Inflammation in Chronic Kidney Disease

C H A P T E R

24 Inflammation in Chronic Kidney Disease Dominic S. Raja, Roberto Pecoits-Filhob, Paul L. Kimmela a

Division of Kidney Diseases and Hypertension, Department of Medicine, George Washington University, Washington, DC, United States; bSchool of Medicine, Pontificia Universidade Catolica do Parana, Curitiba, Brazil

inflammation is common in chronic kidney disease (CKD) and is closely linked to adverse outcomes.3,4

Abstract Systemic low-grade inflammation is common in patients with chronic kidney disease (CKD). The prevalence of signs of inflammation are inversely related to the level of kidney function and positively associated with the magnitude of proteinuria. Cytokines and acute-phase proteins are key mediators as well as markers of inflammation. The etiology of inflammation in CKD is multifactorial. Comorbidities such as older age, minority race, and the presence of diabetes are independent predictors of inflammation in CKD patients. Endotoxin translocation across the gut and damage/danger-associated molecular patterns may contribute to excess inflammation in CKD. Dysregulated immune responses and the resultant inflammation are mediators and/ or catalysts in the progression of renal disease, pathogenesis of cardiovascular disease, and the development of insulin resistance, protein energy wasting, anemia, and abnormal bone-mineral metabolism in patients with CKD. Progress in treatment of inflammation in patients with CKD is hampered by the complexity of the molecular pathways related to inflammation and the essential nature of some of these signaling mechanisms for cell/organism survival. However, a number of novel treatment strategies to attenuate inflammation in CKD are currently being explored.

SCOPE OF THE PROBLEM Prevalence of Inflammation in CKD

INTRODUCTION The word inflammation derives from the Latin term “inflammare,” meaning to set on fire. Inflammation is part of the complex biological response of vascular tissue to injury, infection, ischemia, and autoimmune diseases.1 Within physiological limits, the inflammatory response enables removal of the inciting agent and initiates healing. Inability to eliminate the insulting event and/or separate the inflammatory processes leads to a chronic inflammatory state with undesirable systemic consequences.2 Persistent, low-grade systemic Chronic Renal Disease, Second Edition https://doi.org/10.1016/B978-0-12-815876-0.00024-3

The other face of immunity is inflammation, especially when the immune response is unregulated and misdirected. Kimmel et al. reported that adequate Tcell function is associated with improved survival in patients with end-stage renal disease (ESRD) and elevated levels of proinflammatory cytokines are associated with higher mortality.4 Another study showed that there were no major differences in circulating cytokine levels between long-term dialysis patients and those not yet dialyzed, suggesting uremia per se contributes to the inflammatory state.5 The Chronic Renal Insufficiency Cohort (CRIC) study showed that 86% of participants with CKD have some evidence of inflammation, as defined by increased circulating levels of inflammatory biomarkers.3 However, only about 12% of the study population exhibited profound elevation in markers of inflammation, a finding not different from that reported by Kimmel et al. in ESRD patients6 (Figure 24.1). Gupta et al. demonstrated that plasma levels of proinflammatory cytokines and positive acute-phase proteins were higher in subjects with lower levels of kidney function.3 Furthermore, within each level of estimated glomerular filtration rate (eGFR), the magnitude of proteinuria was associated with a higher level of inflammatory biomarkers3 (Figure 24.2).

Determinants of Inflammation A number of demographic features such as older age, male gender, obesity, and low socioeconomic status

355

© 2020 Elsevier Inc. All rights reserved.

356

24. INFLAMMATION IN CHRONIC KIDNEY DISEASE

FIGURE 24.1 Distribution of high sensitivity Creactive protein (CRP) levels in patients with chronic kidney disease. The concentration of CRP is within normal range in a significant proportion of subjects with chronic kidney disease. Data from the Chronic Renal Insufficiency Cohort (CRIC) study.

80

Percent

60

40

20

0 0

16

32

48

64

80

96

112

128

144

160

176

High Sensitivity CRP

FIGURE 24.2 The percentage of subjects with evidence of inflammation increased across the quartiles of estimated glomerular filtration rate (eGFR) and tertiles of proteinuria (UACR).3 Data from the Chronic Renal Insufficiency Cohort (CRIC) study.

35 30

Percent

25 20 15

<30

30-39

eGFR

were associated with higher level of inflammation in patients without CKD.7 Chronic subclinical inflammation in the elderly population is attributed to an imbalance between inflammatory and antiinflammatory networks.8 Patients with type 2 diabetes mellitus have elevation in Th17 and Th1 cellular subsets and a reduction in the Treg subset, explaining the inflammation noted in this patient population.9 Furthermore, inflammation predicts incident diabetes as well as diabetesrelated complications.10 The CRIC study demonstrated increasing age, minority race, and presence of diabetes

40-49

1 50-59

ml/m in/1.7 3 m2

Te rti les

2

0

of

3

5

UA CR

10

>60

are associated with increased level of inflammation at each level of eGFR3 (Figure 24.3).

Genetics of Inflammation Stimulation of human blood samples with bacterial lipopolysaccharide (LPS) results in large interindividual variations in production of cytokines, suggesting a genetic component related to the inflammatory response. Thus, differences in inflammatory responses between populations may be due to variations in genes

IV. PATHOPHYSIOLOGY

PATHOPHYSIOLOGY OF INFLAMMATION IN CKD

(a)

Plasma IL-6 according to age category

pg/ml

2.5

1.5 21-44 0.5

>60

50-59

45-64

40-49

30-39

≥65 <30

eGFR (ml/min/1.73 m2)

(b) 3

Plasma IL-6 according to diabetic status

357

African Americans have an increased frequency of alleles related to increased production of proinflammatory cytokines, but this finding has not been confirmed by others.13 Environmental factors and behavioral patterns may modify the inflammatory response. Epigenetics refers to a heritable change in the pattern of gene expression mediated by mechanisms specifically not due to alterations in primary nucleotide sequences.14 The epigenome is the interface of genetics and environment, where the plasticity of the epigenetic code modifies the rigid genetic code to determine final phenotypes. Epigenetic regulation of cytokines and transcription factors is important in directing lineage differentiation of Th1 and Th2, as well as Tregs, which play a role in determining the immune response.15 Epigenetic effects seem to allow dividing immune cells to imprint, signaling events that allow immune cells to mount appropriate immune responses.

2

pg/ml

PATHOPHYSIOLOGY OF INFLAMMATION IN CKD 1

Diabetes

No diabetes

0 >60

50-59

40-49

30-39

<30

eGFR (ml/min/1.73 m2) -

(c) 3

Plasma IL-6 according to race

pg/ml

2

1 White

Black

Hispanic

0 >60

50-59 40-49 30-39 eGFR (ml/min/1.73 m2)

<30

FIGURE 24.3 Association of inflammation with age, diabetes, and race in CKD. Data from the Chronic Renal Insufficiency Cohort (CRIC) study.

regulating inflammatory pathways. Using a relaxed linear separability model, Luttropp et al. showed the presence of inflammation in CKD patients, defined by circulating high sensitivity C-reactive protein (hsCRP), is linked to genetic variations.11 Ness et al.12 reported

Mediators of Inflammation The inflammatory state is generally characterized by activation of an array of soluble factors such as cytokines and chemokines.2 Cytokines are secreted polypeptides that orchestrate the inflammatory response through autocrine, paracrine, and endocrine mechanisms. Chemokines are chemotactic cytokines, which control the attraction of leukocytes and mononuclear cells to sites of injury. These biomolecules may be broadly classified as pro- and antiinflammatory and also as ones involved in acute and chronic phases of inflammation. However, cytokines are pleiotropic in their actions, with considerable redundancy between their functions. Cytokines exhibit interactive cascades, in which they induce or repress their own synthesis, as well as that of other cytokines and cytokine receptors2 (Figure 24.4). Circulating cytokine receptors may provide additional information regarding the state of inflammation because they generally have a longer half-life than the cytokines themselves and therefore exhibit more constant levels over time. The interleukin (IL)-1Ra binds to IL-1 receptors and blocks the activity of IL-1 and a soluble form of the p55 tumor necrosis factor (TNF) receptor (TNFsRp55) binds and neutralizes TNF.2 Pereira et al. showed that plasma levels of IL-1Ra and TNF inhibitor TNFsRp55 are significantly higher in patients with CKD.5 They also noted that hemodialysis patients with higher endotoxin-stimulated IL-1Ra synthesis had a higher rate of cardiovascular (CV) events.16 Representative cytokines and their clinical significance are described in Table 24.1.

IV. PATHOPHYSIOLOGY

358

24. INFLAMMATION IN CHRONIC KIDNEY DISEASE

FIGURE 24.4

Cytokines are important modulators of immunoregulation, hematopoiesis, and the inflammatory cascade. These biomolecules act as a highly complex and coordinated network. There is considerable overlap and redundancy between the functions of individual cytokines. Cytokines induce or repress their own synthesis and that of other cytokines. The function of one cytokine is often modified or substituted by another’s. The balance between pro- and antiinflammatory cytokines determines whether the intensity of inflammatory response is within physiological limits or in the pathologic range.

An important component of the inflammatory cascade is the acute-phase response, which is a nonspecific physiological response to diverse forms of systemic and local insults. Under the influence of cytokines, originating from the site of injury, the synthesis of positive acute-phase proteins is upregulated, and negative acute-phase proteins are downregulated, principally in hepatocytes.17 Acute-phase proteins include complement components, antiproteases, and transport proteins, as well as proteins involved in coagulation and fibrinolytic systems. Many of the acute-phase proteins (such as CRP and ferritin) augment the inflammatory response, whereas others have an attenuating effect (e.g. albumin and hepcidin). The causes and mechanisms of downregulation of negative acute-phase protein synthesis are unknown, but this may be because resources need to be redirected toward synthesis of positive acute proteins that are required for survival in times of stress.

Etiology of Inflammation The mechanisms underlying unprovoked inflammation in CKD are under intense investigation. Elevated plasma cytokine levels in CKD patients could be a consequence of decreased elimination and/or increased generation. Although most of the circulating cytokines are secreted from activated macrophages and lymphocytes, adipocytes and skeletal muscle are also possible sources.18,19 It has been estimated that skeletal muscle contributes to about 12% and adipose tissue to about 10e35% of the circulating IL-6 level in patients with and without kidney disease.20,21 Arteriovenous balance studies have shown that there is increased efflux of proinflammatory cytokines from the skeletal muscle of ESRD patients.19,22 Preliminary findings from the CRIC study show that body fat mass as well as muscle mass are associated with circulating levels of several cytokines.23 Myeloperoxidase (MPO) is secreted during

IV. PATHOPHYSIOLOGY

PATHOPHYSIOLOGY OF INFLAMMATION IN CKD

TABLE 24.1

359

Mediators and Markers of Inflammation in Chronic Kidney Disease (CKD)

Biomarker

Study Population

Remark

C-reactive protein (CRP)

CRP is a member of the pentraxin family of innate immune response proteins synthesized by the liver.

Extensively studied in patients with and without kidney disease. Associated with all cause and cardiovascular mortality, atherosclerosis, protein energy wasting, and erythropoietin resistance.

Fibrinogen

Soluble glycoprotein found in the plasma, synthesized by the liver.

Plays a vital role inflammation, atherogenesis, and thrombogenesis. Predictor of mortality in CKD.154

Serum amyloid A protein

Acute-phase protein synthesized by the liver.

