Relationship between urinary potassium excretion, serum potassium levels and cardiac injury in non-dialysis chronic kidney disease: KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD).

Although the cardiovascular benefits of an increased urinary potassium excretion have been suggested, little is known about the potential cardiac association of urinary potassium excretion in patients with chronic kidney disease. In addition, whether the cardiac association of urinary potassium excretion was mediated by serum potassium levels has not been studied yet. We reviewed the data of 1633 patients from a large-scale multicentre prospective Korean study (2011-2016). Spot urinary potassium to creatinine ratio was used as a surrogate for urinary potassium excretion. Cardiac injury was defined as a high-sensitivity troponin T ≥ 14 ng/l. OR and 95 % (CI for cardiac injury were calculated using logistic regression analyses. Of 1633 patients, the mean spot urinary potassium to creatinine ratio was 49·5 (sd 22·6) mmol/g Cr and the overall prevalence of cardiac injury was 33·9 %. Although serum potassium levels were not associated with cardiac injury, per 10 mmol/g Cr increase in the spot urinary potassium to creatinine ratio was associated with decreased odds of cardiac injury: OR 0·917 (95 % CI 0·841, 0·998), P = 0·047) in multivariate logistic regression analysis. In mediation analysis, approximately 6·4 % of the relationship between spot urinary potassium to creatinine ratio and cardiac injury was mediated by serum potassium levels, which was not statistically significant (P = 0·368). Higher urinary potassium excretion was associated with lower odds of cardiac injury, which was not mediated by serum potassium levels.

Plasma Circulating Tumor Necrosis Factor Receptors at Multiple Time Points Can Predict the Outcome of Severe Acute Kidney Injury.

INTRODUCTION: This prospective cohort study investigated the clinical role of circulating tumor necrosis factor receptor (cTNFR) levels as prognostic biomarkers in severe acute kidney injury (AKI) patients requiring continuous renal replacement therapy (CRRT). METHODS: We enrolled 136 patients from 7 hospitals participating in the VENUS (VolumE maNagement Under body composition monitoring in critically ill patientS on CRRT) trial from July 2017 to October 2019. The levels of cTNFR1 and cTNFR2 were measured using plasma samples collected on days 0 (D0), 2 (D2), and 7 (D7). Patients were divided into high- and low-cTNFR groups based on their receptor concentrations. RESULTS: D0 concentrations of cTNFR1 and cTNFR2 were positively correlated with one another (R2 = 0.37, p < 0.001). The high-cTNFR1 group displayed a higher in-hospital mortality rate than the low-TNFR1 group (p = 0.002). Moreover, the mortality rate was significantly higher in the high-TNFR1 group than in the low-TNFR1 group after adjusting for age, sex, and acute physiology, and chronic health evaluation II scores (hazard ratio 1.82, 95% confidence interval 1.09-3.03, p = 0.025). D2 and D7 cTNFR1 levels were also associated with in-hospital mortality; contrastingly, cTNFR2 levels were not associated with this outcome. Additionally, patients were divided into three groups according to the change in cTNFR levels from D0 to D2 (ΔcTNFR). Those in the highest ΔcTNFR tertile had a higher mortality rate than the remaining patients (p = 0.033 for ΔcTNFR1; p = 0.025 for ΔcTNFR2). Patients who underwent AKI-to-chronic kidney disease transition had higher concentrations of cTNFR1 (p = 0.014). DISCUSSION/CONCLUSION: Plasma cTNFR1 concentrations at CRRT initiation and changes in cTNFR1 and 2 levels immediately following CRRT initiation are significant biomarkers for predicting the outcomes of patients with severe AKI.

Nutritional Status is Associated With Preserved Kidney Function in Patients With Autosomal Dominant Polycystic Kidney Disease.

