HMGB1 is a therapeutic target for sterile inflammation and infection.

A key question in immunology concerns how sterile injury activates innate immunity to mediate damaging inflammation in the absence of foreign invaders. The discovery that HMGB1, a ubiquitous nuclear protein, mediates the activation of innate immune responses led directly to the understanding that HMGB1 plays a critical role at the intersection of the host inflammatory response to sterile and infectious threat. HMGB1 is actively released by stimulation of the innate immune system with exogenous pathogen-derived molecules and is passively released by ischemia or cell injury in the absence of invasion. Established molecular mechanisms of HMGB1 binding and signaling through TLR4 reveal signaling pathways that mediate cytokine release and tissue damage. Experimental strategies that selectively target HMGB1 and TLR4 effectively reverse and prevent activation of innate immunity and significantly attenuate damage in diverse models of sterile and infection-induced threat.

PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells.

Expansion and differentiation of antigen-experienced PD-1+TCF-1+ stem-like CD8+ T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade1-4. Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of 'better effector' CD8+ T cells similar to those generated in an acute infection5. IL-2 binding to the IL-2 receptor α-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor ß- and γ-chain (IL-2Rßγ)-biased agonists are currently being developed6-10. Here we show that IL-2Rßγ-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cis to PD-1. Cis binding of PD1-IL2v to PD-1 and IL-2Rßγ on the same cell recovers the ability to differentiate stem-like CD8+ T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.

The P2X7 Receptor in Infection and Inflammation.

Adenosine triphosphate (ATP) accumulates at sites of tissue injury and inflammation. Effects of extracellular ATP are mediated by plasma membrane receptors named P2 receptors (P2Rs). The P2R most involved in inflammation and immunity is the P2X7 receptor (P2X7R), expressed by virtually all cells of innate and adaptive immunity. P2X7R mediates NLRP3 inflammasome activation, cytokine and chemokine release, T lymphocyte survival and differentiation, transcription factor activation, and cell death. Ten human P2RX7 gene splice variants and several SNPs that produce complex haplotypes are known. The P2X7R is a potent stimulant of inflammation and immunity and a promoter of cancer cell growth. This makes P2X7R an appealing target for anti-inflammatory and anti-cancer therapy. However, an in-depth knowledge of its structure and of the associated signal transduction mechanisms is needed for an effective therapeutic development.

Approach to febrile neutropenia in patients undergoing treatments for hematologic malignancies.

Febrile neutropenia (FN) is common among hematologic malignancy patients, including recipients of hematopoietic cell transplantation (HCT) and cellular therapies such as chimeric antigen receptor (CAR)-T-cell therapy. Prompt empiric antibiotic use has been the mainstay for decades but a "one-size-fits-all" approach is no longer broadly accepted, as treatment-related infectious risk are more understood. Growing antimicrobial resistance is an increasing clinical challenge. Evolving strategies on de-escalation of broad-spectrum antibiotics in FN without identified infection are areas of particular interest.

Challenges and recent progress in drug discovery for tropical diseases.

Infectious tropical diseases have a huge effect in terms of mortality and morbidity, and impose a heavy economic burden on affected countries. These diseases predominantly affect the world's poorest people. Currently available drugs are inadequate for the majority of these diseases, and there is an urgent need for new treatments. This Review discusses some of the challenges involved in developing new drugs to treat these diseases and highlights recent progress. While there have been notable successes, there is still a long way to go.

Methylobacterium infection-induced peritonitis in a patient with renal insufficiency: A case report and literature review.

Clinical pharmacists participated in the drug therapy of peritonitis caused by Methylobacterium infection in a patient with renal insufficiency. Based on the knowledge of clinical pharmacy, the patient's condition and laboratory parameters, the literature, and the pharmacokinetic/pharmacodynamic characteristics of antibiotics, amikacin in combination with ciprofloxacin was suggested for anti-infection therapy. During the treatment, clinical pharmacists timely evaluated the efficacy of antibiotics, monitored the adverse reactions, and provided individualized pharmaceutical care in the patient.

The impact of different antibiotic injection regimens on patients with severe infections: A meta-analysis.

