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Review on Inflammation Markers in Chronic Kidney Disease

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Review on Inflammation Markers in Chronic Kidney Disease biomedicines Review Review on Inflammation Markers in Chronic Kidney Disease Tadej Petreski 1,2 , Nejc Piko 1,3 , Robert Ekart 2,3, Radovan Hojs 1,2 and Sebastjan Bevc 1,2,* 1 Department of Nephrology, Clinic for Internal Medicine, University Medical Centre Maribor, Ljubljanska Ulica 5, 2000 Maribor, Slovenia; [email protected] (T.P.); [email protected] (N.P.); [email protected] (R.H.) 2 Department of Internal Medicine and Department of Pharmacology, Faculty of Medicine, University of Maribor, Taborska Ulica 8, 2000 Maribor, Slovenia 3 Department of Dialysis, Clinic for Internal Medicine, University Medical Centre Maribor, Ljubljanska Ulica 5, 2000 Maribor, Slovenia; [email protected] * Correspondence: [email protected]; Tel.: +386-2-321-2845 Abstract: Chronic kidney disease (CKD) is one of the major health problems of the modern age. It represents an important public health challenge with an ever-lasting rising prevalence, which reached almost 700 million by the year 2017. Therefore, it is very important to identify patients at risk for CKD development and discover risk factors that cause the progression of the disease. Several studies have tackled this conundrum in recent years, novel markers have been identified, and new insights into the pathogenesis of CKD have been gained. This review summarizes the evidence on markers of inflammation and their role in the development and progression of CKD. It will focus primarily on cytokines, chemokines, and cell adhesion molecules. Nevertheless, further large, multicenter studies are needed to establish the role of these markers and confirm possible treatment options in everyday clinical practice. Keywords: inflammation markers; chronic kidney disease; cytokines; chemokines; cell adhesion Citation: Petreski, T.; Piko, N.; Ekart, molecules R.; Hojs, R.; Bevc, S. Review on Inflammation Markers in Chronic Kidney Disease. Biomedicines 2021, 9, 182. https://doi.org/10.3390/ 1. Introduction biomedicines9020182 Chronic kidney disease (CKD) represents a condition with reduced renal function, which is defined by glomerular filtration rate (GFR) < 60 mL/min per 1.73 m2 or with Academic Editor: Juan Gambini present markers of kidney damage or both for more than 3 months and with implications for health. Markers of kidney damage are defined by Kidney Disease Improving Global Received: 12 January 2021 Outcomes (KDIGO) guidelines from 2012 as albuminuria, urine sediment abnormalities, Accepted: 9 February 2021 electrolyte, and other abnormalities due to tubular disorders, abnormalities detected by his- Published: 11 February 2021 tology, structural abnormalities detected by imaging, and history of kidney transplantation. CKD should be categorized into categories according to GFR ranging from G1–G5 (GFR in Publisher’s Note: MDPI stays neutral G1 ≥ 90, G2 60–89, G3a 45–59, G3b 30–44, G4 15–29, and G5 ≤ 15 mL/min/1.73 m2), and with regard to jurisdictional claims in published maps and institutional affil- albuminuria should be accounted for in categories from A1–A3 (albumin excretion rate in iations. A1 < 30, A2 30–300, and A3 > 300 mg/24 h) [1]. The pathophysiology of CKD is extremely complex with its clinical course dependent on a broad spectrum of different etiologies all leading towards kidney failure. The main causes of CKD in all high-income and middle- income countries are diabetes mellitus (DM) and arterial hypertension (AH) [2]. The global prevalence of all-stage CKD recorded in 2017 was 697.5 million or 9.1%, and 1.2 million Copyright: © 2021 by the authors. people died from CKD in 2017 [3]. Patients are often asymptomatic or have non-specific Licensee MDPI, Basel, Switzerland. symptoms such as loss of appetite, pruritus, and fatigue, so diagnosis is usually achieved This article is an open access article distributed under the terms and by estimation of GFR using several available equations, or less frequently by measurement conditions of the Creative Commons of GFR via exogenous markers. Additionally, a diagnosis can be made by performing a Attribution (CC BY) license (https:// kidney biopsy, which can commonly show glomerular sclerosis, tubular atrophy, and inter- creativecommons.org/licenses/by/ stitial fibrosis [2]. One of the hallmarks of CKD resulting in its development, progression, 4.0/). and complications is persistent, low-grade inflammation [4,5]. Biomedicines 2021, 9, 182. https://doi.org/10.3390/biomedicines9020182 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, x FOR PEER REVIEW 2 of 17 Biomedicines 2021, 9, 182 2 of 16 atrophy, and interstitial fibrosis [2]. One of the hallmarks of CKD resulting in its develop- ment, progression, and complications is persistent, low-grade