Novel Genetic Variants Associated with Chronic Kidney Disease Progression.

SIGNIFICANCE STATEMENT: eGFR slope has been used as a surrogate outcome for progression of CKD. However, genetic markers associated with eGFR slope among patients with CKD were unknown. We aimed to identify genetic susceptibility loci associated with eGFR slope. A two-phase genome-wide association study identified single nucleotide polymorphisms (SNPs) in TPPP and FAT1-LINC02374 , and 22 of them were used to derive polygenic risk scores that mark the decline of eGFR by disrupting binding of nearby transcription factors. This work is the first to identify the impact of TPPP and FAT1-LINC02374 on CKD progression, providing predictive markers for the decline of eGFR in patients with CKD. BACKGROUND: The incidence of CKD is associated with genetic factors. However, genetic markers associated with the progression of CKD have not been fully elucidated. METHODS: We conducted a genome-wide association study among 1738 patients with CKD, mainly from the KoreaN cohort study for Outcomes in patients With CKD. The outcome was eGFR slope. We performed a replication study for discovered single nucleotide polymorphisms (SNPs) with P <10 -6 in 2498 patients with CKD from the Chronic Renal Insufficiency Cohort study. Several expression quantitative trait loci (eQTL) studies, pathway enrichment analyses, exploration of epigenetic architecture, and predicting disruption of transcription factor (TF) binding sites explored potential biological implications of the loci. We developed and evaluated the effect of polygenic risk scores (PRS) on incident CKD outcomes. RESULTS: SNPs in two novel loci, TPPP and FAT1-LINC02374 , were replicated (rs59402340 in TPPP , Pdiscovery =7.11×10 -7 , PCRIC =8.13×10 -4 , Pmeta =7.23×10 -8 ; rs28629773 in FAT1-LINC02374 , Pdiscovery =6.08×10 -7 , PCRIC =4.33×10 -2 , Pmeta =1.87×10 -7 ). The eQTL studies revealed that the replicated SNPs regulated the expression level of nearby genes associated with kidney function. Furthermore, these SNPs were near gene enhancer regions and predicted to disrupt the binding of TFs. PRS based on the independently significant top 22 SNPs were significantly associated with CKD outcomes. CONCLUSIONS: This study demonstrates that SNP markers in the TPPP and FAT1-LINC02374 loci could be predictive markers for the decline of eGFR in patients with CKD.

Macrophage transcription factor TonEBP promotes systemic lupus erythematosus and kidney injury via damage-induced signaling pathways.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by autoreactive B cells and dysregulation of many other types of immune cells including myeloid cells. Lupus nephritis (LN) is a common target organ manifestations of SLE. Tonicity-responsive enhancer-binding protein (TonEBP, also known as nuclear factor of activated T-cells 5 (NFAT5)), was initially identified as a central regulator of cellular responses to hypertonic stress and is a pleiotropic stress protein involved in a variety of immunometabolic diseases. To explore the role of TonEBP, we examined kidney biopsy samples from patients with LN. Kidney TonEBP expression was found to be elevated in these patients compared to control patients - in both kidney cells and infiltrating immune cells. Kidney TonEBP mRNA was elevated in LN and correlated with mRNAs encoding inflammatory cytokines and the degree of proteinuria. In a pristane-induced SLE model in mice, myeloid TonEBP deficiency blocked the development of SLE and LN. In macrophages, engagement of various toll-like receptors (TLRs) that respond to damage-associated molecular patterns induced TonEBP expression via stimulation of its promoter. Intracellular signaling downstream of the TLRs was dependent on TonEBP. Therefore, TonEBP can act as a transcriptional cofactor for NF-κB, and activated mTOR-IRF3/7 via protein-protein interactions. Additionally, TonEBP-deficient macrophages displayed elevated efferocytosis and animals with myeloid deficiency of TonEBP showed reduced Th1 and Th17 differentiation, consistent with macrophages defective in TLR signaling. Thus, our data show that myeloid TonEBP may be an attractive therapeutic target for SLE and LN.

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.

Effects of intravenous iron therapy on mortality and hospitalization of hemodialysis patients: A prospective cohort study in Korea.