Severe infection is a critical health threat to humans, and antibiotic treatment is one of the main therapeutic approaches. Nevertheless, the efficacy of various antibiotic injection regimens in severe infection patients remains uncertain. This study aimed to comprehensively evaluate the impact of various antibiotic injection strategies on patients with severe infection through a meta-analysis. Relevant research literature was collected by searching databases such as PubMed, Embase, and Cochrane Library. The retrieved literature was screened according to inclusion and exclusion criteria. Relevant data, including study design, sample size, and antibiotic regimens, were extracted from the included studies. The Cochrane Collaboration's Risk of Bias tool was employed to assess the risk of bias in each study. Statistical analysis was performed based on the results of the included studies. A total of 15 articles were included, covering various types of severe infection patients, including pulmonary and abdominal infections. The analysis provided insights into mortality rates, treatment efficacy, adverse reactions (ARs), Acute Physiology and Chronic Health Evaluation (APACHE) scores, among other outcomes. The results indicated that combination therapy was superior to monotherapy in terms of mortality rate, treatment efficacy, and APACHE scores, while the incidence of ARs was lower in the monotherapy group compared to the combination therapy group (p < 0.05). Combination therapy showed better treatment efficacy compared to monotherapy, although it was associated with a higher incidence of ARs.

Facilitated Subcutaneous Immunoglobulin Treatment in Patients with Immunodeficiencies: the FIGARO Study.

PURPOSE: The FIGARO study aims to provide insights on real-world utilization and tolerability of facilitated subcutaneous immunoglobulin (fSCIG) for primary immunodeficiency disease (PID) or secondary immunodeficiency disease (SID). METHODS: This prospective, multicenter, observational study, evaluated medical records, charts, and diaries of patients who had received at least 1 fSCIG infusion for PID or SID. Data were analyzed by cohort (PID, SID) and age groups (pediatric [< 18 years], adult [18-64 years], older adult [≥ 65 years]). Patients were followed up to 36 months. RESULTS: The study enrolled 156 patients: 15 pediatric, 120 adult, 21 older-adult. Twelve-month follow-up data were available for 128 patients. fSCIG was mainly prescribed for PID among patients aged < 65 years and for SID among older adults. At inclusion, 75.6% received their fSCIG infusion at home, and 78.7% self-administered. Adults were more likely to receive their initial infusion at home and self-administer (81.7% and 86.6%, respectively) than pediatric patients (53.3% each) and older adults (57.1% and 52.4%, respectively). At 12 months, the proportion of patients infusing at home and self-administering increased to 85.8% and 88.2%. Regardless of age, most patients self-administered the full fSCIG dose at home every 3-4 weeks and required a single infusion site. The tolerability profile was consistent with previous pivotal trials. Acute severe bacterial infections occurred in 0%-9.1% of patients during follow-up visits (full cohort). CONCLUSIONS: FIGARO confirms the feasibility, tolerability, and good infection control of fSCIG in PID and SID patients across the age spectrum in both the home-setting and medical facility. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03054181.

Establishing the Role of Inflammatory Markers in the Diagnosis and Treatment of Acute Hand Infections in the Pediatric Population.

