Cardiorenal syndrome: acute kidney injury secondary to cardiovascular disease and role of protein-bound uraemic toxins.

Cardiorenal Syndrome: Acute Kidney Injury Secondary to Cardiovascular Disease and Role of Protein-Bound Uremic Toxins Running Title: Cardiorenal Syndrome Suree Lekawanvijit1, Henry Krum2 1

Department of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand, and Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia. 2

Abstract Cardiovascular disease (CVD) and kidney disease are closely interrelated. Disease of one organ can induce dysfunction of the other, ultimately leading to failure of both. Clinical awareness of synergistic adverse clinical outcomes in patients with coexisting CVD and kidney disease or ‘cardiorenal syndrome (CRS)’ has existed. Renal dysfunction, even mild, is a strong independent predictor for adverse clinical outcomes in CVD patients. Developing therapeutic interventions targeting acute kidney injury (AKI) has been limited due mainly to lack of effective tools to accurately detect AKI in a timely manner. Neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 have been recently demonstrated to be potential candidate biomarkers in patients undergoing cardiac surgery. However, further validating AKI biomarkers is needed especially in the setting of acute decompensated heart failure and acute myocardial infarction where AKI commonly occurs. The other concern with regard to understanding the pathogenesis of renal complications in CVD is that mechanistically-oriented study has been relatively rare. Pre-clininal studies have shown that activation of renal inflammation-fibrosis processes, likely triggered by hemodynamic derangement, underlies CVD-associated renal dysfunction. On the other hand, it is postulated that there still are likely missing links in the heart-kidney connection in CRS patients with significant renal dysfunction. At present, nondialyzable protein-bound uremic toxins (PBUTs) appear to be the main focus in this regard. Evidence of the causal role of PBUTs in CRS has been increasingly demonstrated, mainly focusing on indoxyl sulfate (IS) and p-cresyl sulfate (pCS). Both IS and pCS are derived from colonic microbiotic metabolism of dietary amino acids, hence the colon has become a target of treatment in addition to efforts in improving dialysis techniques for better removal of PBUTs. Novel therapy targeting site of toxin production has led to new prospects in early intervention for predialysis patients with chronic kidney disease.

Keywords: Cardiorenal syndrome, acute kidney injury, protein-bound uremic toxin.

Abbreviations ADHF, acute decompensated heart failure; AhR, aryl hydrocarbon receptor; AKI, acute kidney injury; CKD, chronic kidney disease; CRS, cardiorenal syndrome; CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; FGF23, fibroblast growth factor 23; GFR, glomerular filtration rate; HF, heart failure; IL, interleukin; IS, indoxyl sulfate; KIM-1, kidney injury molecule-1; LVH, left ventricular hypertrophy; MCP-1, monocyte chemoattractant protein-1; MI, myocardial infarction; NAG, N-acetyl-β-Dglucodaminidase; NF-κB, nuclear factor-κB; NGAL, neutrophil gelatinase-associated lipocalin; NYHA,

This is an Accepted Article that has been peer-reviewed and approved for publication in the The Journal of Physiology, but has yet to undergo copy-editing and proof correction. Please cite this article as an 'Accepted Article'; doi: 10.1113/jphysiol.2014.273078. This article is protected by copyright. All rights reserved. Downloaded from J Physiol (jp.physoc.org) at CLEMSON UNIV on June 12, 2014

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New York Heart Association; PBUTs, protein-bound uremic toxins; pCS, p-cresyl sulfate; RAAS, reninangiotensin-aldosterone system; STNx, subtotal nephrectomy; TGF-β, transforming growth factor-β.

Introduction The common coexistence of cardiovascular disease (CVD) and kidney disease, the so called “cardiorenal syndrome (CRS)” or “renocardiac syndrome”, is associated with poor clinical outcomes. A bidirectional heart-kidney interaction in CRS usually leads to accelerated progression of both organ failure. Ronco et al (Ronco et al., 2008) has proposed a well-known classification of the CRS by taking the primary diseased organ and the duration of the diseased state defined as either “acute” or “chronic” into account. Type 1 or Acute CRS is defined as a rapid worsening of cardiac function, leading to acute kidney injury; type 2 or Chronic CRS as chronic abnormalities in cardiac function such as chronic heart failure (HF) causing progressive chronic kidney disease (CKD); type 3 or Acute renocardiac syndrome as an abrupt and primary worsening of kidney function such as hypoxicischemic injury, leading to acute cardiac dysfunction such as acute HF, arrhythmia and ischemia; and type 4 or Chronic renocardiac syndrome as a condition of primary CKD contributing to decreased cardiac function, ventricular hypertrophy, diastolic dysfunction, and/or increased risk of adverse cardiovascular (CV) events. An additional subtype of CRS or type 5 or Secondary CRS is defined as the presence of combined cardiac and renal dysfunction due to acute or chronic systemic disorders such as sepsis. Despite advanced progress in management of both CVD and kidney disease, specific interventions for CRS are warranted since CRS is still a burden on global health. Most patients with significant kidney disease have specifically been excluded from most clinical trials on CV interventions, although CV mortality is predominantly responsible for death of patients with CRS irrespective of the primary affected organ. In CRS when the heart is a primary diseased organ especially type 1 CRS, acute kidney injury (AKI) is highly incident and predictive of poor clinical outcomes in many serious CV conditions such as cardiac surgery, acute decompensated heart failure (ADHF) and acute myocardial infarction (MI). AKI needs timely diagnosis and management but there currently appear no satisfactorily effective tools. Clinical evaluation of AKI still depends on laboratory measurement of serum creatinine concentration. In the past, the major problem of defining AKI is lack of standard definition until two serum creatinine-based consensus criteria, the RIFLE (Bellomo et al., 2004) and the Acute Kidney Injury Network (AKIN),(Mehta et al., 2007) have been established in 2002 and 2005, respectively, and increasingly utilized for AKI diagnosis. However, serum creatinine is not a sensitive marker for detecting minor renal parenchymal damage. Recently, two large scale studies (n=2,322 and 1,635) in critically ill patients, predominantly cardiac surgery patients (n=1452), demonstrated that up to one-fifth of the cohorts having subclinical AKI earlier detected by novel kidney injury biomarkers (more specific to intrinsic AKI) but not fulfilling the RIFLE criteria (more specific to prerenal AKI or severe degree of renal parenchymal damage) are associated with a significantly increased risk for renal replacement therapy and in-hospital mortality.(Haase et al., 2011; Nickolas et al., 2012) Many candidate biomarkers for early detecting AKI have been demonstrated in the past decade and have been proposed to incorporate into the future updated AKI criteria. However, performance of individual biomarkers which can be released from other than renal sources and have different characteristic metabolism should be validated in any specific CV conditions at high risk for AKI before becoming widely used. In parallel with AKI detection, mechanistically oriented study of renal changes secondary to CVD is extremely rare despite clinical evidence of its negative impact clearly observed. This article is protected by copyright. All rights reserved. Downloaded from J Physiol (jp.physoc.org) at CLEMSON UNIV on June 12, 2014

