cells Review Uremic Toxins Affect Erythropoiesis during the Course of Chronic Kidney Disease: A Review Eya Hamza 1, Laurent Metzinger 1,* and Valérie Metzinger-Le Meuth 1,2 1 HEMATIM UR 4666, C.U.R.S, Université de Picardie Jules Verne, CEDEX 1, 80025 Amiens, France; [email protected] (E.H.); [email protected] (V.M.-L.M.) 2 INSERM UMRS 1148, Laboratory for Vascular Translational Science (LVTS), UFR SMBH, Université Sorbonne Paris Nord, CEDEX, 93017 Bobigny, France * Correspondence: [email protected]; Tel.: +33-2282-5356 Received: 17 July 2020; Accepted: 4 September 2020; Published: 6 September 2020 Abstract: Chronic kidney disease (CKD) is a global health problem characterized by progressive kidney failure due to uremic toxicity and the complications that arise from it. Anemia consecutive to CKD is one of its most common complications affecting nearly all patients with end-stage renal disease. Anemia is a potential cause of cardiovascular disease, faster deterioration of renal failure and mortality. Erythropoietin (produced by the kidney) and iron (provided from recycled senescent red cells) deficiencies are the main reasons that contribute to CKD-associated anemia. Indeed, accumulation of uremic toxins in blood impairs erythropoietin synthesis, compromising the growth and differentiation of red blood cells in the bone marrow, leading to a subsequent impairment of erythropoiesis. In this review, we mainly focus on the most representative uremic toxins and their effects on the molecular mechanisms underlying anemia of CKD that have been studied so far. Understanding molecular mechanisms leading to anemia due to uremic toxins could lead to the development of new treatments that will specifically target the pathophysiologic processes of anemia consecutive to CKD, such as the newly marketed erythropoiesis-stimulating agents. Keywords: chronic kidney disease; uremic toxins; anemia; erythropoietin; indoxyl sulfate; iron; erythropoiesis 1. Introduction Chronic kidney disease (CKD) is a global public health problem characterized by a progressive loss of kidney function through the accumulation of uremic toxins leading to inflammation and endothelial dysfunction [1,2]. The European Uremic Toxin (EUTox) Work Group has compiled an authoritative list of 146 compounds as known uremic toxins and classified them into 3 groups based on their physicochemical characteristics such as the molecular weight, protein-binding capacity and removal pattern by dialysis [3–7]. Twenty-five solutes (27.8%) extracted from the sum of these uremic compounds are protein bound and are difficult to remove by dialysis, due to their protein binding capacity [8]. Furthermore, uremic toxins interact negatively with biologic functions when they are not eliminated by the kidneys. This interaction will be described more exhaustively in a further part of the manuscript. Instead of being filtered and excreted by kidney, those uremic toxins accumulate in blood and lead to a deficient erythropoietin (EPO) production by the kidney interstitial fibroblasts (peritubular cells of kidneys), resulting in a defective erythropoiesis due to a decrease in erythrocyte production [9,10]. EPO deficiency and iron deficiency are the main reasons contributing to anemia, a well-known consequence of CKD. In this disease, the best available indicator of kidney function is the glomerular filtration rate (GFR), which estimates the total amount of blood filtered by the kidney that passes Cells 2020, 9, 2039; doi:10.3390/cells9092039 www.mdpi.com/journal/cells Cells 2020, 9, 2039 2 of 18 Cells 2020, 9, x 2 of 19 through the glomeruli per unit of time. Patients with CKD are defined with a GFR inferior to through the glomeruli per unit of time. Patients with CKD are defined with a GFR inferior to 60 60 mL/min/1.73 m2 in the span of at least 3 months while the normal GFR of a healthy person is more mL/min/1.73 m2 in the span of at least 3 months while the normal GFR of a healthy person is more than 90 mL/min/1.73 m2 [11–13]. End-stage renal disease (ESRD) occurs when the kidney function is than 90 mL/min/1.73 m2 [11–13]. End-stage renal disease (ESRD) occurs when the kidney function is belowbelow 15%15% of of its its normal normal capacity. capacity. Some Some of theof the risk risk factors factors that that lead lead to common to common complications complications for CKD for areCKD shown are shown in Figure in Figure1[14–16 1]. [14–16]. FigureFigure 1.1. RiskRisk factorsfactors andand commoncommon complicationscomplications forfor CKD.CKD. InIn pinkpink areare representedrepresented thethe risksrisks factors:factors: familyfamily history history of of CKD, CKD, hypertension, hypertension, diabetes, diabetes, heart disease,heart disease, older age, older and age, racial and and