Comparison between the 0- and 30-s balloon dilation time in percutaneous transluminal angioplasty for restenosed arteriovenous fistula among hemodialysis patients: a multicenter, prospective, randomized trial (CARP study).

BACKGROUND: This study aims to compare patency rates of the 0- and 30-s (sec) balloon dilation time in hemodialysis (HD) patients with restenosis after percutaneous transluminal angioplasty (PTA). METHODS: The patients who underwent PTA within 6 months for failed arteriovenous fistula at the forearm were randomly assigned the 0-s or 30-s dilation time group. Effect of dilation time on the 3- and 6-month patency rates after PTA was examined. RESULTS: Fifty patients were enrolled in this study. The 3-month patency rate in the 30-s dilation group was better than that in the 0-s dilation group (P = 0.0050), while the 6-month patency rates did not show a significant difference between the two groups (P = 0.28). Cox's proportional hazard model revealed that 30-s of inflation time (hazard ratio 0.027; P = 0.0072), diameter of the proximal (hazard ratio 0.32; P = 0.031), and dilation pressure (hazard ratio 0.63; P = 0.014) were associated with better 3-month patency. Dilation pressure between previous and present PTA did not differ in the 0-s (P = 0.15) and 30-s dilation groups (P = 0.16). The 6-month patency rate of the present PTA in the 30-s dilation group was higher than that of the previous PTA (P = 0.015). The visual analog scale did not differ between the two groups (P = 0.51). CONCLUSION: The presenting data suggest that 30-s dilation potentially results in a better 3-month patency rate than 0-s dilation in HD patients with restenosis after PTA.

Comparison of survival rates between incident hemodialysis patients and peritoneal dialysis patients: a 5-year prospective cohort study with propensity score matching.

BACKGROUND: The effect of dialytic modality at the start of renal replacement therapy on prognosis is controversial. METHODS: This multicenter, prospective cohort study included patients undergoing incident hemodialysis (HD) (n = 646) and peritoneal dialysis (PD) (n = 72). We excluded patients who lacked complete data for 3 months. One-to-one propensity score (PS) matching was performed before between-group comparison of survival rates (Kaplan-Meier method and log-rank test) and identification of factors affecting prognosis (Cox proportional-hazards regression analysis). RESULTS: We enrolled 621 and 71 patients undergoing HD and PD, respectively (overall mean ± standard deviation age: 74 ± 13 years); 20% had cardiovascular disease (CVD). The median follow-up period was 41 (interquartile range 24-66) months. Following PS matching, we analyzed 65 patients undergoing HD and PD each. The 5-year overall survival rates did not differ between the groups (P = 0.97). The PD group exhibited a better CVD-related survival rate (P = 0.03). PD yielded adjusted hazard ratios for all-cause and CVD-related mortality of 0.99 (95% confidence interval [CI] 0.49-1.99, P = 0.97) and 3.92 (95% CI 1.05-14.7, P = 0.04), respectively. Age (P < 0.001) and the use of a central venous catheter (CVC) at dialytic initiation (P = 0.02) were independent risks for all-cause mortality; whereas, only the use of a CVC (P = 0.01) was an independent risk for CVD-related mortality. CONCLUSION: Although no differences were observed in overall survival, CVD-related survival may be better with dialytic initiation with PD than with HD.

The hypoxia-inducible factor-α prolyl hydroxylase inhibitor FG4592 ameliorates renal fibrosis by inducing the H3K9 demethylase JMJD1A.

