Good and evil, more reasons to study UPR.

The unfolded protein response (UPR) pathway, launched by endoplasmic reticulum, maintains endoplasmic reticulum homeostasis. Dysregulated UPR pathway links disease phenotypes, such as proteinuria, inflammation, and fibrosis, in kidney disease. Although accumulating evidence indicates the beneficial impact of the UPR pathway as a therapeutic target for various diseases, including kidney disease, the control of adaptive UPR status is still difficult for disease treatment. This article may give us a new insight into the strategy for sustaining the kidney protective UPR pathway.

Braided-type stent versus laser-cut-type stent for patients with unresectable distal malignant biliary obstruction: a randomized controlled trial.

BACKGROUND AND AIMS: Fully covered self-expandable metallic stents (SEMSs) are laser-cut (L) or braided (B); however, it remains unclear which approach is more effective for distal malignant biliary obstruction (DMBO). This study compared the clinical outcomes of using L-type and B-type stents because we believe that recurrent biliary obstruction (RBO) is less likely to occur with L-type stents. METHODS: Patients diagnosed with unresectable DMBO were randomly assigned to groups L and B in a stratified block fashion, and outcomes were compared. The primary outcome was the rate of RBO within 1 year; secondary outcomes were adverse events, clinical success rate, time to RBO (TRBO), and overall survival. RESULTS: Of the 60 enrolled participants, 56 (group L, n = 27; group B, n = 29) were included. The rates of RBO within 1 year were 44.4% and 17.2% in groups L and B, respectively (odds ratio, 2.57; 95% confidence interval [CI], 1.045-6.353). Early adverse events, which improved with conservative treatment, included pancreatitis (n = 4) in group L and pancreatitis (n = 3) and cholecystitis (n = 1) in group B (P = .913). The median TRBO (220 days [95% CI, 56-272] vs 418 days [95% CI, 232-454]) was significantly longer in group B than in group L (log-rank test, P = .0118). The median overall survival (group L, 158 days; group B, 204 days) after stenting was not significantly different between groups (P = .8544). CONCLUSIONS: In the setting of DMBO, B-type stents are associated with less recurrent obstruction than L-type stents, although there was no difference in safety. (UMIN Clinical Trials Registry number: UMIN000027239.).

Suprapapillary placement of plastic versus metal stents for malignant biliary hilar obstructions: a multicenter, randomized trial.

BACKGROUND AND AIMS: The efficacy of the suprapapillary placement of inside plastic stents (iPSs) for unresectable malignant hilar biliary obstructions (MHOs) is unknown compared with that of uncovered inside metal stents (iMSs). This randomized controlled trial was designed to evaluate the outcomes of endoscopic placement of these stents for unresectable MHOs. METHODS: This open-label, randomized study was conducted at 12 Japanese institutions. The enrolled patients with unresectable MHOs were allocated to iPS and iMS groups. The primary outcome was defined as the time to recurrent biliary obstruction in patients for whom the intervention was both technically and clinically successful. RESULTS: Among 87 enrollments, 38 patients in the iPS group and 46 patients in the iMS group were analyzed. Technical success rates were 100% (38 of 38) and 96.6% (44 of 46), respectively (P = 1.00). After transferring 1 unsuccessful iMS-group patient to the iPS group (since iPSs were deployed), the clinical success rates were 90.0% (35 of 39) for the iPS group and 88.9% (40 of 45) for the iMS group from a per-protocol analysis (P = 1.00). Among the patients with clinical success, the median times to recurrent biliary obstruction were 250 (95% confidence interval, 85-415) and 361 (95% confidence interval, 107-615) days (log-rank test, P = .34). No differences were detected in rates of adverse events. CONCLUSIONS: This Phase II randomized trial did not show any statistically significant difference in stent patency between suprapapillary plastic versus metal stents. Considering the potential advantages of plastic stents for malignant hilar obstruction, these findings suggest that suprapapillary plastic stents could be a viable alternative to metal stents for this condition.

Urinary single-cell transcriptomics: a promising noninvasive method for assessing acute kidney injury.

Noninvasive methods for obtaining intrarenal information are required to understand the mechanism of acute kidney injury (AKI). Klocke et al. explored the feasibility of using urinary single-cell RNA sequencing in assessing human AKI. Urine samples from patients with AKI included tubular epithelial cells with injury-related dedifferentiation and adaptive phenotypes, which could reflect kidney tissue damage. Thus, urinary single-cell RNA sequencing would provide new insights into human AKI, leading to the identification of novel biomarkers and therapeutic targets.

