Anemia Of Chronic Kidney Disease Research Articles

Identification and single-base gene-editing functional validation of a cis-EPO variant as a genetic predictor for EPO-increasing therapies

SummaryHypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p < 0.05) that genetically predicted long-term rises in endogenous EPO, equivalent to a 2.2-unit increase, increased risk of coronary artery disease (CAD, OR [95% CI] = 1.01 [0.93, 1.07]), myocardial infarction (MI, OR [95% CI] = 0.99 [0.87, 1.15]), or stroke (OR [95% CI] = 0.97 [0.87, 1.07]). We could exclude increased odds of 1.15 for cardiovascular disease for a 2.2-unit EPO increase. A combination of genetic and functional studies provides a powerful approach to investigate the potential therapeutic profile of EPO-increasing therapies for treating anemia in CKD.

Genetically proxied therapeutic prolyl-hydroxylase inhibition and cardiovascular risk.

Prolyl hydroxylase (PHD) inhibitors are in clinical development for anaemia in chronic kidney disease. Epidemiological studies have reported conflicting results regarding safety of long-term therapeutic haemoglobin (Hgb) rises through PHD inhibition on risk of cardiovascular disease. Genetic variation in genes encoding PHDs can be used as partial proxies to investigate the potential effects of long-term Hgb rises. We used Mendelian randomization to investigate the effect of long-term Hgb level rises through genetically proxied PHD inhibition on coronary artery disease (CAD: 60 801 cases; 123 504 controls), myocardial infarction (MI: 42 561 cases; 123 504 controls) or stroke (40 585 cases; 406 111 controls). To further characterize long-term effects of Hgb level rises, we performed a phenome-wide association study (PheWAS) in up to 451 099 UK Biobank individuals. Genetically proxied therapeutic PHD inhibition, equivalent to a 1.00g/dl increase in Hgb levels, was not associated (at P < 0.05) with increased odds of CAD; odd ratio (OR) [95% confidence intervals (CI)] = 1.06 (0.84, 1.35), MI [OR (95% CI) = 1.02 (0.79, 1.33)] or stroke [OR (95% CI) = 0.91 (0.66, 1.24)]. PheWAS revealed associations with blood related phenotypes consistent with EGLN's role, relevant kidney- and liver-related biomarkers like estimated glomerular filtration rate and microalbuminuria, and non-alcoholic fatty liver disease (Bonferroni-adjusted P < 5.42E-05) but these were not clinically meaningful. These findings suggest that long-term alterations in Hgb through PHD inhibition are unlikely to substantially increase cardiovascular disease risk; using large disease genome-wide association study data, we could exclude ORs of 1.35 for cardiovascular risk with a 1.00g/dl increase in Hgb.

Anaemia in Chronic Kidney Disease

Objective: To gauge the frequency of iron deficiency anaemia among chronic renal disease patients and factors related to the presence of anaemia at our hospital.&#x0D; Study Design: Cross-sectional study.&#x0D; Place and Duration of Study: Department of nephrology Pak Emirates Military Hospital Rawalpindi Pakistan, Nine months, Sep 2019 to May 2020.&#x0D; Methodology: Three hundred patients suffering from the chronic renal disease were included in the study. Iron deficiency anaemia was diagnosed based on haemoglobin and ferritin levels. In addition, the relationship between age, gender, duration of chronic kidney disease and stage of chronic kidney disease was assessed with the presence of iron deficiency anaemia among the patients suffering from chronic kidney disease.&#x0D; Results: Out of three hundred patients studied, 139 were males, and 161 were females. Out of 300 patients with chronic kidney disease included in our study, 159 (53.0%) showed the presence of iron deficiency anaemia, while 141 (47.0%) had no anaemia. Chi-square analysis showed that female gender, long duration of illness and more severe illness had a significant association with iron deficiency anaemia among the patients with chronic kidney disease.&#x0D; Conclusion: High frequency of iron deficiency anaemia among the patients of chronic kidney disease in a tertiary care hospital of Pakistan. Routine screening for anaemia should be done, especially on female patients and patients with more severe and long-standing illnesses.

Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease.