INTRODUCTION: Distinguishing the severity of the diagnosis and an appropriate treatment plan in pediatric hand infections can be complex due to the variable amount of information available at the presentation. Inflammatory blood markers, including white blood cell count, erythrocyte sedimentation rate, and C-reactive protein are reported to aid in determining the severity of infection and response to treatment in adult hand infections. The purpose of this study was to identify the relevance of inflammatory marker levels in pediatric patients with hand and wrist infections and to determine their utility in diagnosis and treatment. METHODS: This multicenter, retrospective, cohort study included patients aged 0 to 18 who received treatment for an acute hand or wrist infection between 2009 and 2020. Data collected included demographics, time to presentation, diagnosis, inflammatory markers, culture results, antibiotic treatment, and surgical treatment. Infections were categorized as deep (osteomyelitis, tenosynovitis, abscess) and superficial (paronychia, felon, cellulitis). Exclusion criteria included: patients above 18 years of age, chronic infection, open fractures, and absence of any documented inflammatory markers. Statistically, t tests were used to compare mean differences in inflammatory markers between patients who did and did not receive pretreatment antibiotics and between patients who had superficial versus deep hand infections. RESULTS: A total of 123 patients met the inclusion criteria. Pretreatment with antibiotics before definitive management was not significantly associated with differences in laboratory markers compared with patients not pretreated with antibiotics. Deep hand infections had inflammatory markers similar to superficial infections. Patients with deep hand infections required a bedside or operative procedure 78.9% of the time compared with superficial infections (21.2%) ( P <0.001). Patients with an isolated methicillin-resistant Staphylococcus aureus infection had inflammatory marker values that were not significantly different from patients infected with all other microbes. CONCLUSIONS: Inflammatory markers were not significantly different between patients who received pretreatment with antibiotics and those who did not. While deep infections were often treated with bedside or surgical procedures, the inflammatory marker values were similar to those of superficial infections. The same held true for patients infected with culture-positive, isolated methicillin-resistant Staphylococcus aureus bacteria. Consequently, inflammatory markers may be useful to identify the presence of infection and monitor the response to treatment, they did not aid in determining the specific type of infection or selection of a treatment plan. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Protothecosis in four dogs in New Zealand.

CASE HISTORIES: Medical records of four dogs diagnosed with protothecosis in New Zealand were reviewed. The dogs were aged between 4 and 9 years and three of the four dogs were female. Breeds were one Labrador, one Miniature Schnauzer and two crossbreeds. The reasons for initial veterinary evaluation were a cough and opaque appearance of the right eye (Case 1), diarrhoea (Cases 2 and 3), and cutaneous disease (Case 4). CLINICAL FINDINGS: The ocular signs were characterised by panuveitis, retinal detachment and secondary glaucoma. Gastrointestinal signs included chronic haemorrhagic diarrhoea due to colitis. Three cases had disseminated infection and developed both bilateral, blinding, ocular disease and chronic gastrointestinal disease. Cutaneous signs consisted of draining fistulae over the olecranon, multifocal cutaneous nodules, and ulceration and tracts of the foot pads. Disseminated protothecosis was confirmed by histopathology of biopsied ocular tissues in Cases 1 and 2 and by gastrointestinal biopsies in Case 3. Prototheca spp. were also identified in cytological specimens from Cases 1 and 4 and recovered by culture in Cases 2 and 4. Cutaneous protothecosis was diagnosed in Case 4 initially by cytology and histopathology of skin lesions, and Prototheca zopfii was confirmed by PCR of cultured organisms. TREATMENT AND OUTCOME: Prior to diagnosis of protothecosis, a variety of treatments were prescribed to treat the gastrointestinal and ocular signs. After diagnosis, only Cases 2 and 4 received medication aimed at treating the protothecal infection, which was itraconazole in both cases. Following the progression of clinical signs and concerns about quality of life, all four dogs were euthanised. DIAGNOSIS: Disseminated protothecosis in three dogs, cutaneous protothecosis in one dog. CLINICAL RELEVANCE: Canine protothecosis is rarely reported, despite the ubiquity of the causal algae, and the disease usually carries an extremely grave prognosis when infection is generalised. In New Zealand, protothecosis should be considered as a differential diagnosis in dogs with panuveitis, chorioretinitis or retinal detachment, colitis, or nodular, ulcerative or fistulating cutaneous lesions.

Impact of the first COVID-19 lockdown in Germany on the rate of acute infections during intensive chemotherapy for Hodgkin lymphoma.