Iron replacement therapy is necessary for anemia treatment in patients with advanced chronic kidney disease. Intravenous (IV) iron therapy is an efficient method for iron replacement. However, there are concerns regarding its considerable side effects, including increased risks of infection or major adverse cardiovascular events (MACE). This is a longitudinal study from a multicenter prospective cohort study conducted in the Korean end-stage renal disease population. All-cause mortality, death due to infection or MACE, hospitalization due to infection or MACE, and all adverse event of death or hospitalization due to infection or MACE were compared according to the iron replacement methods during the first 3 months of enrollment. Among 1,680 hemodialysis patients, 29.3% of patients received IV iron therapy, and 38% of patients received oral iron therapy. During the median 632 days follow-up, all-cause mortality, mortality or hospitalization due to infection or MACE, and all adverse events did not differ among iron replacement groups. There were significant differences related to the risk of all adverse events among iron replacement therapies in the log-rank test and univariate Cox regression analysis only in the prevalent dialysis patients; however, the significance was lost in multivariate Cox regression analysis. Similar results were observed in the 1-year short-term outcome analysis. High-dose IV iron did not increase adverse outcomes. All-cause mortality or all adverse events due to infection or MACE were not higher with the current clinical regimen of IV iron replacement therapy than with oral or no iron therapy in Korean hemodialysis patients.

Soluble α-klotho anchors TRPV5 to the distal tubular cell membrane independent of FGFR1 by binding TRPV5 and galectin-1 simultaneously.

Hypercalciuria is one of the early manifestations of diabetic nephropathy (DN). This is partially due to a decrease in the expression of renal transient receptor potential vanilloid type 5 (TRPV5), which is responsible for renal Ca2+ reabsorption. Soluble klotho has been previously determined to increase TRPV5 by cleaving sialic acid, causing TRPV5 to bind to membrane protein galectin-1. However, a recent study showed that soluble klotho binds to α2-3-sialyllactose, where sialic acid is located, on TRPV5, rather than cleave it. Here, we report that soluble klotho tethers TRPV5 on the membrane by binding both TRPV5 and galectin-1, thereby protecting membrane TRPV5 from diabetes-induced endocytosis. In the present study, we injected recombinant soluble α-klotho protein (rKL) into db/db and db/m mice for 8 wk and collected urine and kidneys. We administered rKL, AZD4547 [fibroblast growth factor (FGF) receptor type 1 inhibitor], and OTX008 (galectin-1 inhibitor) to cultured mouse distal tubular cells with or without 30 mM high-glucose (HG) exposure. db/db mice showed increased renal Ca2+ excretion and decreased renal TRPV5 expression. rKL treatment reversed this change. In vitro, TRPV5 expression in distal tubular cells decreased under HG conditions, and rKL successfully upregulated TRPV5 with or without FGF23. Also, immunofluorescence showed colocalization of klotho, TRPV5, and galectin-1 in distal tubule cells, suggesting that klotho binds to both TRPV5 and galectin-1. Moreover, when both FGF receptor type 1 and galectin-1 were inhibited, rKL failed to increase TRPV5 under HG conditions. Our results indicate that soluble klotho prevents TRPV5 from degradation and subsequent diabetes-induced endocytosis by anchoring TRPV5 through binding with both TRPV5 and galectin-1.NEW & NOTEWORTHY Soluble α-klotho anchors transient receptor potential vanilloid type 5 (TRPV5) on the apical membrane of the distal tubule by binding both TRPV5 and a membrane-abundant protein, galectin-1. This newly discovered mechanism works even when fibroblast growth factor (FGF)23 signaling is inhibited by treatment with FGF receptor type 1 inhibitor. Therefore, we identified how soluble α-klotho increases TRPV5 without FGF23. We confirmed this mechanism by observing that soluble α-klotho fails to enhance TRPV5 when both FGF receptor type 1 and galectin-1 are inhibited.

Klotho ameliorates diabetic nephropathy via LKB1-AMPK-PGC1α-mediated renal mitochondrial protection.