Serves as an autocrine factor to influence vascular smooth muscle cells and platelet aggregation.155

IL-6

IL-6 acts via a receptor complex consisting of the cognate IL-6 receptor (IL-6R) and glycoprotein 130 (gp130 or IL6-ST). Signal activation necessitates association of IL-6 with gp130. The antiinflammatory activities of IL-6 are mediated by gp130, whereas its proinflammatory responses are mediated by trans-signaling through the soluble IL-6 receptor.156,157

Elevated IL-6 levels have been linked to malnutrition,158 atherosclerosis,159 and CV and all-cause mortality in patients with kidney disease.4,160

IL-1 family

The IL-1 family consists of two proinflammatory cytokines, IL-1a and IL-1b, and a naturally occurring antiinflammatory agent, the IL-1Ra.

Plasma IL-1 and IL-1Ra have been shown to predict cardiovascular outcomes and mortality in end-stage renal disease (ESRD) patients.4,16,96,161

IL-10

The principal function of IL-10 is to limit and ultimately terminate inflammatory signals.

The IL-10 low producer genotype (-1082 AA) is associated with increased CV mortality in ESRD patients,162 and lower Karnofsky Index and nutritional indices.163

TNF-a

Produced primarily by macrophages and acts through two distinct cell surface receptors of 55 kDa (TNF-R1) and 75 kDa (TNF-R2). Activates NFkB and MAP kinase pathways and induces apoptosis.

Increased TNF-a levels are associated with metabolic syndrome, CVD, congestive heart failure, progression of CKD, and mortality.4,164e166

Soluble TNF-like weak inducer of apoptosis (sTWEAK)

Member of the TNF superfamily.

Elevated sTWEAK and IL-6 plasma concentrations are associated with mortality in HD patients.167

TGF-b

TGF-b has antiatherogenic, antiinflammatory, and profibrotic properties.168,169

Overproduction of TGF-b has been linked to hypertension, left ventricular hypertrophy, vascular remodeling, and renal fibrosis.

High mobility group box chromosomal protein-1(HMGB1)

HMGB1 is a nuclear protein that binds DNA, stabilizes nucleosomes, and facilitates gene transcription. It is a late-phase cytokine, which contributes to chronic inflammation.

HMGB1 levels correlate with GFR and markers of inflammation and malnutrition.170

Myeloperoxidase (MPO)

MPO is an enzyme stored in azurophilic granules of polymorphonuclear neutrophils and macrophages and released into extracellular fluid in the setting of inflammatory process.

Plasma MPO levels are elevated in patients with coronary artery disease, congestive heart failure, and are important predictors of cardiovascular events in the general population.24,171,172 Associated with risk of death in ESRD patients.25

Endotoxin and soluble CD14

Endotoxin is a biologically active substance produced by bacteria, which consists of lipopolysaccharide. Endotoxin provokes an array of host responses by binding to the CD14 receptor.173

Abundant experimental and clinical evidence indicates that subclinical endotoxemia is involved in the pathogenesis of atherosclerosis.174,175 Elevated soluble (s)CD14 level is associated with protein energy wasting and death in ESRD patients.34,127

IV. PATHOPHYSIOLOGY

360

24. INFLAMMATION IN CHRONIC KIDNEY DISEASE

activation of neutrophils, which plays an important role in the defense of the organism. Enhanced MPO generation is one of the major oxidative stress pathways in CKD, and a risk factor for vascular disease.24,25 Other potential causes of inflammation in CKD include chronic subclinical infections,26 volume overload,27 increased oxidative stress,28 sympathetic overactivity,29 poor nutrition, and vitamin D deficiency.30 The gut microbial flora is quantitatively and qualitatively abnormal in patients with kidney disease compared with healthy subjects.31e33 Endotoxin translocation across the gut could be one of the important causes of inflammation in CKD patients.34 Uremic toxins cause dysfunction of both granulocytic and monocytic cell lines and should also be considered a major cause of inflammation. Among circulating monocytes, subpopulations with proinflammatory characteristics are expanded in patients with CKD. Several uremic toxins act as ligands in activation of Toll-like receptors, which are involved in the innate immune response and recognition of LPS.35

DAMPs and PAMPs

FIGURE 24.5

Accelerated cellular aging and augmented apoptosis are common in CKD. Damaged or dying cells release endogenous molecules called damage/dangerassociated molecular patterns (DAMPs).36 These molecules activate the immune system in a manner similar to pathogen-associated molecular patterns (PAMPs) molecules released by pathogenic bacteria or viruses (Figure 24.5). Many DAMPs released during renal injury are capable of activating inflammasomes, which are components of the innate immune system.37 The inflammasome is a complex of proteins in the cytoplasm that is triggered by infectious or sterile injuries.38 Proinflammatory mediators interact with innate danger-signaling platforms. NACHT, LRR, and PYD domainscontaining protein 3 (NLRP3) play a critical role in the pathophysiology of kidney diseases.39 Thus, release of endogenous molecules from dying cells may lead to activation of innate immunity and downstream inflammation.

Resolution of Inflammation Chronic, dysregulated inflammation is associated with several human diseases. The inflammatory response is counterbalanced by the release of “stop signals,” which serve to attenuate an excess inflammatory response and to restore functional homeostasis.40 During this highly regulated active process, synthesis of proinflammatory mediators is halted, preventing further leukocyte influx into tissue. Immune cells are

Mediation of pathogen-specific immune response by pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs). PRRs are essential for initiating immune defenses against invading pathogens. However, they also contribute to persistent and systemic inflammation. Heat shock proteins, fibrinogen, fibronectin, hyaluran, and high mobility group box-1 (HMGB-1) have been defined as danger-associated molecular patterns (DAMPs). Toll-like receptors (TLRs) are involved in the recognition of these endogenous or harmful self-antigens, which are released during noninfectious injury, suggesting their function may not be restricted to the recognition of extrinsic pathogens. RAGE, receptor for advanced glycation end products; TREM-1, triggering receptor expressed on myeloid cells-1; MyD88, myeloid differentiation factor 88; KRAS, Kirsten rat sarcoma viral oncogene homolog; MAPK, mitogen-activated protein kinase; TRAF6, tumor necrosis factor receptor-associated factor 6; IRAK1/IRAK2, IL-1 receptorassociated kinase 1 and 4; NFkB, nuclear factor-kB.

cleared from tissue either by reentry into the systemic circulation or by apoptosis or necrosis. Recent evidence suggests that this process also promotes interaction between the innate and adaptive immune systems leading to immune tolerance.41 The resolution of inflammation is governed by several factors which include chemical mediators (lipoxins, resolvins, protectins, and maresins), gases (hydrogen sulfide, nitric oxide, and low-dose carbon monoxide), and proteins (annexin A1 and galectin1).40,42,43 Kourtzelis et al. identified a new member of the group of proteins, developmental endothelial locus-1 (DEL-1), which governs the resolution response.44 Endothelial cellederived DEL-1 reduces neutrophil infiltration into tissues. Macrophage-derived DEL-1 facilitates efferocytosis through an a vb 3-mediated response and

IV. PATHOPHYSIOLOGY

DIAGNOSIS OF INFLAMMATION

activates lipid X receptors and transforming growth factor (TGF)-b to promote a tissue reparative macrophage phenotype transformation.44 Understanding the cellular pathways by which inflammation is resolved can open new opportunities to pharmacologically enhance the processes. Several promising proresolution therapeutic strategies have been tested in animal models with the potential for translation to human applications in the future.41

DIAGNOSIS OF INFLAMMATION Utility of Inflammatory Biomarkers Although the importance of inflammation in CKD is undisputed, there is no consensus regarding the index biomolecules to be used to identify inflamed subjects with CKD or regarding the appropriate threshold levels of inflammatory markers. Investigators have proposed different biomarkers and different circulating levels, largely based on mean values noted in CKD patients and/or correlations with clinical outcomes. Although the concentrations of proinflammatory cytokines, antiinflammatory cytokines, and acute-phase proteins show a tendency to increase together, there is discordance in the rate and magnitude of the increase of individual molecules involved in the inflammation cascade.1 Thus, it may be important to integrate information from multiple biomarkers to describe the prevailing inflammatory state. Raj and associates computed a composite score ranging from 0 to 5 based on elevated levels of selected cytokines and acute-phase proteins (CRP, fibrinogen, IL6, TNF-a, and IL-1b). They showed the score was inversely related to eGFR and positively related to albuminuria in a large cohort of CKD patients with a wide range of kidney function.3 Zoccali showed an inflammation score composed of CRP, IL-6, IL-1b, IL-18, and TNFa predicts death no better than IL-6 in patients with ESRD.45 Thus, the utility of composite inflammation scores needs further validation. There is substantial intraindividual variation in circulating cytokines levels over time, rendering the validity of a single measurement of cytokines in predicting clinical outcomes tenuous. Preliminary findings suggest that a single baseline measure accurately reflects healthy individuals’ inflammatory status over a four- to sixmonth period.46 Another study showed that despite variability over time, baseline CRP level correlated with time-averaged CRP and the individual median of serial CRP values in ESRD patients.47 Thus, single baseline measurements are adequate, but multiple measurements may be better for predicting outcome or response to interventions.

361

Is CRP an Ideal Biomarker of Inflammation in CKD? CRP belongs to the pentraxin family of calciumdependent ligand-binding plasma proteins. It derives its name from its ability to precipitate the Cpolysaccharide of Streptococcus pneumonia. Circulating CRP is produced primarily by hepatocytes under transcriptional control by IL-6.48 In response to an inciting stimulus, CRP synthesis is rapidly initiated, with the serum concentration peak occurring in about 48 hours. The median concentration of CRP is 0.8 mg/L in healthy subjects, the 90th percentile is 3.0 mg/L, and the 99th percentile is 10 mg/L.49 CRP binds to phosphocholine residues and also to a variety of autologous and extrinsic ligands and aggregates the molecules exhibiting these ligands, leading to activation of the complement cascade.50 CRP is a highly stable analyte in serum or plasma, which can be measured with ease in a reproducible manner. CRP level is a nonspecific measure of inflammation that may be useful for screening and monitoring response to treatment. It has also emerged as an independent risk factor for adverse outcomes in diverse clinical settings. None of the other upstream mediators or downstream effectors of inflammation, including other acute-phase reactants, have such desirable characteristics, rendering CRP the most commonly used measure of inflammation.

Consequences of Inflammation Even minor decreases in kidney function are associated with an increased risk for all-cause and CV death. Abundant evidence has accrued showing inflammation is a mediator of adverse outcomes in patients with CKD.51e53 Inflammation could be a by-product of the original insult and thus an innocent bystander rather than a prime mover. Others claim that inflammation is a partner in crime. CKD complications linked to inflammation are depicted in Figure 24.6.

