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Background: Growth arrest and DNA damage 45G (GADD45G) is a family of proteins involved in DNA damage response and cell growth arrest. In this study, we show evidence that urinary GADD45G protein is associated with the progression of IgA nephropathy. Methods: Patients diagnosed with IgA nephropathy without reversible acute kidney injury at study initiation and with at least one subsequent serum creatinine (SCr) measurement were included. A 50% or greater increase in SCr level was used as an endpoint for the deterioration of renal function. Enzyme-linked immunosorbent assay (ELISA) was performed using a Human GADD45G ELISA kit. Renal biopsy tissues were stained with a monoclonal mouse anti-GADD45G antibody. Results: Forty-five patients whose renal biopsy revealed IgA nephropathy were enrolled. Urinary GADD45G and urinary protein concentrations were 1.26 [0.69–2.20] μg/g creatinine and 0.65 [0.24–1.60] g/g creatinine, respectively. Urinary GADD45G showed significant positive correlations with SCr-slopes and urinary protein. The SCr-slope of the highest tertile group of urinary GADD45G (above 1.95 μg/g creatinine) was significantly higher than that of the lowest tertile group (below 0.90 μg/g). Univariate Cox regression analysis showed that urinary GADD45G was significantly associated with deterioration of renal function. A Kaplan–Meier test showed a significant difference in event-free survival for deterioration of renal function between the highest urinary GADD45G tertile group and other tertile groups. The area under the receiver operating characteristics (ROC) curve indicated urinary GADD45G had a good performance in predicting renal outcome (cut-off point 1.67 μg/g, positive predictive value 36.8%, negative predictive value 100%). Immunohistochemistry showed that GADD45G was expressed across all pathologic grades of IgA nephropathy and mainly detected in the cytoplasm of renal tubules, whereas no staining was noted in normal tissues. Conclusions: Urinary GADD45G excretion was significantly associated with kidney disease progression in patients with IgA nephropathy.

Background Optimal estimated glomerular filtration rate (eGFR) to start maintenance dialysis is controversial. Observational studies have reported that initiation of dialysis at high eGFRs is associated with worse postdialysis survival. Methods We retrospectively investigated 1,038 incident dialysis patients who started maintenance dialysis during 2010–2015. Patients were assessed for comorbidities and adverse events during the transitional period of dialysis initiation. Patients were classified as planned dialysis (PD) vs. unplanned dialysis (UD) according to indications for dialysis initiation. Results UD group comprised 352 patients (33.9%). Mean eGFR at dialysis initiation was higher in UD patients than PD patients (7.9 ± 5.1 vs. 5.9 ± 3.4 mL/min/1.73 m2, p < 0.001). Mean Davies comorbidity index in the UD group was higher (vs. PD group, 1.3 ± 1.0 vs. 0.9 ± 1.0, p < 0.001). Patients with more comorbidities experienced more ischemic heart disease (hazard ratio [HR], 4.36; 95% confidence interval [CI], 1.71–11.14) in the medium-risk group and HR of 8.84 (95% CI, 3.06–25.55) in the high-risk group (vs. low-risk group, p < 0.001)) during the predialysis period. High-risk group had increased postdialysis mortality (HR, 2.48; 95% CI, 1.46–4.20; p = 0.001). Adjusted HR of mortality was higher in the medium-risk group of UD patients (HR, 1.72; 95% CI, 1.16–2.56; p = 0.007). Conclusion Patients with more comorbidities were at increased risk of predialysis ischemic heart disease and postdialysis mortality. UD patients in the medium-risk population had increased risk of postdialysis mortality. Dialysis start should be individualized by considering comorbidities.

Abstract Background In the general population, the trabecular bone score (TBS) represents the bone microarchitecture and predicts fracture risk independent of bone mineral density (BMD). A few studies reported that TBS is significantly reduced in dialysis patients. Chronic kidney disease-mineral and bone disorder (CKD-MBD) are accompanied by increased fracture risk, cardiovascular morbidity, and mortality. We investigated whether TBS is associated with comorbidity related to CKD-MBD or frailty in hemodialysis patients. Methods In this prospective observational study, TBS was obtained using the TBS iNsight software program (Med-Imaps) with BMD dual energy x-ray absorptiometry (DXA) images (L1–L4) from prevalent hemodialysis patients. A Tilburg frailty indicator was used to evaluate frailty, and hand grip strength and bio-impedance (InBody) were measured. A patient-generated subjective global assessment (PG-SGA) was used for nutritional assessment. The history of cardiovascular events (CVE) and demographic, clinical, laboratory, and biomarker data were collated. We then followed up patients for the occurrence of CKD-MBD related complications. Results We enrolled 57 patients in total. The mean age was 56.8 ± 15.9 years (50.9% female). Prevalence of Diabetes mellitus (DM) was 40.4% and CVE was 36.8%. Mean TBS was 1.44 ± 0.10. TBS significantly reduced in the CVE group (1.38 ± 0.08 vs. 1.48 ± 0.10, p