SGLT2 inhibition in chronic kidney disease: a preventive strategy against acute kidney injury at the same time?

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are known to slow down progression of chronic kidney disease. However, theoretical concerns still exist that SGLT2 inhibitors could increase the risk of acute kidney injury. Heerspink et al. revealed that dapagliflozin, an SGLT2 inhibitor, reduced the risk of abrupt declines in kidney function during the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial. Their findings may serve to reassure clinicians prescribing SGLT2 inhibitors to patients with chronic kidney disease.

Lysophosphatidylcholine mediates fast decline in kidney function in diabetic kidney disease.

Some patients with diabetic kidney disease (DKD) show a fast progression of kidney dysfunction and are known as a "fast decliner" (FD). Therefore, it is critical to understand pathomechanisms specific for fast decline. Here, we performed a comprehensive metabolomic analysis of patients with stage G3 DKD and identified increased urinary lysophosphatidylcholine (LPC) in fast decline. This was confirmed by quantification of urinary LPC using mass spectrometry and identified urinary LPC containing saturated fatty acids palmitic (16:0) and stearic (18:0) acids was increased in FDs. The upsurge in urinary LPC levels was correlated with a decline in estimated glomerular filtration rate after 2.5 years. To clarify a pathogenic role of LPC in FD, we studied an accelerated rat model of DKD and observed an increase in LPC (16:0) and (18:0) levels in the urine and kidney tubulointerstitium as the disease progressed. These findings suggested that local dysregulation of lipid metabolism resulted in excessive accumulation of this LPC species in the kidney. Our in vitro studies also confirmed LPC-mediated lipotoxicity in cultured proximal tubular cells. LPC induced accumulation of lipid droplets via activation of peroxisome proliferator-activated receptor-δ followed by upregulation of the lipid droplet membrane protein perilipin 2 and decreased autophagic flux, thereby inducing organelle stress and subsequent apoptosis. Thus, LPC (16:0) and (18:0) may mediate a fast progression of DKD and may serve as a target for novel therapeutic approaches.

Activation of α7 nicotinic acetylcholine receptors attenuates monocyte-endothelial adhesion through FUT7 inhibition.

Cholinergic anti-inflammatory pathway (CAP) describes a neuronal-inflammatory reflex centered on systemic cytokine regulation by α7 nicotinic acetylcholine receptor (α7nAChR) activation of spleen-residue macrophage. However, the CAP mechanism attenuating distal tissue inflammation, inducing a low level of systemic inflammation, is lesser known. In this study, we hypothesized that CAP regulates monocyte accessibility by influencing their adhesion to endothelial cells. Using RNA-seq analysis, we identified that α1,3-Fucosyltransferase 7 (FucT-VII), the enzyme required for processing selectin ligands, was significantly downregulated by α7nAChR agonist among other cell-cell adhesion genes. The α7nAChR agonist inhibited monocytic cell line U-937 binding to P-selectin and adhesion to endothelial cells. Furthermore, α7nAChR agonist selectivity was confirmed by α7nAChR knockdown assays, showing that FUT7 inhibition and adhesion attenuation by the agonist was abolished by siRNA targeting α7nAChR encoding gene. Consistently, FUT7 knockdown inhibited the adhesive properties of U-937 and prevented them to adhere to endothelial cells. Overexpression of FUT7 also abrogated the adhesion attenuation induced by GTS-21 indicating that FUT7 inhibition was sufficient for inhibiting adhesion by α7nAChR activation. Our work demonstrated that α7nAChR activation regulates monocyte adhesion to endothelial cells through FUT7 inhibition, providing a novel insight into the CAP mechanism.

MRI-Based Quantitative R2* Mapping at 3 Tesla Reflects Hepatic Iron Overload and Pathogenesis in Nonalcoholic Fatty Liver Disease Patients.