Progression of CKD Regardless of initial causes, progressive CKD often results in glomerulosclerosis and/or tubulointerstitial fibrosis, characterized by widespread tissue scarring leading to ESRD. A variety of cytokines, chemokines, and growth factors act in concert to create an imbalance in matrix formation and degradation, leading to overall accumulation of extracellular matrix and eventually glomerulosclerosis and interstitial fibrosis.54e59 Expression of IL-1, IL-6, IL-10, and IL-1 receptor antagonist and TGF-b have been reported in experimental and human renal diseases.60e64 In the kidney, cytokines induce resident cells to proliferate,65 promote aberrant

IV. PATHOPHYSIOLOGY

362

24. INFLAMMATION IN CHRONIC KIDNEY DISEASE

FIGURE 24.6 Inflammation in chronic kidney disease (CKD): causes and consequences. Inflammation is the result of multiple mechanisms inherent to CKD, including comorbidities such as adiposity, increased levels of inflammatory cytokines, and uremic toxicity. In turn, inflammation may increase the rate of CKD progression and cause infection, anemia, CVD, and depression.

matrix metabolism,66,67 incite procoagulant endothelial activity,68 generate reactive oxygen/nitrogen species,69 and activate expression of adhesion receptors,70 bioactive lipids,71 and metalloproteinases.72e75 Cytokine expression in the kidney release into the renal vein as well as excretion in the urine are increased in patients with glomerular disease.76e79 Preliminary evidence indicates that urinary cytokine levels may be an indicator of severity and progression of renal disease.77,78,80 Findings from the CRIC study show elevated plasma levels of fibrinogen and TNF-a and decreased serum albumin (S[Alb]) are associated with rapid loss of kidney function in patients with CKD after adjusting for traditional risk factors.81 TNFR-1 is expressed on the cell surface of glomeruli and by the peritubular capillary endothelium of the kidney. In the Multi-Ethnic Study of Atherosclerosis study participants, elevated serum sTNFR-1 concentrations were associated with faster declines in eGFR, independent of traditional risk factors for kidney disease progression.82 In a

cross-sectional study in Japanese patients with T2D and eGFR
30 mL/min/1.73 m2, circulating TNFrelated inflammatory biomarkers (TNFa, progranulin, TNFR1, and TNFR2) were associated with albuminuria.83 During disease more than 30% of fibroblasts originate from tubular epithelia at the site of injury, through the process of epithelial mesenchymal transition, although such notions are controversial.84,85 This molecular reprogramming of the cell is regulated, at least in part, by the profibrotic cytokine TGF-b. Renal arteriovenous balance studies indicate that TGF-b is released from the kidney of patients with diabetes.78 In a population-based study of predominantly White subjects, TNF-receptor 2, WBC count, and IL-6 levels were associated with risk of developing CKD.86 Similarly, in patients with type 2 diabetes mellitus, elevated concentrations of circulating TNF receptors at baseline are strong predictors of subsequent progression to ESRD.58

IV. PATHOPHYSIOLOGY

DIAGNOSIS OF INFLAMMATION

Hypertension and Inflammation The roles of immune dysregulation and inflammation in the pathogenesis of hypertension have been investigated for decades. Virtually every cell type involved in innate and adaptive immunity has been implicated in the pathogenesis of hypertension. RAG1/ mice, which lack both T and B cells, exhibit blunted hypertensive response to Ang II infusion, which is restored by adoptive transfer of T cells.87 Interestingly, CD8þ T cells express the mineralocorticoid receptor, which plays a role in systemic hypertension.88 Arterial wall inflammation is present in patients with CKD even in the absence of atherosclerosis.89 Excess extracellular sodium activates antigen-presenting dendritic cells via immunogenic isolevuglandin-protein, which, in turn, promotes hypertension.90 Proinflammatory cytokines are associated with arterial stiffness in CRIC study participants.91 Thus, the prevalence and severity of hypertension in CKD could be related to inflammation.

363

inflammatory conditions, in which lean body mass is wasted, but the fat depot is relatively underutilized. Cytokines regulate neuroendocrine signaling and promote muscle wasting to sustain acute-phase protein synthesis in hemodialysis patients.97 As a reflection of the trend in the US population, there is an epidemic of obesity among CKD patients.98 Adiposity is associated with inflammation in the general population as well as in CKD patients. Results from the CRIC study show that fat mass and muscle mass are positively associated with hsCRP, fibrinogen, IL-1, IL-1RA, and IL-6 levels.23 One standard deviation increases in fat and muscle mass were associated with 36% and 26% increases in log transformed hsCRP. The association between inflammation and fat mass was stronger in Caucasian than African-American patients with CKD, suggesting that abundant energy depot in conjunction with decreased burden of inflammation may explain the survival advantage observed in African Americans treated with maintenance hemodialysis.

Progression of Cardiovascular Disease Atherosclerosis is described as an indolent, fibroproliferative disease fueled by chronic inflammation.92 Immune cells dominate the atherosclerotic lesion and exhibit evidence of activation. The underlying mechanism for “accelerated atherosclerosis” in CKD may be related to chronic inflammation. Several cross-sectional studies suggest the Framingham risk equation is insufficient to capture the extent of CVD risk in CKD patients, highlighting the importance of novel risk factors such as inflammation in this population. Epidemiologic and clinical studies demonstrate strong and consistent relationships between markers of inflammation and risk for CV events in the general population and in patients with CKD.93 Elevated CRP levels were associated with increased risk for all cause and CV mortality in Modification of Diet in Renal Disease study participants.53 Abundant evidence from clinical studies and laboratory-based investigations suggest that abnormal cardiac geometry and function are related to inflammation in subjects with and without kidney disease.51,94,95 Amdur et al. reported that inflammatory biomarkers and kidney function are independently associated with incident atherosclerotic vascular disease events and death in CKD patients.96 They further showed that traditional CV risk estimates could be improved by adding measures of kidney function and markers of inflammation to traditional risk factors in evaluations.

Protein Energy Wasting is

Protein energy wasting, or its extreme form, cachexia, a maladaptive metabolic state common in

Insulin Resistance Epidemiologic studies show insulin resistance is a risk factor for CKD.99 Chronic inflammation is a common feature of the metabolic syndrome and insulin resistance. Cytokines activate a number of intracellular serine/threonine kinases, including the inhibitor kB kinase (IKK) complex, a regulator of the NF-kB pathway, an important second messenger system in inflammatory cytokine signaling. The IKK complex and TNF-a activated JNK may be involved in the pathogenesis of insulin resistance.100,101

Anemia of CKD Anemia is common in CKD patients. Epidemiologic studies show inflammation is an important predictor of hemoglobin variability and erythropoietin (EPO) hyporesponse in ESRD patients.102,103 Goicoechea and associates demonstrated that EPO resistance is associated with elevated circulating levels of IL-6 and TNFa.104 Anemia in CKD may be related to true or functional deficiency of iron and EPO. The latter has been attributed to inflammation. Hepcidin, a 25-amino acid peptide, is produced predominantly by hepatocytes under the influence of IL-6. As the key regulator of transmembrane iron transport, hepcidin controls the absorption of iron in the intestine, the mobilization of iron from hepatic stores, and iron recycling by macrophages.105 Furthermore, certain proinflammatory cytokines may suppress erythroid progenitor cell proliferation and inhibit EPO production.106

IV. PATHOPHYSIOLOGY

364

24. INFLAMMATION IN CHRONIC KIDNEY DISEASE

Infection and Inflammation in CKD It has long been suspected that subclinical infections may be one of the underlying causes of inflammation in CKD. Paradoxically, systemic inflammation coexists with a state of acquired immunodeficiency in patients with CKD, predisposing to infections.107 Persistent infection/inflammation could induce counterregulatory mechanisms that suppress innate and adaptive immunity in CKD.108 Thus, chronic inflammation could predispose to infection, leading to a vicious cycle with poor outcomes in CKD patients.

Inflammation and Depression The cytokine theory of depression assumes that inflammatory cytokines can trigger depression by acting on the central nervous system.109,110 Studies in subjects without CKD have implicated TNF-a, IL-2, and IL-6 in the pathogenesis of depression. Small studies in CKD patients confirm such associations,111 although the findings are controversial.110

TREATMENT OF INFLAMMATION IN CKD A number of intervention studies targeting established risk factors for mortality in CKD have not yielded the anticipated positive results. Such negative studies could be due to the fact that inflammation in CKD has a competing and possibly overwhelming effect on outcomes, rendering these interventions ineffective.112,113 Preliminary evidence indicates that targeting a single component of the inflammatory cascade is not sufficient in complex diseases and requires the use of broad immnomodulation therapy.114 Alternatively, the redundancy and pleiotropy of the cytokine system renders a nontoxic intervention, a difficult proposition. There are at least three potential therapeutic approaches using inflammation as a target that may result in clinical benefits in CKD patients: pharmacological manipulation of cell responses, reduction of the source of ligands, and direct antiinflammatory therapies. There are an increasing number of studies analyzing the potential impact of these strategies.

Targeting Inflammation Through Pharmacological Manipulation of Inflammatory Cell Responses Renineangiotensin system blockers, with antiinflammatory activity, have been tested in clinical trials in the dialysis population. The results of a randomized trial using fosinopril showed a slight benefit of this agent in

comparison to placebo.115 In another randomized trial with a small number of patients, candesartan significantly reduced CV events and mortality in patients treated with chronic maintenance hemodialysis.116 Suzuki et al.117 showed treatment with an angiotensin receptor blocker was independently associated with reduced fatal and nonfatal cardiovascular disease (CVD) events in a hemodialysis population, although this analysis may be limited because of the small sample size. Statins are another drug class with antiinflammatory actions.118 In observational studies, patients treated with statins had lower mortality than non-statin-using hemodialysis patients.119 These results have not been uniformly confirmed by randomized controlled trials in ESRD hemodialysis patients.120 Although treatment with rosuvastatin had no significant effect on the composite primary endpoint of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke, there was a reduction in mean level of plasma CRP in treated hemodialysis patients.120 Inflammation at baseline was one of the most important risk factors for mortality.120 Inflammation is linked to oxidative stress, and antioxidants may be interesting drugs for antiinflammatory therapeutic interventions. One trial investigated the effect of high-dose vitamin E supplementation on CVD outcomes in hemodialysis patients with preexisting CVD.121 After a median follow-up of 519 days, the use of vitamin E was associated with reduced CVD endpoints and myocardial infarctions.121 In a randomized controlled trial, treatment with N-acetylcysteine, an antioxidant, reduced CV events and mortality in hemodialysis patients.122 Circulating levels of 25-hydroxyvitamin D3 and 1,25dihydroxyvitamin D3 can potentially influence the activity of many tissues and cells,30 including cardiomyocytes, active T and B lymphocytes, and mononuclear and endothelial cells. In observational studies, dialysis patients treated with activated vitamin D and analogs have a survival advantage, perhaps related to the systemic activation of vitamin D receptors, acting as a negative endocrine regulator of renineangiotensin synthesis and inflammation, thus reducing CV complications.123 However, in a randomized controlled trial involving 227 patients with CKD, paricalcitrol failed to alter left ventricular mass index or improve diastolic function.124 The Japan Dialysis Active Vitamin D study, a randomized, open-label multicenter study of 1289 hemodialysis patients without secondary hyperparathyroidism concluded oral alfacalcidol did not reduce the risk of a composite measure of fatal and nonfatal CV events.125 Whether the results of this study are also applicable to patients with secondary hyperparathyroidism remains uncertain.126

IV. PATHOPHYSIOLOGY

TREATMENT OF INFLAMMATION IN CKD

Targeting Inflammation Through Reduction of Source of Ligands Subclinical endotoxemia is associated with inflammation, protein energy wasting, and mortality in ESRD patients.34,127 The human gut harbors 1014 bacteria and endotoxemia resulting from gut microbial imbalance, termed dysbiosis, could promote inflammation. Thus, restoration of gut-microbial symbiosis may have a number of potential benefits in ESRD patients. Prebiotics are nondigestible food ingredients that selectively stimulate growth and/or activity of beneficial bacteria in the colon. Preliminary evidence indicates the prebiotic oligofructose-enriched inulin (p-inulin) may reduce endotoxin generation, attenuate inflammation, and improve metabolic function in patients without kidney disease.128,129 Although the drug had been created to be used as a phosphate binder, sevelamer hydrochloride showed a potential endotoxin-binding effect in the intestinal lumen, reducing systemic inflammation in an experimental model.130 Other potential pleiotropic effects of sevelamer that could have CV impact include a lipidlowering action and reduction in CRP levels.131,132 Stinghen et al.133 demonstrated that sevelamer treatment leads to a decrease in CRP levels accompanied by a parallel decrease in endotoxemia in hemodialysis patients. Periodontal disease, an occult source of inflammation, is associated with CVD.134 CKD patients with moderate-to-severe disease compared with those with mild or no periodontal disease had higher risk of death from CV causes.135 Intervention trials to determine if treating periodontitis (and other hidden infections) reduces CVD mortality in CKD patients would shed light in this important area.