BackgroundMelanoma-associated antigen H1 (MAGEH1) is a protein that belongs to melanoma-associated antigen (MAGE) superfamily. Growth arrest and DNA damage 45G (GADD45G) is a member of the DNA damage-inducible gene family which responds to environmental stresses. We have previously shown that GADD45G is a protein that promotes apoptosis of renal tubular cells in response to a nephrotoxic injury. In this study, we show evidence that MAGEH1 interacts with GADD45G and is involved in the induction of nephrotoxin-induced apoptosis of renal tubular cells.MethodsPrimary human renal tubular epithelial (HRE) cells and human kidney 2 (HK-2) cells were used in this study. To produce stable cell lines in which MAGEH1 expression was silenced, HRE cells were transduced with a lentiviral vector encoding a single guide RNA construct targeting the MAGEH1 gene. To knockdown GADD45G expression in HRE cells, a vector containing short hairpin RNA (shRNA) was used. We used short interfering RNAs (siRNA) to achieve transient silencing of genes in HK-2 cells. Recombinant adenoviruses were synthesized to overexpress MAGEH1 and GADD45G proteins. Human protein microarray was used to identify proteins that binds to GADD45G. Co-immunoprecipitation assays were then performed to confirm microarray results. Cell death was induced by cyclosporine A (CsA). Real-time quantitative PCR assay was used to evaluate gene expression levels. The degree of apoptosis and necrosis of cultured cells was evaluated by flow cytometry. Expression levels of caspases were examined using western blot analysis.ResultsWe found that GADD45G bound to one protein spotted in the protein microarray, which was subsequently identified as MAGEH1. We confirmed the interaction between GADD45G and MAGEH1 protein using the co-immunoprecipitation assay. MAGEH1 gene expression was not altered by CsA-induced cytotoxic injury, whereas GADD45G gene expression was increased significantly upon CsA treatment. MAGEH1 expression was significantly downregulated in GADD45G knockdown HRE stable cells suggesting that MAGEH1 expression may be dependent on GADD45G expression. CsA-induced apoptosis was significantly reduced in MAGEH1 knockdown HRE stable cells which led to an increased survival of these cells. Similar results were observed in GADD45G knockdown HRE stable cells. Accordingly, CsA-induced apoptosis was significantly decreased in MAGEH1 siRNA and GADD45G siRNA transfected HK-2 cells. CsA-induced activation of caspase-7 and caspase-9 was inhibited in MAGEH1 knockdown HRE stable cells, and similarly in GADD45G knockdown HRE stable cells.ConclusionsTo the best of our knowledge, this is the first study to show that MAGEH1 interacts with GADD45G and that MAGEH1 is involved in caspase-dependent apoptosis of renal tubular cells induced by nephrotoxic drugs.

Background : For phosphate control, patient education is essential due to the limited clearance of phosphate by dialysis. However, well-designed randomized controlled trials about dietary and phosphate binder education have been scarce. Methods : We enrolled maintenance hemodialysis patients and randomized them into an education group (n = 48) or a control group (n = 22). We assessed the patients' drug compliance and their knowledge about the phosphate binder using a questionnaire. Results : The primary goal was to increase the number of patients who reached a calcium-phosphorus product of lower than 55. In the education group, 36 (75.0%) patients achieved the primary goal, as compared with 16 (72.7%) in the control group (P = 0.430). The education increased the proportion of patients who properly took the phosphate binder (22.9% vs. 3.5%, P = 0.087), but not to statistical significance. Education did not affect the amount of dietary phosphate intake per body weight (education vs. control: -1.18 ± 3.54 vs. -0.88 ± 2.04 mg/kg, P = 0.851). However, the dietary phosphate-to-protein ratio tended to be lower in the education group (-0.64 ± 2.04 vs. 0.65 ± 3.55, P = 0.193). The education on phosphate restriction affected neither the Patient-Generated Subjective Global Assessment score (0.17 ± 4.58 vs. -0.86 ± 3.86, P = 0.363) nor the level of dietary protein intake (-0.03 ± 0.33 vs. -0.09 ± 0.18, P = 0.569). Conclusion : Education did not affect the calcium-phosphate product. Education on the proper timing of phosphate binder intake and the dietary phosphate-to-protein ratio showed marginal efficacy.