Anaemia occurs in chronic kidney disease (CKD) and is more prevalent with lower levels of kidney function. Anaemia in CKD is associated with death related to cardiovascular (CV) disease and infection. Established treatments include erythropoiesis-stimulating agents (ESAs), iron supplementation and blood transfusions. Oral hypoxia-inducible factors (HIF) stabilisers are now available to manage anaemia in people with CKD. We aimed to assess the benefits and potential harms of HIF stabilisers for the management of anaemia in people with CKD. We searched the Cochrane Kidney and Transplant Register of Studies up to 22 November 2021 through contact with the Information Specialist using search terms relevant to our review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. Randomised and quasi-randomised studies evaluating hypoxia-inducible factors stabilisers compared to placebo, standard care, ESAs or iron supplementation in people with CKD were included. Five authors independently extracted data and assessed the risk of bias. Treatment estimates were summarised using random effects pair-wise meta-analysis and expressed as a relative risk (RR) or mean difference (MD), with a corresponding 95% confidence interval (CI). Evidence certainty was assessed using GRADE. We included 51 studies randomising 30,994 adults. These studies compared HIF stabilisers to either placebo or an ESA. Compared to placebo, HIF stabiliser therapy had uncertain effects on CV death (10 studies, 1114 participants): RR 3.68, 95% CI 0.19 to 70.21; very low certainty evidence), and nonfatal myocardial infarction (MI) (3 studies, 822 participants): RR 1.29, 95% CI 0.31 to 5.36; I² = 0%; very low certainty evidence), probably decreases the proportion of patients requiring blood transfusion (8 studies, 4329 participants): RR 0.51, 95% CI 0.44 to 0.60; I² = 0%; moderate certainty evidence), and increases the proportion of patients reaching the target haemoglobin (Hb) (10 studies, 5102 participants): RR 8.36, 95% CI 6.42 to 10.89; I² = 37%; moderate certainty evidence). Compared to ESAs, HIF stabiliser therapy may make little or no difference to CV death (17 studies, 10,340 participants): RR 1.05, 95% CI 0.88 to 1.26; I² = 0%; low certainty evidence), nonfatal MI (7 studies, 7765 participants): RR 0.91, 95% CI 0.76 to 1.10; I² = 0%; low certainty evidence), and nonfatal stroke (5 studies, 7285 participants): RR 1.06, 95% CI 0.71 to 1.56; I² = 8%; low certainty evidence), and had uncertain effects on fatigue (2 studies, 3471 participants): RR 0.80, 95% CI 0.56 to 1.16; I² = 0%; very low certainty evidence). HIF stabiliser therapy probably decreased the proportion of patients requiring blood transfusion (11 studies, 10,786 participants): RR 0.87, 95% CI 0.76 to 1.00; I² = 25%; moderate certainty evidence), but may make little or no difference on the proportion of patients reaching the target Hb (14 studies, 4601 participants): RR 1.00, 95% CI 0.93 to 1.07; I² = 70%; low certainty evidence), compared to ESA. The effect of HIF stabilisers on hospitalisation for heart failure, peripheral arterial events, loss of unassisted dialysis vascular access patency, access intervention, cancer, infection, pulmonary hypertension and diabetic nephropathy was uncertain. None of the included studies reported life participation. Adverse events were rarely and inconsistently reported. HIF stabiliser management of anaemia had uncertain effects on CV death, fatigue, death (any cause), CV outcomes, and kidney failure compared to placebo or ESAs. Compared to placebo or ESAs, HIF stabiliser management of anaemia probably decreased the proportion of patients requiring blood transfusions, and probably increased the proportion of patients reaching the target Hb when compared to placebo.

Hypoxia-inducible factor prolyl hydroxylase inhibitors for anaemia in maintenance dialysis: a meta-analysis.