Direct Antiinflammatory Therapies Pentoxifylline (PTX) is a nonselective inhibitor of cyclic-30 , 50 -phosphodiesterase (PDE). Inhibition of PDE has been shown to reduce de novo synthesis and tissue accumulation of proinflammatory cytokines.136 Treatment with PTX has been shown to reduce proteinuria in patients with diabetic nephropathy and glomerular diseases.137,138 PTX slows the progression of atherosclerosis and modifies plaque morphology in patients with type 1 diabetes.139 Pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone) is an antifibrotic drug that reduces TGF-b2 protein levels and reverses extracellular matrix accumulation. It has been shown to slow the progression of renal disease in animal models140 as well as in clinical studies.141 In a double-blind randomized controlled study, Sharma et al.142 showed pirfenidone preserves renal function in patients with diabetic nephropathy. In this study, 77

365

subjects with diabetic nephropathy were randomized to escalating doses of pirfenidone (1200 mg/day and 2400 mg/day) or placebo. A significant number of subjects in the high dose group dropped out of the study. Among the 52 subjects who completed the study, the mean eGFR increased in the pirfenidone 1200 mg/day group, whereas the eGFR decreased in the placebo group. Pirfenidone has also been shown to improve cardiac geometry and vascular biology. Although a promising antifibrotic agent, it has a number of adverse effects and is generally not well tolerated.143 Tocilizumab, a humanized mouse antihuman IL-6 receptor antibody, inhibits IL-6 activity by competing for both the membrane-bound and soluble types of IL-6 receptors.144 Preliminary findings indicate that it may be effective in the management of glomerular disease.145 Its potential benefit in the management of anemia of CKD and CVD in patients with CKD is a fertile area for research. Treatment with etanercept, a TNFreceptor antagonist, did not have a significant effect on CRP or IL-6 but had positive effect on S[Alb] and prealbumin in hemodialysis patients.146 Anakinra is a nonglycosylated, recombinant form of human IL-1Ra that, like endogenous IL-1Ra, competitively inhibits IL-1 by binding the IL-1 type I receptor. In a pilot study, Hung et al. showed Anakinra reduced markers of inflammation and increased prealbumin concentrations in patients treated with hemodialysis.147 Furthermore, an IL-1 beta receptor antagonist has been shown to improve coronary flow, left ventricular function, and endothelial function in patients with rheumatoid arthritis.148 In a double-blind trial, 42 adult patients with stages 3e4 CKD were randomized to treatment with an IL-1 trap, rilonacept, or placebo. Rilonacept therapy improved brachial artery flow-mediated dilation and reduced systemic inflammation in patients with CKD.149 Preliminary results from the Canakinumab Anti-inflammatory Thrombosis Outcome Study suggest that major atherosclerotic CV events were reduced with IL-1b inhibition with canakinumab in patients with moderate CKD (HR 0.82; 95% CI: 0.68e1.00, p ¼ 0.05) and in those with normal kidney function (HR 0.86; 95% CI: 0.77e0.97, p ¼ 0.012).150 An emerging therapeutic option is to directly use nanotechnology-based drug delivery systems. Various nanosized materials are currently being developed, including micelles, liposomes, polymeric nanoparticles, dendrimers, carbon nanotubes, and metallic nanoparticles. The inflammatory milieu enhances incorporation of nanosized materials into mononuclear phagocytic systems for delivery to the target organ.151 Bardoxolone methyl is an inducer of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, which can suppress oxidative stress and inflammation. Initial reports showed bardoxolone methyl treatment was

IV. PATHOPHYSIOLOGY

366 TABLE 24.2

24. INFLAMMATION IN CHRONIC KIDNEY DISEASE

Important Issues to be Considered in the Management of Inflammation in Chronic Kidney Disease (CKD)

How should the intensity of inflammation in CKD patients be assessed? What are the therapeutic targets for reduction of inflammation? What is the level to which the inflammation could be reduced without compromising its physiological function? Should specific molecules be targeted or is a broad nonspecific approach appropriate?

associated with improvement in eGFR in patients with advanced CKD and type 2 diabetes.152 The bardoxolone methyl Evaluation in Patients with Chronic Kidney Disease and T2DM: The Occurrence of Renal Events (BEACON) trial, however, was terminated because of excess mortality in the treatment arm.153 Thus, it is important to navigate through the maze of inflammatory pathways while selecting the target, with careful assessment of clinical risk.

CONCLUSION Our understanding of the causes and consequences of inflammation has certainly expanded considerably, but the science is still evolving rapidly, constantly revealing new molecules and novel pathways. Besides contributing to the progression of renal disease, inflammation is now recognized as a potential catalyst that may accelerate kidney disease complications. Lack of clear understanding has hampered our progress in the management of uremia-associated inflammation, but we have made considerable strides during the last two decades. Challenges and questions still remaining to be addressed are listed in Table 24.2. While investigators are seeking answers, a number of drugs that target inflammation are in development, and small studies have reported some encouraging results.

References 1. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation [erratum appears in N Engl J Med 1999;340(17):1376.]. [Review] [64 refs] N Engl J Med 1999;340: 448e54. 2. Feghali CA, Wright TM. Cytokines in acute and chronic inflammation. Front Biosci 1997;2:d12e26. 3. Gupta J, Mitra N, Kanetsky PA, Devaney J, Wing MR, Reilly M, Shah VO, Balakrishnan VS, Guzman NJ, Girndt M, Periera BG, Feldman HI, Kusek JW, Joffe MM, Raj DS. Association between albuminuria, kidney function, and inflammatory biomarker profile. Clin J Am Soc Nephrol 2012;7:1938e46.

4. Kimmel PL, Phillips TM, Simmens SJ, Peterson RA, Weihs KL, Alleyne S, Cruz I, Yanovski JA, Veis JH. Immunologic function and survival in hemodialysis patients. Kidney Int 1998;54: 236e44. 5. Pereira BJ, Shapiro L, King AJ, Falagas ME, Strom JA, Dinarello CA. Plasma levels of IL-1 beta, TNF alpha and their specific inhibitors in undialyzed chronic renal failure, CAPD and hemodialysis patients. Kidney Int 1994;45:890e6. 6. Cohen SD, Phillips TM, Khetpal P, Kimmel PL. Cytokine patterns and survival in haemodialysis patients. Nephrol Dial Transplant 2010;25:1239e43. 7. Ranjit N, Diez-Roux AV, Shea S, Cushman M, Ni H, Seeman T. Socioeconomic position, race/ethnicity, and inflammation in the Multi-Ethnic Study of Atherosclerosis. Circulation 2007;116: 2383e90. 8. Macaulay R, Akbar AN, Henson SM. The role of the T cell in agerelated inflammation. Age (Dordr) 2013;35:563e72. 9. Jagannathan-Bogdan M, McDonnell ME, Shin H, Rehman Q, Hasturk H, Apovian CM, Nikolajczyk BS. Elevated proinflammatory cytokine production by a skewed Tcell compartment requires monocytes and promotes inflammation in type 2 diabetes. J Immunol 2011;186:1162e72. 10. Duncan BB, Schmidt MI, Pankow JS, Ballantyne CM, Couper D, Vigo A, Hoogeveen R, Folsom AR, Heiss G. Low-grade systemic inflammation and the development of type 2 diabetes: the Atherosclerosis Risk In Communities study. Diabetes 2003;52:1799e805. 11. Luttropp K, Debowska M, Lukaszuk T, Bobrowski L, Carrero JJ, Qureshi AR, Stenvinkel P, Lindholm B, Waniewski J, Nordfors L. Genotypic and phenotypic predictors of inflammation in patients with chronic kidney disease. Nephrol Dial Transplant 2016;31:2033e40. 12. Ness RB, Haggerty CL, Harger G, Ferrell R. Differential distribution of allelic variants in cytokine genes among African Americans and White Americans. Am J Epidemiol 2004;160:1033e8. 13. Van Dyke AL, Cote ML, Wenzlaff AS, Land S, Schwartz AG. Cytokine SNPs: comparison of allele frequencies by race and implications for future studies. Cytokine 2009;46:236e44. 14. Dwivedi RS, Herman JG, McCaffrey TA, Raj DS. Beyond genetics: epigenetic code in chronic kidney disease. Kidney Int 2011;79: 23e32. 15. Wilson CB, Rowell E, Sekimata M. Epigenetic control of T-helpercell differentiation. Nat Rev Immunol 2009;9:91e105. 16. Balakrishnan VS, Schmid CH, Jaber BL, Natov SN, King AJ, Pereira BJ. Interleukin-1 receptor antagonist synthesis by peripheral blood mononuclear cells: a novel predictor of morbidity among hemodialysis patients. J Am Soc Nephrol 2000;11:2114e21. 17. Morley JJ, Kushner I. Serum C-reactive protein levels in disease. Ann N Y Acad Sci 1982;389:406e18. 18. Kimmel PL, Phillips TM, Phillips E, Bosch JP. Effect of renal replacement therapy on cellular cytokine production in patients with renal disease. Kidney Int 1990;38:129e35. 19. Raj DSC, Dominic EA, Pai A, Osman F, Morgan M, Pickett G, Shah VO, Ferrando A, Moseley P. Skeletal muscle, cytokines and oxidative stress in end-stage renal disease. Kidney Int 2005; 68:2338e44. 20. Garibotto G, Sofia A, Procopio V, Villaggio B, Tarroni A, Di MM, Cappelli V, Gandolfo MT, Aloisi F, De CF, Sala MR, Verzola D. Peripheral tissue release of interleukin-6 in patients with chronic kidney diseases: effects of end-stage renal disease and microinflammatory state. Kidney Int 2006;70:384e90. 21. Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 1998;83:847e50. 22. Boivin MA, Battah SI, Dominic EA, Kalantar-Zadeh K, Ferrando A, Tzamaloukas AH, Dwivedi R, Ma TA, Moseley P,

IV. PATHOPHYSIOLOGY

REFERENCES

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36. 37. 38.

39.