OBJECTIVE: Malnutrition is a common complication in autosomal dominant polycystic kidney disease (ADPKD). We examined whether nutritional status is associated with the preservation of kidney function, using a cohort of typical ADPKD. METHODS: We enrolled ambulatory ADPKD patients in 9 tertiary medical centers in Korea from May 2019 to December 2021. We excluded patients who were aged less than 18 years, who had known end-stage kidney disease at the time of enrollment, who had a diagnosis of atypical ADPKD, and who were Tolvaptan users. The primary outcome was an estimated glomerular filtration rate (eGFR) decline >3 mL/min/1.73 m2, based on nutritional status assessed by subjective global assessment (SGA). We also evaluated an eGFR decline >1 mL/min/1.73 m2, an increase in urine protein-creatinine ratio (UPCR) > 0, and an increase in UPCR >0.3 as secondary outcomes, based on SGA after the 1-year follow-up. A logistic regression (LR) model was used to calculate the odds ratio (OR) for the primary outcome. Because there were differences in several baseline variables, such as Mayo classification, serum hemoglobin, serum creatinine, and UPCR between SGA groups, we matched propensity scores. RESULTS: In total, 805 patients were prospectively enrolled. Among them, 236 patients who had 1-year follow-up data and typical imaging findings were analyzed to evaluate the effect of nutritional status on kidney function. SGA was used to assess the nutritional status. The mean age was 45.0 ± 13.3 years, and 49.6% of the patients were female. The mean eGFR was 81.9 mL/min/1.73 m2. Among the 236 patients, 91 (38.6%) experienced a 1-year eGFR decline >3 mL/min/1.73 m2. When a multivariable LR was applied, SGA 3-6 was identified as a significant factor related to a 1-year eGFR decline >3 mL/min/1.73 m2 (adjusted OR = 1.22 [1.04-1.43]; P = .017). Despite matching propensity scores, the 1-year eGFR decline >3 mL/min/1.73 m2 was still higher in the SGA 3-6 group regardless of proteinuria. CONCLUSION: Good nutritional status is associated with better-preserved kidney function in non-obese typical ADPKD patients who do not take Tolvaptan.

Factors Associated With the Development and Severity of Polycystic Liver in Patients With Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Factors related to the development and severity of polycystic liver disease (PLD) have not been well established. We aimed to evaluate the genetic and epidemiologic risk factors of PLD in patients with autosomal dominant polycystic kidney disease (ADPKD). METHODS: Adult patients with inherited cystic kidney disease were enrolled from May 2019 to May 2021. Demographic, clinical, and laboratory data were collected at the initial study visit. The severity of PLD was graded based on the height-adjusted total liver volume: < 1,000 mL/m (Gr1), 1,000-1,800 mL/m (Gr2), and > 1,800 mL/m (Gr3). Targeted exome sequencing was done by a gene panel including 89 ciliopathy-related genes. We searched out the relative factors to the presence and the severity of PLD using logistic regression analysis. RESULTS: Of 602 patients with typical ADPKD, 461 (76.6%) patients had PLD. The patients with PLD showed female predominance and a higher frequency of other ADPKD-related complications. The genetic variants with truncating mutation of PKD1 (PKD1-protein-truncating [PT]) or PKD2 commonly affected the development and severity of PLD. An older age, female sex, and higher kidney volume with Mayo classification 1C-1E was significantly associated with the development of PLD, but not with the severity of PLD. On the other hand, higher body mass index, lower hemoglobin, and higher alkaline phosphatase (ALP) were the significant risk factors of severe PLD (≥ Gr2). CONCLUSION: Hepatic involvement in ADPKD could be related to kidney manifestations and genetic variants including PKD1-PT or PKD2. Monitoring hemoglobin and ALP and evaluating the genetic variants might help predict severe PLD. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0005580.

KLC3 Regulates Ciliary Trafficking and Cyst Progression in CILK1 Deficiency-Related Polycystic Kidney Disease.

BACKGROUND: Ciliogenesis-associated kinase 1 (CILK1) is a ciliary gene that localizes in primary cilia and regulates ciliary transport. Mutations in CILK1 cause various ciliopathies. However, the pathogenesis of CILK1-deficient kidney disease is unknown. METHODS: To examine whether CILK1 deficiency causes PKD accompanied by abnormal cilia, we generated mice with deletion of Cilk1 in cells of the renal collecting duct. A yeast two-hybrid system and coimmunoprecipitation (co-IP) were used to identify a novel regulator, kinesin light chain-3 (KLC3), of ciliary trafficking and cyst progression in the Cilk1-deficient model. Immunocytochemistry and co-IP were used to examine the effect of KLC3 on ciliary trafficking of the IFT-B complex and EGFR. We evaluated the effects of these genes on ciliary trafficking and cyst progression by modulating CILK1 and KLC3 expression levels. RESULTS: CILK1 deficiency leads to PKD accompanied by abnormal ciliary trafficking. KLC3 interacts with CILK1 at cilia bases and is increased in cyst-lining cells of CILK1-deficient mice. KLC3 overexpression promotes ciliary recruitment of IFT-B and EGFR in the CILK1 deficiency condition, which contributes to the ciliary defect in cystogenesis. Reduction in KLC3 rescued the ciliary defects and inhibited cyst progression caused by CILK1 deficiency. CONCLUSIONS: Our findings suggest that CILK1 deficiency in renal collecting ducts leads to PKD and promotes ciliary trafficking via increased KLC3.

