urinary chloride as a biomarker of clinical outcomes. Here, we studied the relationship between urinary chloride concentration and chronic kidney disease (CKD) progression. METHODS: We included 2086 participants with CKD from the KoreaN cohort study for Outcomes in patients With Chronic Kidney Disease. Patients were categorized into three groups, according to baseline urinary chloride concentration tertiles. The study endpoint was a composite of ≥50% decrease in estimated glomerular filtration rate from baseline values, or end-stage kidney disease. RESULTS: During a median follow-up period of 3.4 years (7452 person-years), 565 participants reached the primary endpoint. There was a higher rate of CKD progression events in the lowest and middle tertiles than in the highest tertile. Compared with the lowest tertile, the highest tertile was associated with 33% [95% confidence interval (CI) 0.49-0.90] lower risk for the primary outcome in a cause-specific hazard model after adjustment for confounding variables. In addition, for every 25 mEq/L increase in urinary chloride concentration, there was 11% (95% CI 0.83-0.96) lower risk for CKD progression. This association was consistent in a time-varying model. Urinary chloride concentration correlated well with tubule function and kidney injury markers, and its predictive performance for CKD progression was comparable to that of these markers. CONCLUSIONS: In this hypothesis-generating study, low urinary chloride concentration was associated with a higher risk for CKD progression.

Associations of Systolic Blood Pressure With Incident CKD G3-G5: A Cohort Study of South Korean Adults.

RATIONALE & OBJECTIVE: Clinical practice guidelines recommend a target blood pressure (BP)<130/80 mm Hg to reduce cardiovascular risk. However, the optimal BP to prevent chronic kidney disease (CKD) is unknown. STUDY DESIGN: Population-based retrospective cohort study. SETTING & PARTICIPANTS: 10.5 million adults who participated in the National Health Insurance Service National Health Checkup Program in South Korea between 2009 and 2015 and had an estimated glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m2 at the beginning of follow-up. PREDICTORS: Baseline and time-updated systolic BP (SBP) as a continuous variable and categorized as<110, 110 to 119, 120 to 129, 130 to 139, or≥140 mm Hg. OUTCOME: Incident CKD GFR categories 3 to 5 (CKD G3-G5), defined as de novo development of estimated GFR<60 mL/min/1.73 m2 for at least 2 consecutive assessments confirmed at least 90 days apart. ANALYTICAL APPROACH: Cox proportional hazards regression for baseline BP and marginal structural analysis for time-updated BP. RESULTS: During 49,169,311 person-years of follow-up, incident CKD G3-G5 developed in 172,423 (1.64%) individuals with a crude event rate of 3.51 (95% CI, 3.49-3.52) per 1,000 person-years. Compared to a baseline SBP of 120 to 129 mm Hg, HRs for incident CKD G3-G5 for the<110, 110 to 119, 130 to 139, and≥140 mm Hg categories were 0.84 (95% CI, 0.82-0.85), 0.92 (95% CI, 0.91-0.94), 1.11 (95% CI, 1.09-1.12), and 1.30 (95% CI, 1.28-1.31), respectively. For time-updated SBPs, corresponding HRs were 0.57 (95% CI, 0.56-0.59), 0.79 (95% CI, 0.78-0.80), 1.58 (95% CI, 1.55-1.60), and 2.49 (95% CI, 2.45-2.53), respectively. Treated as a continuous exposure, each 10-mm Hg higher SBP was associated with 35% higher risk for incident CKD G3-G5 (95% CI, 1.35-1.36). LIMITATIONS: Use of International Classification of Diseases codes to assess comorbid condition burden; residual confounding, and potential selection bias cannot be excluded. CONCLUSIONS: In this large national cohort study, higher SBPs were associated with higher risk for incident CKD G3-G5. These findings support evaluation of SBP-lowering strategies to reduce the development of CKD.

Lower serum beta-2 microglobulin levels are associated with worse survival in incident peritoneal dialysis patients.

