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.

Effect of low-density lipoprotein level and mortality in older incident statin-naïve hemodialysis patients.

BACKGROUND: This study aimed to analyze low-density lipoprotein cholesterol (LDL-C) levels and their relationship with mortality in order to identify the appropriate lipid profile for older Korean hemodialysis patients. METHODS: We enrolled a total of 2,732 incident hemodialysis patients aged > 70 years from a retrospective cohort of the Korean Society of Geriatric Nephrology from 2010 Jan to 2017 Dec, which included 17 academic hospitals in South Korea. Of these patients, 1,709 were statin-naïve, and 1,014 were analyzed after excluding those with missing LDL-C level data. We used multivariate Cox regression analysis to select risk factors from 20 clinical variables among the LDL-C groups. RESULTS: The mean age of the entire patient population was 78 years, with no significant differences in age between quartiles Q1 to Q4. However, the proportion of males decreased as the quartiles progressed towards Q4 (p < 0.001). The multivariate Cox regression analysis, which included all participants, showed that low LDL-C levels were associated with all-cause mortality. In the final model, compared to Q1, the hazard ratios (95% confidence interval) were 0.77 (0.620-0.972; p = 0.027), 0.85 (0.676-1.069; p = 0.166), and 0.65 (0.519-0.824; p < 0.001) for Q2, Q3, and Q4, respectively, after adjusting for covariates, such as conventional and age-specific risk factors. The final model demonstrated that all-cause mortality increased as LDL-C levels decreased, as confirmed by a restrictive cubic spline plot. CONCLUSIONS: In older hemodialysis patients who had not previously received dyslipidemia treatment, elevated LDL-C levels were not associated with increased all-cause mortality. Intriguingly, lower LDL-C levels appear to be associated with an unfavorable effect on all-cause mortality among high-risk hemodialysis patients.

Economic Impact of Donating a Kidney on Living Donors: A Korean Cohort Study.

RATIONALE & OBJECTIVE: Although existing studies have reported adverse health outcomes after kidney donation, its socioeconomic impact on living donors requires further study. STUDY DESIGN: A retrospective observational cohort study including a matched comparison group. SETTING & PARTICIPANTS: 1,285 living kidney donors from 7 tertiary hospitals between 2003 and 2016, and a matched comparison group consisting of the same number of health screening examinees with similar baseline clinical characteristics and socioeconomic status. All participants were receiving Korean national health insurance. EXPOSURE: Kidney donation as reflected in the Korean National Health Insurance System (NHIS) database. OUTCOME: Changes in household economic status estimated by Korean national health insurance fees and changes in employment status reflected in the NHIS database. ANALYTICAL APPROACH: The outcomes of the donor group and matched control group were compared annually using multivariable logistic regression analyses adjusted for clinical and demographic characteristics. RESULTS: The median ages of the donors and matched controls were 45 and 46 years, respectively; 44.6% of both groups were male. Compared to the comparison group, living donors were at higher risk of being unemployed or losing employment during the first 2 years after donation (eg, first-year loss of employment: odds ratio (OR), 2.27 [95% CI, 1.55-3.33]); however, this association did not persist. Donors also had a significantly lower odds of improvement in economic status (OR, 0.57 [95% CI, 0.47-0.71]) and a higher odds of deterioration in financial status (OR, 1.54 [95% CI, 1.23-1.93]) in the first year after transplantation and subsequently. LIMITATIONS: Unmeasured differences between donors and matched controls creating residual selection bias and confounding. CONCLUSIONS: Living kidney donors may suffer loss of employment and poor economic status after their voluntary donation. The socioeconomic impact on these donors should be considered in conjunction with the potential long-term adverse health outcomes after donation.

Consistency of the estimated target weights and ECW/TBW using BIA after hemodialysis in patients between standing and lying-down positions.