Background: Plasmapheresis has become an essential element of kidney transplantation (KT). In the present study, we report clinical outcomes of filtration plasmapheresis using continuous renal replacement therapy machines with a single filter for the first time in Korea. Methods: We retrospectively analyzed six patients who underwent filtration plasmapheresis for KT in our center; plasmapheresis was performed using the Plasmaflex (Baxter®) with a TPE 2000 filter set (Baxter®) in our hemodialysis unit. Five percent albumin was used as the replacement fluid, and intravenous immunoglobulin G was administered after each plasmapheresis session. The target preoperative ABO isoagglutinin titer was less than 1:8. Results: Filtration plasmapheresis was performed in four patients for ABO-incompatible KT, one for antibody-mediated rejection after KT, and the last one for positive T cell crossmatch. Altogether, 46 sessions of plasmapheresis were performed. ABO isoagglutinin titers successfully declined to or below the target level in all patients, and all patients successfully received KT with no significant antibody titer rebound. Acute antibody-mediated rejection and positive T cell crossmatch were well treated with filtration plasmapheresis, and no patient required fresh frozen plasma infusion for coagulopathy. There were one episode of hypotension and three of hypocalcemia. No patients experienced bleeding, infection, or allergic reaction. Conclusion: Filtration plasmapheresis was effective and safe. Although our result is from a single center, our protocol appears to be promising.

BackgroundGrowth Arrest and DNA Damage 45γ (GADD45γ) is a member of the DNA damage-inducible gene family which responds to environmental stresses. Apoptosis is a critical mode of renal tubular cell death in nephrotoxin-induced acute kidney injury. In this study, we investigated the role of GADD45γ in renal tubular cell apoptosis induced by nephrotoxic drugs.MethodsPrimary human renal tubular epithelial (HRE) cells were used in this study. To derive stable cell lines in which GADD45γ expression was silenced, HRE cells were transduced with a plasmid encoding GADD45γ-specific shRNA. The recombinant adenovirus containing the GADD45γ gene was synthesized to overexpress GADD45γ protein. Cell death was induced by cisplatin and cyclosporine A (CsA). To prevent apoptotic cell death, pan-caspase inhibitor ZVAD-FMK was used. To prevent non-apoptotic cell death, necrostatin-1 and ferrostatin-1 were used. The degree of apoptosis and necrosis of cultured cells were evaluated by flow cytometry.ResultsExpression of the GADD45γ gene was significantly upregulated in response to treatment with CsA and cisplatin. Apoptosis and necrosis induced by these drugs were significantly reduced by silencing of GADD45γ, and significantly augmented by the overexpression of GADD45γ. The activation of caspase-3 and caspase-7 as well as caspase-9 induced by cisplatin or CsA was reduced by silencing of GADD45γ, and was augmented by the overexpression of GADD45γ, indicating that caspase activation is dependent on the expression of GADD45γ. ZVAD-FMK significantly inhibited apoptosis induced by cisplatin or CsA, indicating a role of caspases in mediating apoptotic cell death. ZVAD-FMK was effective to prevent necrosis as well, indicating that the observed necrosis was a secondary event following apoptosis at least in part.ConclusionsTo our knowledge, this is the first study to show that GADD45γ is required for the caspase-dependent apoptosis of renal tubular cells induced by nephrotoxic drugs.