Diabetic nephropathy (DN) is associated with renal mitochondrial injury and decreased renal klotho expression. Klotho is known as an aging suppressor, and mitochondrial dysfunction is the hallmark of aging. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a master regulator of mitochondrial biogenesis, and adenosine monophosphate-activated protein kinase (AMPK) is known as a guardian of mitochondria. Here, we report that recombinant soluble klotho protein (rKL) protects against DN in db/db mice via PGC1α-AMPK-mediated mitochondrial recovery in the kidney. We injected rKL into db/db and db/m mice for 8 weeks and collected the serum and kidney tissue. We treated murine renal tubular cells with rKL in vitro, with and without exposure to 30 mM high glucose (HG). rKL treatment ameliorated major disorders from diabetes, such as obesity, hyperglycemia, and intrarenal reactive oxygen species (ROS) generation, in db/db mice. rKL also diminished albuminuria, recovered renal proximal tubular mitochondria, increased renal p-AMPK and PGC1α, and down-regulated mTOR/TGF-ß in db/db mice. In S1 mouse proximal tubular cells, rKL treatment ameliorated HG-mediated cellular and mitochondrial damage and enhanced oxidative phosphorylation, with an increase in PGC1α-AMPK-induced mitochondrial recovery. Our data suggest that klotho exerts a mitochondrial protective effect in diabetic kidney disease by inducing AMPK-PGC1α expression.

Measured sodium excretion is associated with CKD progression: results from the KNOW-CKD study.

BACKGROUND: Diet is a modifiable factor of chronic kidney disease (CKD) progression. However, the effect of dietary salt intake on CKD progression remains unclear. Therefore, we analyzed the effect of dietary salt intake on renal outcome in Korean patients with CKD. METHODS: We measured 24-h urinary sodium (Na) excretion as a marker of dietary salt intake in the prospective, multi-center, longitudinal KoreaN cohort study for Outcome in patients With CKD (KNOW-CKD). Data were analyzed from CKD patients at Stages G3a to G5 (n = 1254). We investigated the association between dietary salt intake and CKD progression. Patients were divided into four quartiles of dietary salt intake, which was assessed using measured 24-h urinary Na excretion. The study endpoint was composite renal outcome, which was defined as either halving the estimated glomerular filtration rate or developing end-stage renal disease. RESULTS: During a median (interquartile range) follow-up of 4.3 (2.8-5.8) years, 480 (38.7%) patients developed the composite renal event. Compared with the reference group (Q2, urinary Na excretion: 104.2 ≤ Na excretion < 145.1 mEq/day), the highest quartile of measured 24-h urinary Na excretion was associated with risk of composite renal outcome [Q4, urinary Na excretion ≥192.9 mEq/day, hazard ratio 1.8 (95% confidence interval 1.12-2.88); P = 0.015] in a multivariable hazards model. Subgroup analyses showed that high-salt intake was particularly associated with a higher risk of composite renal outcome in women, in patients <60 years of age, in those with uncontrolled hypertension and in those with obesity. CONCLUSIONS: High salt intake was associated with increased risk of progression in CKD.

Clinical Factors Associated with the Risk of Intracranial Aneurysm Rupture in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: The occurrence of intracranial aneurysms is higher in patients with autosomal dominant polycystic kidney disease (ADPKD) than in the healthy population. However, research concerning the factors related to the risk of intracranial aneurysm rupture in patients with ADPKD is still insufficient. OBJECTIVES: The aim of the study was to investigate the prevalence of intracranial aneurysms and aneurysmal subarachnoid hemorrhage (SAH) and to analyze the systemic factors associated with high-risk aneurysms in patients with ADPKD. METHODS: We screened patients who underwent cerebral angiography between January 2007 and May 2017 in the ADPKD registry. Patients were examined for the presence of intracranial aneurysms and subsequently reclassified into 3 groups based on the risk of aneurysmal rupture: the aneurysm-negative (group 1), low-risk aneurysm (group 2), or high-risk aneurysm (group 3). Various systemic factors were compared, and independent factors associated with high-risk aneurysms were analyzed. RESULTS: Among the 926 patients, 148 (16.0%) had intracranial aneurysms and 11 (1.2%) had previous aneurysmal SAH. Patients with intracranial aneurysms were further classified into group 2 (low-risk aneurysms, 15.5%) or group 3 (high-risk aneurysms, 84.5%). Age (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01-1.05, p = 0.004), female sex (OR 3.13, 95% CI 1.94-5.0 6, p < 0.001), dolichoectasia (OR 8.57, 95% CI 1.53-48.17, p = 0.015), and mitral inflow deceleration time (DT) (OR 1.01, 95% CI 1.00-1.01, p = 0.046) were independently associated with high-risk aneurysms, whereas hypercholesterolemia (OR 0.46, 95% CI 0.29-0.72, p = 0.001) was negatively associated. CONCLUSION: In the present study among patients with ADPKD, the prevalence of intracranial aneurysms and aneurysmal SAH was 16 and 1.2%, respectively. Age, female sex, dolichoectasia, and mitral inflow DT were positively associated with high-risk aneurysms, whereas hypercholesterolemia was negatively associated. A subsequent large-scaled longitudinal study is needed to define the plausibility of the clinical parameters.

