1-year tolvaptan efficacy in ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) develops into end-stage kidney disease by 65 years of age in an estimated 45%-70% of patients. Recent trials revealed that tolvaptan inhibits disease progression both in early-stage or late-stage ADPKD ; however, stratified analysis showed a difference of favorable factors correlated with tolvaptan efficacy between early-stage and late-stage ADPKD. Thus, we examined the efficacy of tolvaptan in ADPKD with a wide range of estimated glomerular filtration rates (eGFR). We enrolled 24 patients with eGFR 35.3 (28.0-65.5) ml / min / 1.73m2 and evaluated treatment effect as ΔΔeGFR (ml / min / 1.73m2 / year) or ΔΔtotal kidney volume (TKV) (% / year) that was calculated as post-treatment annual change - pre-treatment annual change. Pre ΔeGFR was significantly low in eGFR responders, defined as ΔΔeGFR > 0 ml / min / 1.73m2 / year. In eGFR responders, pre ΔeGFR, post ΔeGFR, eGFR, TKV, and proteinuria were significantly correlated with ΔΔeGFR. In TKV responders defined as ΔΔTKV > 5 % / year, we identified hypertension history, proteinuria, TKV, and post ΔTKV as significantly correlated factors with ΔΔTKV. In conclusion, pre ΔeGFR may be a predictive factor of therapeutic efficacy on kidney function. Tolvaptan may have greater efficacy in early-stage ADPKD with rapid GFR decline or with well-controlled blood pressure

A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-α and TGF-β1 pathways

Renal fibrosis is closely related to chronic inflammation and is under the control of epigenetic regulations. Because the signaling of transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) play key roles in progression of renal fibrosis, dual blockade of TGF-β1 and TNF-α is desired as its therapeutic approach. Here we screened small molecules showing anti-TNF-α activity in the compound library of indole derivatives. 11 out of 41 indole derivatives inhibited the TNF-α effect. Among them, Mitochonic Acid 35 (MA-35), 5-(3, 5-dimethoxybenzyloxy)-3-indoleacetic acid, showed the potent effect. The anti-TNF-α activity was mediated by inhibiting IκB kinase phosphorylation, which attenuated the LPS/GaIN-induced hepatic inflammation in the mice. Additionally, MA-35 concurrently showed an anti-TGF-β1 effect by inhibiting Smad3 phosphorylation, resulting in the downregulation of TGF-β1-induced fibrotic gene expression. In unilateral ureter obstructed mouse kidney, which is a renal fibrosis model, MA-35 attenuated renal inflammation and fibrosis with the downregulation of inflammatory cytokines and fibrotic gene expressions. Furthermore, MA-35 inhibited TGF-β1-induced H3K4me1 histone modification of the fibrotic gene promoter, leading to a decrease in the fibrotic gene expression. MA-35 affects multiple signaling pathways involved in the fibrosis and may recover epigenetic modification; therefore, it could possibly be a novel therapeutic drug for fibrosis

Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases

Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model “Mitomouse” (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial

Sucroferric oxyhydroxide decreases serum phosphorus level and fibroblast growth factor 23 and improves renal anemia in hemodialysis patients

Abstract Objective Sucroferric oxyhydroxide, a novel iron-based phosphate-binder, has been shown to have beneficial effects in lowering serum phosphorus levels and improving renal anemia in clinical studies. Although an effect of this agent on fibroblast growth factor 23 (FGF23) has been reported in an animal study, there is little clinical data supporting this finding. This study aimed to evaluate the effect on chronic kidney disease-mineral and bone disorder, FGF23, renal anemia, iron-related parameters, adverse events of sucroferric oxyhydroxide in hemodialysis patients. Results Hemodialysis patients, receiving existing hyperphosphatemia drugs with insufficient benefit, were administered sucroferric oxyhydroxide with/without calcium carbonate for 16 weeks. Serum phosphorus level declined rapidly in Week 8 (p < 0.0001) and this decrease persisted until Week 16 (p < 0.0001). FGF23 decreased (p = 0.0412, Week 16), and hemoglobin increased (p < 0.0001, Week 16). Cumulative dose of erythropoiesis-stimulating agents (p = 0.0122, Week 16), and intravenous iron (p = 0.0233, Week 12) decreased. All adverse reactions were mild, and diarrhea was the most frequently observed adverse reaction (16.7%). Therefore, hyperphosphatemia treatment with sucroferric oxyhydroxide may safely improve serum phosphorus level, renal anemia, FGF23, and other factors that affect the prognosis of hemodialysis patients

Improved survival on super high-flux albumin-leaking hemodialysis and online hemodiafiltration with high albumin leakage in patients with mild hypoalbuminemia: evidence and a hypothesis