Trajectory of AKI and hospital mortality among patients with COVID-19.

BACKGROUND: Acute kidney injury (AKI) in COVID-19 patients is associated with poor prognosis. Characterization of AKI by timing and trajectory and early prediction of AKI progression is required for better preventive management and the prediction of patient outcomes. METHODS: A total of 858 patients who were hospitalized due to coronavirus disease 2019 (COVID-19) were retrospectively enrolled from December 2020 to August 2021. The occurrence of AKI was evaluated throughout hospitalization. The hazard ratios (HRs) of mortality outcomes according to the trajectory of AKI were measured using Cox regression models after adjustment for multiple variables. RESULTS: Among 858 patients, 226 (26.3%) presented AKI at admission, and 44 (5.1%) developed AKI during hospitalization. Patients with AKI at admission or hospital-acquired AKI had a higher risk of mortality than those without AKI, with HRs of 9.87 (2.81-34.67) and 13.74 (3.57-52.84), respectively. Of 226 patients with AKI at admission, 104 (46.0%) recovered within 48 hr, 83 (36.7%) had AKI beyond 48 hr and recovered in 7 days, and 39 (17.3%) showed no recovery from AKI on Day 7. Delayed recovery and persistent AKI were significantly associated with an increased risk of mortality, with HRs of 4.39 (1.06-18.24) and 24.33 (7.10-83.36), respectively. CONCLUSIONS: The onset and progression of AKI was significantly associated with in-hospital mortality in patients with COVID-19. A thorough observation of the recovery trajectory of early AKI after infection is necessary.

Genetic identification of inherited cystic kidney diseases for implementing precision medicine: a study protocol for a 3-year prospective multicenter cohort study.

BACKGROUND: Inherited cystic kidney disease is a spectrum of disorders in which clusters of renal cysts develop as the result of genetic mutation. The exact methods and pipelines for defining genetic mutations of inherited cystic kidney disease are not clear at this point. This 3-year, prospective, multicenter, cohort study was designed to set up a cohort of Korean patients with inherited cystic kidney disease, establish a customized genetic analysis pipeline for each disease subtype, and identify modifying genes associated with the severity of the disease phenotype. METHODS/DESIGN: From May 2020 to May 2022, we aim to recruit 800 patients and their family members to identify pathogenic mutations. Patients with more than 3 renal cysts in both kidneys are eligible to be enrolled. Cases of simple renal cysts and acquired cystic kidney disease that involve cyst formation as the result of renal failure will be excluded from this study. Demographic, laboratory, and imaging data as well as family pedigree will be collected at baseline. Renal function and changes in total kidney volume will be monitored during the follow-up period. Genetic identification of each case of inherited cystic kidney disease will be performed using a targeted gene panel of cystogenesis-related genes, whole exome sequencing (WES) and/or family segregation studies. Genotype-phenotype correlation analysis will be performed to elucidate the genetic effect on the severity of the disease phenotype. DISCUSSION: This is the first nationwide cohort study on patients with inherited cystic kidney disease in Korea. We will build a multicenter cohort to describe the clinical characteristics of Korean patients with inherited cystic kidney disease, elucidate the genotype of each disease, and demonstrate the genetic effects on the severity of the disease phenotype. TRIAL REGISTRATION: This cohort study was retrospectively registered at the Clinical Research Information Service ( KCT0005580 ) operated by the Korean Center for Disease Control and Prevention on November 5th, 2020.

Rapid Weight Change Over Time Is a Risk Factor for Adverse Outcomes in Patients With Predialysis Chronic Kidney Disease: A Prospective Cohort Study.