PURPOSE: Evidence on the effect of self-protection via social distancing and wearing face-masks on infections during chemotherapy is currently not available. We asked if the occurrence of acute infections during chemotherapy for advanced-stage Hodgkin lymphoma (HL) decreased when COVID-19 protection measures were in effect. METHODS: We analyzed the occurrence of infections during all documented eBEACOPP cycles starting between 01 March and 30 June of 2017 to 2020 in patients treated within the GHSG HD21 study in Germany and compared the infection rates and characteristics by logistic regression models and means of descriptive statistics. RESULTS: We analyzed 911 cycles of 313 adult patients treated with 4 to 6 cycles of eBEACOPP. We found a significant decrease in the occurrence of infections during chemotherapy for HL during COVID-19 lockdown from 131 (19.6%) of 670 cycles in 2017-2019 to 30 (12.6%) of 239 cycles during COVID-19 lockdown [OR 0.574 (95% CI 0.354-0.930), P = 0.024]. The strongest effect was evident for unspecified infections with 39 cycles (5.8%) during 2017-2019 in comparison to 5 cycles (2.1%) during COVID-19 lockdown. 20 (24.1%) of 83 patients had an infection during the COVID-19 lockdown versus 99 (43.2%) of 229 patients in the years 2017-2019 (P = 0.0023). CONCLUSION: The significant decrease of infections during chemotherapy for HL during COVID-19 lockdown reveals the protective measures' potential to shield patients from transmissible pathogens. We conclude that these measures could be recommended for HL patients at risk for infections during chemotherapy.

Point-of-care C-reactive protein test results in acute infections in children in primary care: an observational study.

BACKGROUND: Acute infections are a common reason for children to consult primary care. Serious infections are rare but differentiating them from self-limiting illnesses remains challenging. This can lead to inappropriate antibiotic prescribing. Point-of-care C-reactive protein testing is used to guide antibiotic prescribing in adults. However, in children its use remains unclear. The purpose of this study was to assess point-of-care CRP test levels with respect to patients' characteristics, care setting, preliminary diagnosis, and management. METHODS: A prospective observational study was performed in children with an acute infection presenting to ambulatory care in Belgium. RESULTS: In this study 8280 cases were analysed, of which 6552 had a point-of-care CRP value available. A total of 276 physicians participated. The median patient age was 1.98 years (IQR 0.97 to 4.17), 37% of children presented to a general practitioner, 33% to a paediatric out-patient clinic, and 30% to the emergency department. A total of 131 different preliminary diagnoses were found, with acute upper airway infection as the most frequent. In 6% (n = 513) patients were diagnosed with a serious infection. The most common serious infection was pneumonia. Antibiotics were prescribed in 28% (n = 2030) of all episodes. The median CRP over all infectious episodes was 10 mg/L (IQR < 5-29). Children below 5 years of age and those presenting to a paediatrician had a higher median CRP. Median CRP in patients with serious infections was 21 mg/L (IQR 6 to 63.5). Pneumonia had a median CRP of 48 mg/L (IQR 13-113). In the episodes with antibiotics prescription, median CRP level was 29 mg/L (IQR 10-58) compared to 7 mg/L (IQR < 5-19) when they were not prescribed. CONCLUSION: A low POC CRP as a standalone tool did not seem to be sufficient to rule out serious infections, but its potential in assessing serious infections could increase when integrated in a clinical decision rule. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02024282 (registered on 31/12/2013).

Metal Complexes-A Promising Approach to Target Biofilm Associated Infections.

Microbial biofilms are represented by sessile microbial communities with modified gene expression and phenotype, adhered to a surface and embedded in a matrix of self-produced extracellular polymeric substances (EPS). Microbial biofilms can develop on both prosthetic devices and tissues, generating chronic and persistent infections that cannot be eradicated with classical organic-based antimicrobials, because of their increased tolerance to antimicrobials and the host immune system. Several complexes based mostly on 3D ions have shown promising potential for fighting biofilm-associated infections, due to their large spectrum antimicrobial and anti-biofilm activity. The literature usually reports species containing Mn(II), Ni(II), Co(II), Cu(II) or Zn(II) and a large variety of multidentate ligands with chelating properties such as antibiotics, Schiff bases, biguanides, N-based macrocyclic and fused rings derivatives. This review presents the progress in the development of such species and their anti-biofilm activity, as well as the contribution of biomaterials science to incorporate these complexes in composite platforms for reducing the negative impact of medical biofilms.

Health outcomes of 1000 children born to mothers with inflammatory bowel disease in their first 5 years of life.