Abstract It has been reported that survival on mild hypoalbuminemia due to high albumin leakage did not worsen in patients on hemodialysis (HD) or online hemodiafiltration (OHDF) even though the level of serum albumin is a classic nutrition marker associated with mortality. Survival was also equivalent on HD and OHDF for patients with similar levels of albumin leakage and serum albumin. Furthermore, survival on HD using a super high-flux (SHF) albumin-leaking membrane was better than that on HD using a SHF membrane, and survival on SHF albumin-leaking HD with high albumin leakage was better than that on OHDF with low albumin leakage. The following hypothesis regarding crosstalk between α1-microglobulin (α1MG) and albumin is proposed that can explain the mechanism by which the level of serum human mercaptoalbumin (HMA) increases postdialysis and decreases predialysis. At initiation of and during dialysis, the production of free α1MG in the liver increases by upregulation of the α1MG-bikunin precursor gene. The free α1MG rapidly reacts with some substances that are reversibly bound to human nonmercaptoalbumin (HNA)-1, resulting in the conversion to HMA and free α1MG with reduced activity (i.e., free α1MG with reduced or no antioxidant capacity) during dialysis and in the increased serum HMA level postdialysis. In addition, it is possible that both hypoalbuminemia and the conversion of HNA-1 to HMA increase the free form of indoxyl sulfate, which is removed by diffusion. The antioxidant capacity in serum after dialysis is mainly due to the very large amount of HMA, resulting in the conversion to HNA and the decreased serum HMA level before dialysis. However, the very small amount of free α1MG produced in the liver has strong antioxidant activity after dialysis

Legislative Documents

Also, variously referred to as: House bills; House documents; House legislative documents; legislative documents; General Court documents

MOESM2 of Sucroferric oxyhydroxide decreases serum phosphorus level and fibroblast growth factor 23 and improves renal anemia in hemodialysis patients

Additional file 2: Figure S1. Patient disposition. A total of 54 patients were enrolled in this study, all of whom received sucroferric oxyhydroxide and were included in the safety analysis set (the population consisting of study subjects who received sucroferric oxyhydroxide at least once). Among these patients, 40 completed the observations in Week 8 and were included in the efficacy analysis set (the population consisting of patients who were continuing sucroferric oxyhydroxide treatment in Week 8 and have at least 1 analyzable data point for the efficacy endpoints in and after Week 8). Six patients were newly administered calcium carbonate after the start of the study. Ten patients were administered sucroferric oxyhydroxide in addition to calcium carbonate monotherapy (Adding group). Therefore, 24 patients were switched from existing hyperphosphatemia agents to sucroferric oxyhydroxide (Switching group). After the start of the study, 21 patients discontinued, and 33 patients completed the observations in Week 16

Acetate-containing bicarbonate dialysate increases all-cause mortality more than acetate-free bicarbonate dialysate containing citrate in hemodialysis patients

Abstract Background No studies have compared mortality between acetate-containing bicarbonate dialysate (ABD) and acetate-free bicarbonate dialysate containing citrate (AFD) in hemodialysis (HD) or online hemodiafiltration (OHDF). We therefore compared mortality between ABD and AFD in each modality. Methods This retrospective observational study included 738 patients who were receiving super high-flux (SHF) or SHF albumin-leaking HD (n = 310: ABD 235 and AFD 75) or OHDF (n = 428: ABD 321 and AFD 107) at our institution between 1 April and 1 July 2017. Three-year all-cause mortality was compared between ABD and AFD in the HD or OHDF groups using a propensity score matching model. Kaplan–Meier survival curves were compared using the log-rank test, and then Cox regression analysis with adjustments was performed for some covariates that remained significant. Results After propensity score matching, mortality on ABD was not significantly different from that on AFD in the HD group [n = 75; hazard ratio (HR) 2.271, 95% confidence interval (CI) 0.863–5.981, P = 0.087] or in the OHDF group (n = 107; HR 1.944, 95% CI 0.585–6.458, P = 0.269) without adjustments. However, with adjustments using some covariates, mortality was significantly higher on ABD than on AFD (adjusted HR 4.501, 95% CI 1.434–14.125, P = 0.010) in the HD group, but not in the OHDF group. Conclusions These findings suggest that ABD worsens mortality more than AFD in patients on SHF and SHF albumin-leaking HD. Trial registration: UMIN Clinical Trials Registry, UMIN000053090. Prospectively registered 13 December 2023, https://center6.umin.ac.jp/cgi-bin/ctr/ctr_view_reg.cgi?recptno=R000060581

Cilostazol-induced acute tubulointerstitial nephritis accompanied by IgA nephropathy: a case report

Abstract Background Cilostazol is an antiplatelet drug that is widely prescribed for the prevention of secondary stroke. Adverse reactions to cilostazol include headaches, palpitations, and diarrhea. Little is known about the nephrotoxicity of cilostazol, such as acute kidney injury. We report a biopsy-proven case of diffuse tubulointerstitial nephritis induced by cilostazol. Case presentation A 69-year-old woman prescribed cilostazol was hospitalized for acute kidney injury. On admission, her renal function deteriorated, with an increased serum creatinine level. Urinalysis showed hematuria, proteinuria, and hyper-beta2-microglobulinuria. A renal biopsy revealed diffuse tubulointerstitial nephritis associated with IgA nephropathy, and gallium-67 scintigraphy showed uptake in the bilateral kidneys. A drug lymphocyte stimulation test for cilostazol was positive, and the patient was diagnosed with cilostazol-induced acute tubulointerstitial nephritis. Despite discontinuation of cilostazol, her renal function rapidly worsened and steroid pulse therapy was initiated, followed by oral high-dose glucocorticoid therapy. After steroid treatment, her serum creatinine level normalized in parallel with urine beta2-microglobulin. Conclusion Cilostazol can induce acute tubulointerstitial nephritis