OBJECTIVE: Both obesity and being underweight are risk factors for adverse outcomes in chronic kidney disease (CKD) patients. However, the effects of longitudinal weight changes on patients with predialysis CKD have not yet been studied. In this study, we analyzed the effects of weight change over time on the adverse outcomes in predialysis CKD population. METHODS: Longitudinal data from a multicenter prospective cohort study (KNOW-CKD) were analyzed. In a total of 2,022 patients, the percent weight change per year were calculated using regression analysis and the study subjects were classified into five categories: group 1, ≤ -5%/year; group 2, -5< to ≤ -2.5%/year; group 3, -2.5< to <2.5%/year; group 4, 2.5≤ < 5%/year; and group 5, ≥5%/year. The incidences of end-stage renal disease (ESRD) and the composite outcome of cardiovascular disease (CVD) and death were calculated in each group and compared to group 3 as reference. RESULTS: During a median 4.4 years of follow-up, 414 ESRD, and 188 composite of CVD and mortality events occurred. Both weight gain and loss were independent risk factors for adverse outcomes. There was a U-shaped correlation between the degree of longitudinal weight change and ESRD (hazard ratio 3.61, 2.15, 1.86 and 3.66, for group 1, 2, 4 and 5, respectively) and composite of CVD and death (hazard ratio 2.92, 2.15, 1.73 and 2.54, respectively), when compared to the reference group 3. The U-shape correlation was most prominent in the subgroup of estimated glomerular filtration rate <45 mL/min/1.73 m2. CONCLUSION: Both rapid weight gain and weight loss are associated with high risk of adverse outcomes, particularly in the advanced CKD.

Urinary cMet as a prognostic marker in immunoglobulin A nephropathy.

The prediction of prognosis in patients with immunoglobulin A nephropathy (IgAN) is challenging. We investigated the correlation between urinary cMet (ucMet) levels and clinical parameters and examined the effects of cMet agonistic antibody (cMet Ab) in an in vitro IgAN model. Patients diagnosed with IgAN (n = 194) were divided into three groups representing undetectable (Group 1), below-median (Group 2) and above-median (Group 3) levels of ucMet/creatinine (ucMet/Cr). Stained kidney biopsy samples were graded according to cMet intensity. Primary-cultured human mesangial cells were stimulated with recombinant tumour necrosis factor (TNF)-α and treated with cMet Ab. Our results showed that ucMet/Cr levels positively correlated with proteinuria (P < .001). During the follow-up, patients in Group 3 showed a significantly lower probability of complete remission (CR; uPCr < 300 mg/g) than those in groups 1 and 2, after adjusting for blood pressure, estimated glomerular filtration rate, and proteinuria, which influence clinical prognosis (HR 0.60, P = .038); moreover, ucMet/Cr levels were also associated with glomerular cMet expression. After TNF-α treatment, the proliferation of mesangial cells and increased interleukin-8 and intercellular adhesion molecule-1 expression were markedly reduced by cMet Ab in vitro. In conclusion, ucMet/Cr levels significantly correlated with proteinuria, glomerular cMet expression, and the probability of CR. Further, cMet Ab treatment alleviated the inflammation and proliferation of mesangial cells. Hence, ucMet could serve as a clinically significant marker for treating IgAN.

cMet agonistic antibody attenuates apoptosis in ischaemia-reperfusion-induced kidney injury.

Acute kidney injury (AKI) is a very common complication with high morbidity and mortality rates and no fundamental treatment. In this study, we investigated whether the hepatocyte growth factor (HGF)/cMet pathway is associated with the development of AKI and how the administration of a cMet agonistic antibody (Ab) affects an AKI model. In the analysis using human blood samples, cMet and HGF levels were found to be significantly increased in the AKI group, regardless of underlying renal function. The administration of a cMet agonistic Ab improved the functional and histological changes after bilateral ischaemia-reperfusion injury. TUNEL-positive cells and Bax/Bcl-2 ratio were also reduced by cMet agonistic Ab treatment. In addition, cMet agonistic Ab treatment significantly increased the levels of PI3K, Akt and mTOR. Furthermore, after 24 hours of hypoxia induction in human proximal tubular epithelial cells, treatment with the cMet agonistic Ab also showed dose-dependent antiapoptotic effects similar to those of the recombinant HGF treatment. Even when the HGF axis was blocked with a HGF-blocking Ab, the cMet agonistic Ab showed an independent dose-dependent antiapoptotic effect. In conclusion, cMet expression is associated with the occurrence of AKI. cMet agonistic Ab treatment attenuates the severity of AKI through the PI3K/Akt/mTOR pathway and improves apoptosis. cMet agonistic Ab may have important significance for the treatment of AKI.

Hepcidin, iron indices and bone mineral metabolism in non-dialysis chronic kidney disease.