BACKGROUND: As hemodialysis is administered with the patient lying down, the distribution of body fluid is stable in the lying position, which is why this position is recommended for bioimpedance analysis (BIA). Although the InBody S10 is widely used for hemodialysis patients in the lying position, clinicians must make the measurements in person. In contrast, patients can use the InBody 770 to obtain measurements by themselves in the standing position, which may be more convenient. Therefore, this study compared the measurements of hemodialysis patients' estimated target weight and ECW/TBW obtained lying down using the S10 to those obtained in the standing position using the 770. METHODS: This study was conducted among maintenance hemodialysis patients at Chuncheon Sacred Heart Hospital in October 2020. Measurements from 56 patients before and after hemodialysis were obtained using the 2 machines. Each (S10 or 770) estimated target weight, both pre- and post-hemodialysis, was considered ideal when the ECW/TBW ratio was 0.380. R2 was calculated and the Bland-Altman test was performed. RESULTS: The patients' median age was 64 years old, and 51% were men. The actual ultrafiltration was 2 kg, and the mean TBW change measured using the InBody devices was 1.5 L (R2 = 0.718) for the S10 and 1.7 L (R2 = 0.616) for the 770. The estimated target weight at pre- and post-hemodialysis showed a remarkably high correlation with the patients' actual pre- and post-hemodialysis weight (R2 > 0.095). The correlation between these measurements (lying vs. standing) before and after hemodialysis was also very close (R2 = 1.0000). In addition, ECW/TBW had a good correlation (R2 ≥ 0.970) The Bland-Altman test of dry weight and ECW/TBW yielded similar results. CONCLUSIONS: This study showed that patients' estimated target weights in the lying position using the InBody S10 device and in the standing position using the InBody 770 device were consistent in both pre- and post-hemodialysis states.

Serum uric acid is associated with coronary artery calcification in early chronic kidney disease: a cross-sectional study.

BACKGROUND: Although uric acid (UA) is regarded as a risk factor for cardiovascular disease, whether UA is an independent risk factor contributing to coronary artery calcification in chronic kidney disease (CKD) is not well known. We evaluated whether UA level is associated with coronary artery calcium (CAC) score in a predialysis CKD cohort. METHODS: A total of 1,350 subjects who underwent coronary computed tomography as part of the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease were analysed. We conducted a logistic regression analysis to evaluate the association between UA and the presence of CAC. RESULTS: CAC was detected in 705 (52.2 %) patients, and the level of UA was significantly higher in CAC > 0 patients. UA showed a positive relationship with CAC > 0 in age- and sex-adjusted logistic regression analysis (Odds ratio (OR) 1.11, 95 % confidence interval (CI) 1.04-1.19, P = 0.003). However, UA showed no association with CAC > 0 in multivariate analysis. Further analysis showed that UA showed a positive association with CAC > 0 only in estimated glomerual filtration rate (eGFR) > 60 ml/min/1.73 m2 (OR 1.23, 95 % CI 1.02-1.49, P = 0.036) but not in eGFR 30-59 ml/min/1.73 m2 (OR 0.92, 95 % CI 0.78-1.08, P = 0.309) or < 30 ml/min/1.73 m2 (OR 0.92, 95 % CI 0.79-1.08, P = 0.426). CONCLUSIONS: UA level was significantly associated with CAC in early CKD, but not in advanced CKD.

RNA-Seq identifies condition-specific biological signatures of ischemia-reperfusion injury in the human kidney.