Background: There is a general consensus that elevated serum beta-2 microglobulin (B2M) levels measured at a single time-point are significantly associated with mortality in patients on maintenance dialysis. To date, the majority of prior studies that have examined B2M-associated mortality have been conducted in prevalent hemodialysis patients with little residual renal function (RRF). However, studies in incident peritoneal dialysis (PD) patients are lacking. Moreover, changes in serum B2M levels over time have not been considered in this population. Methods: We examined the association of time-updated and baseline serum B2M levels with mortality in a 10-year cohort of 725 incident PD patients who were maintained on dialysis between January 2006 and December 2011 using Cox proportional hazards regression analyses. Patients were categorized into tertiles according to B2M levels. Results: During a median follow-up of 38 (interquartile range 23-64) months, 258 (35.4%) deaths occurred, including 106 (14.6%) and 86 (11.9%) deaths from cardiovascular and infectious causes, respectively. The lowest B2M tertile was associated with a higher risk of all-cause and infectious mortality compared with the middle tertile: the hazard ratios (95% confidence interval) for all-cause deaths were 2.12 (1.38-3.26) and 2.20 (0.96-5.05) in time-varying analyses and 1.52 (1.07-2.17) and 2.41 (1.19-4.88) in baseline analyses. Subgroup analyses showed that this association was particularly observed in females, older patients, those with comorbidities such as diabetes, a lower body mass index, lower albumin levels or those with higher RRF (all P for interactions <0.05). Conclusions: In incident PD patients, lower B2M levels were independently associated with overall and infectious mortality. These associations can be potentially modified by malnutrition, inflammation and RRF.

Investigation of the Biological Activities and Characterization of Bioactive Constituents of Ophiorrhiza rugosa var. prostrata (D.Don) & Mondal Leaves through In Vivo, In Vitro, and In Silico Approaches.

Ophiorrhiza rugosa var. prostrata is one of the most frequently used ethnomedicinal plants by the indigenous communities of Bangladesh. This study was designed to investigate the antidiarrheal, anti-inflammatory, anthelmintic and antibacterial activities of the ethanol extract of O. rugosa leaves (EEOR). The leaves were extracted with ethanol and subjected to in vivo antidiarrheal screening using the castor oil-induced diarrhea, enteropooling, and gastrointestinal transit models. Anti-inflammatory efficacy was evaluated using the histamine-induced paw edema test. In parallel, in vitro anthelmintic and antibacterial activities were evaluated using the aquatic worm and disc diffusion assays respectively. In all three diarrheal models, EEOR (100, 200 and 400 mg/kg) showed obvious inhibition of diarrheal stool frequency, reduction of the volume and weight of the intestinal contents, and significant inhibition of intestinal motility. Also, EEOR manifested dose-dependent anti-inflammatory activity. Anthelmintic action was deemed significant (P < 0.001) with respect to the onset of paralysis and helminth death. EEOR also resulted in strong zones of inhibition when tested against both Gram-positive and Gram-negative bacteria. GC-MS analysis identified 30 compounds within EEOR, and of these, 13 compounds documented as bioactive showed good binding affinities to M3 muscarinic acetylcholine, 5-HT3, tubulin and GlcN-6-P synthase protein targets in molecular docking experiments. Additionally, ADME/T and PASS analyses revealed their drug-likeness, likely safety upon consumption and possible pharmacological activities. In conclusion, our findings scientifically support the ethnomedicinal use and value of this plant, which may provide a potential source for future development of medicines.

Association between volume status assessed by bioelectrical impedance analysis, lung ultrasound, or weight change and mortality in patients with sepsisassociated acute kidney injury receiving continuous kidney replacement therapy.

BACKGROUND: Fluid overload is an independent risk factor of mortality in patients with acute kidney injury (AKI) receiving continuous kidney replacement therapy (CKRT). However, the association between fluid status, as assessed by bioelectrical impedance analysis (BIA) or lung ultrasound, and survival in patients with AKI requiring CKRT has not been established. METHODS: We analyzed 36 participants with sepsis-associated AKI who received CKRT at a tertiary hospital. The main exposures were volume surrogates: 1) overhydration normalized by extracellular water (OH/ECW, L/L) assessed by BIA, 2) the number of B-lines measured by lung ultrasound, and 3) weight change ([body weight at CKRT initiation - body weight at admission] × 100/body weight at admission). The primary outcome was the 28-day mortality. RESULTS: Seventeen participants (47.2%) died within 28 days. There were no significant correlations between OH/ECW and weight change (R2 = 0.040, p = 0.24), number of B-lines and OH/ECW (R2 = 0.056, p = 0.16), or weight change and number of B-lines (R2 = 0.014, p = 0.49). Kaplan-Meier analyses revealed that patients in the highest tertile of OH/ECW showed a significantly lower cumulative 28-day survival probability than the others (the lowest + middle tertiles). The survival probability of participants in the highest tertile of the number of B-lines or weight change did not differ from that of their counterparts. In a multivariate Cox proportional hazard model, the hazard ratio for the highest tertile of OH/ECW was 3.83 (95% confidence interval, 1.04-14.03). CONCLUSION: Volume overload assessed using BIA (OH/ECW) was associated with the 28-day survival rate in patients with sepsis-associated AKI who received CKRT.