BACKGROUND: The role of hepatic iron overload (HIO) in nonalcoholic fatty liver disease (NAFLD) pathogenesis has not been fully elucidated. PURPOSE: This study aimed to investigate the effect of HIO and examine the diagnostic usefulness of magnetic resonance imaging (MRI)-based R2* quantification in evaluating hepatic iron content (HIC) and pathological findings in NAFLD. STUDY TYPE: Prospective and retrospective. POPULATION: A prospective study of 168 patients (age, 57.2 ± 15.0; male/female, 80/88) and a retrospective validation study of 202 patients (age, 57.0 ± 14.4; male/female, 113/89) with liver-biopsy-confirmed NAFLD were performed. FIELD STRENGTH/SEQUENCE: 3 T; chemical-shift encoded multi-echo gradient echo. ASSESSMENT: Using liver tissues obtained by liver biopsy, HIC was prospectively evaluated in 168 patients by atomic absorption spectrometry. Diagnostic accuracies of HIC and R2* for grading hepatic inflammation plus ballooning (HIB) as an indicator of NAFLD activity were assessed. STATISTICAL TESTS: Student's t-test and analysis of variance (ANOVA) with Scheffe's multiple testing correction for univariate comparisons; multivariate logistic analysis. P-value less than 0.05 is statistically significant. RESULTS: HIC was significantly correlated with HIB grades (r = 0.407). R2* was significantly correlated with HIC (r = 0.557) and HIB grades (r = 0.569). R2* mapped an area under the receiver operating characteristic (AUROC; 0.774) for HIC ≥808 ng/mL (median value) with cutoff value of 62.5 s-1 . In addition, R2* mapped AUROC of HIB for grades ≥3 was 0.799 with cutoff value of 58.5 s-1 . When R2* was <62.5 s-1 , R2* correlated weakly with HIC (r = 0.372) as it was affected by fat deposition and did not correlate with HIB grades (P = 0.052). Conversely, when R2* was ≥62.5 s-1 , a significant correlation of R2* with HIC (r = 0.556) and with HIB grades was observed (P < 0.0001) with being less affected by fat deposition. DATA CONCLUSION: R2* ≥ 62.5 s-1 is a promising modality for non-invasive diagnosis of clinically important high grades (≥3) of HIB associated with increased HIC. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Learning Curve of Endoscopic Retrograde Cholangiopancreatography Using Single-Balloon Enteroscopy.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) in patients with surgically altered anatomy is technically difficult. Extensive training is required to develop the ability to perform this procedure. AIMS: To investigate the learning curve of single-balloon-assisted enteroscopy ERCP (SBE-ERCP). METHODS: We conducted a retrospective, observational case series at a single center. We evaluated the SBE-ERCP procedures between April 2011 and February 2021. The main outcomes were the rate of reaching the target site and the success rate of the entire procedure. These parameters were additionally expressed as a learning curve. RESULTS: A total of 687 SBE-ERCP procedures were analyzed. The learning curve was analyzed in blocks of 10 cases. In this study, seven endoscopists, experts in conventional ERCP, were included. The overall SBE-ERCP procedural success rate was 92.2% (634/687 cases). Combining all data from individual endoscopists' evaluation periods, the insertion and success rates of the SBE-ERCP procedures gradually increased with increased experience performing SBE-ERCP. The insertion success rates for the number of SBE-ERCP cases (< 20, 21-30, > 30) were 82.9%, 92.9%, and 94.3%, respectively; the procedure success rates were 74.3%, 81.4%, and 92.9%, respectively. The endoscopists who had performed > 30 SBE-ERCP cases had a success rate of ≥ 90%. CONCLUSIONS: Our results suggest that performing > 30 cases is one of the targets for conventional ERCP experts to become competent in performing SBE-ERCP in patients with a surgically altered anatomy.

Activation of Sympathetic Signaling in Macrophages Blocks Systemic Inflammation and Protects against Renal Ischemia-Reperfusion Injury.

BACKGROUND: The sympathetic nervous system regulates immune cell dynamics. However, the detailed role of sympathetic signaling in inflammatory diseases is still unclear because it varies according to the disease situation and responsible cell types. This study focused on identifying the functions of sympathetic signaling in macrophages in LPS-induced sepsis and renal ischemia-reperfusion injury (IRI). METHODS: We performed RNA sequencing of mouse macrophage cell lines to identify the critical gene that mediates the anti-inflammatory effect of ß2-adrenergic receptor (Adrb2) signaling. We also examined the effects of salbutamol (a selective Adrb2 agonist) in LPS-induced systemic inflammation and renal IRI. Macrophage-specific Adrb2 conditional knockout (cKO) mice and the adoptive transfer of salbutamol-treated macrophages were used to assess the involvement of macrophage Adrb2 signaling. RESULTS: In vitro, activation of Adrb2 signaling in macrophages induced the expression of T cell Ig and mucin domain 3 (Tim3), which contributes to anti-inflammatory phenotypic alterations. In vivo, salbutamol administration blocked LPS-induced systemic inflammation and protected against renal IRI; this protection was mitigated in macrophage-specific Adrb2 cKO mice. The adoptive transfer of salbutamol-treated macrophages also protected against renal IRI. Single-cell RNA sequencing revealed that this protection was associated with the accumulation of Tim3-expressing macrophages in the renal tissue. CONCLUSIONS: The activation of Adrb2 signaling in macrophages induces anti-inflammatory phenotypic alterations partially via the induction of Tim3 expression, which blocks LPS-induced systemic inflammation and protects against renal IRI.