The transcription factors hypoxia-inducible factor-1α and -2α (HIF-1α/2α) are the major regulators of the cellular response to hypoxia and play a key role in renal fibrosis associated with acute and chronic kidney disease. Jumonji domain-containing 1a (JMJD1A), a histone H3 lysine 9 (H3K9) demethylase, is reported to be an important target gene of HIF-α. However, whether JMJD1A and H3K9 methylation status play a role in renal fibrosis is unclear. Here, we investigated the involvement of HIF-α, JMJD1A, and monomethylated/dimethylated H3K9 (H3K9me1/H3K9me2) levels in unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Intraperitoneal administration of FG4592, an inhibitor of HIF-α prolyl hydroxylase, which controls HIF-α protein stability, significantly attenuated renal fibrosis on days 3 and 7 following UUO. FG4592 concomitantly increased JMJD1A expression, decreased H3K9me1/me2 levels, reduced profibrotic gene expression, and increased erythropoietin expression in renal tissues of UUO mice. The beneficial effects of FG4592 on renal fibrosis were inhibited by the administration of JMJD1A-specific siRNA to mice immediately following UUO. Incubation of normal rat kidney-49F and/or -52E cells with transforming growth factor-ß1 (TGF-ß1) in vitro resulted in upregulated expression of α-smooth muscle actin and H3K9me1/me2, and these effects were inhibited by cotreatment with FG4592. In contrast, FG4592 treatment further enhanced the TGF-ß1-stimulated upregulation of JMJD1A but had no effect on TGF-ß1-stimulated expression of the H3K9 methyltransferase euchromatic histone-lysine N-methyltransferase 2. Collectively, these findings establish a crucial role for the HIF-α1/2-JMJD1A-H3K9me1/me2 regulatory axis in the therapeutic effect of FG4592 in renal fibrosis.NEW & NOTEWORTHY Using a mouse model of renal fibrosis and transforming growth factor-ß1-stimulated rat cell lines, we show that treatment with FG4592, an inhibitor of hypoxia-inducible factor-1α and -2α (HIF-1α/2α) prolyl hydroxylase decreases renal fibrosis and concomitantly reduces methylated lysine 9 of histone H3 (H3K9) levels via upregulation of Jumonji domain-containing 1a (JMJD1A). The results identify a novel role for the HIF-1α/2α-JMJD1A-H3K9 regulatory axis in suppressing renal fibrosis.

Upregulation of Mineralocorticoid Receptor Contributes to Development of Salt-Sensitive Hypertension after Ischemia-Reperfusion Injury in Rats.

The ischemia-reperfusion injury (IRI) of rat kidneys is used as a model of acute kidney injury. Salt-sensitive hypertension occurs in rats after IRI, and the distal nephrons play important roles in the development of this condition. We investigated the role of the mineralocorticoid receptor (MR) in the progression of IRI-induced salt-sensitive hypertension in rats. Fourteen days after right-side nephrectomy, IRI was induced by clamping the left renal artery, with sham surgery performed as a control. IRI rats were provided with normal water or water with 1.0% NaCl (IRI/NaCl), or they were implanted with an osmotic mini-pump to infuse vehicle or aldosterone (IRI/Aldo). Esaxerenone, a non-steroidal MR blocker (MRB), was administered to IRI/NaCl and IRI/Aldo rats for 6 weeks. MR expression increased by day 7 post-IRI. Blood pressure and urinary protein excretion increased in IRI/NaCl and IRI/Aldo rats over the 6-week period, but these effects were negated by MRB administration. The MRB attenuated the expression of the gamma-epithelial sodium channel (ENaC) and renal damage. The ENaC inhibitor, amiloride, ameliorated hypertension and renal damage in IRI/NaCl and IRI/Aldo rats. Our findings thus showed that MR upregulation may play a pivotal role in ENaC-mediated sodium uptake in rats after IRI, resulting in the development of salt-sensitive hypertension in response to salt overload or the activation of the renin-angiotensin-aldosterone system.

N-terminal pro-brain natriuretic peptide predicts hospitalization for ischemic stroke in Japanese hemodialysis patients.

BACKGROUND: The association between N-terminal pro-brain natriuretic peptide (NT-proBNP) and stroke in Japanese hemodialysis (HD) outpatients is unclear. Therefore, in this study, we investigate whether high NT-proBNP levels are associated with future stroke events in this population. METHODS: This was a multicenter prospective observational study with post hoc analysis. Baseline NT-proBNP levels were measured at the first HD session of the week and classified into tertiles (first tertile: < 2255 pg/mL; second tertile: ≥ 2255 and < 5657 pg/mL; third tertile: ≥ 5657 pg/mL). Overall hospitalization-free survival rates were compared using the Kaplan-Meier method. The association between NT-proBNP level and hospitalization for stroke was assessed using the multivariate Cox proportional hazards models. RESULTS: During a 5-year follow-up of 1,229 patients, 103 (8.4%) were hospitalized and 23 (1.9%) died from stroke. The hospitalization-free survival rate for ischemic stroke was lowest in the third tertile (P < 0.01). The crude hazard ratio (HR) of hospitalization was higher in the third tertile compared with the first tertile for both ischemic stroke (HR: 3.92; 95% confidence interval [CI] 2.08-7.37; P < 0.01) and hemorrhagic stroke (HR: 3.75; 95% CI 1.35-10.43; P = 0.01). On multivariate Cox hazard analysis, the adjusted HRs for ischemic stroke were higher in the third tertile. The hospitalization-free survival rates for hemorrhagic stroke and the adjusted HRs did not differ significantly. CONCLUSIONS: Elevated NT-proBNP level was associated with hospitalization for ischemic stroke, suggesting that NT-proBNP level is a valid biomarker for predicting hospitalization for ischemic stroke in HD outpatients.