BACKGROUND: Few studies have examined the association between hepcidin, iron indices and bone mineral metabolism in non-dialysis chronic kidney disease (CKD) patients. METHODS: We reviewed the data of 2238 patients from a large-scale multicenter prospective Korean study (2011-16) and excluded 214 patients with missing data on markers and related medications of iron and bone mineral metabolism, hemoglobin, blood pressure and causes of CKD. Multivariate linear regression analysis was used to identify the association between iron and bone mineral metabolism. RESULTS: The proportion of CKD Stages 1-5 were 16.2, 18.7, 37.1, 21.6 and 6.4%, respectively. Per each 10% increase in transferrin saturation (TSAT), there was a 0.013 mmol/L decrease in phosphorus [95% confidence interval (CI) -0.021 to -0.004; P = 0.003] and a 0.022 nmol/L increase in logarithmic 25-hydroxyvitamin D (Ln-25OHD) levels (95% CI 0.005-0.040; P = 0.019). A 1 pmol/L increase in Ln-ferritin was associated with a 0.080 ng/L decrease in Ln-intact parathyroid hormone (Ln-iPTH; 95% CI -0.122 to -0.039; P < 0.001). Meanwhile, beta (95% CI) per 1 unit increase in phosphorus, Ln-25OHD and Ln-iPTH for the square root of the serum hepcidin were 0.594 (0.257-0.932; P = 0.001), -0.270 (-0.431 to -0.108; P = 0.001) and 0.115 (0.004-0.226; P = 0.042), respectively. In subgroup analysis, the relationship between phosphorus, 25OHD and hepcidin was strongest in the positive-inflammation group. CONCLUSIONS: Markers of bone mineral metabolism and iron status, including hepcidin, were closely correlated to each other. Potential mechanisms of the relationship warrant further studies.

Discrepant glomerular filtration rate trends from creatinine and cystatin C in patients with chronic kidney disease: results from the KNOW-CKD cohort.

BACKGROUND: Serum creatinine (Cr) and cystatin C (CysC) can both be used to estimate glomerular filtration rate (eGFRCr and eGFRCysC). However, certain conditions may cause discrepancies between eGFR trends from Cr and CysC, and these remain undetermined in patients with chronic kidney disease (CKD). METHODS: A total of 1069 patients from the Korean CKD cohort (KNOW-CKD), which enrolls pre-dialytic CKD patients, whose Cr and CysC had been followed for more than 4 years were included in the sample. We performed trajectory analysis using latent class mixed modeling and identified members of the discrepancy group when patient trends between eGFRCr and eGFRCysC differed. Multivariate logistic analyses with Firth's penalized likelihood regression models were performed to identify conditions related to the discrepancy. RESULTS: Trajectory patterns of eGFRCr were classified into three groups: two groups with stable eGFRCr (stable with high eGFRCr and stable with low eGFRCr) and one group with decreasing eGFRCr. Trajectory analysis of eGFRCysC also showed similar patterns, comprising two groups with stable eGFRCysC and one group with decreasing eGFRCysC. Patients in the discrepancy group (decreasing eGFRCr but stable & low eGFRCysC; n = 55) were younger and had greater proteinuria values than the agreement group (stable & low eGFRCr and eGFRCysC; n = 706), differences that remained consistent irrespective of the measurement period (4 or 5 years). CONCLUSIONS: In the present study, we identify conditions related to discrepant trends of eGFRCr and eGFRCysC. Clinicians should remain aware of such potential discrepancies when tracing both Cr and CysC.

Relationship between Cardiac Geometry and Serum Hepcidin in Chronic Kidney Disease: Analysis from the KNOW-CKD Study.

BACKGROUND: Few studies have examined the relationship between cardiac function and geometry and serum hepcidin levels in patients with chronic kidney disease (CKD). We aimed to identify the relationship between cardiac function and geometry and serum hepcidin levels. METHODS: We reviewed data of 1,897 patients in a large-scale multicenter prospective Korean study. Logistic regression analysis was used to identify the relationship between cardiac function and geometry and serum hepcidin levels. RESULTS: The mean relative wall thickness (RWT) and left ventricular mass index (LVMI) were 0.38 and 42.0 g/m2.7, respectively. The mean ejection fraction (EF) and early diastolic mitral inflow to annulus velocity ratio (E/e') were 64.1% and 9.9, respectively. Although EF and E/e' were not associated with high serum hepcidin, RWT and LVMI were significantly associated with high serum hepcidin levels in univariate logistic regression analysis. In multivariate logistic regression analysis after adjusting for variables related to anemia, bone mineral metabolism, comorbidities, and inflammation, however, only each 0.1-unit increase in RWT was associated with increased odds of high serum hepcidin (odds ratio, 1.989; 95% confidence interval, 1.358-2.916; P < 0.001). In the subgroup analysis, the independent relationship between RWT and high serum hepcidin level was valid only in women and patients with low transferrin saturation (TSAT). CONCLUSION: Although the relationship was not cause-and-effect, increased RWT was independently associated with high serum hepcidin, particularly in women and patients with low TSAT. The relationship between cardiac geometry and serum hepcidin in CKD patients needs to be confirmed in future studies.