Nocturnal systolic blood pressure dipping and progression of chronic kidney disease.

The relationship between declining nocturnal blood pressure (BP) and adverse cardiovascular outcomes is well-recognized. However, the relationship between diurnal BP profile and the risk of chronic kidney disease (CKD) progression is unclear. Herein, we examined the association between nocturnal systolic SBP (SBP) dipping and CKD progression in 1061 participants at the Cardiovascular and Metabolic Disease Etiology Research Center-High Risk (CMERC-HI). The main exposure was diurnal systolic BP (SBP) profile and diurnal SBP difference ([nighttime SBP-daytime SBP] × 100/daytime SBP). The primary outcome was CKD progression, defined as a composite of ≥ a 50% decline in the estimated glomerular filtration rate from baseline or the initiation of kidney replacement therapy. During 4749 person-years of follow-up (median, 4.8 years), the composite outcome occurred in 380 (35.8%) participants. Compared to dippers, the hazard ratios (HRs) for the risk of adverse kidney outcomes were 1.02 (95% confidence interval [CI], 0.64-1.62), 1.30 (95% CI, 1.02-1.66), and 1.40 (95% CI, 1.03-1.90) for extreme dipper, non-dipper, and reverse dipper, respectively. In a continuous modeling, a 10% increase in diurnal SBP difference was associated with a 1.21-fold (95% CI, 1.07-1.37) higher risk of CKD progression. Thus, decreased nocturnal SBP decline was associated with adverse kidney outcomes in patients with CKD. Particularly, patients with non-dipping and reverse dipping patterns were at higher risk for CKD progression than those with a dipping pattern.

Volume control strategy and patient survival in sepsis-associated acute kidney injury receiving continuous renal replacement therapy: a randomized controlled trial with secondary analysis.

Optimal strategy for volume control and the clinical implication of achieved volume control are unknown in patients with sepsis-associated acute kidney injury (AKI) receiving continuous renal replacement therapy (CRRT). This randomized controlled trial aimed to compare the survival according to conventional or bioelectrical impedance analysis (BIA)-guided volume control strategy in patients with sepsis-associated AKI receiving CRRT. We also compared patient survival according to achieved volume accumulation rate ([cumulative fluid balance during 3 days × 100]/fluid overload measured by BIA at enrollment) as a post-hoc analysis. We randomly assigned patients to conventional volume control strategy (n = 39) or to BIA-guided volume control strategy (n = 34). There were no differences in 28-day mortality (HR, 1.19; 95% CI, 0.63-2.23) or 90-day mortality (HR, 0.99; 95% CI 0.57-1.75) between conventional and BIA-guided volume control group. In the secondary analysis, achieved volume accumulation rate was significantly associated with patient survival. Compared with the achieved volume accumulation rate of ≤ - 50%, the HRs (95% CIs) for the risk of 90-day mortality were 1.21 (0.29-5.01), 0.55 (0.12-2.48), and 7.18 (1.58-32.51) in that of - 50-0%, 1-50%, and > 50%, respectively. Hence, BIA-guided volume control in patients with sepsis-associated AKI receiving CRRT did not improve patient outcomes. In the secondary analysis, achieved volume accumulation rate was associated with patient survival.

Association between progression of coronary artery calcification and development of kidney failure with replacement therapy: Findings from KNOW-CKD study.

BACKGROUND AND AIMS: High coronary artery calcification (CAC) burden is a significant risk factor for adverse cardiovascular and kidney outcomes. However, it is unknown whether changes in the coronary atherosclerotic burden can accompany changes in kidney disease progression. Here, we evaluated the relationship between CAC progression and the risk of kidney failure with replacement therapy (KFRT). METHODS: We analyzed 1173 participants with chronic kidney disease (CKD) G1 to G5 without kidney replacement therapy from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD). Participants were categorized into three groups according to the change in the CAC score between enrollment and year 4 (non-progressors, ≤0 AU; moderate progressors, 1-199 AU; and severe progressors, ≥200 AU). The primary outcome was the development of KFRT. RESULTS: During a follow-up period of 4690 person-years (median, 4.2 years), the primary outcome occurred in 230 (19.6 %) participants. The incidence of KFRT was 37.6, 54.3, and 80.9 per 1000 person-years in the non-, moderate, and severe progressors, respectively. In the multivariable cause-specific hazard model, the hazard ratios (HRs) for the moderate and severe progressors were 1.71 (95 % confidence interval [CI], 1.02-2.87) and 2.55 (95 % CI, 1.07-6.06), respectively, compared with non-progressors. A different definition of CAC progression with a threshold of 100 AU yielded similar results in a sensitivity analysis. CONCLUSIONS: CAC progression is associated with an increased risk of KFRT in patients with CKD. Our findings suggest that coronary atherosclerosis changes increase the risk of CKD progression.