Anaemia is a common complication of end-stage renal disease (ESRD) that relies on dialysis. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) is a new class of small-molecule oral drugs for the treatment of anaemia in chronic kidney disease. They demonstrate several advantages over traditional exogenous erythropoietin (EPO). We conducted a meta-analysis of studies that compared the efficacy of HIF-PHI in erythropoiesis and iron metabolism, and its safety with EPO in maintenance dialysis patients. A sensitive search strategy in the PubMed, EMBASE and Cochrane databases identified all citations for randomised controlled trials (RCTs) comparing HIF-PHI agents with EPO/placebo through December 2021. Fourteen RCTs were identified, which included 2738 patients. No statistical difference was found in haemoglobin increase (p = 0.37) between HIF-PHI treatment and EPO using the random-effects model. HIF-PHI administration upregulated transferrin (MD 36.12, 95% CI 27.04-45.20) and soluble transferrin receptors (sTfR) (MD 1.28, 95% CI 0.44-2.13), but did not statistically reduce hepcidin level (p = 0.37). Total and LDL-cholestrol levels were suppressed by HIF-PHI (MD - 0.99, 95% CI - 1.34 to - 0.63) (MD - 0.99, 95% CI - 1.34 to - 0.64), while triglyceride (TG) was not different between HIF-PHI and EPO (p = 0.74). The total incident rates of treatment-emergent adverse events (TEAE) (p = 0.20) from HIF-PHI treatment were not different from those of erythropoietin, while the treatment-emergent serious adverse events (TSAE) (p = 0.02) were higher in the HIF-PHI group than those in the EPO controls with the fixed-effect model. HIF-PHI could effectively upregulate and maintain haemoglobin levels in patients with anaemia receiving maintenance dialysis. Furthermore, HIF-PHI could elevate iron metabolism activity and utility without inducing treatment-associated serious adverse events. Robust data from larger RCTs with longer treatment duration and follow-up are needed.

Efficacy and safety of vadadustat compared to darbepoetin alfa on anemia in patients with chronic kidney disease: a meta-analysis.

As a novel oral agent in treating anemia of chronic kidney disease (CKD), several clinical trials of vadadustat have been conducted to compare with darbepoetin alfa. This study systematically reviews and investigates the efficacy and safety of vadadustat in the anemia treatment with different duration in both nondialysis-dependent CKD (NDD-CKD) and dialysis-dependent CKD (DD-CKD). Several main databases were searched for randomized controlled trials (RCTs) reporting vadadustat vs darbepoetin alfa for anemia patients with CKD. The outcome indicators were focused on hemoglobin (Hb), the percentage of patients within the target Hb, the need for RBC (Red Blood Cell) transfusions, and serious adverse events (SAEs). Four eligible studies with 8,026 participants were included. The changes of Hb levels from the baseline in the darbepoetin alfa group were significantly higher than that in the vadadustat group with DD-CKD (mean difference (MD) -0.19, [95% confidence interval (CI), -0.21 to -0.17], p < 0.0001). In NDD-CKD patients, the changes of Hb levels in the two groups are not significantly different (MD = -0.06, [95% CI, -0.18 to 0.05], p = 0.006), especially, during the treatment duration of 20-36weeks (MD = 0.02, [95% CI, -0.04 to 0.08], p = 0.51). The percentage of patients within the target Hb was significantly lower in the vadadustat group than that in the darbepoetin alfa group in DD-CKD patients (MD = 0.9, [95% CI, 0.86 to 0.94], p < 0.00001), while in NDD-CKD patients, there was no significant difference (MD = 1.05, [95% CI, 0.99 to 1.12], p < 0.00001). In terms of safety, the two agents had no significant difference in the incidence of RBC transfusions and SAEs (RR = 1.26 [95% CI, 0.99 to 1.61], p = 0.52; RR = 0.97, [95% CI, 0.94 to 1.01], p = 0.19; respectively). Compared to darbepoetin alfa, vadadustat had the same effect in raising the hemoglobin level in NDD-CKD patients in the short term. Vadadustat may become an effective and safe alternative for the treatment of patients with anemia and CKD, especially in NDD-CKD patients. As the application of vadadustat is still under exploration, future research should compensatefor the limitations of our study to estimate the vadadustat's value.

Is HIF-PHI the Answer to Tackle ESA Hyporesponsiveness in the Elderly?