Background: Estimated glomerular filtration rate (eGFR) is one of the most important guidelines in deciding the optimal timing of dialysis initiation. In the present study, we calculated the eGFR at the time of hemodialysis (HD) initiation using 5 commonly used equations to relate them with clinical and laboratory characteristics of the patients and to evaluate which of these equations best define the eGFR at HD initiation. Methods: We retrospectively analyzed 409 end-stage renal disease patients who were newly started on HD treatment in our institution. The eGFR was calculated using the Cockcroft–Gault equation, the Cockcroft–Gault equation corrected for body surface area, the Modification of Diet in Renal Disease (MDRD) equation, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, and the Nankivell equation. Results: The mean eGFRs at HD start were significantly different across the equations. The mean eGFR was 7.8 mL/min for the corrected Cockcroft–Gault equation, 7.7 mL/min for the Cockcroft–Gault equation, 6.2 mL/min/1.73 m2 for the MDRD equation, and 5.6 mL/min/1.73 m2 for the CKD-EPI equation. The corrected Cockcroft–Gault, the MDRD, and the CKD-EPI equations were well correlated with all CKD-specific complications including hypertension, anemia, hyperkalemia, metabolic acidosis, hypocalcemia, hyperphosphatemia, and hyperparathyroidism. The mean eGFR calculated by the corrected Cockcroft–Gault equation showed the lowest coefficient of variation among all the equations. Conclusions: The eGFR at HD initiation are significantly different according to the used eGFR equations, and the corrected Cockcroft–Gault equation may be the best in defining the eGFR at HD initiation.

Mushroom-related poisoning can cause acute kidney injury. Here we report a case of acute kidney injury after ingestion of Amanita punctata, which is considered an edible mushroom. Gastrointestinal symptoms occurred within 24 hours from the mushroom intake and were followed by an asymptomatic period, acute kidney injury, and elevation of liver and pancreatic enzymes. Kidney function recovered with supportive care. Nephrotoxic mushroom poisoning should be considered as a cause of acute kidney injury.

PURPOSE:We aimed to develop a model of chronic kidney disease (CKD) progression for predicting the probability and time to progression from various CKD stages to renal replacement therapy (RRT), using 6 months of clinical data variables routinely measured at healthcare centers. METHODS:Data were derived from the electronic medical records of Ajou University Hospital, Suwon, South Korea from October 1997 to September 2012. We included patients who were diagnosed with CKD (estimated glomerular filtration rate [eGFR] < 60 mL·min-1·1.73 m-2 for ≥ 3 months) and followed up for at least 6 months. The study population was randomly divided into training and test sets. RESULTS:We identified 4,509 patients who met reasonable diagnostic criteria. Patients were randomly divided into 2 groups, and after excluding patients with missing data, the training and test sets included 1,625 and 1,618 patients, respectively. The integral mean was the most powerful explanatory (R2 = 0.404) variable among the 8 modified values. Ten variables (age, sex, diabetes mellitus[DM], polycystic kidney disease[PKD], serum albumin, serum hemoglobin, serum phosphorus, serum potassium, eGFR (calculated by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]), and urinary protein) were included in the final risk prediction model for CKD stage 3 (R2 = 0.330). Ten variables (age, sex, DM, GN, PKD, serum hemoglobin, serum blood urea nitrogen[BUN], serum calcium, eGFR(calculated by Modification of Diet in Renal Disease[MDRD]), and urinary protein) were included in the final risk prediction model for CKD stage 4 (R2 = 0.386). Four variables (serum hemoglobin, serum BUN, eGFR(calculated by MDRD) and urinary protein) were included in the final risk prediction model for CKD stage 5 (R2 = 0.321). CONCLUSION:We created a prediction model according to CKD stages by using integral means. Based on the results of the Brier score (BS) and Harrel's C statistics, we consider that our model has significant explanatory power to predict the probability and interval time to the initiation of RRT.

Purpose: Since patients on hemodialysis (HD) are known to be vulnerable to coronavirus disease 2019 (COVID-19), many studies were conducted regarding the effectiveness of the COVID-19 vaccine in HD patients in Western countries. Here, we assessed antibody response of HD patients for 6 months post-vaccination to identify the duration and effectiveness of the COVID-19 vaccine in the Asian population. Materials and Methods: We compared antibody response of the COVID-19 vaccine in HD patients with healthy volunteers. Patient and control groups had two doses of ChAdOx1 nCoV- 19 and mRNA-1273, respectively. Immunoglobulin G (IgG) was measured before vaccination, 2 weeks after the first dose, 2 and 4 weeks, 3 and 6 months after the second dose. Neutralizing antibody was measured before vaccination and at 2 weeks, 3 and 6 months after second dose. Since the third dose was started in the middle of the study, we analyzed the effect of the third dose as well. Results: Although antibody production was weaker than the control group (n=22), the patient group (n=39) showed an increase in IgG and neutralizing antibody after two doses. And, 21/39 patients and 14/22 participants had a third dose (BNT162b2 or mRNA-1273 in the patient group, mRNA-1273 in the control group), and it did not affect antibody response in both group. Trend analysis showed IgG and neutralizing antibody did not decrease over time. Age, sex, and HD vintage did not affect antibody production in HD patients. Patients with higher body mass index displayed better seroresponse, while those on immunosuppressants showed poor seroresponse. Conclusion: Two doses of vaccination led to significant antibody response in HD patients, and the antibody did not wane until 6 months. [ABSTRACT FROM AUTHOR]