inflammation [4,5]. InflammationInflammation is a isnatural a natural and andnecessary necessary body body response response to different to different stimuli. stimuli. It is re- It is sponsibleresponsible for the for migration the migration of immune of immune system system cells to cells the to stimuli the stimuli target target site following site following a seriesa series of steps of facilitated steps facilitated and coordinated and coordinated by cytokines, by cytokines, chemokines, chemokines, and acute-phase and acute-phase pro- teins.proteins. In the acute In the setting, acute this setting, provides this provides a resolution a resolution of the problem of the and problem enables and the enables return the to thereturn status to thequo. status Chronic quo. inflammation Chronic inflammation on the other on thehand other can hand lead canto tissue lead todamage tissue damageand fibrosis.and fibrosis.As such it As has such been it hasassociated been associated with numerous with numerous diseases, CKD diseases, included CKD [6]. included We are [6]. onlyWe beginning are only to beginning understand to understandthis very fine-tuned this very mechanism fine-tuned and mechanism research is and still research ongo- is ing.still Until ongoing. now, several Untilnow, different several pathways different of pathways inflammation of inflammation response have response been discov- have been ered,discovered, such as p38 such mitogen-activated as p38 mitogen-activated protein kinase protein (p38 kinaseMAPK), (p38 interleukin-6 MAPK), interleukin-6 (IL-6)/Janus (IL- kinase6)/Janus (JAK)/signal kinase (JAK)/signaltransducer and transducer activator andof transcription activator of 3 transcription (STAT3), and 3 (STAT3),phospho- and inositidephosphoinositide 3-kinase (PI3K) 3-kinase [7]. (PI3K) [7]. ThisThis review review will will summarize summarize recent recent evidence evidence on markers on markers of inflammation of inflammation in CKD. in CKD. It It willwill focus focus primarily primarily on cytokines, on cytokines, such such as inte as interleukinsrleukins (ILs), (ILs), tumor tumor necrosis necrosis factor factor (TNF), (TNF), interferoninterferon (IFN), (IFN), and and transforming transforming growth growth factor factor (TGF), (TGF), chemokines, chemokines, and and cell cell adhesion adhesion moleculesmolecules (CAMs) (CAMs) (Figure (Figure 1). 1 ). TNF Interferons Interleukins Cytokines TGF-β Inflammation CXC IgSF markers in CKD family Cadherins CAMs Chemokines CC family CX3C Selectins Integrins family FigureFigure 1. Groups 1. Groups of inflammation of inflammation markers markers that that have have a role a role in inchronic chronic kidney kidney disease. disease. CKD— CKD—Chronic Chronickidney kidney disease; disease; TNF—Tumor TNF—Tumor necrosis necrosis factor; factor; TGF-β TGF-—Transformingβ—Transforming growth growth factor beta;factor CAMs—Cell beta; CAMs—Celladhesion adhesion molecules; molecules; IgSF—Immunoglobulin IgSF—Immunoglobulin superfamily. superfamily. 2. Cytokines2. Cytokines Cytokines are small proteins (15–20 kDa) involved in the development and activity of Cytokines are small proteins (15–20 kDa) involved in the development and activity the immune system. They have an important effector and messenger role with involvement of the immune system. They have an important effector and messenger role with involve- in autocrine, paracrine, and endocrine signaling [8,9]. Their short half-life suggests they ment in autocrine, paracrine, and endocrine signaling [8,9]. Their short half-life suggests are usually rapidly eliminated to ensure limited bioactivity but can exhibit systemic effects they are usually rapidly eliminated to ensure limited bioactivity but can exhibit systemic if necessary. The acute phase is usually short term and sufficient to resolve the injury. effects if necessary. The acute phase is usually short term and sufficient to resolve the Persistent inflammation, either due to prolonged stimulation by biological, chemical, or injury. Persistent inflammation, either due to prolonged stimulation by biological, chem- physical stimuli, or inappropriate reaction against self-antigens, however, can prove to be ical, or physical stimuli, or inappropriate reaction against self-antigens, however, can problematic, as it can lead to development of chronic inflammation [6]. Possible association prove to be problematic, as it can lead to development of chronic inflammation [6]. Possi- of cytokines with diabetic nephropathy was already observed almost 30 years ago [10]. ble association of cytokines with diabetic nephropathy was already observed almost 30 years2.1. ago Interleukins [10]. Interleukins are a group of cytokines first seen to be expressed by leukocytes. Due to receptor complexes that interact with various interleukins, they have been divided
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