BACKGROUND: Acute kidney injury (AKI) is defined as a sudden event of kidney failure or kidney damage within a short period. Ischemia-reperfusion injury (IRI) is a critical factor associated with severe AKI and end-stage kidney disease (ESKD). However, the biological mechanisms underlying ischemia and reperfusion are incompletely understood, owing to the complexity of these pathophysiological processes. We aimed to investigate the key biological pathways individually affected by ischemia and reperfusion at the transcriptome level. RESULTS: We analyzed the steady-state gene expression pattern of human kidney tissues from normal (pre-ischemia), ischemia, and reperfusion conditions using RNA-sequencing. Conventional differential expression and self-organizing map (SOM) clustering analyses followed by pathway analysis were performed. Differential expression analysis revealed the metabolic pathways dysregulated in ischemia. Cellular assembly, development and migration, and immune response-related pathways were dysregulated in reperfusion. SOM clustering analysis highlighted the ischemia-mediated significant dysregulation in metabolism, apoptosis, and fibrosis-related pathways, while cell growth, migration, and immune response-related pathways were highly dysregulated by reperfusion after ischemia. The expression of pro-apoptotic genes and death receptors was downregulated during ischemia, indicating the existence of a protective mechanism against ischemic injury. Reperfusion induced alterations in the expression of the genes associated with immune response such as inflammasome and antigen representing genes. Further, the genes related to cell growth and migration, such as AKT, KRAS, and those related to Rho signaling, were downregulated, suggestive of injury responses during reperfusion. Semaphorin 4D and plexin B1 levels were also downregulated. CONCLUSIONS: We show that specific biological pathways were distinctively involved in ischemia and reperfusion during IRI, indicating that condition-specific therapeutic strategies may be imperative to prevent severe kidney damage after IRI in the clinical setting.

Genetic risk score raises the risk of incidence of chronic kidney disease in Korean general population-based cohort.

BACKGROUND: Chronic kidney disease (CKD) is a common disease, affecting about 10% of the general population. The genetic component about CKD incidence in Asian population is not well known. The aim of the study is to find the genetic loci associated with incident CKD and to figure out the effect of genetic variation on the development of CKD. METHODS: We conducted a genome-wide association (GWA) study regarding the development of CKD based on two population-based cohorts of Korean Genome Epidemiology Study. 3617 Koreans from two different cohorts, aged 40-49 years without CKD at initial visit, were included in our analysis. We used 2510 individuals in Ansan as the discovery set and another 1107 individuals from Ansung as the replication set. At baseline, members of both cohorts provided information on creatinine, and DNA samples were collected for genotyping. Single nucleotide polymorphisms that surpassed a significance threshold of P < 5 × 10-3 were selected. RESULTS: A total of 281 among 3617 developed CKD during the follow-up period. Incident CKD group was older (P < 0.001), included more female (P < 0.001), and had more hypertension and diabetes (P < 0.001). We identified 12 SNPs that are associated with incident CKD in the GWA study and made genetic risk score using these SNPs. In multiple Cox regression analysis, genetic risk score was still a significant associated factor (HR 1.311, CI 1.201, 1.431, P < 0.001). CONCLUSIONS: We identified several loci highly associated with incident CKD. The findings suggest the need for further investigations on the genetic propensity for incident CKD.

Long-term outcomes in acute kidney injury patients who underwent continuous renal replacement therapy: a single-center experience.

INTRODUCTION: Acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) is the most severe form of AKI associated with poor short- and long-term patient outcomes. The aim of this study was to evaluate the variables associated with long-term patient survival in our clinic. METHODS: This was a single-center retrospective study with AKI survivors who received CRRT from March 2011 to February 2015. During the study period, all consecutive AKI survivors who underwent CRRT were included. Patients on maintenance dialysis prior to CRRT were excluded. Data were collected by reviewing the patients' medical charts. Long-term follow-up data were gathered through February 2018. RESULTS: A total of 430 patients were included, and 62.8% of the patients were male. The mean age of the patients was 63.4 ± 14.6 years. The mean serum creatinine level at the time of CRRT initiation was 3.5 ± 2.5 mg/dL. At the time of discharge, the mean eGFR and serum creatinine levels were 58.4 ± 46.7 and 1.7 ± 1.6 mg/dL, respectively. After 3 years, 44.9% of the patients had survived. When we investigated the factors associated with long-term patient mortality, a longer stay in the ICU [OR 1.034 (1.016-1.053), p < 0.001], a history of cancer [OR 3.830 (1.037-3.308), p = 0.037], a prolonged prothrombin time [OR 1.852 (1.037-3.308), p = 0.037] and a lower eGFR at the time of discharge [OR 0.988 (0.982-0.995), p = 0.001] were independently associated with long-term patient mortality. CONCLUSION: Our study demonstrates that long-term mortality after CRRT is associated with longer ICU stays and lower eGFRs at the time of hospital discharge. Our data imply the importance of renal recovery for long-term survival of AKI patients treated with CRRT.