Raj DS. Activation of caspase-3 in the skeletal muscle during haemodialysis. Eur J Clin Invest 2010;40:903e10. Wing MR, Yang W, Teal V, Navaneethan S, Tao K, Ojo A, Guzman NN, Reilly M, Wolman M, Rosas SE, Cuevas M, Fischer M, Lustigova E, Master SR, Xie D, Appleby D, Joffe M, Kusek J, Feldman HI, Raj DS. Race modifies the association between adiposity and inflammation in patients with chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort study. Obesity (Silver Spring) 2014;22: 1359e66. Baldus S, Heeschen C, Meinertz T, Zeiher AM, Eiserich JP, Munzel T, Simoons ML, Hamm CW. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation 2003;108:1440e5. Kalantar-Zadeh K, Brennan ML, Hazen SL. Serum myeloperoxidase and mortality in maintenance hemodialysis patients. Am J Kidney Dis 2006;48:59e68. Ioannidou E, Swede H, Dongari-Bagtzoglou A. Periodontitis predicts elevated C-reactive protein levels in chronic kidney disease. J Dent Res 2011;90:1411e5. Goncalves S, Pecoits-Filho R, Perreto S, Barberato SH, Stinghen AE, Lima EG, Fuerbringer R, Sauthier SM, Riella MC. Associations between renal function, volume status and endotoxaemia in chronic kidney disease patients. Nephrol Dial Transplant 2006;21:2788e94. Ramos LF, Shintani A, Ikizler TA, Himmelfarb J. Oxidative stress and inflammation are associated with adiposity in moderate to severe CKD. J Am Soc Nephrol 2008;19:593e9. Safieh-Garabedian B, Poole S, Haddad JJ, Massaad CA, Jabbur SJ, Saade NE. The role of the sympathetic efferents in endotoxininduced localized inflammatory hyperalgesia and cytokine upregulation. Neuropharmacology 2002;42:864e72. Sterling KA, Eftekhari P, Girndt M, Kimmel PL, Raj DS. The immunoregulatory function of vitamin D: implications in chronic kidney disease. Nat Rev Nephrol 2012;8:403e12. Hida M, Aiba Y, Sawamura S, Suzuki N, Satoh T, Koga Y. Inhibition of the accumulation of uremic toxins in the blood and their precursors in the feces after oral administration of Lebenin, a lactic acid bacteria preparation, to uremic patients undergoing hemodialysis. Nephron 1996;74:349e55. Vaziri ND, Wong J, Pahl M, Piceno YM, Yuan J, Desantis TZ, Ni Z, Nguyen TH, Andersen GL. Chronic kidney disease alters intestinal microbial flora. Kidney Int 2013;83(2):308e15. Ramezani A, Massy ZA, Meijers B, Evenepoel P, Vanholder R, Raj DS. Role of the gut microbiome in uremia: a potential therapeutic target. Am J Kidney Dis 2016;67:483e98. Raj DS, Carrero JJ, Shah VO, Qureshi AR, Barany P, Heimburger O, Lindholm B, Ferguson J, Moseley PL, Stenvinkel P. Soluble CD14 levels, interleukin 6, and mortality among prevalent hemodialysis patients. Am J Kidney Dis 2009; 54:990e2. Gollapudi P, Yoon JW, Gollapudi S, Pahl MV, Vaziri ND. Leukocyte toll-like receptor expression in end-stage kidney disease. Am J Nephrol 2010;31:247e54. Kono H, Rock KL. How dying cells alert the immune system to danger. Nat Rev Immunol 2008;8:279e89. Anders HJ, Muruve DA. The inflammasomes in kidney disease. J Am Soc Nephrol 2011;22:1007e18. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002;10:417e26. Vilaysane A, Chun J, Seamone ME, Wang W, Chin R, Hirota S, Li Y, Clark SA, Tschopp J, Trpkov K, Hemmelgarn BR, Beck PL, Muruve DA. The NLRP3 inflammasome promotes renal inflammation and contributes to CKD. J Am Soc Nephrol 2010;21: 1732e44.

367

40. Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature 2014;510:92e101. 41. Fullerton JN, Gilroy DW. Resolution of inflammation: a new therapeutic frontier. Nat Rev Drug Discov 2016;15:551e67. 42. Buckley CD, Gilroy DW, Serhan CN. Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity 2014;40:315e27. 43. Serhan CN, Levy BD. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest 2018; 128:2657e69. 44. Kourtzelis I, Li X, Mitroulis I, Grosser D, Kajikawa T, Wang B, Grzybek M, von RJ, Czogalla A, Troullinaki M, Ferreira A, Doreth C, Ruppova K, Chen LS, Hosur K, Lim JH, Chung KJ, Grossklaus S, Tausche AK, Joosten LAB, Moutsopoulos NM, Wielockx B, Castrillo A, Korostoff JM, Coskun U, Hajishengallis G, Chavakis T. DEL-1 promotes macrophage efferocytosis and clearance of inflammation. Nat Immunol 2019;20: 40e9. 45. Zoccali C, Tripepi G, Mallamaci F. Dissecting inflammation in ESRD: do cytokines and C-reactive protein have a complementary prognostic value for mortality in dialysis patients? J Am Soc Nephrol 2006;17:S169e73. 46. Navarro SL, Brasky TM, Schwarz Y, Song X, Wang CY, Kristal AR, Kratz M, White E, Lampe JW. Reliability of serum biomarkers of inflammation from repeated measures in healthy individuals. Cancer Epidemiol Biomarkers Prev 2012;21:1167e70. 47. Snaedal S, Heimburger O, Qureshi AR, Danielsson A, Wikstrom B, Fellstrom B, Fehrman-Ekholm I, Carrero JJ, Alvestrand A, Stenvinkel P, Barany P. Comorbidity and acute clinical events as determinants of CRP variation in hemodialysis patients: implications on patient survival. Am J Kidney Dis 2009;53:1033. 48. Castell JV, Gomez-Lechon MJ, David M, Fabra R, Trullenque R, Heinrich PC. Acute-phase response of human hepatocytes: regulation of acute-phase protein synthesis by interleukin-6. Hepatology 1990;12:1179e86. 49. Shine B, de Beer FC, Pepys MB. Solid phase radioimmunoassays for human C-reactive protein. Clin Chim Acta 1981;117:13e23. 50. Pepys MB, Rowe IF, Baltz ML. C-reactive protein: binding to lipids and lipoproteins. Int Rev Exp Pathol 1985;27:83e111. 51. Zoccali C, Benedetto FA, Mallamaci F, Tripepi G, Cutrupi S, Parlongo S, Malatino LS, Bonanno G, Rapisarda F, Fatuzzo P, Seminara G, Nicocia G, Buemi M. Fibrinogen, inflammation and concentric left ventricular hypertrophy in chronic renal failure. Eur J Clin Invest 2003;33:561e6. 52. Stenvinkel P, Heimburger O, Paultre F, Diczfalusy U, Wang T, Berglund L, Jogestrand T. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int 1999;55:1899e911. 53. Menon V, Greene T, Wang X, Pereira AA, Marcovina SM, Beck GJ, Kusek JW, Collins AJ, Levey AS, Sarnak MJ. C-reactive protein and albumin as predictors of all-cause and cardiovascular mortality in chronic kidney disease. Kidney Int 2005;68:766e72. 54. Baldwin DS. Chronic glomerulonephritis: nonimmunologic mechanisms of progressive glomerular damage. Kidney Int 1982; 21:109e20. 55. Rao M, Wong C, Kanetsky P, Girndt M, Stenvinkel P, Reilly M, Raj DS. Cytokine gene polymorphism and progression of renal and cardiovascular diseases. Kidney Int 2007;72(5):549e56. 56. Wiggins JE, Patel SR, Shedden KA, Goyal M, Wharram BL, Martini S, Kretzler M, Wiggins RC. NFkappaB promotes inflammation, coagulation, and fibrosis in the aging glomerulus. J Am Soc Nephrol 2010;21:587e97. 57. Qin W, Chung AC, Huang XR, Meng XM, Hui DS, Yu CM, Sung JJ, Lan HY. TGF-{beta}/Smad3 signaling promotes renal fibrosis by inhibiting miR-29. J Am Soc Nephrol 2011;22:1462e74.

IV. PATHOPHYSIOLOGY

368

24. INFLAMMATION IN CHRONIC KIDNEY DISEASE

58. Niewczas MA, Gohda T, Skupien J, Smiles AM, Walker WH, Rosetti F, Cullere X, Eckfeldt JH, Doria A, Mayadas TN, Warram JH, Krolewski AS. Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes. J Am Soc Nephrol 2012;23:507e15. 59. Suthanthiran M, Gerber LM, Schwartz JE, Sharma VK, Medeiros M, Marion R, Pickering TG, August P. Circulating transforming growth factor-beta1 levels and the risk for kidney disease in African Americans. Kidney Int 2009;76:72e80. 60. Taniguchi Y, Yorioka N, Oda H, Yamakido M. Platelet-derived growth factor, interleukin (IL)-1 beta, IL-6R and tumor necrosis factor-alpha in IgA nephropathy. An immunohistochemical study. Nephron 1996;74:652e60. 61. Chen WP, Lin CY. Augmented expression of interleukin-6 and interleukin-1 genes in the mesangium of IgM mesangial nephropathy. Nephron 1994;68:10e9. 62. Cheng J, Grande JP. Transforming growth factor-beta signal transduction and progressive renal disease. Exp Biol Med (Maywood) 2002;227:943e56. 63. Taniguchi Y, Yorioka N, Kumagai J, Katsutani M, Kuratsune M, Amimoto D, Yamakido M. Interleukin-6 localization and the prognosis of IgA nephropathy. Nephron 1999;81:94e8. 64. Boswell JM, Yui MA, Burt DW, Kelley VE. Increased tumor necrosis factor and IL-1 beta gene expression in the kidneys of mice with lupus nephritis. J Immunol 1988;141:3050e4. 65. Nakamura T, Miller D, Ruoslahti E, Border WA. Production of extracellular matrix by glomerular epithelial cells is regulated by transforming growth factor-beta 1. Kidney Int 1992;41:1213e21. 66. Coleman DL, Ruef C. Interleukin-6: an autocrine regulator of mesangial cell growth. Kidney Int 1992;41:604e6. 67. Horii Y, Muraguchi A, Iwano M, Matsuda T, Hirayama T, Yamada H, Fujii Y, Dohi K, Ishikawa H, Ohmoto Y. Involvement of IL-6 in mesangial proliferative glomerulonephritis. J Immunol 1989;143:3949e55. 68. Bevilacqua MP, Pober JS, Majeau GR, Fiers W, Cotran RS, Gimbrone Jr MA. Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1. Proc Natl Acad Sci USA 1986;83:4533e7. 69. Sharma K, Cook A, Smith M, Valancius C, Inscho EW. TGF-beta impairs renal autoregulation via generation of ROS. Am J Physiol Renal Physiol 2005;288:F1069e77. 70. Park S, Chang YH, Cho YJ, Ahn H, Yang WS, Park JS, Lee JD. Cytokine-regulated expression of vascular cell adhesion molecule-1 in human glomerular endothelial cells. Transplant Proc 1998;30:2395e7. 71. Zager RA, Johnson A. Renal cortical cholesterol accumulation is an integral component of the systemic stress response. Kidney Int 2001;60:2299e310. 72. Nee LE, McMorrow T, Campbell E, Slattery C, Ryan MP. TNFalpha and IL-1beta-mediated regulation of MMP-9 and TIMP-1 in renal proximal tubular cells. Kidney Int 2004;66:1376e86. 73. Sedor JR, Nakazato Y, Konieczkowski M. Interleukin-1 and the mesangial cell. Kidney Int 1992;41:595e9. 74. Atkins RC. Interleukin-1 in crescentic glomerulonephritis. Kidney Int 1995;48:576e86. 75. Baud L, Ardaillou R. Tumor necrosis factor alpha in glomerular injury. Kidney Int Suppl 1994;45:S32e6. 76. Goumenos DS, Tsakas S, el Nahas AM, Alexandri S, Oldroyd S, Kalliakmani P, Vlachojannis JG. Transforming growth factorbeta(1) in the kidney and urine of patients with glomerular disease and proteinuria. Nephrol Dial Transplant 2002;17:2145e52. 77. Noh JW, Wiggins R, Phan SH. Urine transforming growth factorbeta activity is related to the degree of scarring in crescentic nephritis in the rabbit. Nephron 1993;63:73e8.