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.

Erratum: Correction of Text and Table in the Article "Establishing a Patient-centered Longitudinal Integrated Clerkship: Early Results from a Single Institution".

This corrects the article on p. e419 in vol. 35, PMID: 33372421.

Core Outcome Domains for Trials in Autosomal Dominant Polycystic Kidney Disease: An International Delphi Survey.

RATIONALE & OBJECTIVE: Outcomes reported in trials involving patients with autosomal dominant polycystic kidney disease (ADPKD) are heterogeneous and rarely include patient-reported outcomes. We aimed to identify critically important consensus-based core outcome domains to be reported in trials in ADPKD. STUDY DESIGN: An international 2-round online Delphi survey was conducted in English, French, and Korean languages. SETTING & PARTICIPANTS: Patients/caregivers and health professionals completed a 9-point Likert scale (7-9 indicating critical importance) and a Best-Worst Scale. ANALYTICAL APPROACH: The absolute and relative importance of outcomes were assessed. Comments were analyzed thematically. RESULTS: 1,014 participants (603 [60%] patients/caregivers, 411 [40%] health professionals) from 56 countries completed round 1, and 713 (70%) completed round 2. The prioritized outcomes were kidney function (importance score, 8.6), end-stage kidney disease (8.6), death (7.9), blood pressure (7.9), kidney cyst size/growth (7.8), and cerebral aneurysm (7.7). Kidney cyst-related pain was the highest rated patient-reported outcome by both stakeholder groups. Seven themes explained the prioritization of outcomes: protecting life and health, directly encountering life-threatening and debilitating consequences, specificity to ADPKD, optimizing and extending quality of life, hidden suffering, destroying self-confidence, and lost opportunities. LIMITATIONS: Study design precluded involvement from those without access to internet or limited computer literacy. CONCLUSIONS: Kidney function, end-stage kidney disease, and death were the most important outcomes to patients, caregivers, and health professionals. Kidney cyst-related pain was the highest rated patient-reported outcome. Consistent reporting of these top prioritized outcomes may strengthen the value of trials in ADPKD for decision making.

Foods contributing to nutrients intake and assessment of nutritional status in pre-dialysis patients: a cross-sectional study.

BACKGROUND: For chronic kidney disease (CKD) patients, management of nutritional status is critical for delaying progression to end-stage renal disease. The purpose of this study is to provide the basis for personalized nutritional intervention in pre-dialysis patients by comparing the foods contributing to nutrients intake, nutritional status and potential dietary inflammation of CKD patients according to the diabetes mellitus (DM) comorbidity and CKD stage. METHODS: Two hundred fifty-six outpatients referred to the Department of Nephrology at SNUH from Feb 2016 to Jan 2017 were included. Subjects on dialysis and those who had undergone kidney transplantation were excluded. Bioelectrical impedance analysis (BIA), subjective global assessment (SGA), dietary intake, and biochemical parameters were collected. Subjects were classified into 4 groups according to DM comorbidity (DM or Non-DM) and CKD stage (Early or Late) by kidney function. Two-way analysis of variance and multinomial logistic regression analysis were performed for statistical analysis. RESULTS: Total number of malnourished patients was 31 (12.1%), and all of them were moderately malnourished according to SGA. The body mass index (BMI) of the DM-CKD group was significantly higher than the Non-DM-CKD group. The contribution of whole grains and legumes to protein intake in the DM-CKD group was greater than that in the Non-DM-CKD group. The DM- Early-CKD group consumed more whole grains and legumes compared with the Non-DM-Early-CKD group. The subjects in the lowest tertile for protein intake had lower phase angle, SGA score and serum albumin levels than those in the highest tertile. The potential for diet-induced inflammation did not differ among the groups. CONCLUSIONS: Significant differences in intakes of whole grains and legumes between CKD patients with or without DM were observed. Since contribution of whole grains and legumes to phosphorus and potassium intake were significant, advice regarding whole grains and legumes may be needed in DM-CKD patients if phosphorus and potassium intake levels should be controlled. The nutritional status determined by BIA, SGA and serum albumin was found to be different depending on the protein intake. Understanding the characteristics of food sources can provide a basis for individualized nutritional intervention for CKD patients depending on the presence of diabetes.