Relationships of hyperchloremia with hypertension and proteinuria in patients with chronic kidney disease.

BACKGROUND: A few previous clinical studies have shown that chloride (Cl) contributes to the progression and development of hypertension or proteinuria. Therefore, we aimed to determine whether hyperchloremia is associated with hypertension or proteinuria in patients with chronic kidney disease (CKD) and to define the relationships between the reduction in serum Cl concentration associated with CKD treatment and improvements in hypertension and/or proteinuria. METHODS: We performed a retrospective observational study of new or referred patients with CKD who had hyperchloremia, moderate proteinuria, renal dysfunction, and hypertension. Patients taking medication for metabolic acidosis or with a history of dialysis were excluded. The participants' systolic and diastolic blood pressure (BP), serum sodium (Na) and Cl concentrations, and urinary protein (UP) concentration were measured at baseline and after 1 month of CKD treatment. RESULTS: Fifty-one patients with CKD were included in the study. Their serum Cl concentration independently correlated with sBP and UP at baseline (P = 0.022 and P = 0.033, respectively). After 1 month's CKD treatment, their serum Na and Cl concentrations, sBP, and UP were significantly lower. The change in sBP during the month (ΔsBP) correlated with the change in serum Cl (ΔCl) (P = 0.012) but not with the change in serum Na. Multivariate analysis showed that ΔsBP was independently associated with ΔCl (P = 0.029). CONCLUSIONS: Hyperchloremia is an independent predictor of hypertension and proteinuria for patients with CKD.

Coronary artery calcification is a risk factor for intradialytic hypotension in patients undergoing hemodialysis.

INTRODUCTION: We investigated the association between intradialytic hypotension (IDH) and coronary artery calcification and their effects on mortality in hemodialysis (HD) patients. METHODS: Consecutive patients undergoing maintenance HD were enrolled. The study timeline included the baseline (day 1), exposure assessment (day 1-day 22), and outcome assessment (day 23-3 years) periods. IDH was defined as a nadir systolic blood pressure (SBP) of <100 mmHg or vasopressor use during at least 2 of 10 HD sessions in the exposure assessment period. The clinical data at baseline and the Agatston coronary artery calcium score (CACS) were assessed in the exposure assessment period. FINDINGS: The median age and dialysis vintage were 67 years [60-75 years] and 73 months [37-138 months], respectively. IDH occurred in 37 patients (21.4%), and the CACS was higher in the IDH group than in the non-IDH group (p = 0.08). IDH was associated with CACS, diabetes mellitus, mean predialysis SBP, and mean ultrafiltration volume (p < 0.05). The cutoff CACS for mortality was 1829 (sensitivity: 69%, specificity: 77%). In all, 45 all-cause deaths and 19 cardiovascular deaths occurred over 3 years. Patients with both IDH and a CACS of ≥1829 had a lower 3-year cumulative survival from cardiovascular death (66.7%) than those with a CACS of ≥1829 (80.3%), IDH (88.5%), or neither (95.5%) (p < 0.01). IDH, a CACS of ≥1829, and IDH + CACS of ≥1829 were predictors of 3-year all-cause and cardiovascular mortality (p < 0.05). The hazard ratio for cardiovascular mortality was highest in the group with IDH + CACS ≥ 1829. DISCUSSION: A high CACS may be a biomarker for IDH. Both IDH and CACS were risk factors for all-cause and cardiovascular mortality in patients undergoing HD, and there was a synergistic interaction between IDH and high CACS for cardiovascular mortality.

Convection volume, ß2-microglobulin and α1-microglobulin reduction ratios, and body composition in pre-dilution online haemodiafiltration.