Background and Aim: Clinical use of angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) is associated with hyperkalemia as an adverse drug reaction. Although it has significant clinical implications, the incidence and relative risks of hyperkalemia with various ARBs have not yet been fully evaluated. The purpose of this study was to determine the risk of hyperkalemic events in hospitalized patients treated with different ARBs and to compare the risk among them. Methods: We constructed a retrospective cohort composed of hospitalized adult patients who took ARBs in a single tertiary teaching hospital between April 2004 and March 2010. We estimated the incidence of hyperkalemia (serum potassium level >5.5 mEq/L) with various ARBs, and then compared the risk between them using a multivariate Cox proportional hazard model based on age, sex, Charlson co-morbidity score, baseline serum potassium, underlying diseases, and concomitant drugs. Results: We identified 6992 evaluable intervals from 5449 patients treated with one of the seven ARBs during hospitalization over the 71-month study period with 2521.6 patient-months. We found 381 hyperkalemic events (5.4 %) during the study period and an overall event rate of 15.1/100 patient-months. Moderate to fatal hyperkalemia was relatively rare ( >6.0 mEq/L, 2.1 % [moderate]; >6.5 mEq/L, 0.9 % [severe]; >7.0 mEq/L, 0.3% [fatal]). After adjustment for covariates, telmisartan showed a lower risk of hyperkalemia (hazard ratio 0.67; 95% confidence interval 0.51, 0.89) compared with all other ARBs. Conclusion: The risk of hyperkalemic events in hospitalized patients treated with different ARBs was defined. Telmisartan showed a relatively lower hyperkalemic risk profile in hospitalized patients compared with other ARBs. [ABSTRACT FROM AUTHOR]

Effects of suppressing intrarenal angiotensinogen on renal transforming growth factor-β1 expression in acute ureteral obstruction.Background.Angiotensin II (Ang II) mediates the up-regulation of fibrogenic factors such as transforming growth factor-β1 (TGF-β1) in chronic renal diseases. In addition, it has been proposed that the intrarenal renin-angiotensin system (RAS) is as important as the systemic RAS in kidney disease progression.Methods.We suppressed angiotensinogen (AGT) gene expression in the kidney by transferring recombinant adenoviral vectors carrying a transgene expressing AGT antisense mRNA, and determined the effect of the local inhibition of the RAS on TGF-β1 synthesis in the kidneys of rats with unilateral ureteral obstruction (UUO). Immediately after UUO, recombinant adenovirus vectors were injected intraparenchymally into the cortex of obstructed kidneys.Results.β-galactosidase (β-gal)–stained kidney sections revealed the efficient transduction of the recombinant adenoviral vectors into tubular epithelial cells. Kidney cortex injected with AGT antisense showed significantly lower native AGT mRNA and protein expressions than control UUO kidneys at 24 hours and 5 days post-UUO. TGF-β1 was significantly up-regulated in the renal cortex 24 hours and 5 days post-UUO, whereas AGT antisense–injected UUO rats showed significantly reduced TGF-β1 expression compared to control UUO rats. Both fibronectin and collagen type I expressions were increased 24 hours and 5 days post-UUO, and these augmentations were considerably reduced by AGT antisense RNA treatment.Conclusion. This study demonstrates that the suppression of intrarenal RAS prevents the formation of renal cortical TGF-β1, and of related fibrogenic factors, in early UUO. [ABSTRACT FROM AUTHOR]

Background Patients undergoing hemodialysis are susceptible to sarcopenia. As intracellular reservoirs of water, skeletal muscles are important contributors to intradialytic hypotension. This study was designed to determine the role of skeletal muscle mass in intradialytic hypotension. Methods In a cross-sectional study, the body composition of 177 patients was measured immediately after hemodialysis using bioelectrical impedance analysis. The parameters measured were skeletal muscle mass, intracellular and extracellular water contents, total body water, and cell-membrane functionality (in phase angle at 50 kHz). Data from laboratory tests, chest radiography, measurements of handgrip strength and mid-arm circumference, and questionnaires were collected. The main outcome was intradialytic hypotension, defined as more than two episodes of hypotension (systolic blood pressure of