OBJECTIVE: The aim of this study was to describe the long-term health outcomes of children born to mothers with inflammatory bowel disease (IBD) and to assess the impact of maternal IBD medication use on these outcomes. DESIGN: We performed a multicentre retrospective study in The Netherlands. Women with IBD who gave birth between 1999 and 2018 were enrolled from 20 participating hospitals. Information regarding disease characteristics, medication use, lifestyle, pregnancy outcomes and long-term health outcomes of children was retrieved from mothers and medical charts. After consent of both parents, outcomes until 5 years were also collected from general practitioners. Our primary aim was to assess infection rate and our secondary aims were to assess adverse reactions to vaccinations, growth, autoimmune diseases and malignancies. RESULTS: We included 1000 children born to 626 mothers (381 (61%) Crohn's disease, 225 (36%) ulcerative colitis and 20 (3%) IBD unclassified). In total, 196 (20%) had intrauterine exposure to anti-tumour necrosis factor-α (anti-TNF-α) (60 with concomitant thiopurine) and 240 (24%) were exposed to thiopurine monotherapy. The 564 children (56%) not exposed to anti-TNF-α and/or thiopurine served as control group. There was no association between adverse long-term health outcomes and in utero exposure to IBD treatment. We did find an increased rate of intrahepatic cholestasis of pregnancy (ICP) in case thiopurine was used during the pregnancy without affecting birth outcomes and long-term health outcomes of children. All outcomes correspond with the general age-adjusted population. CONCLUSION: In our study, we found no association between in utero exposure to anti-TNF-α and/or thiopurine and the long-term outcomes antibiotic-treated infections, severe infections needing hospital admission, adverse reactions to vaccinations, growth failure, autoimmune diseases and malignancies.

Short-Chain Fatty Acids as a Potential Treatment for Infections: a Closer Look at the Lungs.

Short-chain fatty acids (SCFAs) are the main metabolites produced by the gut microbiota via the fermentation of complex carbohydrates and fibers. Evidence suggests that SCFAs play a role in the control of infections through direct action both on microorganisms and on host signaling. This review summarizes the main microbicidal effects of SCFAs and discusses studies highlighting the effect of SCFAs in the virulence and viability of microorganisms. We also describe the diverse and complex modes of action of the SCFAs on the immune system in the face of infections with a specific focus on bacterial and viral respiratory infections. A growing body of evidence suggests that SCFAs protect against lung infections. Finally, we present potential strategies that may be leveraged to exploit the biological properties of SCFAs for increasing effectiveness and optimizing patient benefits.

Biologics During Pregnancy in Women With Inflammatory Bowel Disease and Risk of Infantile Infections: A Systematic Review and Meta-Analysis.

INTRODUCTION: Biologics, such as tumor necrosis factor inhibitors, anti-integrins and anticytokines, are therapies for inflammatory bowel disease (IBD) that may increase the risk of infection. Most biologics undergo placental transfer during pregnancy and persist at detectable concentrations in exposed infants. Whether this is associated with an increased risk of infantile infections is controversial. We performed a systematic review and meta-analysis evaluating the risk of infantile infections after in utero exposure to biologics used to treat IBD. METHODS: We searched PubMed, Embase, Scopus, Web of Science, and CENTRAL from inception to June 2020 to evaluate the association of biologic therapy during pregnancy in women with IBD and risk of infantile infections. Odds ratios of outcomes were pooled and analyzed using a random effects model. RESULTS: Nine studies met the inclusion criteria comprising 8,013 women with IBD (5,212 Crohn's disease, 2,801 ulcerative colitis) who gave birth to 8,490 infants. Biologic use during pregnancy was not associated with an increased risk of all infantile infections (odds ratio [OR] 0.91, 95% confidence interval [CI] 0.73-1.14, I2 = 30%). In a subgroup analysis for the type of infection, biologic use was associated with increased infantile upper respiratory infections (OR 1.57, 95% CI 1.02-2.40, I2 = 4%). Biologic use during pregnancy was not associated with infantile antibiotic use (OR 0.91, 95% CI 0.73-1.14, I2 = 30%) or infection-related hospitalizations (OR 1.33, 95% CI 0.95-1.86, I2 = 26%). DISCUSSION: Biologics use during pregnancy in women with IBD is not associated with the overall risk of infantile infections or serious infections requiring antibiotics or hospitalizations but is associated with an increased risk of upper respiratory infections.