The association between socioeconomic disparities and left ventricular hypertrophy in chronic kidney disease: results from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD).

BACKGROUND: Left ventricular hypertrophy (LVH) is one of the risk factors for cardiovascular (CV) disease and mortality. However, the relationship between socioeconomic status (SES) and LVH in chronic kidney disease remains unclear. METHODS: Data were collected from the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD, NCT01630486 at http://www.clinicaltrials.gov ). Subjects with CKD and aged ≥50 were included. SES was characterized based on monthly income and educational attainment, each of which was divided into three strata. LVH was defined as LV mass/height2.7 ≥ 47 g/m2.7 in female and ≥ 50 g/m2.7 in male. Age, sex, diabetes, CKD stage, body mass index, blood pressure and physical activity were included as covariates. RESULTS: A total of 1361 patients were included. Mean age was 60.9 ± 6.9 years, and 63.2% were men. Higher education level was associated with higher monthly income (P for trend < 0.001). The lowest education level was independently associated with LVH (lower than high school, adjusted odds ratio [OR] 1.485, 95% CI 1.069-2.063, P = 0.018; completed high school, adjusted OR 1.150, 95% confidence interval [CI] 0.834-1.584, P = 0.394; highest education level as the reference). Monthly income level was marginally associated with LVH after adjusting for covariates ($1500-4500, adjusted OR 1.230, 95% CI 0.866-1.748, P = 0.247; < $1500, adjusted OR 1.471, 95% CI 1.002-2.158, P = 0.049; > $4500; reference). CONCLUSIONS: In the CKD population, lower SES, defined by educational attainment and low income level exhibited a significant association with LVH, respectively. Longitudinal follow-up will reveal whether lower SES is associated with poor CKD outcomes.

Correction to: The association between socioeconomic disparities and left ventricular hypertrophy in chronic kidney disease: results from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD).

Following publication of the original article [1], an error in one of the author names was reported. In this Correction the incorrect and correct author names are listed.

The two isoforms of matrix metalloproteinase- 2 have distinct renal spatial and temporal distributions in murine models of types 1 and 2 diabetes mellitus.

BACKGROUND: We recently reported on the enhanced tubular expression of two discrete isoforms of the MMP-2 (full length and N-terminal truncated, FL-MMP-2, NTT-MMP-2) in a murine model and human diabetic kidneys. In the present study, we examined in more detail the temporal and spatial distributions of MMP-2 isoform expression in murine models of Type 1 and Type 2 diabetes mellitus. METHODS: Diabetic models were streptozotocin (STZ)-induced diabetes (Type 1 diabetes mellitus) and db/db mice (Type 2 diabetes mellitus). We quantified the abundance of two isoforms of MMP-2 transcripts by qPCR. A spatial distribution of two isoforms of MMP-2 was analyzed semi-quantitatively according to time after injection of STZ and with increasing age of db/db mice. Furthermore, immunohistochemistry for nitrotyrosine was performed to examine a potential association between oxidative stress and MMP-2 isoform expression. RESULTS: Both isoforms of MMP-2 were upregulated in whole kidneys from STZ and db/db mice. In the case of FL-MMP-2, mRNA levels significantly increased at 12 and 24 weeks in STZ mice, while the isoform expression was significantly increased only at 16 weeks, in the db/db mice. FL-MMP-2 protein levels increased in the cortices and outer medullae of both STZ and db/db mice as a function of the duration of diabetes. For NTT-MMP-2, mRNA levels increased earlier at 4 weeks in STZ mice and at 10 weeks of age in db/db mice. The expression of NTT-MMP-2 also increased, primarily in the cortices of STZ and db/db mice, as a function of the duration of diabetes. Quantitatively, these findings were consistent with the qPCR results in the case of NTT-MMP-2, respectively (STZ 24 weeks, 3.24 ± 3.70 fold; 16 weeks db/db, 4.49 ± 0.55 fold). In addition, nitrotyrosine was expressed primarily in cortex as compared to medulla as a function of the duration of diabetes similar to NTT-MMP-2 expression. CONCLUSIONS: Two isoforms of MMP-2 are highly inducible in two diabetic murine models and become more abundant as a function of time. As the expression patterns were not the same in the two isoforms of MMP-2, it is possible that each isoform has a discrete role in the development of diabetic renal injury.