AIM: The effect of convection volume (CV) in patients on pre-dilution online haemodiafiltration (Pre-OL-HDF) was evaluated. METHODS: We conducted a retrospective, cross-sectional study in 126 patients on Pre-OL-HDF. Dialysis conditions, laboratory data, and same day post-dialysis body composition measurements using bioimpedance spectroscopy were assessed. Patients were divided into two groups according to their CV: ≥ median value and < median value. Linear regression analyses for reduction ratios (RRs) of ß2-microglobulin and α1-microglobulin, and body composition, were conducted. RESULTS: Age, dialysis vintage, and CVs of the study patients were 64 ± 12 years, 81 (48-154) months, and 43.2 (38.5-55.9) L/session, respectively. The higher CV (≥ 43 L/session) group (n = 66) had significantly higher RRs of ß2-microglobulin and α1-microglobulin, lean tissue index, body cell mass index, total body water (TBW), extracellular water (ECW), and intracellular water (ICW) compared with the lower CV (< 43 L/session) group (n = 60, p <  .01). Serum albumin and fat tissue index were not significantly different between the groups. CV/ECW, CV/TBW, and CV/ICW but not un-adjusted CV, were significant determinants for ß2-microglobulin and α1-microglobulin RRs (p <  .05). Lean tissue and body cell mass indexes, but not the fat tissue index, showed significant associations with CV, and RRs of ß2-microglobulin and α1-microglobulin (p < kb.05). CONCLUSIONS: Among patients on Pre-OL-HDF, higher values in the lean tissue index and body cell mass index were observed in those with higher CV versus lower CV, and CV adjusted to body water may be useful to prescribe individualized conditions for Pre-OL-HDF.

A Combination of Iohexol Treatment and Ionizing Radiation Exposure Enhances Kidney Injury in Contrast-Induced Nephropathy by Increasing DNA Damage.

Contrast media has been shown to induce nephropathy (i.e., contrast-induced nephropathy) after various types of radiological examinations. The molecular mechanism of contrast-induced nephropathy has been unclear. In this study, we investigated the mechanism of contrast-induced nephropathy by examining the effects of combined treatment of contrast medium and ionizing radiation on kidney cells in vitro and kidney tissue in vivo. In human renal tubular epithelium cells, immunofluorescence analysis revealed that iohexol increased the numbers of radiation-induced γH2AX nuclear foci. The numbers of γH2AX nuclear foci remained high at 24 h, suggesting that some radiation-induced double-strand breaks remain unrepaired in the presence of iohexol. We established a mouse model of contrast-induced nephropathy, then showed that iohexol and ionizing radiation synergistically reduced renal function and induced double-strand breaks. Importantly, iohexol induced significant macrophage accumulation and oxidative DNA damage in the kidneys of contrast-induced nephropathy model mice in the absence of ionizing radiation; these effects were amplified by ionizing radiation. The results suggest that underlying inflammation and oxidative DNA damage caused by iohexol contribute to the enhancement of radiation-induced double-strand breaks, leading to contrast-induced nephropathy.

Klotho overexpression protects against renal aging along with suppression of transforming growth factor-ß1 signaling pathways.

Klotho is an antiaging protein reported to suppress transforming growth factor-ß1 (TGF-ß1) signaling. Aging kidneys are characterized by interstitial fibrosis, accumulation of cell cycle-arrested cells, and increased levels of oxidative stress. TGF-ß1 signaling is involved in these processes. In this study, we investigated whether klotho overexpression improves these features in the kidneys of aging mice and examined the inhibitory effect of klotho on signaling molecules related to transforming growth of TGF-ß1. Klotho transgenic (KLTG) and wild-type (WT) mice were used, and 8-wk-old and 24-mo-old mice were defined as young and aging, respectively. We found that klotho expression was decreased in aging WT mice, but it was maintained in aging KLTG mice. Klotho overexpression improved the survival of 24-mo-old mice. Although the serum Ca2+ level was significantly lower in aging KLTG mice than in aging WT mice, the serum phosphate level did not differ between these mice. Klotho overexpression attenuated the increases in blood pressure, serum blood urea nitrogen level, and serum creatinine level in aging mice. Interstitial fibrosis, accumulation of cell cycle-arrested cells, and oxidative stress did not differ between young KLTG and WT mice, but they were significantly suppressed in aging KLTG mice compared with aging WT mice. Furthermore, the expression of TGF-ß1-related signaling molecules was increased in aging WT mice, whereas it was inhibited in aging KLTG mice. These data suggest that klotho overexpression protects against kidney aging along with suppression of TGF-ß1 signaling pathways.NEW & NOTEWORTHY Klotho is considered as an antiaging protein, and its overexpression may be a candidate therapy for protection against kidney damage with advanced aging. Although multiple factors are involved in the aging process, we showed that klotho overexpression inhibited interstitial fibrosis, accumulation of cell cycle-arrested cells, and increased levels of oxidative stress in the kidneys of aging mice, suppressing transforming growth factor-ß1-related signaling pathways. The present data showed that klotho overexpression protects against age-associated kidney damage.

