G C A T T A C G G C A T genes Review DNA Methylation Dysfunction in Chronic Kidney Disease Diego Ingrosso 1,* and Alessandra F. Perna 2 1 Department of Precision Medicine, School of Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy 2 Department of Medical Translational Sciences, School of Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; [email protected] * Correspondence: [email protected] Received: 19 May 2020; Accepted: 9 July 2020; Published: 16 July 2020 Abstract: Renal disease is the common denominator of a number of underlying disease conditions, whose prevalence has been dramatically increasing over the last two decades. Two aspects are particularly relevant to the subject of this review: (I) most cases are gathered under the umbrella of chronic kidney disease since they require—predictably for several lustrums—continuous clinical monitoring and treatment to slow down disease progression and prevent complications; (II) cardiovascular disease is a terrible burden in this population of patients, in that it claims many lives yearly, while only a scant minority reach the renal disease end stage. Why indeed a review on DNA methylation and renal disease? As we hope to convince you, the present evidence supports the role of the existence of various derangements of the epigenetic control of gene expression in renal disease, which hold the potential to improve our ability, in the future, to more effectively act toward disease progression, predict outcomes and offer novel therapeutic approaches. Keywords: CKD; ESRD; dialysis; renal failure; DNA methylation; methylation reactions; epigenetic regulation; disease markers 1. Introduction Kidney disease mostly refers to chronic kidney disease (CKD), which is a frequent complication of common metabolic, inflammatory and cardiovascular diseases. CKD represents the bulk of renal failure cases; these conditions evolve chronically in a matter of several years. On the other hand, various predisposing extra-renal (e.g., cardiovascular shock, thrombosis of the renal artery) or renal (e.g., toxic drug-induced tubular necrosis), or urinary (e.g., ureter obstruction) causes may rapidly (days or hours) evolve towards acute kidney injury (AKI), a condition which, if not promptly reversed, may soon require replacement therapy or evolve towards CKD. Various lines of evidence support the existence of epigenetic alterations in CKD, particularly as modifications of DNA methylation either global or at specific sites, or both. The meaning of these alterations, relevant to possible dysfunction of the epigenetic control of gene expression and the issue of their possible implication in the disease progression and the occurrence of CKD complications, are discussed, as well as the potential role of DNA methylation modification as disease markers. This review is organized in chapters, the first of which is dedicated to the epidemiology of renal disease, thus focusing on the global extent of the phenomenon and of its complications, which may as well relate to epigenetics. The subsequent chapters will be dedicated to specific aspects of renal disease and DNA methylation, which are relevant to: (I) anemia and erythropoietin in CKD (II) metabolic and biochemical aspects (e.g., hyperhomocysteinemia (HHcy), a strong cardiovascular risk factor with high Genes 2020, 11, 811; doi:10.3390/genes11070811 www.mdpi.com/journal/genes Genes 2020, 11, 811 2 of 22 prevalence in CKD. (III) Inflammation, fibrosis and disease progression. (IV) Epigenetic alterations of Genesdiagnostic, 2020, 11, x prognostic FOR PEER REVIEW and/or therapeutic potential. (V) Onconephrology. 2 of 22 2. Chronic Kidney Disease: A Worldwide Pandemic 2. Chronic Kidney Disease: A Worldwide Pandemic Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function, Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function, present for more than 3 months, with implications for health, monitored by a reduced glomerular present for more than 3 months, with implications for health, monitored by a reduced glomerular filtration rate (GFR) and/or other markers, such as proteinuria [1,2]. Kidney disease is steadily filtration rate (GFR) and/or other markers, such as proteinuria [1,2]. Kidney disease is steadily increasing worldwide, accounting for about 10% of the general population [3,4]. This is due to classical increasing worldwide, accounting for about 10% of the general population [3,4]. This is due to underlying causes, such as glomerulonephritis, as well as to a dramatic increase of a number of classical underlying causes, such as glomerulonephritis, as well as to a dramatic increase of a number highly prevalent noncommunicable diseases, particularly hypertension and diabetes, whose frequent of highly prevalent noncommunicable diseases, particularly hypertension and diabetes, whose complication is kidney end-organ damage (Figure1). frequent complication is kidney end-organ damage (Figure 1). FigureFigure 1. 