The P2X7 receptor antagonist, oxidized adenosine triphosphate, ameliorates renal ischemia-reperfusion injury by expansion of regulatory T cells.

Extracellular adenosine triphosphate (ATP) binds to purinergic receptors and, as a danger molecule, promotes inflammatory responses. Here we tested whether periodate-oxidized ATP (oATP), a P2X7 receptor (P2X7R) antagonist can attenuate renal ischemia-reperfusion injury and clarify the related cellular mechanisms. Treatment with oATP prior to ischemia-reperfusion injury decreased blood urea nitrogen, serum creatinine, the tubular injury score, and tubular epithelial cell apoptosis after injury. The infiltration of dendritic cells, neutrophils, macrophages, CD69+CD4+, and CD44+CD4+ T cells was attenuated, but renal Foxp3+CD4+ Treg infiltration was increased by oATP. The levels of IL-6 and CCL2 were reduced in the oATP group. Additionally, oATP treatment following injury improved renal function, decreased the infiltration of innate and adaptive effector cells, and increased the renal infiltration of Foxp3+CD4+ Tregs. Post-ischemia-reperfusion injury oATP treatment increased tubular cell proliferation and reduced renal fibrosis. oATP treatment attenuated renal functional deterioration after ischemia-reperfusion injury in RAG-1 knockout mice; however, Treg depletion using PC61 abrogated the beneficial effects of oATP in wild-type mice. Furthermore, oATP treatment after transfer of Tregs from wild-type mice improved the beneficial effects of Tregs on ischemia-reperfusion injury, but treatment after transfer of Tregs from P2X7R knockout mice did not. Renal ischemia-reperfusion injury was also attenuated in P2X7R knockout mice. Experiments using bone marrow chimeras established that P2X7R expression on hematopoietic cells rather than non-hematopoietic cells, such as tubular epithelial cells, plays a major role in ischemia-reperfusion injury. Thus, oATP attenuated acute renal damage and facilitated renal recovery in ischemia-reperfusion injury by expansion of Tregs.

Poor predictability of QuantiFERON-TB assay in recipients and donors for tuberculosis development after kidney transplantation in an intermediate-TB-burden country.

BACKGROUND: Tuberculosis (TB) is a common opportunistic infection after kidney transplantation (KT). The QuantiFERON-TB-Gold In-Tube test (QFT) is widely used for assessing latent TB; however, it is currently unclear whether the pre-KT QFT of the recipient and donor can predict post-KT TB. METHODS: We retrospectively reviewed patients who received KT between January 2009 and December 2015 at Seoul National University Hospital. The QFT was performed in 458 KT recipients and 239 paired living donors, and 138 KT recipients underwent both the QFT and tuberculin skin test (TST). After excluding 12 patients diagnosed as having clinically latent TB, we evaluated whether the QFT of the recipient and donor was predictive for new-onset active TB after KT. RESULTS: The QFT was positive in 101 (22.1%) recipients and associated with clinically latent TB before KT (P < 0.05). However, agreement between the TST and QFT was poor (κ = 0.327). Post-KT TB occurred in 1 of 95 recipients with a positive QFT, and 2 cases of TB occurred among 351 patients with a negative or indeterminate QFT. The incidence of TB was 242 cases/100,000 person-years among 446 KT recipients with a median follow-up of 30.2 months. The QFT of recipients could not predict post-KT TB in Poisson regression analysis (relative risk [RR], 1.847; 95% confidence interval [CI], 0.168-20.373; P = 0.616). Of 234 living donor-recipient pairs, the QFT of the recipient (RR, 5.012; 95% CI, 0.301-83.430; P = 0.261) and QFT of the donor (RR, 1.758; 95% CI, 0.106-29.274; P = 0.694) could not predict post-KT TB. CONCLUSION: The QFT of recipients or living donors pre-KT cannot predict the short-term development of post-KT TB in an intermediate TB-burden country.