Anemia in chronic kidney disease (CKD) has become an important clinical issue with the increased prevalence of elderly patients living with CKD progressing to kidney failure. The causes of anemia in elderly individuals tend to be multifactorial, exacerbated by the physiological effects of aging, frailty and declining kidney function. Erythropoiesis-stimulating agents (ESAs) are the conventional therapeutic option for anemia in CKD. However, ESA hyporesponsiveness is a commonly observed issue in clinical practice and an issue that is more challenging to resolve in elderly patients living with frailty, kidney disease, and multi-morbidities. Following the emergence of oral hypoxia-induced factor prolyl-hydroxylase inhibitors (HIF-PHI) in recent years, there is discussion on whether it is a solution to the conundrum of ESA hyporesponsiveness, as HIF-PHI treats anemia via an alternative physiological pathway. There remains uncertainty on the suitability of HIF-PHI use in elderly patients, given a lack of data on its safety over long-term follow-up for the elderly population. Further study is needed to provide answers, considering the clinical significance of this issue within a public-health scale.

Preclinical Characterization of Vadadustat (AKB-6548), an Oral Small Molecule Hypoxia-Inducible Factor Prolyl-4-Hydroxylase Inhibitor, for the Potential Treatment of Renal Anemia.

Pharmacological inhibition of prolyl-4-hydroxylase domain (PHD) enzymes stabilizes hypoxia-inducible factors (HIFs), transcription factors that activate target genes that, among others, increase erythropoietin (EPO) synthesis, resulting in the production of new red blood cells (RBCs). Herein, we summarize the preclinical characteristics of the small molecule HIF prolyl-4-hydroxylase inhibitor vadadustat (AKB-6548), which is in development for the treatment of anemia in patients with chronic kidney disease (CKD). Vadadustat inhibits the enzyme activity of all three human PHD isozymes, PHD1, PHD2, and PHD3, with similar low nanomolar inhibitory constant values. PHD enzyme inhibition by vadadustat is competitive with endogenous cofactor 2-oxoglutarate and is insensitive to free iron concentration. In the human hepatocellular carcinoma cell line (Hep 3B) and human umbilical vein endothelial cells, PHD inhibition by vadadustat leads to the time- and concentration-dependent stabilization of HIF-1α and HIF-2α In Hep 3B cells, this in turn results in the synthesis and secretion of EPO; vascular endothelial growth factor is not measured at detectable levels. A single oral dose of vadadustat in rats potently increases circulating levels of EPO, and daily oral dosing for 14 days increases RBC indices in healthy rats and in the 5/6 nephrectomy model of CKD. In mice and dogs, once-daily repeat oral dosing increases hemoglobin and hematocrit. Vadadustat has a relatively short half-life in all nonclinical species evaluated and does not accumulate when administered as a single bolus dose (oral or intravenous) or upon repeat oral dosing. The pharmacological profile of vadadustat supports continued development for treatment of renal anemia. SIGNIFICANCE STATEMENT: Vadadustat (AKB-6548) is an orally bioavailable small molecule prolyl-4-hydroxylase inhibitor in development for anemia of chronic kidney disease. It is an equipotent inhibitor of the three human prolyl-4-hydroxylase domain isoforms, which activates erythropoiesis through stabilization of hypoxia-inducible factor (HIF)-1α and HIF-2α, increasing production of erythropoietin, without detectable stimulation of vascular endothelial growth factor.

Anemia in Chronic Kidney Disease: The State of the Art

The aging of the population has led to an increased prevalence of chronic diseases such as chronic kidney disease. Anemia is one of the most frequent complications of chronic kidney disease, with an impact not only on the quality of life but also on the patient's prognosis and associated costs. Knowledge in this therapeutic area has increased significantly: from the appearance of recombinant erythropoietin in 1989, through the use of increasing doses of parenteral iron and, more recently, to new molecules such as hypoxia-inducible factor inhibitors. The aim of this article is to present a pragmatic review of the state of the art in the epidemiology, pathophysiology, diagnosis and treatment of anemia associated with chronic kidney disease.

Roxadustat A promising treatment for anaemia in chronic kidney disease

Roxadustat A promising treatment for anaemia in chronic kidney disease

Improving Detection and Management of Anemia in CKD.

At the end of the activity, participants will be able to:Describe approaches to improve recognition of chronic kidney disease (CKD) and anemia in primary care. Explain the importance of early management of anemia in CKD to reduce adverse outcomes and improve symptoms. Prescribe evidence-based treatment for patients with anemia in CKD who can be managed in the primary care setting. Discuss emerging evidence for new agents being studied for treating anemia in CKD.

Regulation of Erythropoiesis by the Hypoxia-Inducible Factor Pathway: Effects of Genetic and Pharmacological Perturbations.