Klotho deficiency intensifies hypoxia-induced expression of IFN-α/ß through upregulation of RIG-I in kidneys.

Hypoxia is a common pathway to the progression of end-stage kidney disease. Retinoic acid-inducible gene I (RIG-I) encodes an RNA helicase that recognizes viruses including SARS-CoV2, which is responsible for the production of interferon (IFN)-α/ß to prevent the spread of viral infection. Recently, RIG-I activation was found under hypoxic conditions, and klotho deficiency was shown to intensify the activation of RIG-I in mouse brains. However, the roles of these functions in renal inflammation remain elusive. Here, for in vitro study, the expression of RIG-I and IFN-α/ß was examined in normal rat kidney (NRK)-52E cells incubated under hypoxic conditions (1% O2). Next, siRNA targeting RIG-I or scramble siRNA was transfected into NRK52E cells to examine the expression of RIG-I and IFN-α/ß under hypoxic conditions. We also investigated the expression levels of RIG-I and IFN-α/ß in 33 human kidney biopsy samples diagnosed with IgA nephropathy. For in vivo study, we induced renal hypoxia by clamping the renal artery for 10 min in wild-type mice (WT mice) and Klotho-knockout mice (Kl-/- mice). Incubation under hypoxic conditions increased the expression of RIG-I and IFN-α/ß in NRK52E cells. Their upregulation was inhibited in NRK52E cells transfected with siRNA targeting RIG-I. In patients with IgA nephropathy, immunohistochemical staining of renal biopsy samples revealed that the expression of RIG-I was correlated with that of IFN-α/ß (r = 0.57, P<0.001, and r = 0.81, P<0.001, respectively). The expression levels of RIG-I and IFN-α/ß were upregulated in kidneys of hypoxic WT mice and further upregulation was observed in hypoxic Kl-/- mice. These findings suggest that hypoxia induces the expression of IFN-α/ß through the upregulation of RIG-I, and that klotho deficiency intensifies this hypoxia-induced expression in kidneys.

Serum-free medium and hypoxic preconditioning synergistically enhance the therapeutic effects of mesenchymal stem cells on experimental renal fibrosis.

BACKGROUND: Mesenchymal stem cells (MSCs) repair injured tissue in a paracrine manner. To enhance their therapeutic properties, preconditioning with various factors has been researched. We have previously showed that MSCs cultured in serum-free medium (SF-MSCs) promote their immunosuppressive ability, thereby enhancing their anti-fibrotic effect. Here, we examined whether serum-free medium and hypoxic preconditioning synergistically enhance the therapeutic effects of MSCs on renal fibrosis in rats with ischemia-reperfusion injury (IRI). METHODS: SF-MSCs were incubated under 1% O2 conditions (hypo-SF-MSCs) or 21% O2 conditions (normo-SF-MSCs) for 24 h before collection. After IRI procedure, hypo-SF-MSCs or normo-SF-MSCs were injected through the abdominal aorta. At 7 or 21 days post-injection, the rats were killed and their kidneys were collected to evaluate inflammation and fibrosis. In in vitro experiments, we investigated whether hypo-SF-MSCs enhanced secretion of anti-fibrotic humoral factors using transforming growth factor (TGF)-ß1-stimulated HK-2 cells incubated with conditioned medium from hypo-SF-MSCs or normo-SF-MSCs. RESULTS: Normo-SF-MSCs showed attenuation of senescence, which increased their proliferative capacity. Although no significant difference in cellular senescence was found between normo-SF-MSCs and hypo-SF-MSCs, hypo-SF-MSCs further increased their proliferative capacity compared with normo-SF-MSCs. Additionally, administration of hypo-SF-MSCs more strongly ameliorated renal fibrosis than that of normo-SF-MSCs. Moreover, although hypo-SF-MSCs strongly attenuated infiltration of inflammatory cells compared with the control rats, which were treated with PBS, this attenuation was almost equal between normo-SF-MSCs and hypo-SF-MSCs. In vitro experiments revealed that hypo-SF-MSCs more significantly inhibited transforming growth factor (TGF)-ß/Smad signaling compared with normo-SF-MSCs. Moreover, hypoxic preconditioning increased hepatocyte growth factor (HGF) secretion even under serum-free conditions, whereas knockdown of HGF in hypo-SF-MSCs attenuated inhibition of TGF-ß/Smad signaling. CONCLUSIONS: These results indicate that administration of ex vivo-expanded, hypoxia-preconditioned SF-MSCs may be a useful cell therapy to prevent renal fibrosis.