78. Sharma K, Ziyadeh FN, Alzahabi B, McGowan TA, Kapoor S, Kurnik BR, Kurnik PB, Weisberg LS. Increased renal production of transforming growth factor-beta1 in patients with type II diabetes. Diabetes 1997;46:854e9. 79. Kalantarinia K, Awad AS, Siragy HM. Urinary and renal interstitial concentrations of TNF-alpha increase prior to the rise in albuminuria in diabetic rats. Kidney Int 2003;64:1208e13. 80. Harada K, Akai Y, Kurumatani N, Iwano M, Saito Y. Prognostic value of urinary interleukin 6 in patients with IgA nephropathy: an 8-year follow-up study. Nephron 2002;92:824e6. 81. Amdur RL, Feldman HI, Gupta J, Yang W, Kanetsky P, Shlipak M, Rahman M, Lash JP, Townsend RR, Ojo A, Roy-Chaudhury A, Go AS, Joffe M, He J, Balakrishnan VS, Kimmel PL, Kusek JW, Raj DS. Inflammation and progression of CKD: the CRIC study. Clin J Am Soc Nephrol 2016;11:1546e56. 82. Bhatraju PK, Zelnick LR, Shlipak M, Katz R, Kestenbaum B. Association of soluble TNFR-1 concentrations with long-term decline in kidney function: the Multi-Ethnic Study of Atherosclerosis. J Am Soc Nephrol 2018;29:2713e21. 83. Kamei N, Yamashita M, Nishizaki Y, Yanagisawa N, Nojiri S, Tanaka K, Yamashita Y, Shibata T, Murakoshi M, Suzuki Y, Gohda T. Association between circulating tumor necrosis factorrelated biomarkers and estimated glomerular filtration rate in type 2 diabetes. Sci Rep 2018;8:15302. 84. Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 2002;110:341e50. 85. LeBleu VS, Taduri G, O’Connell J, Teng Y, Cooke VG, Woda C, Sugimoto H, Kalluri R. Origin and function of myofibroblasts in kidney fibrosis. Nat Med 2013;19:1047e53. 86. Shankar A, Sun L, Klein BE, Lee KE, Muntner P, Nieto FJ, Tsai MY, Cruickshanks KJ, Schubert CR, Brazy PC, Coresh J, Klein R. Markers of inflammation predict the long-term risk of developing chronic kidney disease: a population-based cohort study. Kidney Int 2011;80:1231e8. 87. Norlander AE, Madhur MS, Harrison DG. The immunology of hypertension. J Exp Med 2018;215:21e33. 88. Sun XN, Li C, Liu Y, Du LJ, Zeng MR, Zheng XJ, Zhang WC, Liu Y, Zhu M, Kong D, Zhou L, Lu L, Shen ZX, Yi Y, Du L, Qin M, Liu X, Hua Z, Sun S, Yin H, Zhou B, Yu Y, Zhang Z, Duan SZ. T-cell mineralocorticoid receptor controls blood pressure by regulating interferon-gamma. Circ Res 2017;120: 1584e97. 89. Bernelot Moens SJ, Verweij SL, van der Valk FM, van Capelleveen JC, Kroon J, Versloot M, Verberne HJ, Marquering HA, Duivenvoorden R, Vogt L, Stroes ES. Arterial and cellular inflammation in patients with CKD. J Am Soc Nephrol 2017;28:1278e85. 90. Barbaro NR, Foss JD, Kryshtal DO, Tsyba N, Kumaresan S, Xiao L, Mernaugh RL, Itani HA, Loperena R, Chen W, Dikalov S, Titze JM, Knollmann BC, Harrison DG, Kirabo A. Dendritic cell amiloridesensitive channels mediate sodium-induced inflammation and hypertension. Cell Rep 2017;21:1009e20. 91. Peyster E, Chen J, Feldman HI, Go AS, Gupta J, Mitra N, Pan Q, Porter A, Rahman M, Raj D, Reilly M, Wing MR, Yang W, Townsend RR. Inflammation and arterial stiffness in chronic kidney disease: findings from the CRIC study. Am J Hypertens 2017; 30:400e8. 92. Reiss AB, Glass AD. Atherosclerosis: immune and inflammatory aspects. J Investig Med 2006;54:123e31. 93. Weiner DE, Tighiouart H, Elsayed EF, Griffith JL, Salem DN, Levey AS, Sarnak MJ. Inflammation and cardiovascular events in individuals with and without chronic kidney disease. Kidney Int 2008;73:1406e12.

IV. PATHOPHYSIOLOGY

REFERENCES

94. Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res 2002;91:988e98. 95. Oral H, Sivasubramanian N, Dyke DB, Mehta RH, Grossman PM, Briesmiester K, Fay WP, Pagani FD, Bolling SF, Mann DL, Starling MR. Myocardial proinflammatory cytokine expression and left ventricular remodeling in patients with chronic mitral regurgitation. Circulation 2003;107:831e7. 96. Amdur RL, Feldman HI, Dominic EA, Anderson AH, Beddhu S, Rahman M, Wolf M, Reilly M, Ojo A, Townsend RR, Go AS, He J, Xie D, Thompson S, Budoff M, Kasner S, Kimmel PL, Kusek JW, Raj DS. Use of measures of inflammation and kidney function for prediction of atherosclerotic vascular disease events and death in patients with CKD: findings from the CRIC study. Am J Kidney Dis 2019;73(3):344e53. 97. Raj DS, Moseley P, Dominic EA, Onime A, Tzamaloukas AH, Boyd A, Shah VO, Glew R, Wolfe R, Ferrando A. Interleukin-6 modulates hepatic and muscle protein synthesis during hemodialysis. Kidney Int 2008;73:1061. 98. Kramer HJ, Saranathan A, Luke A, Durazo-Arvizu RA, Guichan C, Hou S, Cooper R. Increasing body mass index and obesity in the incident ESRD population. J Am Soc Nephrol 2006; 17:1453e9. 99. Chen J, Muntner P, Hamm LL, Fonseca V, Batuman V, Whelton PK, He J. Insulin resistance and risk of chronic kidney disease in nondiabetic US adults. J Am Soc Nephrol 2003;14:469e77. 100. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001;293:1673e7. 101. Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature 2002;420:333e6. 102. Barany P, Divino Filho JC, Bergstrom J. High C-reactive protein is a strong predictor of resistance to erythropoietin in hemodialysis patients. Am J Kidney Dis 1997;29:565e8. 103. de Francisco AL, Stenvinkel P, Vaulont S. Inflammation and its impact on anaemia in chronic kidney disease: from haemoglobin variability to hyporesponsiveness. NDT Plus 2009;2:i18e26. 104. Goicoechea M, Martin J, de Sequera P, Quiroga JA, Ortiz A, Carreno V, Caramelo C. Role of cytokines in the response to erythropoietin in hemodialysis patients. Kidney Int 1998;54:1337e43. 105. De D I, Ward DM, Langelier C, Vaughn MB, Nemeth E, Sundquist WI, Ganz T, Musci G, Kaplan J. The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell 2007;18:2569e78. 106. Faquin WC, Schneider TJ, Goldberg MA. Effect of inflammatory cytokines on hypoxia-induced erythropoietin production. Blood 1992;79:1987e94. 107. Girndt M, Sester M, Sester U, Kaul H, Kohler H. Molecular aspects of T- and B-cell function in uremia. Kidney Int Suppl 2001; 78:S206e11. 108. Moser B, Roth G, Brunner M, Lilaj T, Deicher R, Wolner E, Kovarik J, Boltz-Nitulescu G, Vychytil A, Ankersmit HJ. Aberrant T cell activation and heightened apoptotic turnover in end-stage renal failure patients: a comparative evaluation between nondialysis, haemodialysis, and peritoneal dialysis. Biochem Biophys Res Commun 2003;308:581e5. 109. Smith RS. The macrophage theory of depression. Med Hypotheses 1991;35:298e306. 110. Cukor D, Cohen SD, Peterson RA, Kimmel PL. Psychosocial aspects of chronic disease: ESRD as a paradigmatic illness. J Am Soc Nephrol 2007;18:3042e55. 111. Kalender B, Ozdemir AC, Koroglu G. Association of depression with markers of nutrition and inflammation in chronic kidney disease and end-stage renal disease. Nephron Clin Pract 2006;102: c115e21.

369

112. Carrero JJ, Stenvinkel P. Persistent inflammation as a catalyst for other risk factors in chronic kidney disease: a hypothesis proposal. Clin J Am Soc Nephrol 2009;4(Suppl. 1):S49e55. 113. Raj DS, Adeniyi O, Dominic EA, Boivin MA, McClelland S, Tzamaloukas AH, Morgan N, Gonzales L, Wolfe R, Ferrando A. Amino acid repletion does not decrease muscle protein catabolism during hemodialysis. Am J Physiol Endocrinol Metab 2007; 292:E1534e42. 114. Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS, Djian J, Drexler H, Feldman A, Kober L, Krum H, Liu P, Nieminen M, Tavazzi L, van Veldhuisen DJ, Waldenstrom A, Warren M, Westheim A, Zannad F, Fleming T. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 2004;109:1594e602. 115. Zannad F, Kessler M, Lehert P, Grunfeld JP, Thuilliez C, Leizorovicz A, Lechat P. Prevention of cardiovascular events in end-stage renal disease: results of a randomized trial of fosinopril and implications for future studies. Kidney Int 2006;70:1318e24. 116. Takahashi A, Takase H, Toriyama T, Sugiura T, Kurita Y, Ueda R, Dohi Y. Candesartan, an angiotensin II type-1 receptor blocker, reduces cardiovascular events in patients on chronic haemodialysis–a randomized study. Nephrol Dial Transplant 2006;21:2507e12. 117. Suzuki H, Kanno Y, Sugahara S, Ikeda N, Shoda J, Takenaka T, Inoue T, Araki R. Effect of angiotensin receptor blockers on cardiovascular events in patients undergoing hemodialysis: an open-label randomized controlled trial. Am J Kidney Dis 2008;52: 501e6. 118. Krane V, Wanner C. Statins, inflammation and kidney disease. Nat Rev Nephrol 2011;7:385e97. 119. Seliger SL, Weiss NS, Gillen DL, Kestenbaum B, Ball A, Sherrard DJ, Stehman-Breen CO. HMG-CoA reductase inhibitors are associated with reduced mortality in ESRD patients. Kidney Int 2002;61:297e304. 120. Fellstrom BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J, Chae DW, Chevaile A, Cobbe SM, Gronhagen-Riska C, De Lima JJ, Lins R, Mayer G, McMahon AW, Parving HH, Remuzzi G, Samuelsson O, Sonkodi S, Sci D, Suleymanlar G, Tsakiris D, Tesar V, Todorov V, Wiecek A, Wuthrich RP, Gottlow M, Johnsson E, Zannad F. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009;360:1395e407. 121. Boaz M, Smetana S, Weinstein T, Matas Z, Gafter U, Iaina A, Knecht A, Weissgarten Y, Brunner D, Fainaru M, Green MS. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet 2000;356:1213e8. 122. Tepel M, Echelmeyer M, Orie NN, Zidek W. Increased intracellular reactive oxygen species in patients with end-stage renal failure: effect of hemodialysis. Kidney Int 2000;58:867e72. 123. Valdivielso JM, Ayus JC. Role of vitamin D receptor activators on cardiovascular risk. Kidney Int Suppl 2008;111:S44e9. 124. Thadhani R, Appelbaum E, Pritchett Y, Chang Y, Wenger J, Tamez H, Bhan I, Agarwal R, Zoccali C, Wanner C, LloydJones D, Cannata J, Thompson BT, Andress D, Zhang W, Packham D, Singh B, Zehnder D, Shah A, Pachika A, Manning WJ, Solomon SD. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. J Am Med Assoc 2012;307: 674e84. 125. Shoji T, Inaba M, Fukagawa M, Ando R, Emoto M, Fujii H, Fujimori A, Fukui M, Hase H, Hashimoto T, Hirakata H, Honda H, Hosoya T, Ikari Y, Inaguma D, Inoue T, Isaka Y, Iseki K, Ishimura E, Itami N, Ito C, Kakuta T, Kawai T, Kawanishi H, Kobayashi S, Kumagai J, Maekawa K, Masakane I, Minakuchi J, Mitsuiki K, Mizuguchi T, Morimoto S,

IV. PATHOPHYSIOLOGY

370

126. 127.