Red blood cells transport O2 from the lungs to body tissues. Hypoxia stimulates kidney cells to secrete erythropoietin (EPO), which increases red cell mass. Hypoxia-inducible factors (HIFs) mediate EPO gene transcriptional activation. HIF-α subunits are subject to O2-dependent prolyl hydroxylation and then bound by the von Hippel-Lindau protein (VHL), which triggers their ubiquitination and proteasomal degradation. Mutations in the genes encoding EPO, EPO receptor, HIF-2α, prolyl hydroxylase domain protein 2 (PHD2), or VHL cause familial erythrocytosis. In addition to O2, α-ketoglutarate is a substrate for PHD2, and analogs of α-ketoglutarate inhibit hydroxylase activity. In phase III clinical trials evaluating the treatment of anemia in chronic kidney disease, HIF prolyl hydroxylase inhibitors were as efficacious as darbepoetin alfa in stimulating erythropoiesis. However, safety concerns have arisen that are focused on thromboembolism, which is also a phenotypic manifestation of VHL or HIF-2α mutation, suggesting that these events are on-target effects of HIF prolyl hydroxylase inhibitors.

EPH161 A Scoping Review on Estimation of Economic Burden of Chronic Kidney Diseases in India

Chronic Kidney Disease (CKD) is an important public health problem with high prevalence, morbidity and mortality. A large number of patients are below the poverty line and have low monetary allocations for healthcare, increasing the economic burden of treatment of CKD. In non-dialysis-dependent (NDD) patients, untreated anemia of CKD leads to higher costs, higher healthcare resource utilization (HRU), and lower health-related quality of life (HRQoL). Limited resources and lack of protection against catastrophic health spending have led to over-reliance on out-of-pocket health expenditure.

Effects of Low-Flux and High-Flux Dialysis Membranes on Erythropoietin Responsiveness in Hemodialysis Patients.

Background Chronic kidney disease (CKD) is often accompanied by anemia. High-flux membranes contribute to a reasonable removal of uremic toxins which cause anemia in CKD. Inadequate data have described the efficiency of high-flux dialysis in promoting erythropoietin responsiveness in CKD patients in the Middle East. This study was conducted to compare the efficiency of maintaining high-flux hemodialysis versus low-flux dialysis for ≥1 year in promoting erythropoietin responsiveness and to show the factors associated with erythropoietin hyporesponsiveness in Arab chronic hemodialysis patients. Methods It was a retrospective cohort study that involved 110 subjects who were categorized into group 1 (50 patients receiving low-flux dialysis) and group 2 (60 patients receiving high-flux dialysis). History taking, examination, and laboratory investigations were conducted for all patients every 3 months from January 2021 to January 2022. Results Group 2 had significantly higher weight and body mass index than group 1 but lower cholesterol and intact parathyroid hormone levels than group 1. Erythropoietin resistance index levels did not differ between the two groups upon repeated measures over a 1-year follow-up. Significant risk factors for erythropoietin hyporesponsiveness on multivariate analysis were lower weight (Odds ratio (OR): 0.966; 95% Confidence interval (CI): 0.94–0.992; p=0.011), longer hemodialysis vintage (OR: 1.172; 95% CI: 1.036–1.325; p=0.012), lower hemoglobin levels (OR: 0.531; 95% CI: 0.362–0.779; p=0.001), and higher neutrophil-to-lymphocyte ratio (OR: 2.436; 95% CI: 1.321–4.493; p=0.004). Conclusion High-flux dialysis was not superior to low-flux dialysis in improving erythropoietin responsiveness.

Anemia and fibroblast growth factor 23 elevation in chronic kidney disease: homeostatic interactions and emerging therapeutics.