Lower Geriatric Nutritional Risk Index (GNRI) Is Associated with Higher Risk of Fractures in Patients Undergoing Hemodialysis.

BACKGROUND: Although malnutrition and bone fracture are both major complications in patients undergoing hemodialysis, their association has not been clarified. The aim of our study was to clarify the association between the geriatric nutritional risk index (GNRI), an indicator of nutritional status, and the incidence of bone fractures in patients undergoing hemodialysis. METHODS: We included 1342 registered patients undergoing hemodialysis and performed a post hoc analysis. We divided patients into the high GNRI group (≥92), considered to have a low risk of malnutrition, and the low GNRI group (<92), considered to have a high risk of malnutrition. Fracture-free survival in the low and high GNRI groups was evaluated by the Kaplan-Meier method. Cox proportional hazards models were used to identify the risk factors for fractures requiring hospitalization. All results were stratified by sex. RESULTS: New bone fractures developed in 108 (8.0%) patients in 5 years of follow-up. Bone fractures occurred more frequently in the low GNRI group compared with the high GNRI group (HR: 3.51, 95% CI: 1.91-6.42, p < 0.01 in males; HR: 2.47, 95% CI: 1.52-4.03, p < 0.01 in females). A low GNRI was significantly associated with an increased incidence of bone fractures, even after adjustment for covariates. However, the serum levels of calcium, phosphate, parathyroid hormone, and alkaline phosphatase were not associated with the incidence of bone fractures. CONCLUSIONS: A low GNRI is an independent risk factor for bone fractures in patients undergoing hemodialysis. Early intervention for the low GNRI group may be important in preventing the occurrence of fractures.

N-terminal pro brain natriuretic peptide predicts both all-cause and cardiovascular disease mortality in Japanese hemodialysis patients.

BACKGROUND: The association between N-terminal pro brain natriuretic peptide (NT-proBNP) level and long-term mortality in Japanese hemodialysis patients has not been fully assessed. METHODS: This prospective, multicenter study included 1428 hemodialysis outpatients. Baseline NT-proBNP levels were measured at the first hemodialysis session of the week and participants were followed for 5 years. The areas under the curve were calculated from receiver operating characteristic curves. Groups determined by quartiles of baseline NT-proBNP level were assessed by the Kaplan-Meier method and log-rank test. The association between NT-proBNP level and mortality was assessed using multivariate Cox proportional hazards models. RESULTS: During the 5-year follow-up, we observed 370 deaths and 256 censored cases. The areas under the curve of pre-hemodialysis NT-proBNP for all-cause mortality and cardiovascular disease mortality after 1 year were 0.75 and 0.78, respectively, and significantly greater than the areas under the curve at the 3- and 5-year follow-up. Cut-off values for all-cause mortality and cardiovascular disease mortality after 1 year were 4550 and 5467 ng/L, respectively (sensitivity: 82% and 81%; specificity: 59% and 64%). Kaplan-Meier survival analysis showed that the group with pre-hemodialysis NT-proBNP ≥ 8805 ng/L had increased all-cause mortality (P < 0.001) and cardiovascular disease mortality (P < 0.001). Finally, multivariate Cox analysis showed that NT-proBNP level was associated with all-cause mortality (P < 0.001) and cardiovascular disease mortality (P = 0.004) independently from other clinical parameters. CONCLUSION: NT-proBNP is a useful marker to predict both all-cause and cardiovascular disease mortality in hemodialysis patients.

Localization and Maintenance of Engrafted Mesenchymal Stem Cells Administered via Renal Artery in Kidneys with Ischemia-Reperfusion Injury.