Urinary Angiotensinogen in addition to Imaging Classification in the Prediction of Renal Outcome in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Intrarenal renin-angiotensin system (RAS) is known to play the major role in the development of hypertension and renal progression in autosomal dominant polycystic kidney disease (ADPKD). Urinary angiotensinogen to creatinine ratio (AGT/Cr) was suggested as a novel biomarker to reflect intrarenal RAS activity. This study was performed to evaluate urinary AGT/Cr as a predictive biomarker for renal function decline in addition to imaging classification in a prospective ADPKD cohort. METHODS: From 2011 to 2016, a total of 364 ADPKD patients were enrolled in the prospective cohort called the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD). Among them, a total of 207 subjects in chronic kidney disease stage 1-4 with baseline urinary AGT and total kidney volume and subsequent renal function follow-up data over more than 1 year were included in the analysis. Patients were defined as slow progressors (SP) if they are classified as 1A or 1B by imaging classification whereas rapid progressors (RP) if they are classified as 1C-1E. Patients were divided according to AGT/Cr quartiles and annual estimated glomerular filtration rate (eGFR) slope was compared among highest quartile (hAGT group) and the rest of quartiles (lAGT group). Patients were divided into 4 groups to evaluate the predictive value of urinary AGT/Cr in addition to imaging classification: SP/lAGT, SP/hAGT, RP/lAGT, and RP/hAGT. The Cox regression model was used to evaluate the hazard ratio (HR) between groups. RESULTS: The mean age was 45.9 years and 88.9% had hypertension. Baseline eGFR was 79.0 ± 28.4 mL/min/1.73 m² and median height-adjusted total kidney volume was 788.2 (471.2; 1,205.2) mL/m. The patients in the hAGT group showed lower eGFR (72.4 ± 24.8 vs. 81.1 ± 29.2 mL/min/1.73 m², P = 0.039), lower plasma hemoglobin (13.0 ± 1.4 vs. 13.7 ± 1.6 g/dL, P = 0.007), higher urinary protein to creatinine ratio (0.14 [0.09, 0.38] vs. 0.07 [0.04, 0.12] g/g, P = 0.007) compared to the lAGT group. The hAGT group was an independent risk factor for faster eGFR decline after adjusting for gender, RP, baseline eGFR, and other known risk factors. During median follow-up duration of 4.6 years, a total of 29 renal events (14.0%) occurred. The SP/hAGT group showed significantly higher risk of developing renal outcome compared to SP/lAGT group (HR, 13.4; 95% confidence interval, 1.282-139.324; P = 0.03). CONCLUSION: Urinary AGT/Cr can be a useful predictive marker in the patients with relatively small ADPKD. Various biomarkers should be considered to define RP when implementing novel treatment in the patients with ADPKD.

Periostin induces kidney fibrosis after acute kidney injury via the p38 MAPK pathway.

Periostin plays a crucial role in fibrosis, and acute kidney injury results in a high risk of progression to chronic kidney disease. Therefore, we hypothesized that periostin was involved in the progression of acute kidney injury to kidney fibrosis. Unilateral ischemia-reperfusion injury (UIRI) was induced in 7- to 8-wk-old male wild-type and periostin-null mice, and the animals were observed for 6 wk. In vitro, human kidney-2 cells and primary-cultured human tubular epithelial cells were incubated under hypoxic conditions (5% O2, 5% CO2, and 90% N2) for 5 days. The cells were also cultured with recombinant periostin (rPeriostin) and a p38 mitogen-activated protein kinase (MAPK) inhibitor in a hypoxic incubator. At 6 wk after UIRI, interstitial fibrosis/tubular atrophy was significantly alleviated in periostin-null mice compared with wild-type controls. In addition, periostin-null mice had attenuated expression of fibrosis/apoptosis markers and phosphorylated-p38 MAPK compared with wild-type controls. In vitro, hypoxic injury increased the expression of fibrosis markers, periostin, and phosphorylated-p38 MAPK, which was comparable to or substantially greater than their expression levels following treatment with recombinant transforming growth factor-ß1 under normoxic conditions. Furthermore, rPeriostin treatment under hypoxic conditions enhanced fibrosis/apoptosis markers and phosphorylated-p38 MAPK. In contrast, p38 MAPK inhibition ameliorated hypoxia-induced fibrosis, and the addition of the p38 MAPK inhibitor to rPeriostin significantly ameliorated the changes induced by rPeriostin. In conclusion, periostin promotes kidney fibrosis via the p38 MAPK pathway following acute kidney injury triggered by a hypoxic or ischemic insult. Periostin ablation may protect against chronic kidney disease progression.

eGFR and coronary artery calcification in chronic kidney disease.