Plastic or self-expandable metal stent: Which is the most suitable for patients with pancreatic head cancer in the upcoming era of neoadjuvant chemotherapy? A review.

Obstructive jaundice is a major symptom of pancreatic head cancer, and although its amelioration is required before scheduling chemotherapy, the decision to perform biliary drainage for resectable pancreatic cancer has remained controversial. In recent years, the effectiveness of neoadjuvant therapy for pancreatic cancer has been reported. Preoperative biliary drainage has become increasingly necessary, making the choice of stent an important one; thus, the longer the waiting period extends through neoadjuvant chemotherapy, the more durable stents - such as self-expandable metallic stents, rather than plastic stents - would be desired as an option. Still, there is insufficient evidence regarding surgical outcomes and long-term prognosis, and further confirmatory studies are needed. Through this review, we aim to provide an update on the characteristics of biliary stents and preoperative biliary drainage for potentially resectable pancreatic cancer.

Decreased IFT88 expression with primary cilia shortening causes mitochondrial dysfunction in cisplatin-induced tubular injury.

The relevance of primary cilia shortening in kidney disease and its pathomechanism are largely unknown. Tubular damage in acute kidney injury (AKI) is strongly associated with mitochondrial dysfunction. Thus, we investigated the interaction between primary cilia and mitochondria in cisplatin-induced AKI mouse models. We observed that the expression of intraflagellar transport 88 (IFT88), a ciliary maintenance protein, was decreased in the renal cortex following tubular damage due to cisplatin-induced AKI. This result was consistent with the decreased IFT88 expression in cisplatin-treated RPTEC/TERT1 cells (human primary proximal tubular cells) parallel to the shortening of primary cilia, suggesting a causative link between tubular damage and IFT88-mediated cilia regulation. To address the effect of impaired primary cilia with decreased IFT88 expression on tubular function, RPTEC/TERT1 cells treated with cisplatin and knocked down for IFT88 using siRNA (IFT88-KD) were assessed for phenotypic changes and mitochondrial metabolic function. Both cisplatin and IFT88-KD caused primary cilia shortening, downregulated mitochondrial oxidative phosphorylation capacity, and had defective fatty acid oxidation and decreased ATP production. Furthermore, IFT88 overexpression enhanced mitochondrial respiration, which partially counteracted cisplatin-induced defective fatty acid oxidation. These results are indicative of the contribution of IFT88 to mitochondrial homeostasis. Our findings suggest that tubular mitochondrial dysfunction in cisplatin-induced AKI is mediated, at least in part, by a decrease in IFT88 expression with primary cilia shortening. That is, tubular mitochondrial damage followed by tubular injury in AKI may occur through alteration of IFT88 expression and subsequent ciliary shortening in tubular cells.NEW & NOTEWORTHY Here, we demonstrated organelle cross-talk between primary cilia and mitochondria of proximal tubular cells in cisplatin-induced acute kidney injury. The primary cilia-mitochondria interaction may open new avenues for the development of novel therapeutic approaches in the treatment of acute kidney injury.

Harnessing Metabolomics to Describe the Pathophysiology Underlying Progression in Diabetic Kidney Disease.

PURPOSE OF REVIEW: Diabetic kidney disease (DKD), a leading cause of end-stage kidney disease, is the result of metabolic network alterations in the kidney. Therefore, metabolomics is an effective tool for understanding its pathophysiology, finding key biomarkers, and developing a new treatment strategy. In this review, we summarize the application of metabolomics to DKD research. RECENT FINDINGS: Alterations in renal energy metabolism including the accumulation of tricarboxylic acid cycle and glucose metabolites are observed in the early stage of DKD, and they finally lead to mitochondrial dysfunction in advanced DKD. Mitochondrial fission-fusion imbalance and dysregulated organelle crosstalk might contribute to this process. Moreover, metabolomics has identified several uremic toxins including phenyl sulfate and tryptophan derivatives as promising biomarkers that mediate DKD progression. Recent advances in metabolomics have clarified the role of dysregulated energy metabolism and uremic toxins in DKD pathophysiology. Integration of multi-omics data will provide additional information for identifying critical drivers of DKD.