racial ethnic and minorities. ethnic Inminorities. blue are representedIn blue are therepresented common the complications: common complications: anemia, heart anemia, disease, heart mineral disease, and bone mineral disease, and fluidbone buildup,disease, fluid and high buildup, potassium. and high potassium. AmongAmong them,them, anemia,anemia, heartheart disease,disease, mineralmineral andand bonebone diseasedisease (e.g.,(e.g., osteoporosisosteoporosis andand uremicuremic vascularvascular calcification),calcification), highhigh potassiumpotassium (hyperkalemia)(hyperkalemia) andand fluidfluid buildupbuildup (when(when extraextra fluidfluid fromfrom thethe bloodblood are not removed removed by by the the kidneys) kidneys) constitute constitute common common complications complications of ESRD of ESRD [17]. [In17 ].some In somecases, cases,the complications the complications could couldbe the beconsequence the consequence of a strate of agy strategy treatment treatment of a risk of factor. a risk factor.It is the It case is the of casethe development of the development of hyperkalemia of hyperkalemia that is common that is common in patients in patientswith heart with and heart kidney and disease. kidney Because disease. Becauseof the increasing of the increasing use of drugs use of that drugs antagonize that antagonize the renin-angiotensin-aldo the renin-angiotensin-aldosteronesterone system (RAAS), system (RAAS),hyperkalemia hyperkalemia is encountered is encountered frequently frequently in patients in patients with established with established cardiovascular cardiovascular diseases diseases (CVD) (CVD)[18]. [18]. InIn thisthis review,review, wewe mainlymainly focusfocus onon CKD-associatedCKD-associated anemiaanemia asas itit aaffectsffects nearlynearly allall patientspatients withwith ESRDESRD [19[19].]. Anemia Anemia is definedis defined by the by World the HealthWorld OrganizationHealth Organization (WHO) as a(WHO) hemoglobin as a concentration hemoglobin inferiorconcentration to 13 g /inferiordL in men to 13 and g/dL less in than men 12 and g/dL less in than women 12 g/dL [20]. in Numerous women [20]. studies Numerous have reported studies that have a highreported percentage, that a high approximately percentage, half approximately of patients with half ESRD of patients in the with United ESRD States, in the suff Uniteder from States, anemia suffer due tofrom EPO anemia deficiency due [to11 EPO,21,22 deficiency]. As shown [11,21,22]. in Figure As2, accumulationshown in Figure of uremic2, accumulation toxins impairs of uremic renal toxins EPO synthesis,impairs renal compromising EPO synthesis, the growth compromising and differentiation the growth of and red differentiation blood cells (RBCs) of red in blood the bone cells marrow. (RBCs) in the bone marrow. Cells 2020, 9, 2039 3 of 18 Cells 2020, 9, x 3 of 19 Figure 2. Anemia in CKD. Accumulation of of uremic toxi toxinsns induces a decrease of EPO production in thethe kidney. The The decreased EPO synthesis compromise compromisess erythropoeisis in in the bone marrow. This in turnturn results results in in a adecrease decrease of ofRBCs RBCs production production lead leadinging to CKD-associated to CKD-associated anemia. anemia. Abbreviations: Abbreviations: CKD, chronicCKD, chronic kidney kidneydisease; disease;EPO, erythropoietin; EPO, erythropoietin; RBCs, Red RBCs,Blood Cells; Red Blood IS, indoxyl Cells; sulfate; IS, indoxyl PCS, P-cresyl sulfate; sulfate.PCS, P-cresyl sulfate. This in in turn turn results results in in a decrease a decrease of RBCs of RBCs production production leading leading to CKD–associated to CKD–associated anemia. anemia. This exposesThis exposes patients patients to a high-risk to a high-risk for CVD for CVD (patients (patients withwith hypertension hypertension and andheart heart failure), failure), which which are the are mainthe main cause cause of death of death for forthose those patients patients [23,24]. [23,24 ].Among Among them, them, we we note note the the development development and progression of a heart failure and of a a left left ventricular ventricular hypertrophy hypertrophy (LVH) (LVH) that is is commonly commonly associated associated with CKD and anemia [[25]25] (Figure2 2).). The mostmost common common form form of anemia of anemia classically classically seen in CKDseen is in typically CKD normocytic,is typically normochromic, normocytic, normochromic,and hypoproliferative. and hypoproliferative. Actually, anemia Actually, in CKD anem isia a in multifactorial CKD is a multifactorial condition, and condition, asidefrom and asideEPO deficiency,from EPO irondeficiency, is also recognizediron is also as recognized a major contributor as a major in thiscontributor disease [in26 ].this Understanding