The role of the specialized team in the operation of continuous renal replacement therapy: a single-center experience.

BACKGROUND: The requirement of continuous renal replacement therapy (CRRT) is increasing with the growing incidence of acute kidney injury (AKI). The decision to initiate CRRT is not difficult if an adequate medical history is obtained. However, the handling and maintenance of CRRT constitute a labor-intensive intervention that requires specialized skills. For these reasons, our center organized a specialized CRRT team in March 2013. The aim of this study is to report on the role of a specialized CRRT team and to evaluate the team's outcome. METHODS: This retrospective single-center study evaluated AKI patients who underwent CRRT in the intensive care unit (ICU) from March 2011 to February 2015. Patients were divided into two groups based on whether they received specialized CRRT team intervention. We collected information on demographic characteristics, laboratory parameters, SOFA score, CRRT initiation time, actual delivered dose and CRRT down-time. In-hospital mortality was defined by medical chart review. Binary logistic regression analysis was used to define factors associated with in-hospital mortality. RESULTS: A total of 1104 patients were included in this study. The mean patient age was 63.85 ± 14.39 years old, and 62.8% of the patients were male. After the specialized CRRT team intervention, there was a significant reduction in CRRT initiation time (5.30 ± 13.86 vs. 3.60 ± 11.59 days, p = 0.027) and CRRT down-time (1.78 ± 2.23 vs. 1.38 ± 2.08 h/day, p = 0.002). The rate of in-hospital mortality decreased after the specialized CRRT team intervention (57.5 vs. 49.2%, p = 0.007). When the multivariable analysis was adjusted, delayed CRRT initiation (HR 1.054(1.036-1.072), p < 0.001) was a significant factor in predicting in-hospital mortality, along with an increased SOFA score, lower serum albumin and prolonged prothrombin time. CONCLUSIONS: Our study shows that specialized CRRT team intervention reduced CRRT initiation time, down-time and in-hospital mortality. This study could serve as a logical basis for implementing specialized CRRT teams hospital-wide.

VDJ gene usage among B-cell receptors in ABO-incompatible kidney transplantation determined by RNA-seq Transcriptomic analysis.

BACKGROUND: Studies on B-cell subtypes and V(D)J gene usage of B-cell receptors in kidney transplants are scarce. This study aimed to investigate V(D)J gene segment usage in ABO-incompatible (ABOi) kidney transplant (KT) patients compared to that in ABO-compatible (ABOc) KT patients. METHODS: We selected 16 ABOi KT patients with accommodation (ABOiA), 6 ABOc stable KT patients (ABOcS), and 6 ABOi KT patients with biopsy-proven acute antibody-mediated rejection (ABOiR) at day 10, whose graft tissue samples had been stored in the biorepository between 2010 and 2014. Complete transcriptomes of graft tissues were sequenced and analyzed through RNA sequencing (RNA-seq). The international ImMunoGeneTics information system (IMGT®) was used for in-depth comparison of V(D)J gene segment usage. RESULTS: The mean age of the 28 KT recipients was 43.3 ± 12.8 years, and 53.6% were male. By family, IGHV3, IGHJ4, IGLV2, and IGLJ3 gene segments were most frequently used in all groups, and their usage was not statistically different among the three patient groups. While IGKV3 was most frequently used in both the ABOiA and ABOiR groups, IGKV1 was most commonly used in the ABOcS group. In addition, while IGKJ1 was most commonly used in the ABOiA and ABOcS groups, IGKJ4 was most frequently used in the ABOiR group. According to individual gene segments, IGHV4-34 and IGHV4-30-2 were more commonly used in the ABOiR group than in the ABOiA group, and IGHV6-1 was more commonly used in the ABOcS group than in the ABOiR group. IGLV7-43 was more commonly used in the ABOcS group than in the ABOi group. However, technical variability, small sample size, and potential confounding effects of Rituximab or HLA mismatching are limitations of our study. CONCLUSIONS: Our findings suggest that RNA-seq transcriptomic analyses can provide information on the V(D)J gene usage of B-cell receptors and the mechanisms of accommodation and immune reaction in ABOi KT.