128.

129.

130. 131.

132.

133.

134.

135.

136.

137.

138. 139.

140.

141.

24. INFLAMMATION IN CHRONIC KIDNEY DISEASE

Murohara T, Nakatani T, Negi S, Nishi S, Nishikawa M, Ogawa T, Ohta K, Ohtake T, Okamura M, Okuno S, Shigematsu T, Sugimoto T, Suzuki M, Tahara H, Takemoto Y, Tanaka K, Tominaga Y, Tsubakihara Y, Tsujimoto Y, Tsuruya K, Ueda S, Watanabe Y, Yamagata K, Yamakawa T, Yano S, Yokoyama K, Yorioka N, Yoshiyama M, Nishizawa Y. Effect of oral alfacalcidol on clinical outcomes in patients without secondary hyperparathyroidism receiving maintenance hemodialysis: the J-DAVID randomized clinical trial. J Am Med Assoc 2018;320:2325e34. Hall RK, Scialla JJ. Vitamin D receptor agonists for patients undergoing hemodialysis. J Am Med Assoc 2018;320:2319e21. Raj DS, Shah VO, Rambod M, Kovesdy CP, Kalantar-Zadeh K. Association of soluble endotoxin receptor CD14 and mortality among patients undergoing hemodialysis. Am J Kidney Dis 2009; 54(6):1062e71. Cani PD, Neyrinck AM, Fava F, Knauf C, Burcelin RG, Tuohy KM, Gibson GR, Delzenne NM. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia 2007;50:2374e83. Gibson GR, Beatty ER, Wang X, Cummings JH. Selective stimulation of bifidobacteria in the human colon by oligofructose and inulin. Gastroenterology 1995;108:975e82. Perianayagam MC, Jaber BL. Endotoxin-binding affinity of sevelamer hydrochloride. Am J Nephrol 2008;28:802e7. Ferramosca E, Burke S, Chasan-Taber S, Ratti C, Chertow GM, Raggi P. Potential antiatherogenic and anti-inflammatory properties of sevelamer in maintenance hemodialysis patients. Am Heart J 2005;149:820e5. Evenepoel P, Selgas R, Caputo F, Foggensteiner L, Heaf JG, Ortiz A, Kelly A, Chasan-Taber S, Duggal A, Fan S. Efficacy and safety of sevelamer hydrochloride and calcium acetate in patients on peritoneal dialysis. Nephrol Dial Transplant 2009;24:278e85. Stinghen AE, Gonc¸alves SM, Bucharles S, Branco FS, Gruber B, Hauser AB, Pecoits-Filho R. Sevelamer decreases systemic inflammation in parallel to a reduction in endotoxemia. Blood Purif 2010; 29(4):352e6. https://doi.org/10.1159/000302723. Epub 2010 March 31. Pussinen PJ, Tuomisto K, Jousilahti P, Havulinna AS, Sundvall J, Salomaa V. Endotoxemia, immune response to periodontal pathogens, and systemic inflammation associate with incident cardiovascular disease events. Arterioscler Thromb Vasc Biol 2007;27: 1433e9. Craig RG, Pernat AM, Pecoits-Filho R, Levin NW, Kotanko P. Periodontal diseases and systemic inflammation. Semin Dial 2013;26: 23e8. D’Hellencourt CL, Diaw L, Cornillet P, Guenounou M. Differential regulation of TNF alpha, IL-1 beta, IL-6, IL-8, TNF beta, and IL-10 by pentoxifylline. Int J Immunopharmacol 1996;18:739e48. McCormick BB, Sydor A, Akbari A, Fergusson D, Doucette S, Knoll G. The effect of pentoxifylline on proteinuria in diabetic kidney disease: a meta-analysis. Am J Kidney Dis 2008;52:454e63. Ducloux D, Bresson-Vautrin C, Chalopin J. Use of pentoxifylline in membranous nephropathy. Lancet 2001;357:1672e3. Atabek ME, Kurtoglu S, Selver B, Baykara M. Effectiveness of pentoxifylline on the cross-sectional area of intima media thickness and functions of the common carotid artery in adolescents with type 1 diabetes. J Pediatr Endocrinol Metab 2011;24:945e51. Shimizu T, Fukagawa M, Kuroda T, Hata S, Iwasaki Y, Nemoto M, Shirai K, Yamauchi S, Margolin SB, Shimizu F, Kurokawa K. Pirfenidone prevents collagen accumulation in the remnant kidney in rats with partial nephrectomy. Kidney Int Suppl 1997;63: S239e43. Cho ME, Smith DC, Branton MH, Penzak SR, Kopp JB. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 2007;2:906e13.

142. Sharma K, Ix JH, Mathew AV, Cho M, Pflueger A, Dunn SR, Francos B, Sharma S, Falkner B, McGowan TA, Donohue M, Ramachandrarao S, Xu R, Fervenza FC, Kopp JB. Pirfenidone for diabetic nephropathy. J Am Soc Nephrol 2011;22:1144e51. 143. Jiang C, Huang H, Liu J, Wang Y, Lu Z, Xu Z. Adverse events of pirfenidone for the treatment of pulmonary fibrosis: a metaanalysis of randomized controlled trials. PLoS One 2012;7:e47024. 144. Alten R, Maleitzke T. Tocilizumab: a novel humanized antiinterleukin 6 (IL-6) receptor antibody for the treatment of patients with non-RA systemic, inflammatory rheumatic diseases. Ann Med 2013;45:357e63. 145. Iijima T, Suwabe T, Sumida K, Hayami N, Hiramatsu R, Hasegawa E, Yamanouchi M, Hoshino J, Sawa N, Takaichi K, Oohashi K, Fujii T, Ubara Y. Tocilizumab improves systemic rheumatoid vasculitis with necrotizing crescentic glomerulonephritis. Mod Rheumatol 2015;25(1):138e42. 146. Don BR, Kim K, Li J, Dwyer T, Alexander F, Kaysen GA. The effect of etanercept on suppression of the systemic inflammatory response in chronic hemodialysis patients. Clin Nephrol 2010;73: 431e8. 147. Hung AM, Ellis CD, Shintani A, Booker C, Ikizler TA. IL-1beta receptor antagonist reduces inflammation in hemodialysis patients. J Am Soc Nephrol 2011;22:437e42. 148. Ikonomidis I, Lekakis JP, Nikolaou M, Paraskevaidis I, Andreadou I, Kaplanoglou T, Katsimbri P, Skarantavos G, Soucacos PN, Kremastinos DT. Inhibition of interleukin-1 by anakinra improves vascular and left ventricular function in patients with rheumatoid arthritis. Circulation 2008;117:2662e9. 149. Nowak KL, Chonchol M, Ikizler TA, Farmer-Bailey H, Salas N, Chaudhry R, Wang W, Smits G, Tengesdal I, Dinarello CA, Hung AM. IL-1 inhibition and vascular function in CKD. J Am Soc Nephrol 2017;28:971e80. 150. Ridker PM, MacFadyen JG, Glynn RJ, Koenig W, Libby P, Everett BM, Lefkowitz M, Thuren T, Cornel JH. Inhibition of interleukin-1beta by canakinumab and cardiovascular outcomes in patients with chronic kidney disease. J Am Coll Cardiol 2018; 71:2405e14. 151. Katsuki S, Matoba T, Nakashiro S, Sato K, Koga J, Nakano K, Nakano Y, Egusa S, Sunagawa K, Egashira K. Nanoparticlemediated delivery of pitavastatin inhibits atherosclerotic plaque destabilization/rupture in mice by regulating the recruitment of inflammatory monocytes. Circulation 2014;129:896e906. 152. Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, Krauth M, Ruiz S, Audhya P, Christ-Schmidt H, Wittes J, Warnock DG. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med 2011;365:327e36. 153. de Zeeuw D, Akizawa T, Agarwal R, Audhya P, Bakris GL, Chin M, Krauth M, Lambers Heerspink HJ, Meyer CJ, McMurray JJ, Parving HH, Pergola PE, Remuzzi G, Toto RD, Vaziri ND, Wanner C, Warnock DG, Wittes J, Chertow GM. Rationale and trial design of bardoxolone methyl evaluation in patients with chronic kidney disease and type 2 diabetes: the occurrence of renal events (BEACON). Am J Nephrol 2013;37:212e22. 154. Goicoechea M, de Vinuesa SG, Gomez-Campdera F, Aragoncillo I, Verdalles U, Mosse A, Luno J. Serum fibrinogen levels are an independent predictor of mortality in patients with chronic kidney disease (CKD) stages 3 and 4. Kidney Int Suppl 2008:S67e70. 155. Kumon Y, Hosokawa T, Suehiro T, Ikeda Y, Sipe JD, Hashimoto K. Acute-phase, but not constitutive serum amyloid A (SAA) is chemotactic for cultured human aortic smooth muscle cells. Amyloid 2002;9:237e41. 156. Jones SA, Horiuchi S, Topley N, Yamamoto N, Fuller GM. The soluble interleukin 6 receptor: mechanisms of production and implications in disease. FASEB J 2001;15:43e58. 157. Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, Achong MK. IL-6 is an antiinflammatory cytokine required for

IV. PATHOPHYSIOLOGY

371

REFERENCES

158. 159.

160.

161.

162.

163.

164.

165.

166.

167.

168.

169. 170.

171.

172.

controlling local or systemic acute inflammatory responses. J Clin Invest 1998;101:311e20. Raj DS. Role of interleukin-6 in the anemia of chronic disease. Semin Arthritis Rheum 2009;38(5):382e8. Stenvinkel P, Heimburger O, Jogestrand T. Elevated interleukin-6 predicts progressive carotid artery atherosclerosis in dialysis patients: association with Chlamydia pneumoniae seropositivity. Am J Kidney Dis 2002;39:274e82. Rao M, Guo D, Perianayagam MC, Tighiouart H, Jaber BL, Pereira BJ, Balakrishnan VS. Plasma interleukin-6 predicts cardiovascular mortality in hemodialysis patients. Am J Kidney Dis 2005; 45:324e33. Biasucci LM, Liuzzo G, Fantuzzi G, Caligiuri G, Rebuzzi AG, Ginnetti F, Dinarello CA, Maseri A. Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of inhospital coronary events. Circulation 1999;99:2079e84. Girndt M, Kaul H, Sester U, Ulrich C, Sester M, Georg T, Kohler H. Anti-inflammatory interleukin-10 genotype protects dialysis patients from cardiovascular events. Kidney Int 2002;62:949e55. Balakrishnan VS, Guo D, Rao M, Jaber BL, Tighiouart H, Freeman RL, Huang C, King AJ, Pereira BJ. Cytokine gene polymorphisms in hemodialysis patients: association with comorbidity, functionality, and serum albumin. Kidney Int 2004;65: 1449e60. Nilsson J, Jovinge S, Niemann A, Reneland R, Lithell H. Relation between plasma tumor necrosis factor-alpha and insulin sensitivity in elderly men with non-insulin-dependent diabetes mellitus. Arterioscler Thromb Vasc Biol 1998;18:1199e202. Ridker PM, Rifai N, Pfeffer M, Sacks F, Lepage S, Braunwald E. Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Circulation 2000;101:2149e53. Egido J, Gomez-Chiarri M, Ortiz A, Bustos C, Alonso J, GomezGuerrero C, Gomez-Garre D, Lopez-Armada MJ, Plaza J, Gonzalez E. Role of tumor necrosis factor-alpha in the pathogenesis of glomerular diseases. Kidney Int Suppl 1993;39: S59e64. Carrero JJ, Ortiz A, Qureshi AR, Martin-Ventura JL, Barany P, Heimburger O, Marron B, Metry G, Snaedal S, Lindholm B, Egido J, Stenvinkel P, Blanco-Colio LM. Additive effects of soluble TWEAK and inflammation on mortality in hemodialysis patients. Clin J Am Soc Nephrol 2008;4:110e8. Grainger DJ, Metcalfe JC, Grace AA, Mosedale DE. Transforming growth factor-beta dynamically regulates vascular smooth muscle differentiation in vivo. J Cell Sci 1998;111(Pt 19): 2977e88. Segal R, Fine LG. Polypeptide growth factors and the kidney. Kidney Int Suppl 1989;27:S2e10. Bruchfeld A, Qureshi AR, Lindholm B, Barany P, Yang L, Stenvinkel P, Tracey KJ. High Mobility Group Box Protein-1 correlates with renal function in chronic kidney disease (CKD). Mol Med 2008;14:109e15. Tang WH, Brennan ML, Philip K, Tong W, Mann S, Van LF, Hazen SL. Plasma myeloperoxidase levels in patients with chronic heart failure. Am J Cardiol 2006;98:796e9. Zhang R, Brennan ML, Fu X, Aviles RJ, Pearce GL, Penn MS, Topol EJ, Sprecher DL, Hazen SL. Association between

173.