[The Efficacy of Combined Use of Pertuzumab and Trastuzumab-Based Neoadjuvant Chemotherapy for HER2 Positive Breast Cancer].

NeoSphere trial showed that combined use of pertuzumab and trastuzumab-based chemotherapy for HER2 positive breast cancer improved the rate of pathological complete response (pCR). We retrospectively examined the efficacy of combined use of pertuzumab and trastuzumab-based neoadjuvant chemotherapy for HER2 positive breast cancer. Eleven patients with HER2 positive breast cancer who had completed neoadjuvant chemotherapy and undergone surgery included in this study. Four patients were hormone-receptor-positive and HER2 positive, 7 patients were hormone-receptor-negative and HER2 positive. Ten patients were treated with 4 courses of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), followed by 4 courses of docetaxel with trastuzumab and pertuzumab (HPD). One patient was treated with 4 courses of HPD. The rate of pCR (ypT0/is and ypN0) was 81.8%, and this outcome was better than the NeoSphere trial and the TRYPHAENA trial. As a result, our study suggested an additional therapeutic effect of 4 courses of FEC followed by 4 courses of HPD.

The oral hypoxia-inducible factor prolyl hydroxylase inhibitor enarodustat counteracts alterations in renal energy metabolism in the early stages of diabetic kidney disease.

Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors, also known as HIF stabilizers, increase endogenous erythropoietin production and serve as novel therapeutic agents against anemia in chronic kidney disease. HIF induces the expression of various genes related to energy metabolism as an adaptive response to hypoxia. However, it remains obscure how the metabolic reprogramming in renal tissue by HIF stabilization affects the pathophysiology of kidney diseases. Previous studies suggest that systemic metabolic disorders such as hyperglycemia and dyslipidemia cause alterations of renal metabolism, leading to renal dysfunction including diabetic kidney disease. Here, we analyze the effects of enarodustat (JTZ-951), an oral HIF stabilizer, on renal energy metabolism in the early stages of diabetic kidney disease, using streptozotocin-induced diabetic rats and alloxan-induced diabetic mice. Transcriptome analysis revealed that enarodustat counteracts the alterations in diabetic renal metabolism. Transcriptome analysis showed that fatty acid and amino acid metabolisms were upregulated in diabetic renal tissue and downregulated by enarodustat, whereas glucose metabolism was upregulated. These symmetric changes were confirmed by metabolome analysis. Whereas glycolysis and tricarboxylic acid cycle metabolites were accumulated and amino acids reduced in renal tissue of diabetic animals, these metabolic disturbances were mitigated by enarodustat. Furthermore, enarodustat increased the glutathione to glutathione disulfide ratio and relieved oxidative stress in renal tissue of diabetic animals. Thus, HIF stabilization counteracts alterations in renal energy metabolism occurring in incipient diabetic kidney disease.

Effect of preventive closure of the frenulum after endoscopic papillectomy: A prospective pilot study.

BACKGROUND AND AIM: The usefulness of preventive closure of the frenulum after endoscopic papillectomy (EP) could reduce bleeding. The feasibility and safety of clipping were evaluated in this prospective pilot study. METHODS: This study involved 40 consecutive patients who underwent preventive closure of the frenulum by clipping just after EP. The outcome data were compared with those of the previous 40 patients in whom no preemptive closure had been performed (no-closure group) (UMIN000014783). Additionally, the bleeding sites were examined. RESULTS: The clipping procedure was successful in all patients. As compared to the no-closure group, the rate of bleeding (P = 0.026) and period of hospital stay (P < 0.001) were significantly reduced in the closure group. There was no difference in the procedure time between the two groups. Furthermore, the incidence rates of pancreatitis and perforation were comparable in the two groups. The bleeding was noted in the frenulum area rather than at any other site in 90.9% of cases. CONCLUSION: Preventive closure of the frenulum after EP is an effective, safe, rational, and economical method to reduce the incidence of delayed bleeding, without prolonging the procedure time or increasing the risk of post-procedure pancreatitis perforation.