Chronic kidney disease (CKD) is a progressive disorder that is associated with development of elevated fibroblast growth factor 23 (FGF23) levels and anemia. Here, we review recent literature that extends our current knowledge on the interactions between FGF23 and anemia in CKD and the impact of anemia-targeting therapeutics on FGF23 elevation in CKD. The anemia of CKD is primarily driven by a lack of erythropoietin (EPO) and iron deficiency. In addition to EPO and iron replacement, novel drug classes to treat anemia have been approved or are in clinical development. A recent observational study provides supportive evidence for the hypothesis that FGF23 elevation in CKD mediates adverse effects of iron deficiency on the cardiovascular system in patients with CKD. Preclinical and clinical studies revealed that ferric citrate (FC), and hypoxia-induced factor-prolyl hydroxylase inhibitor (HIF-PHI) treatment may reduce elevated FGF23 levels in CKD, suggesting that correcting anemia in CKD could potentially lower FGF23 levels. However, as we describe, HIF-PHI have context-dependent effects. Moreover, whether a reduction in FGF23 will improve patient outcomes in patients with CKD remains to be determined. With the emergence of novel therapeutics to treat oxygen and iron utilization deficits in CKD, studies have investigated the impact of these new drugs on FGF23. Several of these drugs, including FC and HIF-PHIs, alleviate iron homeostasis alterations in CKD and are associated with FGF23 reduction. Herein, we review the relationships between oxygen/iron sensing and FGF23 in CKD, recent findings which link FGF23 with cardiac dysfunction, as well as future translational and clinical avenues.

A STUDY ON THE MANAGEMENT OF ANAEMIA IN CHRONIC KIDNEY DISEASE

Anaemia is a common complication for patients with Chronic Kidney Disease and is associated with cardiovascular comorbidities and reduced Quality of Life. Susceptibility may change depending upon the stage of chronic kidney disease, age, and social habits. A Prospective and Observational study was designed to assess the demographics of patients and variables in Anaemia along with the management of Anaemia in Chronic Kidney Disease. The suspected patient’s blood samples were tested for their Haemoglobin, Erythrocyte Sedimentation Rate, and Packed Cell Volume analysed. Among 115 patients, 79 were males, and 36 were females. 58 patients (50.43%) were identified in the age group &gt;60 years due to diabetes, hypertension and other comorbidities. The patients were given Epoetin Alpha (9.6%) and Iron Sucrose (2.3%) along with Ferrous ascorbate and folic acid (2.7%). In 113 patients (98.3%) and 109 patients (94.78%), the Haemoglobin and Packed Cell Volume were increased due to reduced immune response, comorbidity and severity of Chronic Kidney Disease. Non-pharmacotherapy was provided, and the most common was exercise, meditation (25%), Iron-rich food (2.17%) and a renal low salt diet (1.73%). Follow-up was conducted to check the improvement and found that 95.6% of patients recovered.

The relationships among gut microbiota, hypoxia-inducible factor and anaemia with chronic kidney disease.

Gut microbiota plays a vital role in human intestinal homeostasis, correlating strongly with the progression of numerous diseases. Recent researches provide powerful evidence that the connections exist between gut microbiota and renal anaemia. Gut microbiota may have an impact on renal anaemia by regulating the hypoxia-inducible factor (HIF) signalling, iron metabolism and inflammatory state. Because of this relationship, there may be potential treatments for renal anaemia. In this review, we will first provide an overview of current research progression on anaemia in chronic kidney disease and then introduce the relations among gut microbiota, HIF, and renal anaemia to explore the possible treatment options.

Prévalence de la malnutrition et de l’anémie avec carence en fer absolue et fonctionnelle dans l’insuffisance rénale chronique chez des patients non dialysés et hémodialysés de la ville d’Alger (Algérie)

In chronic kidney disease, anemia and malnutrition coupled with inflammation as malnutrition-inflammation complex syndrom are common and considered as morbidity-mortality factors. The link between these two factors has been described at length in the literature highlighting an association of malnutrition with iron deficiency considered itself as one of the causes of anemia in chronic kidney disease (non-dialysis and hemodialysis). Our study aims to know the prevalence of these two factors in a population of chronic kidney disease (non-dialysis and hemodialysis) of Algiers and to highlight the possible associations between them. Patients and methodsThis is a multicentre, cross-sectional and descriptive study carried out over a period of 6months (August 2018 to January 2019). Anemia and malnutrition were assessed by various biological and clinical tools such as the malnutrition inflammation score and the International Society of Renal Nutrition and Metabolism criteria. Statistical tests were performed on the R studio software, considering P<0.05 as a statistically significant value. ResultsTwo hundred and nine patients on chronic kidney disease were included (90 non dialysis and 119 hemodialysis). The median age was 70 (IQR=16) for non dialysis and 56 (IQR=16.5) for hemodialysis. The prevalence of anemia was 66.66% (n=60) in non dialysis and 70.58% (n=84) in hemodialysis. Absolute iron deficiency anemia was higher in non dialysis (48.33%; n=29) while functional iron deficiency anemia was higher in hemodialysis (34.52%; n=29). The prevalence of malnutrition by malnutrition inflammation score was relatively low. Only functional iron deficiency anemia was associated with malnutrition. ConclusionThe prevalence of anemia was higher in Algerian chronic kidney disease (non-dialysis and hemodialysis) unlike malnutrition which remains associated with functional iron deficiency anemia.