Cancer development and mortality differences in patients with glomerulonephritis after renal biopsy: a single center retrospective cohort study.

BACKGROUND: The association between glomerulonephritis (GN) and cancer has been well known for decades. However, studies evaluating long-term de novo cancer development in patients with GN are limited. This study aimed to evaluate the incidence of cancer development among patients with renal biopsy-proven GN during post-biopsy follow-up and the differences in outcomes according to cancer occurrence. METHODS: We conducted a retrospective cohort study of adult patients who underwent renal biopsy at Seoul National Bundang Hospital between 2003 and 2017. After excluding 778 patients with age < 18 years, cancer diagnosis before or within 6 months after renal biopsy, immunosuppressant therapy before renal biopsy, or pathologic diagnoses other than GN, 822 patients were included in the analysis. Data on baseline clinical characteristics, renal biopsy results, and types and doses of immunosuppressant agents were collected from electronic medical records. The incidence of cancer was censored on the date when the first cancer was diagnosed. We evaluated rates of mortality and end-stage renal disease (ESRD) development during follow-up. RESULTS: During a mean follow-up period of 58.9 ± 44.5 months, 45 subjects (5.5%) developed de novo cancer. A comparison of clinical characteristics between subjects who did and did not develop cancer revealed that cancer patients were older and had higher comorbidities and immunosuppressant use. Overall, patients with GN had an elevated standardized incidence ratio (SIR) of 7.16 (95% confidence interval (CI): 5.22-9.61) relative to the age- and sex-matched general population. In particular, the SIR was significantly higher in GNs such as membranous nephropathy (MN), IgA nephropathy, lupus nephritis, and focal segmental glomerulosclerosis. Multivariable Cox proportional hazard model revealed that patients with MN had an increased risk of cancer development, with a hazard ratio of 2.30 [95% CI: 1.06-4.98]. Patients with MN who developed cancer had a significantly higher risk of mortality (hazard ratio: 6.59; 95% CI: 1.22-35.56, P = 0.03) than those without cancer, but there was a non-significant difference in ESRD development. CONCLUSIONS: Patients with GN without concurrent cancer, particularly those with MN, have significantly higher risks of cancer development and subsequent mortality and should remain aware of the potential development of malignancy during follow-up.

Establishing a Patient-centered Longitudinal Integrated Clerkship: Early Results from a Single Institution.

BACKGROUND: Longitudinal integrated clerkships (LICs) have been adopted by medical schools to overcome the limitations of traditional block clerkship rotations and to promote continuity of care. In 2018, Seoul National University College of Medicine introduced a patient-centered LIC program as part of a new curriculum in parallel with traditional block rotation clerkships. The purpose of this study was to present the patient-centered LIC program and to investigate its educational effects. METHODS: In 2018 and 2019, a total of 298 third-year medical students participated in the LIC program. We divided the students into groups of eight, which were organized into corresponding discussion classes. Throughout the academic year, students followed up patients by interviewing them at the hospital or reviewing their electric medical records. Discussion classes on set topics were held seven times per year with facilitators and clinical faculites. Students completed a course evaluation questionnaire at the end of the academic year. The questionnaire included 22 items measured on a 5-point scale and two open-ended questions asking about the benefits and limitations of the program. The items covered three domains: student experience, satisfaction, and self-assessment. Final reflective essays were collected as both student assessments and data for qualitative analysis. RESULTS: During the study period, the overall experience of the students improved. We increased the number of faculty members and patients and decreased the number of students in each discussion class. We also provided additional feedback through an e-portfolio. Students' satisfaction changed positively. Compared to the rotational clerkship, students answered that the LIC provided additional help in learning the two core competencies. During the first 2 years of the program, the percentage of students who answered that the program was more helpful than the rotational clerkship increased from 23.7% to 46.4% for continuity of care (P < 0.001), and from 20.5% to 50.7% for patient-centered care (P < 0.001). CONCLUSION: Our patient-centered LIC, in parallel with traditional block rotation clerkships, had a positive effect on students' experience of continuity of care and patient-centered care.