BACKGROUND: The independent association between eGFR and coronary artery calcification (CAC) is complex and not clear. The aim of this study was to investigate the relationship between eGFR calculated from different equations and CAC in predialysis CKD patients in Korea. METHODS: In this cross-sectional study, we analysed 1533 patients from the KNOW-CKD cohort. eGFR was calculated by a four-variable MDRD equation (eGFRMDRD ), CKD-EPI creatinine equations (eGFRCr ), CKD-EPI cystatin C equation (eGFRCys ) and CKD-EPI creatinine-cystatin equation (eGFRCrCys ). Participants were divided into eGFR categories (<30, 30-59, 60-89, ≥90 mL/min/1.73 m2 ). CACS (coronary artery calcium score) was measured using cardiac computed tomography. CAC was defined as CACS >100. RESULTS: Coronary artery calcification was found in 334 (21.8%) patients and was more prevalent in the lower eGFR groups (P < 0.001). In multivariate Tobit regression, CACS increased gradually as eGFRCrCys decreased (P for trend = 0.034). In multivariate logistic regression, there were gradual associations between lower eGFR and CAC when an eGFRCys or eGFRCrCys was used. The adjusted OR for CAC in the group with eGFR <30 mL/min/1.73 m2 compared to the group with eGFR ≥90 mL/min/1.73 m2 was 2.64 (95% CI, 1.09-3.60) when eGFRCrCys was used. Of the four eGFR formulas, only adding eGFRCrCys significantly improved CAC prediction models without eGFR (P = 0.046). CONCLUSIONS: There was a gradual and independent association between low eGFR and CAC in a predialysis CKD cohort in Korea. eGFRCrCys predicted CAC better than other equations in this population.

High fibroblast growth factor 23 is associated with coronary calcification in patients with high adiponectin: analysis from the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD) study.

Background: The association between fibroblast growth factor 23 (FGF23) and coronary artery calcification (CAC) was inconclusive. Recently it was shown that adiponectin modulates renal handling of calcium and phosphorus. We hypothesized that adiponectin plays a role in the effect of FGF23 on CAC and explored whether the association between FGF23 and CAC is modified by serum adiponectin level in chronic kidney disease (CKD) patients. Methods: This cross-sectional study analyzed 1435 predialysis CKD patients from the Korean Cohort Study for Outcome in Patients with CKD cohort. Participants were divided into two groups according to their serum adiponectin (upper half and lower half). Each group was further divided into three groups according to their FGF23 levels as follows: low (<5.0 RU/mL), middle (5.0-29.9 RU/mL) and high (≥30.0 RU/mL). The coronary artery calcium score (CACS) was assessed using cardiac computed tomography and CAC was defined as a CACS >100. Results: The median CACS did not differ between the low and high adiponectin groups {3.2 [interquartile range (IQR) 0.0-98.1] versus 0.5 [0.0-99.5], P = 0.988}. The CACS ratio comparing high FGF23 to low FGF23 was significantly increased in the high adiponectin group, but not in the low adiponectin group [2.35 (IQR 1.14-4.85) versus 1.10 (0.60-2.03)]. The odds ratio for CAC in the high FGF23 group compared with the low group was 1.97 (IQR 1.10-3.53). The association between FGF23 and CAC was modified significantly by adiponectin level (P for interaction = 0.023). Conclusions: High serum FGF23 was associated with CAC in CKD patients with high adiponectin, but not in those with low adiponectin. Further studies are warranted to verify the role of adiponectin in FGF23-related CAC.

Body Mass Index, waist circumference, and health-related quality of life in adults with chronic kidney disease.