Comprehensive three-dimensional analysis (CUBIC-kidney) visualizes abnormal renal sympathetic nerves after ischemia/reperfusion injury.

The sympathetic nervous system is critical in maintaining the homeostasis of renal functions. However, its three-dimensional (3D) structures in the kidney have not been elucidated due to limitation of conventional imaging methods. CUBIC (Clear, Unobstructed Brain/Body Imaging Cocktails and Computational analysis) is a newly developed tissue-clearing technique, which enables whole-organ 3D imaging without thin-sectioning. Comprehensive 3D imaging by CUBIC found that sympathetic nerves are primarily distributed around arteries in the mouse kidney. Notably, the sympathetic innervation density was significantly decreased 10 days after ischemia-reperfusion injury (voluminal ratio of innervation area to kidney) by about 70%. Moreover, norepinephrine levels in kidney tissue (output of sympathetic nerves) were significantly reduced in injured kidneys by 77%, confirming sympathetic denervation after ischemia-reperfusion injury. Time-course imaging indicated that innervation partially recovered although overall denervation persisted 28 days after injury, indicating a continuous sympathetic nervous abnormality during the progression of chronic kidney disease. Thus, CUBIC-kidney, the 3D imaging analysis, can be a strong imaging tool, providing comprehensive, macroscopic perspectives for kidney research.

Clinical features of isolated proximal-type immunoglobulin G4-related sclerosing cholangitis.

BACKGROUND AND AIM: Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) presents as isolated proximal-type sclerosing cholangitis (i-SC). The present study sought to clarify the imaging differences between i-SC and Klatskin tumor. Differences between i-SC and IgG4-SC associated with autoimmune pancreatitis (AIP-SC) were also studied. METHODS: Differentiating factors between i-SC and Klatskin tumor were studied. Serum IgG4 level, CA19-9 level, computed tomography (CT) findings, cholangiography findings (symmetrical smooth long stricture extending into the upper bile duct [SSLS]), endosonographic features (continuous symmetrical mucosal lesion to the hilar part [CSML]), endoscopic biopsy results, treatment, relapse, and survival were also compared between patients with i-SC and those with AIP-SC. RESULTS: For a differential diagnosis between i-SC (N = 9) and Klatskin tumor (N = 47), the cut-off value of serum IgG4 level was 150 mg/dL (sensitivity, 0.857, specificity, 0.966). Logistic regression analysis indicated that serum IgG4 level, presence of SSLS, presence of CSML, and presence of swollen ampulla are independent factor for identifying i-SC. Relapse rate was significantly higher in the IgG4-SC with AIP group than in the i-SC group (log rank, P = 0.046). CONCLUSION: Isolated proximal-type sclerosing cholangitis presents as a nodular lesion with SSLS and/or CSML mimicking a Klatskin tumor. Those endoscopic features might provide a diagnostic clue for i-SC. i-SC is likely to have a more favorable prognosis than IgG4-SC with AIP.

Hypoxia-inducible factor stabilizers for treating anemia of chronic kidney disease.

PURPOSE OF REVIEW: Small-molecule inhibitors of prolyl hydroxylase domain enzymes (PHD inhibitors) are novel renal anemia therapies that increase endogenous erythropoietin (EPO) production by stabilizing hypoxia-inducible factor (HIF). This review summarizes recent findings and future perspectives of PHD inhibitors (HIF stabilizers) in chronic kidney disease (CKD)-associated anemia. RECENT FINDINGS: Clinical trials have demonstrated that HIF stabilizers effectively increase hemoglobin levels of both nondialysis and dialysis CKD patients without causing serious adverse effects. HIF stabilizers not only restore EPO production but also optimize iron metabolism by reducing hepcidin levels. Considering the pleiotropic roles of the PHD-HIF pathway, HIF stabilizers might have both advantageous and disadvantageous effects in humans, in addition to erythropoiesis. Results of studies in animal models have suggested that HIF stabilizers alleviate ischemia-reperfusion injury and play protective roles against metabolic diseases. In contrast, a theoretical concern exists regarding the potential for tumorigenesis due to HIF stabilization. SUMMARY: At least five HIF stabilizers are now in phase III trials and may appear on the market in 1-2 years. The long-term effects and safety of HIF stabilization should be carefully examined in future basic and clinical studies.