Baseline General Characteristics of the Korean Chronic Kidney Disease: Report from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD).

The KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD) was developed to investigate various clinical courses and risk factors for progression of Korean chronic kidney disease (CKD). The KNOW-CKD study consists of nine clinical centers in Korea, and patients aged between 20 and 75 years with CKD from stage 1 to 5 (predialysis) were recruited. At baseline, blood and urine samples were obtained and demographic data including comorbidities, drugs, quality of life, and health behaviors were collected. Estimated glomerular filtration rate (eGFR) was calculated by 4-variable Modification of Diet in Renal Disease (MDRD) equation using isotope dilution mass spectrometry (IDMS)-calibrated serum creatinine measured at a central laboratory. As a dynamic cohort, a total of 2,341 patients were enrolled during the enrollment period from 2011 until 2015, among whom 2,238 subjects were finally analyzed for baseline profiles. The mean age of the cohort was 53.7 ± 12.2 year and 61.2% were men. Mean eGFR was 50.5 ± 30.3 mL/min/1.73 m². The participants with lower eGFR had a tendency to be older, with more comorbidities, to have higher systolic blood pressure (BP) and pulse pressure, with lower income level and education attainment. The patients categorized as glomerulonephritis (GN) were 36.2% followed by diabetic nephropathy (DN, 23.2%), hypertensive nephropathy (HTN, 18.3%), polycystic kidney disease (PKD, 16.3%), and other unclassified disease (6.1%). The KNOW-CKD participants will be longitudinally followed for 10 years. The study will provide better understanding for physicians regarding clinical outcomes, especially renal and cardiovascular outcomes in CKD patients.

Outcomes of dialysis and the transplantation options for patients with diabetic end-stage renal disease in Korea.

BACKGROUND: The best therapeutic option for diabetic end-stage renal disease (DMESRD) has not been established among living donor kidney transplantation (LDKT), deceased donor kidney transplantation (DDKT), simultaneous pancreas and kidney transplantation (SPK), and dialysis. METHODS: We retrospectively analyzed the outcomes of DMESRD patients at two Korean centers from February 2000 to December 2011. RESULTS: Among 674 patients, 295 underwent kidney transplantation (LDKT, 175; DDKT, 72; and SPK, 48), while 379 were still on dialysis. The dialysis group had a higher mortality rate than the transplantation group. From the time after dialysis initiation, LDKT group had a better patient survival rate than DDKT registration group and SPK registration group. From the time after transplantation, LDKT had a better patient survival rate than DDKT; however, there was no significant difference between LDKT and SPK. In SPK, patient survival and kidney or pancreas graft survival rates were not different between types 1 and 2 DMESRD. CONCLUSION: LDKT is better than waiting for SPK/DDKT in DMESRD patients, if a living donor is available, and this conclusion may be unique to Korea where waiting time for SPK is long. SPK can be used in non-obese Asians with type 2 as well as type 1 DMESRD.

Comparison of volume-reductive therapies for massive polycystic liver disease in autosomal dominant polycystic kidney disease.

AIM: Polycystic liver disease (PLD) in autosomal dominant polycystic kidney disease (ADPKD) patients can induce massive hepatomegaly-related symptoms. Volume-reductive therapies for symptomatic PLD include transcatheter arterial embolization (TAE), liver resection and liver transplantation; however, consensus has not been reached regarding treatment selection. We compared three volume-reductive therapies for a better understanding of PLD treatment strategies. METHODS: We retrospectively analyzed 28 ADPKD patients who underwent TAE, liver resection or liver transplantation for PLD at a single center, and compared their outcomes. RESULTS: Of 18 TAE patients, five required repeat TAE, and five required rescue liver transplantation or liver resection because of refractory symptoms or hepatic failure. The treatment failure rate for TAE was high (69.6%). Nine underwent liver resection, and the degree of volume reduction in the liver resection group was greater than that in the TAE group (52.4% vs 7.6%, P < 0.001). One liver resection patient required rescue liver transplantation because of hepatic failure. Seven patients underwent liver transplantations. All liver transplant patients had successfully controlled symptoms or hepatic failure, and had good graft function. Three patients in the TAE group died of infections or hepatic failure, whereas no mortality occurred after surgical therapy. CONCLUSION: Liver resection is a good first-line therapy in patients that have severe symptoms, cyst involvement in several segments with some spared segments and preserved liver function. Liver transplantation is a preferred first-line therapy in patients with poor liver function or whole-liver involvement. Liver transplantation is also a good rescue therapy following TAE or liver resection.