Indoxyl sulfate impairs in vitro erythropoiesis by triggering apoptosis and senescence.

Anemia is a major complication in over 50% of chronic kidney disease (CKD) patients. One of the main causes of anemia in CKD is the reduction of erythropoietin (EPO) synthesis from renal tubular cells. Therefore, first-line treatment of CKD is EPO administration; however, EPO unresponsiveness in several patients is frequently found. More undefined causes of anemia in CKD are under interest, especially uremic toxins, which are a group of solutes accumulated in CKD patients. The highly detectable protein-bound uremic toxin, indoxyl sulfate (IS) was investigated for its effects on in vitro erythropoiesis in this study. CD34+ hematopoietic stem cells were isolated from human umbilical cord blood and differentiated toward erythrocyte lineage for 14 days in various concentrations of IS (12.5, 25, 50, and 100 µg/mL). The effects of IS on cell proliferation, differentiation, apoptosis, and senescence were determined. Cell proliferation was investigated by manual cell counting. Cell surface marker expression was analyzed by flow cytometry. Wright's staining was performed to evaluate cell differentiation capacity. Apoptosis and senescence marker expression was measured using reverse transcription polymerase chain reaction (RT-PCR). TUNEL assay was performed to detect apoptotic DNA fragmentation. Our results demonstrated that IS reduced cell proliferation and impaired erythrocyte differentiation capacity. In addition, this study confirmed the effects of IS on cell apoptosis and senescence during erythropoietic differentiation. Therefore, the promotion of apoptosis and senescence might be one of the possible mechanisms caused by uremic toxin accumulation leading to anemia in CKD patients.

EPO synthesis induced by HIF-PHD inhibition is dependent on myofibroblast transdifferentiation and colocalizes with non-injured nephron segments in murine kidney fibrosis.

Erythropoietin (EPO) is regulated by hypoxia-inducible factor (HIF)-2. In the kidney, it is produced by cortico-medullary perivascular interstitial cells, which transdifferentiate into collagen-producing myofibroblasts in response to injury. Inhibitors of prolyl hydroxylase domain (PHD) dioxygenases (HIF-PHIs) activate HIF-2 and stimulate kidney and liver EPO synthesis in patients with anemia of chronic kidney disease (CKD). We examined whether HIF-PHIs can reactivate EPO synthesis in interstitial cells that have undergone myofibroblast transdifferentiation in established kidney fibrosis. We investigated Epo transcription in myofibroblasts andcharacterized the histological distribution of kidney Epo transcripts by RNA in situ hybridization combined with immunofluorescence in mice with adenine nephropathy (AN) treated with HIF-PHI molidustat. Lectin absorption chromatography was used to assess liver-derived EPO. In addition, we examined kidney Epo transcription in Phd2 knockout mice with obstructive nephropathy. In AN, molidustat-induced Epo transcripts were not found in areas of fibrosis and did not colocalize with interstitial cells that expressed α-smooth muscle actin, a marker of myofibroblast transdifferentiation. Epo transcription was associated with megalin-expressing, kidney injury molecule 1-negative nephron segments and contingent on residual renal function. Liver-derived EPO did not contribute to serum EPO in molidustat-treated mice. Epo transcription was not associated with myofibroblasts in Phd2 knockout mice with obstructive nephropathy. Our studies suggest that HIF-PHIs do not reactivate Epo transcription in interstitial myofibroblasts and that their efficacy in inducing kidney EPO in CKD is dependent on the degree of myofibroblast formation, the preservation of renal parenchyma and the level of residual renal function.