Mesenchymal stem cells (MSCs) are a potential therapeutic tool for preventing the progression of acute kidney injury (AKI) to chronic kidney disease (CKD). Herein, we investigated the localization and maintenance of engrafted human bone marrow-derived MSCs in rats subjected to a renal ischemia-reperfusion injury (IRI) and compared the effectiveness of two intravascular injection routes via the renal artery or inferior vena cava. Renal artery injection of MSCs was more effective than intravenous injection at reducing IRI-induced renal fibrosis. Additionally, MSCs injected through the renal artery persisted in injured kidneys for over 21 days, whereas MSCs injected through the inferior vena cava survived for less than 7 days. This difference may be attributed to the antifibrotic effects of MSCs. Interestingly, MSCs injected through the renal artery were localized primarily in glomeruli until day 3 post-IRI, and they decreased in number thereafter. In contrast, the number of MSCs localized in tubular walls, and the interstitium increased gradually until day 21 post-IRI. This localization change may be related to areas of damage caused by IRI because ischemia-induced AKI leads to tubular cell damage. Taken together, these findings suggest renal artery injection of MSCs may be useful for preventing the progression of AKI to CKD.

Mesenchymal stem cells cultured in serum-free medium ameliorate experimental peritoneal fibrosis.

BACKGROUND: Mesenchymal stem cells (MSCs) provide potential treatments for peritoneal fibrosis. However, MSCs cultured in media containing serum bring risks of infection and other problems. In this study, we compared the effect of human MSCs in serum-free medium (SF-MSCs) on peritoneal fibrosis with that of MSCs cultured in medium containing 10% fetal bovine serum (10%MSCs). METHODS: Peritoneal fibrosis was induced by intraperitoneally injecting 0.1% chlorhexidine gluconate (CG). SF-MSCs or 10%MSCs were intraperitoneally administered 30 min after the CG injection. Ten days after the CG and MSC injections, we performed histological analyses and peritoneal equilibrium testing. In the in vitro experiments, we used transforming growth factor (TGF)-ß1-stimulated human peritoneal mesothelial cells incubated in conditioned medium from MSCs to examine whether the SF-MSCs showed enhanced ability to produce antifibrotic humoral factors. RESULTS: Histological staining showed that the SF-MSCs significantly suppressed CG-induced cell accumulation and thickening compared with that of the 10%MSCs. Additionally, the SF-MSCs significantly inhibited mesenchymal cell expression, extracellular matrix protein deposition and inflammatory cell infiltration. Peritoneal equilibration testing showed that compared with administering 10%MSCs, administering SF-MSCs significantly reduced the functional impairments of the peritoneal membrane. The in vitro experiments showed that although the conditioned medium from MSCs suppressed TGF-ß1 signaling, the suppression did not significantly differ between the SF-MSCs and 10%MSCs. CONCLUSIONS: Serum-free culture conditions can enhance the antifibrotic abilities of MSCs by suppressing inflammation. Administering ex vivo expanded SF-MSCs may be a potential therapy for preventing peritoneal fibrotic progression.

Iron, coronary artery calcification, and mortality in patients undergoing hemodialysis.

OBJECTIVE: A high coronary artery calcification score (CACS) may be associated with high mortality in patients undergoing hemodialysis (HD). Recently, effects of iron on vascular smooth muscle cell calcification have been described. We aimed to investigate the relationships between iron, CACS, and mortality in HD patients. METHODS: We studied 173 consecutive patients who were undergoing maintenance HD. Laboratory data and Agatston's CACS were obtained at baseline for two groups of patients: those with CACS ≥400 (n = 109) and those with CACS <400 (n = 64). Logistic regression analyses for CACS ≥400 and Cox proportional hazard analyses for mortality were conducted. RESULTS: The median (interquartile range) age and duration of dialysis of the participants were 67 (60-75) years and 73 (37-138) months, respectively. Serum iron (Fe) and transferrin saturation (TSAT) levels were significantly lower in participants with CACS ≥400 than in those with CACS <400, although the serum ferritin concentration did not differ between the groups. TSAT ≥21% was significantly associated with CACS ≥400 (odds ratio 0.46, p<0.05). TSAT ≥17%, Fe ≥63 µg/dL, and ferritin ≥200 ng/mL appear to protect against 5-year all-cause mortality in HD patients, independent of conventional risk factors of all-cause mortality (p < 0.05). CONCLUSION: We have identified associations between iron, CACS, and mortality in HD patients. Lower TSAT was found to be an independent predictor of CACS ≥400, and iron deficiency (low TSAT, iron, or ferritin) was a significant predictor of 5-year all-cause mortality in HD patients.

Interferon-γ enhances the therapeutic effect of mesenchymal stem cells on experimental renal fibrosis.