Tea bioactive components prevent carcinogenesis via anti-pathogen, anti-inflammation, and cell survival pathways.

Cancer seriously impairs human health and survival. Many perturbations, such as increased oxidative stress, pathogen infection, and inflammation, promote the accumulation of DNA mutations, and ultimately lead to carcinogenesis. Tea is one of the most highly consumed beverages worldwide and has been linked to improvements in human health. Tea contains many active components, including tea polyphenols, tea polysaccharides, L-theanine, tea pigments, and caffeine among other common components. Several studies have identified components in tea that can directly or indirectly reduce carcinogenesis with some being used in a clinical setting. Many previous studies, in vitro and in vivo, have focused on the mechanisms that functional components of tea utilized to protect against cancer. One particular mechanism that has been well described is an improvement in antioxidant capacity seen with tea consumption. However, other mechanisms, including anti-pathogen, anti-inflammation and alterations in cell survival pathways, are also involved. The current review focuses on these anti-cancer mechanisms. This will be beneficial for clinical utilization of tea components in preventing and treating cancer in the future.

How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) therapy has changed dramatically with the introduction of several targeted therapeutics. Ibrutinib was the first approved for use in 2014 and now is used for initial and salvage therapy of CLL patients. With its widespread use in clinical practice, ibrutinib's common and uncommon adverse events reported less frequently in earlier clinical trials have been experienced more frequently in real-world practice. In particular, atrial fibrillation, bleeding, infections, and arthralgias have been reported. The management of ibrutinib's adverse events often cannot be generalized but must be individualized to the patient and their long-term risk of additional complications. When ibrutinib was initially developed, there were limited therapeutic alternatives for CLL, which often resulted in treating through the adverse events. At the present time, there are several effective alternative agents available, so transition to an alternative CLL directed therapy may be considered. Given the continued expansion of ibrutinib across many therapeutic areas, investigation of the pathogenesis of adverse events with this agent and also clinical trials examining therapeutic approaches for complications arising during therapy are needed. Herein, we provide strategies we use in real-world CLL clinical practice to address common adverse events associated with ibrutinib.

Managing Anemia across the Stages of Kidney Disease in Those Hyporesponsive to Erythropoiesis-Stimulating Agents.

BACKGROUND: Patients with CKD frequently have anemia that results from iron-restricted erythropoiesis and inflammation. Anemia of CKD is currently managed with iron supplements and erythropoiesis-stimulating agents (ESAs) to promote erythropoiesis and with RBC transfusion in severe cases. Hyporesponse to ESAs, or the need for larger than usual doses to attain a given hemoglobin (Hb) level, is associated with increased morbidity and mortality and presents a pressing clinical challenge, particularly for patients on dialysis. This paper reviews ESA hyporesponse and potential new therapeutic options in the management of anemia of CKD. SUMMARY: The most common causes of ESA hyporesponse include iron deficiency and inflammation, and to a lesser degree, secondary hyperparathyroidism, inadequate dialysis, malnutrition, and concomitant medications. Management of ESA hyporesponse is multipronged and involves treating low level infections, ensuring adequate nutrition, and optimizing iron status and dialysis modality, although some patients can remain refractory. Inflammation directly increases production and secretion of hepcidin, contributes to an impaired response to hypoxia, and suppresses proliferation of erythroid progenitors. Coordination of renal and hepatic erythropoietin (EPO) production and iron metabolism is under the control of hypoxia-inducible factors (HIF), which are in turn regulated by HIF-prolyl hydroxylases (HIF-PHs). HIF-PHs and hepcidin are therefore attractive potential drug targets particularly in patients with ESA hyporesponse. Several oral HIF-PH inhibitors have been evaluated in patients with anemia of CKD and have been shown to increase Hb and reduce hepcidin regardless of inflammation, iron status, or dialysis modality. These sustained effects are achieved through more modest increases in endogenous EPO compared with ESAs. Key Messages: Treatments that address ESA hyporesponse remain a significant unmet clinical need in patients with anemia of CKD. New therapies such as HIF-PH inhibitors have the potential to address fundamental aspects of ESA hyporesponse and provide a new therapeutic option in these patients.