PURPOSE: Obesity is linked to poor health-related quality of life (HRQOL) in the general population, but its role in chronic kidney disease (CKD) is uncertain. METHODS: We conducted a cross-sectional study that investigated 1880 participants from the KoreaN cohort study for Outcome in patients With CKD (KNOW-CKD) who underwent complete baseline laboratory tests, health questionnaires, and HRQOL. HRQOL was assessed by physical component summary (PCS) and mental component summary (MCS) of the SF-36 questionnaire. We used multivariable linear regression models to examine the relationship between Body Mass Index (BMI) and sex-specific waist circumference (WC) with HRQOL. RESULTS: Adults with higher BMI and greater WC showed lower PCS. After adjusting for age, sex, socioeconomic state, comorbidities, and laboratory findings, we found that WC, but not BMI, was associated with PCS. Greater WC quintiles were associated with lower PCS [WC-4th quintile (ß, - 2.63, 95% CI - 5.19 to - 0.06) and WC-5th quintile (ß, - 3.71, 95% CI - 6.28 to - 1.15)]. The association between WC and PCS was more pronounced in older adults, woman, patients with diabetes, cardiovascular disease, or lower eGFR. The relationship between BMI and WC with MCS was not significant. CONCLUSIONS: In adults with CKD, WC is a better indicator of poor physical HRQOL than BMI. The association between WC and physical HRQOL is modified by age, sex, eGFR, and comorbidities such as diabetes and cardiovascular disease.

Identifying patient-important outcomes in polycystic kidney disease: An international nominal group technique study.

AIM: Patients with autosomal dominant polycystic kidney disease (ADPKD) are at increased risk of premature mortality, morbidities and complications, which severely impair quality of life. However, patient-centered outcomes are not consistently reported in trials in ADPKD, which can limit shared decision-making. We aimed to identify outcomes important to patients and caregivers and the reasons for their priorities. METHODS: Nominal group technique was adopted involving patients with ADPKD and caregivers who were purposively selected from eight centres across Australia, France and the Republic of Korea. Participants identified, ranked and discussed outcomes for trials in ADPKD. We calculated an importance score (0-1) for each outcome and conducted thematic analyses. RESULTS: Across 17 groups, 154 participants (121 patients, 33 caregivers) aged 19 to 78 (mean 54.5 years) identified 55 outcomes. The 10 highest ranked outcomes were: kidney function (importance score 0.36), end-stage kidney disease (0.32), survival (0.21), cyst size/growth (0.20), cyst pain/bleeding (0.18), blood pressure (0.17), ability to work (0.16), cerebral aneurysm/stroke (0.14), mobility/physical function (0.12), and fatigue (0.12). Three themes were identified: threatening semblance of normality, inability to control and making sense of diverse risks. CONCLUSION: For patients with ADPKD and their caregivers, kidney function, delayed progression to end-stage kidney disease and survival were the highest priorities, and were focused on achieving normality, and maintaining control over health and lifestyle. Implementing these patient-important outcomes may improve the meaning and relevance of trials to inform clinical care in ADPKD.

Association between vitamin D level and hematuria from a dipstick test in a large scale population based study: Korean National Health and nutrition examination survey.

BACKGROUND: Vitamin D deficiency is an important health concern because it is related to several comorbidities and mortality. However, its relationship with the risk of hematuria remains undetermined in the general population. In this study, we analyzed the association between vitamin D deficiency and hematuria. METHODS: We conducted cross-sectional analysis using data of participants from the Korean National Health and Nutrition Examination Survey (KNHANES) 2010-2014. A total of 20,240 participants, aged ≥18 years old, were analyzed. Serum 25-hydroxyvitamin D (25(OH)D) levels were measured in a central laboratory and hematuria was defined as ≥1+ on a dipstick test. Multivariate logistic regression was conducted to calculate the odds ratio (OR) of hematuria risk according to serum 25(OH)D quartiles, after adjusting several covariates. RESULTS: A total 3144 (15.5%) participants had hematuria. The mean 25(OH)D level was 17.4 ± 6.2 ng/mL (median, 16.6 ng/mL (interquartile range, 13.1-20.8 ng/mL)). The 3rd and 4th quartiles had a higher risk of hematuria than the 1st quartile, with adjusted ORs 1.26 (1.114-1.415) and 1.40 (1.240-1.572) in the 3rd and 4th quartiles, respectively. However, this relationship was only significant in women, not in men. When stratified analyses were conducted according to menopausal status, there was a significant increase of hematuria risk according to quartiles in postmenopausal but not in premenopausal women. CONCLUSION: We found that vitamin D deficiency is correlated with hematuria in women, particularly after menopause. Further interventional studies are warranted to address whether correcting vitamin D deficiency can lower the risk of hematuria.