Blood pressure control in diabetic kidney disease: a post-hoc analysis of the FANTASTIC trial.

BACKGROUND: The target blood pressure (BP) value is unclear for diabetic kidney disease (DKD). Therefore, we aimed to evaluate the effect of strict BP control or 'on treatment' BP on clinical outcomes in patients with DKD. METHODS: A post-hoc analysis of the prespecified secondary outcomes of the FimAsartaN proTeinuriA SusTaIned reduCtion in comparison with losartan in diabetic chronic kidney disease (FANTASTIC) trial, a randomized multicenter double-blind phase III trial. Eligible patients were aged ≥ 19 years with DKD. We assigned 341 participants with DKD to BP control strategy (standard-systolic BP [SBP] < 140 mmHg versus strict-SBP < 130 mmHg). The outcome was the occurrence of cardiovascular events and renal events. Separate analyses were performed to compared the risk of outcome according to achieved average BP levels. RESULTS: A total of 341 participants were included in the analysis. Over a median follow-up of 2.8 years, cardiovascular/renal events were observed in 25 (7.3%) participants. Mean (SD) SBPs in the standard and strict BP control group were 140.2 (11.6) and 140.2 (11.9) mmHg, respectively. The strict BP control group did not show significantly reduced risk of cardiovascular/renal events (HR 1.32; 95% CI 0.60-2.92]). In the post-hoc analyses using achieved BP, achieved average SBP of 130-139 mmHg resulted in reduced risk of cardiovascular/renal events (HR 0.15; 95% CI 0.03-0.67) compared to achieved average SBP ≥ 140 mmHg, whereas further reduction in achieved average SBP < 130 mmHg did not impart additional benefits. CONCLUSION: In patients with DKD, targeting a SBP of less than 130 mmHg, as compared with less than 140 mmHg, did not reduce the rate of a composite of cardiovascular and renal events. Achieved SBP of 130-139 mmHg was associated with a decreased risk for the primary outcome in patients with DKD. TRIAL REGISTRATION: ClinicalTirals.gov Identifier: NCT02620306, registered December 3, 2015. ( https://clinicaltrials.gov/study/NCT02620306 ).

Bidirectional association between SBP variability and arterial stiffness in patients with chronic kidney disease: findings from KNOW-CKD study.

OBJECTIVE: Studies on the mutual relationship between blood pressure (BP) variability and arterial stiffness using time-dependent changes in arterial stiffness are scarce. METHODS: In this prospective cohort of Korean patients with chronic kidney disease (CKD) G1-G5 without kidney replacement therapy, we studied the bidirectional association between visit-to-visit SBP variability (VVSV) and arterial stiffness in 1036 participants who underwent brachial-ankle pulse wave velocity (baPWV) measurement at baseline and year four. We constructed multivariable logistic regression models using two analytical sets. First, we determined the VVSV [standard deviation (SD)] of all SBP readings over 4 years, and then calculated the odds ratios (ORs) for arterial stiffness progression according to tertiles of VVSV. Arterial stiffness progression was defined as at least 75th percentile of the difference in baPWV between baseline and year four. Second, we analysed the ORs for at least 75th percentile of the 4-year VVSV according to tertiles of baseline baPWV. RESULTS: Compared with the lowest tertile of VVSV (SD), the ORs [95% confidence interval (95% CI)] for arterial stiffness progression were 1.42 (0.96-2.10) and 1.64 (1.11-2.43) for the middle and highest tertiles, respectively. In the second analysis based on tertiles of baseline baPWV, the ORs for at least 75th percentile of VVSV (SD) were 1.41 (95% CI, 0.95-2.10) and 1.64 (95% CI, 1.04-2.61) for the middle and highest tertiles, respectively. This association was similar in both analytical models when VVSV and baPWV were treated as continuous variables. CONCLUSION: There is a bidirectional relationship between BP variability and arterial stiffness in patients with CKD.