174.

175.

176.

177.

178.

179.

180.

181.

182.

183.

184.

185.

186.

myeloperoxidase levels and risk of coronary artery disease. J Am Med Assoc 2001;286:2136e42. Pugin J, Heumann ID, Tomasz A, Kravchenko VV, Akamatsu Y, Nishijima M, Glauser MP, Tobias PS, Ulevitch RJ. CD14 is a pattern recognition receptor. Immunity 1994;1:509e16. Wiedermann CJ, Kiechl S, Dunzendorfer S, Schratzberger P, Egger G, Oberhollenzer F, Willeit J. Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck Study. J Am Coll Cardiol 1999;34: 1975e81. Stoll LL, Denning GM, Weintraub NL. Potential role of endotoxin as a proinflammatory mediator of atherosclerosis. Arterioscler Thromb Vasc Biol 2004;24:2227e36. Panichi V, Paoletti S, Mantuano E, Manca-Rizza G, Filippi C, Santi S, Taccola D, Donadio C, Tramonti G, Innocenti M, Casto G, Consani C, Sbragia G, Franzoni F, Galetta F, Panicucci E, Barsotti G. In vivo and in vitro effects of simvastatin on inflammatory markers in pre-dialysis patients. Nephrol Dial Transplant 2006;21:337e44. Brull DJ, Sanders J, Rumley A, Lowe GD, Humphries SE, Montgomery HE. Impact of angiotensin converting enzyme inhibition on post-coronary artery bypass interleukin 6 release. Heart 2002;87:252e5. Gunnell J, Yeun JY, Depner TA, Kaysen GA. Acute-phase response predicts erythropoietin resistance in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis 1999;33:63e72. Sarnak MJ, Coronado BE, Greene T, Wang SR, Kusek JW, Beck GJ, Levey AS. Cardiovascular disease risk factors in chronic renal insufficiency. Clin Nephrol 2002;57:327e35. Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 1999;55:648e58. Ballmer PE, McNurlan MA, Grant I, Garlick PJ. Down-regulation of albumin synthesis in the rat by human recombinant interleukin-1 beta or turpentine and the response to nutrients. JPEN J Parenter Enteral Nutr 1995;19:266e71. Steensberg A, Febbraio MA, Osada T, Schjerling P, van Hall G, Saltin B, Pedersen BK. Interleukin-6 production in contracting human skeletal muscle is influenced by pre-exercise muscle glycogen content. J Physiol 2001;537:633e9. Febbraio MA, Steensberg A, Keller C, Starkie RL, Nielsen HB, Krustrup P, Ott P, Secher NH, Pedersen BK. Glucose ingestion attenuates interleukin-6 release from contracting skeletal muscle in humans. J Physiol 2003;549:607e12. Higuchi T, Kuno T, Takahashi S, Kanmatsuse K. Influence of dialysis membranes on interleukin-1 beta and interleukin-1 receptor antagonist production by peripheral blood mononuclear cells. Artif Organs 1997;21:265e71. Lopez-Gomez JM, Perez-Flores I, Jofre R, Carretero D, Rodriguez-Benitez P, Villaverde M, Perez-Garcia R, Nassar GM, Niembro E, Ayus JC. Presence of a failed kidney transplant in patients who are on hemodialysis is associated with chronic inflammatory state and erythropoietin resistance. J Am Soc Nephrol 2004;15:2494e501. Nassar GM, Fishbane S, Ayus JC. Occult infection of old nonfunctioning arteriovenous grafts: a novel cause of erythropoietin resistance and chronic inflammation in hemodialysis patients. Kidney Int Suppl 2002:49e54.

IV. PATHOPHYSIOLOGY

372

24. INFLAMMATION IN CHRONIC KIDNEY DISEASE

QUESTIONS AND ANSWERS Question 1 A 52-year-old African-American man with CKD was seen in the nephrology clinic. He complained of fatigue and diffuse joint pain. He denied any urinary symptoms. On physical examination, he was afebrile; his blood pressure was 154/98 mm Hg with a pulse rate of 78 beats per minute. Oral cavity was normal. No lymphadenopathy was noted nor was there any focus of infection. His current medications include amlodipine 10 mg/day, asprin 75 mg daily, and a multivitamin. The following laboratory investigations were obtained: WBC 4.7, neutrophils 31%, hemoglobin 9.8 g/dL Albuminuria by spot urine albumin:creatinine ratio (UACR): 3.1 g/day BUN: 32 mg/dL Serum creatinine (S[Cr]): 2.5 mg/dL Glucose: 289 mg/dL. HbAIC: 9% hsCRP 4.5 mg/L Which one of these statements is true? A. Stable patients with CKD who are not yet on dialysis do not have elevated CRP B. A single measurement of CRP has no clinical significance. Multiple measurements are required to determine the level of inflammation in a given patient C. The contribution of traditional risk factors for inflammation such as age, sex, obesity, and diabetic status are minimal and attenuated by the presence of CKD D. Proteinuria is an independent predictor of inflammation Answer: D3 A is not correct. Plasma levels of cytokines are not significantly different in dialysis patients and CKD patients not yet on dialysis.5 B is not true. CRP levels fluctuate over time, but baseline CRP levels correlate with time-averaged CRP measurements and the median of serial CRP values in patients with kidney disease.47 C is not true. Older age, male sex, obesity, and diabetic status are associated with inflammation in patients with CKD.3

Question 2 The same patient returns for a follow-up visit six months later. His blood pressure remains elevated at 158/94 mm Hg. Laboratory investigations showed

WBC 4.2, hemoglobin 9.7 g/dL. Total cholesterol 230 mg/dL, BUN 30 mg/dL, S[Cr] 2.8 mg/dL, Kþ 3.4 mEq/dL, HCO3- 21 mEq/L, Caþþ 9.6 mg/dL, PO4 5.2 mg/dL, hsCRP 5.2 mg/L. Albuminuria by spot UACR suggests urinary losses of 3.4 g/day Choose the most appropriate response A. Lisinopril will not reduce albuminuria and preserve GFR in this patient B. Besides a cardioprotective effect, statins therapy may reduce inflammation in this patient C. Sevelamer has no advantage over calcium-based phosphate binders in reducing systemic inflammation in CKD patients D. Pirfenidone will be an established adjunct therapy, which should be considered in this patient, to slow the progression of CKD Answer: B B is correct. Treatment with statins reduces CRP and proinflammatory cytokine levels in patients with and without CKD.176 A is not correct. Preliminary evidence indicates that ACE inhibitor treatment is associated with reduction in markers of inflammation.177,178 C is not correct. Treatment with sevelamer hydrochloride lowers circulating biomarkers of inflammation in patients with CKD. D is not correct. Studies in human subjects and animal models suggest that pirfenidone has antifibrotic properties, but it has a number of adverse effects precluding clinical use.

Question 3 The patient subsequently underwent angioplasty with stent placement for acute myocardial infarction. He was started on atorvastatin 40 mg/day and metoprolol 50 mg twice daily. Laboratory investigation showed WBC 4.4, hemoglobin 9.7 g/dL. Total cholesterol 170 mg/dL. BUN 34 mg/dL, S[Cr] increased to 3.1 mg/dL, hsCRP 4.9 mg/L, S[Alb] decreased to 3.1 g/dL. Fibrinogen was 4 g/L. Which of the following statements is correct? A. Augmented inflammation in CKD contributes to accelerated atherogenesis in CKD B. S[Alb] is a marker of nutrition. Nutrient supplementation alone is sufficient to improve the level of S[Alb] in this patient C. In CKD patients, cytokines are derived exclusively from macrophages and adipocytes D. Excess inflammation is this patient is due to decreased clearance of cytokines. There is insufficient evidence that cytokines contribute to the progression of CKD beyond traditional risk factors

IV. PATHOPHYSIOLOGY

QUESTIONS AND ANSWERS

Answer: A A is correct. In an analysis that applied the Framingham risk equation to a population with CKD, the predicted CVD risk was similar to and not substantially higher than that of the general population,179 leading to the speculation that traditional risk factors may have a qualitatively and quantitatively different risk relationship with CVD in CKD patients compared with the general population. Several studies have demonstrated a relationship between chronic inflammation and presence of atherosclerosis and CV mortality in patients with CKD and ESRD.52,180 B is not correct. In addition to being nutritionally modulated, albumin is also a negative acute-phase protein. Ballmer et al.181 showed that proinflammatory cytokines stimulated total liver protein synthesis, but decreased albumin synthesis rate and also inhibited nutrient-induced increases in albumin synthesis C is not correct. Human skeletal muscle cells have the ability to express a variety of cytokines, including IL6.19,182 Muscle-derived IL-6 functions as an exocrine hormone, exerting its effect on the liver and adipose tissue.183 D is not correct. Cytokine production by mononuclear cells in undialyzed CKD patients and in patients treated with maintenance hemodialysis is increased.184 There is evidence that many inflammatory cytokines and chemokines play significant roles in the progression of CKD. They may be potential therapeutic targets.

Question 4 The patient returned after 3 months and had no specific complaints except fatigue. On examination he appeared pale. His blood pressure was 138/74 mm Hg. Laboratory investigations showed WBC 4.2, hemoglobin

373

7.9 g/dL. Total cholesterol 130 mg/dL. BUN 34 mg/dL, S[Cr] 3.4 mg/dL, hsCRP 5.2 mg/L. He had hypochromic microcytic anemia. Iron profile and PTH were appropriate. Which of the statement is true? A. The primary function of hepcidin is host defense against infection B. This patient will show a robust response to erythropoiesis-stimulating agents C. With EPO therapy, the patient will effectively utilize iron for hematopoiesis D. Reducing inflammation will improve EPO hyporesponsiveness in this patient Answer: D D is correct. Reducing inflammation (such as removal of a rejected kidney allograft185 or nonfunctioning arteriovenous grafts with occult infection186) and treatment directed toward reducing inflammation improve response to EPO therapy. A is not correct. In addition to its antimicrobial properties, hepcidin is the main regulator of iron metabolism and controls both the amount of dietary iron absorbed in the duodenum and iron release by reticuloendothelial cells. Elevated serum hepcidin levels in CKD may contribute to the development and severity of anemia and to resistance to erythropoiesisstimulating agents. B is not correct. EPO resistance is manifested in the presence of elevated cytokines and positive acutephase response.178 C is not correct. There is a functional iron deficiency in patients with CKD. Iron is not effectively utilized for hematopoiesis.

IV. PATHOPHYSIOLOGY