Granulocyte colony-stimulating factor treatment ameliorates lupus nephritis through the expansion of regulatory T cells.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) can induce regulatory T cells (Tregs) as well as myeloid-derived suppressor cells (MDSCs). Despite the immune modulatory effects of G-CSF, results of G-CSF treatment in systemic lupus erythematosus are still controversial. We therefore investigated whether G-CSF can ameliorate lupus nephritis and studied the underlying mechanisms. METHODS: NZB/W F1 female mice were treated with G-CSF or phosphate-buffered saline for 5 consecutive days every week from 24 weeks of age, and were analyzed at 36 weeks of age. RESULTS: G-CSF treatment decreased proteinuria and serum anti-dsDNA, increased serum complement component 3 (C3), and attenuated renal tissue injury including deposition of IgG and C3. G-CSF treatment also decreased serum levels of BUN and creatinine, and ultimately decreased mortality of NZB/W F1 mice. G-CSF treatment induced expansion of CD4+CD25+Foxp3+ Tregs, with decreased renal infiltration of T cells, B cells, inflammatory granulocytes and monocytes in both kidneys and spleen. G-CSF treatment also decreased expression levels of MCP-1, IL-6, IL-2, and IL-10 in renal tissues as well as serum levels of MCP-1, IL-6, TNF-α, IL-10, and IL-17. When Tregs were depleted by PC61 treatment, G-CSF-mediated protective effects on lupus nephritis were abrogated. CONCLUSIONS: G-CSF treatment ameliorated lupus nephritis through the preferential expansion of CD4+CD25+Foxp3+ Tregs. Therefore, G-CSF has a therapeutic potential for lupus nephritis.

Increased urinary Angiotensinogen/Creatinine (AGT/Cr) ratio may be associated with reduced renal function in autosomal dominant polycystic kidney disease patients.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary kidney diseases that frequently result in renal failure. In this cross-sectional observational cohort study, we evaluated urinary angiotensinogen (AGT) as a potential biomarker to assess renal function in ADPKD. METHODS: Urinary AGT was measured in 233 ADPKD patients and its association with estimated glomerular filtration rate (eGFR) and height-adjusted total kidney volume (htTKV) were evaluated. The localization of AGT and other renin-angiotensin system (RAS)-related molecules were identified using immunohistochemistry in human ADPKD tissues. RESULTS: Baseline urinary AGT/Cr was negatively correlated with CKD-EPI eGFR (r(2) = 0.162, P < 0.001) and positively correlated with htTKV (r(2) = 0.107, P < 0.001). Both urinary AGT/Cr and plasma renin activity levels were significantly elevated in hypertensive ADPKD patients. Among hypertensive subjects, urinary AGT/Cr was significantly increased in the advanced CKD stages (III-V) compared to early CKD stages (I-II) (28.6 ± 60.3 vs. 93.2 ± 139.3 µg/g, P < 0.001). Immunohistochemical study showed strong expression of AGT along the cyst-lining epithelial cells as well as the nearby compressed tubular epithelial cells. CONCLUSIONS: Our results suggested that urinary AGT/Cr may be a valuable biomarker for renal damage in ADPKD since intrarenal ischemic insults induced by cyst growth and subsequent intrarenal RAS activation may play a potential role in the development of hypertension and renal dysfunction in ADPKD.