1. PrevalencePrevalence of of Chronic Chronic Kidney Kidney Disease Disease (CKD (CKD)) and and other other associated associated and and underlying underlying diseases diseases inin the the United United States States of of America. America. Data Data are are from from the the National National Institute Institute of of Diabetes Diabetes and and Digestive Digestive and and KidneyKidney Disease Disease—U.S.—U.S. Department Department of of Health Health and and Human Human Services Services [modifie [modifiedd from: from: [ [5].5]. In In the the pie pie graphgraph CKD CKD accounts accounts for for 13.6 13.6 % % of of the the total total area. area. CKD; CKD; chronic chronic kidney kidney disease. disease. DM; DM; diabetes diabetes mellitus. mellitus. CVD;CVD; cardiovascular cardiovascular disease. disease. TheThe endpoint inin the the clinical clinical history history of CKD of patientsCKD patients is end-stage is end renal-stage disease renal (ESRD), disease characterized (ESRD), 2 characterizedby a GFR <15 by mL a/ minGFR/1.73 <15 mmL/, themin retention/1.73 m2, of the at retention least 88 di offferent at least solutes 88 different (so-called solutes “uremic (so toxins”)-called “uremicand, eventually, toxins”) and, the needeventually, for renal the replacementneed for renal therapy replacement (dialysis therapy or transplantation) (dialysis or transplantation) [6]. This is a [6].clinically-defined This is a clinically situation,-defined see situation, [2], affecting see only[2], affecting about 1% o ofnly overall about CKD 1% of patients, overall characterized CKD patients, by characterizedthe uremic syndrome, by the uremic i.e., the syndrome, terminal clinical i.e., the manifestation terminal clinical of kidney manifestation failure, frequently of kidney including failure, an frequentlyassociation including of signs andan association symptoms of related signs toand the symptoms CKD complications related to the listed CKD in Tablecomplications1. Most of listed CKD inpatients Table 1. are Most indeed of C affKDected patients by a high, are indeed premature affected death by rate a duehigh, to premature these complications, death rate as due discussed to these in complications,the next paragraphs as discussed [2,3]. in the next paragraphs [2,3]. CKD is characterized by many frequent complications, which often threaten the patients’ lives (Table 1). Many, if not all, CKD complications have been associated with altered DNA methylation patters and/or deranged expression of epigenetically regulated genes by DNA methylation. In some cases, these findings suggest new potential therapeutic strategies. The availability of modern molecular biology nanobiotechnologies prompted substantial improvements in the study of DNA methylation in various diseases, thus including CKD, since the turn of this millennium, as described in the following sessions. In Table 1, all common complications in CKD are listed. Anemia and cardiovascular disease (CVD) are particularly important because anemia is almost constantly associated with CKD and requires careful intervention in order to restore hematocrit to an acceptable Genes 2020, 11, 811 3 of 22 Table 1. CKD complications. Parameters/Symptoms/ Complication Related Lab Markers Prevention/Therapy Ref. Nosological Entities Fatigue Low Hb conc • Anemia • Dyspnoea Erythropoietin [7] Low Ht • • Hypoxia • Dyslipidemia CVD events (myocardial infarction, Control of cardiovascular risk Cardiovascular disease (CVD) Hyperhomocysteinemia Other [8] stroke, thrombosis) factors metabolic alterations Hyperkalemia Heart dysfunction (ECG abnormalities, Specific electrolyte correction Electrolyte imbalance • [9] Hyponatriemia (*) arrhythmias) (cation exchange resins; diuretics) • Diuretics Increased plasma volume; • • (furosemide, tolvaptan) Fluid retention Decreased plasma oncotic Edema [10] • Dialysis (end-stage pressure from protein loss • renal disease) Arthritis • Xanthine oxidase inhibitors Gout High uric acid (**) Kidney stones [11] • (allopurinol, febuxostat) CVD risk factor • Organ injury (headache, chest and bone Arterial Blood Gas (ABG) alterations pain, palpitation, dyspnoea, nausea, Specific therapy based on correction Metabolic acidosis (low pH, low bicarbonate, low BE, vomiting, weakness, and bone pain. [12] of pH and bicarbonate alterations. compensatory low paCO2) anxiety, mental derangements, seizures, coma, heart arrhythmia. Phosphate binders (Sevelamer; • High PTH aluminum hydroxide); • Secondary hyperparathyroidism