Intrarenal Renin-Angiotensin System Activation Alters Relationship Between Systolic Blood Pressure and Progression of Chronic Kidney Disease.

BACKGROUND: Elevated blood pressure and intrarenal renin-angiotensin system activity are closely related to chronic kidney disease (CKD) progression. However, interrelationship between blood pressure and intrarenal renin-angiotensin system activity on the risk of CKD progression is unknown. METHODS: We analyzed 2076 participants from the Korean Cohort Study for Outcomes in Patients With CKD. The main exposure was systolic blood pressure (SBP). The urinary angiotensinogen-to-creatinine ratio was stratified according to the median value (3.65 µg/gCr). The primary outcome was a composite kidney outcome of a ≥50% decline in estimated glomerular filtration rate from baseline measurement or initiation of kidney replacement therapy. RESULTS: During 10 550 person-years of follow-up (median, 5.2 years), the composite outcome occurred in 800 (38.5%) participants. In the multivariable cause-specific hazard model, higher SBP was associated with an increased risk of CKD progression. There was a significant interaction between SBP and urinary angiotensinogen-to-creatinine ratio on the risk of the primary outcome (P value for interaction=0.019). In patients with urinary angiotensinogen-to-creatinine <3.65 µg/gCr, the hazard ratios (95% CIs) for SBP 120 to 129, 130 to 139, and ≥140 mmHg were 1.46 (1.07-1.99), 1.71 (1.25-2.35), and 2.40 (1.73-3.32), respectively, compared with SBP <120 mmHg. However, these associations were not observed in patients with urinary angiotensinogen-to-creatinine ≥3.65 µg/gCr. CONCLUSIONS: In this prospective CKD cohort, higher SBP was associated with CKD progression when urinary angiotensinogen levels were low, while this association was not seen when urinary angiotensinogen levels were high. This finding suggests that intrarenal renin-angiotensin system activity may modify the relationship between SBP and adverse kidney outcome.

TGF-ß Inhibitors for Therapeutic Management of Kidney Fibrosis.

Kidney fibrosis is a common pathophysiological mechanism of chronic kidney disease (CKD) progression caused by several underlying kidney diseases. Among various contributors to kidney fibrosis, transforming growth factor-ß1 (TGF-ß1) is the major factor driving fibrosis. TGF-ß1 exerts its profibrotic attributes via the activation of canonical and non-canonical signaling pathways, which induce proliferation and activation of myofibroblasts and subsequent accumulation of extracellular matrix. Over the past few decades, studies have determined the TGF-ß1 signaling pathway inhibitors and evaluated whether they could ameliorate the progression of CKD by hindering kidney fibrosis. However, therapeutic strategies that block TGF-ß1 signaling have usually demonstrated unsatisfactory results. Herein, we discuss the therapeutic concepts of the TGF-ß1 signaling pathway and its inhibitors and review the current state of the art regarding regarding TGF-ß1 inhibitors in CKD management.

Canagliflozin protects against cisplatin-induced acute kidney injury by AMPK-mediated autophagy in renal proximal tubular cells.

Sodium-glucose cotransporter 2 inhibitors, which are recently introduced as glucose-lowering agents, improve cardiovascular and renal outcomes in patients with diabetes mellitus. These drugs also have beneficial effects in various kidney disease models. However, the effect of SGLT2 inhibitors on cisplatin-induced acute kidney injury (AKI) and their mechanism of action need to be elucidated. In this study, we investigated whether canagliflozin protects against cisplatin-induced AKI, depending on adenosine monophosphate-activated protein kinase (AMPK) activation and following induction of autophagy. In the experiments using the HK-2 cell line, cell viability assay and molecular analysis revealed that canagliflozin protected renal proximal tubular cells from cisplatin, whereas addition of chloroquine or compound C abolished the protective effect of canagliflozin. In the mouse model of cisplatin-induced AKI, canagliflozin protected mice from cisplatin-induced AKI. However, treatment with chloroquine or compound C in addition to administration of cisplatin and canagliflozin eliminated the protective effect of canagliflozin. Collectively, these findings indicate that canagliflozin protects against cisplatin-induced AKI by activating AMPK and autophagy in renal proximal tubular cells.

Association Between Systolic Blood Pressure Variability and Major Adverse Cardiovascular Events in Korean Patients With Chronic Kidney Disease: Findings From KNOW-CKD.