Dietary Assessment of Korean Non-dialysis Chronic Kidney Disease Patients with or without Diabetes.

BACKGROUND: Dietary intervention at the early stage of chronic kidney disease (CKD) is important for preventing progression to the end-stage renal disease (ESRD). However, few studies have investigated dietary intake of CKD patients in non-dialysis stage. Therefore, we investigated the dietary intake of Korean non-dialysis CKD patients and aimed to establish baseline data for the development of dietary education and intervention strategies for CKD patients. METHODS: Three hundred fifty CKD patients who visited Seoul National University Hospital outpatient clinic from February 2016 to January 2017 were recruited for this cross-sectional study. Subjects on dialysis and those who had undergone kidney transplantation were excluded. Dietary intake, demographic information, and biochemical characteristics of 256 subjects who completed three-day dietary records were analyzed. Subjects were divided into four groups based on diabetes mellitus (DM) (DM-CKD and Non-DM-CKD groups) and kidney function (Early-CKD and Late-CKD groups). RESULTS: Total energy intake was lower in the Late-CKD group compared with the Early-CKD group. In men, carbohydrate intake was higher and protein and fat intakes tended to be lower in the Late-CKD group compared with the Early-CKD group. In women, carbohydrate intake tended to be lower in the DM-CKD group than the Non-DM-CKD group. Protein intake tended to be higher in the DM-CKD groups. Phosphorus and sodium intakes were higher in the DM-CKD groups compared with the Non-DM-CKD groups in women, and tended to be higher in the DM-CKD groups in men. CONCLUSION: DM and kidney function affected energy and nutrient intakes. Subjects in the Late-CKD group consumed less energy than those in the Early-CKD group. Non-DM subjects seemed to restrict protein intake starting from the Early-CKD stage than subjects with DM. Subjects in this study had low energy and high sodium intakes compared with recommended levels. Protein intake was lower in advanced CKD patients, but their intake level was still higher than the recommendation. Dietary intervention strategies for non-dialysis CKD patients need to be customized depending on the presence of DM and kidney function.

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.

AICAR, an AMPK activator, protects against cisplatin-induced acute kidney injury through the JAK/STAT/SOCS pathway.

Cisplatin causes acute kidney injury (AKI) through proximal tubular injury. We investigated the protective effect of the adenosine monophosphate protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) against cisplatin-induced AKI. We investigated whether the AMP-kinase activator AICAR ameliorates cisplatin-induced AKI through the JAK/STAT/SOCS pathway. Male Sprague-Dawley (SD) rats were randomly divided into four groups: control, AICAR, cisplatin, and cisplatin + AICAR. As appropriate to their treatment group, the rats were injected with a single dose of cisplatin (7 mg/kg, i.p.). AICAR was administered to the rats at 100 mg/kg i.p. daily. Blood urea nitrogen (BUN) and serum creatinine were measured. Renal damage was analyzed in sections stained with hematoxylin and eosin (H&E). Renal tissues were also examined by immunohistochemistry and western blot for p-AMPK, Kim-1, cleaved caspase 3, and JAK/STAT/SOCS. For in vitro studies, NRK-52E normal rat kidney cells were treated with cisplatin and/or AICAR. By western blot, we confirmed the expression of p-AMPK and the JAK/STAT/SOCS pathway in NRK-52E cells. AICAR was protective against cisplatin-induced acute tubular injury by up-regulating p-AMPK expression in NRK-52E cells. Protein expression levels of JAK2/STAT1 were markedly ameliorated in NRK-52E cells by AICAR. The protective mechanism of AICAR may be associated with suppression of the JAK2/STAT1 pathway and up-regulation of SOCS1, an inhibitor of the JAK2/STAT1 pathway. The present study demonstrates the protective effects of AICAR against cisplatin-induced AKI and shows a new renoprotective mechanism through the JAK2/STAT1/SOCS1 pathway and apoptosis inhibition. This study suggests that activation of the AMPK activator AICAR might ameliorate cisplatin-induced AKI.

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.