Mesenchymal stem cells (MSCs) administered for therapeutic purposes can be activated by interferon-γ (IFN-γ) secreted from natural killer cells in injured tissues and exert anti-inflammatory effects. These processes require a substantial period of time, leading to a delayed onset of MSCs' therapeutic effects. In this study, we investigated whether pretreatment with IFN-γ could potentiate the anti-fibrotic ability of MSCs in rats with ischemia-reperfusion injury (IRI) and unilateral ureter obstruction. Administration of MSCs treated with IFN-γ strongly reduced infiltration of inflammatory cells and ameliorated interstitial fibrosis compared with control MSCs without IFN-γ treatment. In addition, conditioned medium obtained from IFN-γ-treated MSCs decreased fibrotic changes in cultured cells induced by transforming growth factor-ß1 more efficiently than that from control MSCs. Most notably, secretion of prostaglandin E2 from MSCs was significantly increased by treatment with IFN-γ. Increased prostaglandin E2 in conditioned medium obtained from IFN-γ-treated MSCs induced polarization of immunosuppressive CD163 and CD206-positive macrophages. In addition, knockdown of prostaglandin E synthase weakened the anti-fibrotic effects of MSCs treated with IFN-γ in IRI rats, suggesting the involvement of prostaglandin E2 in the beneficial effects of IFN-γ. Administration of MSCs treated with IFN-γ might represent a promising therapy to prevent the progression of renal fibrosis.

Clinical characteristics of inflammatory bowel disease patients with immunoglobulin A nephropathy.

BACKGROUND/AIMS: Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract. Some patients with this condition have been reported to present with immunoglobulin A nephropathy (IgAN), a renal complication that can cause end-stage renal failure, but the frequency of this comorbidity has not been described. Thus, the aim of this study was to investigate the frequency of IgAN in patients with IBD. METHODS: This study included 620 patients with IBD (338 with ulcerative colitis [UC] and 282 with Crohn's disease [CD]) from the Hiroshima University Hospital outpatient department. IgAN cases were identified from medical interviews, blood examinations (serum immunoglobulin A), and urinalyses (occult blood, proteinuria). Definitive IgAN cases were diagnosed by renal biopsies, while those detected through the clinical course and test results, but not clinically recommended for renal biopsy, were defined as suspected IgAN. RESULTS: We analyzed 427 cases meeting the inclusion criteria (220 with UC and 207 with CD). The incidence of IgAN across all patients with IBD was 3.0%. The frequency of IgAN was significantly higher in patients with CD (11/207, 5.3%) than in those with UC (2/220, 0.9%) (P< 0.01). Moreover, a significant correlation was found between CD patients with ileostomy or colostomy and a diagnosis of IgAN. CONCLUSIONS: Patients with IBD present a high incidence of IgAN, especially those with CD who have undergone ileostomy or colostomy.

Different risk factors are associated with vascular access patency after construction and percutaneous transluminal angioplasty in patients starting hemodialysis.

BACKGROUND: The objective of this multicenter, prospective observational study was to determine the factors related to patency rates after construction of vascular access (VA) and the first percutaneous transluminal angioplasty (PTA). METHODS: The 24-month primary and secondary patency rates after construction of a radiocephalic arteriovenous fistula (RC-AVF) and arteriovenous graft (AVG) were evaluated using the Kaplan-Meier method and log-rank test. The 12-month post-PTA patency rate was also investigated. A Cox proportional hazard model was used to identify clinical parameters associated with the primary patency rate and the post-PTA patency rate. RESULTS: A total of 611 patients were enrolled in the study. The primary patency rate after VA construction was lower in hemodialysis (HD) patients with an AVG than in those with an AVF. Aging (hazard ratio [HR], 1.02 per 1 year; p < 0.001), female sex (HR, 1.41; p = 0.03), diabetes mellitus (HR, 1.37; p = 0.03), low serum albumin (HR, 0.76 per 1-g/dL decrease; p = 0.02), and use of an erythropoietin-stimulating agent (HR, 1.62; p = 0.02) were risk factors for VA problems. The post-PTA patency rate was associated with aging (HR, 1.02; p < 0.001), diabetes mellitus (HR, 1.49; p = 0.02), polycystic kidney disease (HR, 2.14; p = 0.01), temporary catheter use for initiation of HD (HR, 1.60; p = 0.02), and period from VA construction to use (HR, 0.99; p = 0.04). CONCLUSION: Although a poor patency rate is commonly associated with advanced age and diabetes, different risk factors affect patency between VA construction and the first PTA.