Background Whether visit-to-visit systolic blood pressure (SBP) variability can predict major adverse cardiovascular events (MACE) in patients with chronic kidney disease is unclear. Methods and Results We investigated the relationship between SDs of visit-to-visit SBP variability during the first year of enrollment and MACE among 1575 participants from KNOW-CKD (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease). Participants were categorized into 3 groups according to tertiles of visit-to-visit SBP variability (SD). The study end point was MACE, defined as a composite of nonfatal myocardial infarction, unstable angina, revascularization, nonfatal stroke, hospitalization for heart failure, or cardiac death. During 6748 patient-years of follow-up (median, 4.2 years), MACE occurred in 64 participants (4.1%). Compared with the lowest tertile of visit-to-visit SBP variability (SD), the hazard ratios (HRs) for the middle and the highest tertile were 1.64 (95% CI, 0.80-3.36) and 2.23 (95% CI, 1.12-4.44), respectively, in a multivariable cause-specific hazard model. In addition, the HR associated with each 5-mm Hg increase in visit-to-visit SBP variability (SD) was 1.21 (95% CI, 1.01-1.45). This association was consistent in sensitivity analyses with 2 additional definitions of SBP variability determined by the coefficient of variation and variation independent of the mean. The corresponding HRs for the middle and highest tertiles were 2.11 (95% CI, 1.03-4.35) and 2.28 (95% CI, 1.12-4.63), respectively, in the analysis with the coefficient of variation and 1.76 (95% CI, 0.87-3.57) and 2.04 (95% CI, 1.03-4.03), respectively, with the variation independent of the mean. Conclusions Higher visit-to-visit SBP variability is associated with an increased risk of MACE in patients with chronic kidney disease. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01630486.

Inflammasome-Dependent Peroxiredoxin 2 Secretion Induces the Classical Complement Pathway Activation.

Peroxiredoxins (Prxs) are ubiquitously expressed peroxidases that reduce hydrogen peroxide or alkyl peroxide production in cells. Prxs are released from cells in response to various stress conditions, and they function as damage-associated molecular pattern molecules. However, the secretory mechanism of Prxs and their roles have not been elucidated. Thus, we aimed to determine whether inflammasome activation is a secretory mechanism of Prxs and subsequently identify the effect of the secreted Prxs on activation of the classical complement pathway. Using J774A.1, a murine macrophage cell line, we demonstrated that NLRP3 inflammasome activation induces Prx1, Prx2, Prx5, and Prx6 secretion in a caspase-1 dependent manner. Using HEK293T cells with a transfection system, we revealed that the release of Prx1 and Prx2 relies on gasdermin-D (GSDMD)-mediated secretion. Next, we confirmed the binding of both Prx1 and Prx2 to C1q; however, only Prx2 could induce the C1q-mediated classical complement pathway activation. Collectively, our results suggest that inflammasome activation is a secretory mechanism of Prxs and that GSDMD is a mediator of their secretion. Moreover, secreted Prx1 and Prx2 bind with C1q, but only Prx2 mediates the classical complement pathway activation.

Phytoglycoprotein (75 kDa) suppresses release of histamine and expression of IL-4 and IFN- gamma in BPA-treated RBL-2H3 cells.

The current study investigated whether the phytoglycoprotein (75 kDa) isolated from Cudrania tricuspidata Bureau (CTB glycoprotein) has anti-allergic inflammatory potential. Bisphenol A (BPA) is well known to promote development of allergy-related immune dysfunction. This experiment evaluated the release of histamine, increased intracellular Ca(2+) level, and the activities of protein kinase C alpha (PKC alpha), transcription factors NFkappaB and cytokines (IL-4, and IFN-gamma) in BPA-treated RBL-2H3 cells. The results in this study showed that the phytoglycoprotein (75 kDa) inhibits the intracellular Ca(2+) level, translocation of PKC alpha from cytosol to membrane and the translocation of NF-kappaB in cells. We also found that the phytoglycoprotein (75 kDa) inhibits the release of histamine, and the expressions of cytokines (IL-4 and IFN-gamma) in the presence of BPA in RBL-2H3 cells. The results obtained from these experiments indicated that the phytoglycoprotein (75 kDa) inhibits release of histamine and expressions of IL-4, and IFN-gamma via down regulations of Ca(2+)/PKCalpha and NF-kappaB on the stage of degranulation induced by BPA. From point of view, we speculated that the phytoglycoprotein (75 kDa) is one of natural compounds that can block allergic-inflammation caused by BPA.