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In CRS when the kidney as a primary diseased organ especially type 4 CRS, CKD has become a major concern worldwide due to its increasing incidence as well as high CV morbidity and mortality. There are several known CKD-specific/related, non-traditional CV risk factors underlying CV complications in the CKD population such as anemia, hypertension and abnormal calciumphosphorus homeostasis, however CV death is still high despite such risk factors being controlled. This suggests that there are still missing links. Protein-bound uremic toxins (PBUTs) are currently the main focus of the missing links due to recently emerging evidence regarding their causal role in the pathogenesis of CRS. Collectively, at this stage there appear to be knowledge gaps with regard to CRS that need to be further validated as the following: 1) lack of effective tools for early detection of AKI in specific CV conditions 2) incomplete understanding of the pathophysiology of renal changes secondary to CVD and 3) missing links between heart-kidney crosstalk (or not yet identified CRS risk factors) in CKD patients. 1. Renal complications in patients with cardiovascular disease AKI, a frequent accompaniment of CVD, is one of the strongest predictors of mortality in patients with either MI or with HF. Renal dysfunction, even mild, is associated with increased risk for long-term mortality.(Parikh et al., 2008) AKI occurs in 10-20% of hospitalized patients with acute MI.(Parikh et al., 2008) Approximately 24-45 % of these MI patients with AKI die during hospitalization that is 4.4-8.8 times higher than those without AKI.(Goldberg et al., 2005; Goldberg et al., 2009) Importantly, decline in renal function post-MI tends to progress with time.(Hillege et al., 2003) The incidence of AKI, defined as increased serum creatinine > 0.3 mg/dl according to the AKIN criteria, is 27% in patients hospitalized for worsening HF or ADHF. In HF patients, 21-43% have concomitant renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) or estimated creatinine clearance < 60 ml/min (equivalent to chronic kidney disease (CKD) stage 3 onward).(Weinfeld et al., 1999; Dries et al., 2000; Shlipak, 2003; Hillege et al., 2006) Absolute serum creatinine levels of greater than 1.5 mg/dl have been demonstrated as a risk predictor in HF patients.(McClellan et al., 2002; Akhter et al., 2004) One study has reported that every increase in serum creatinine of 0.5 mg/dl is associated with a more than 10-15% increased risk of mortality in these patients.(Smith et al., 2005) Common risk factors for AKI in CVD patients include history of MI, angina pectoris, stroke and HF, hypertension, diabetes mellitus, advanced New York Heart Association (NYHA) functional class, previous hospitalizations for HF, old age and male gender.(Dries et al., 2000; Forman et al., 2004; Adams et al., 2005; Hillege et al., 2006; Santolucito et al., 2010) Notably, approximately three quarters of patients with acute MI or ADHF develop AKI within 72 hours after admission.(Gottlieb et al., 2002; Goldberg et al., 2005; Liang et al., 2008) This is in keeping with the AKIN criteria indicating that an abrupt decline in renal function within 48 hours is associated with adverse outcomes.(Mehta et al., 2007) Although the adverse impact of renal impairment is clear, there still is no detailed guideline management specific to the CVD population with renal insufficiency. This may be explained by 3 reasons. First, 90% of major CV trials fail to provide adequate information on kidney function and only 3% have performed subgroup analysis of the intervention effects stratified by renal function.(Coca et al., 2006) Furthermore, approximately 60% of major clinical trials of CVD specifically exclude patients with kidney disease. Second, given that the clinical manifestations of renal insufficiency are a late phenomenon of kidney damage and change in creatinine levels may be influenced by factors other than kidney damage. More accurate and timely detection of kidney injury by biomarkers with better sensitivity and specificity could lead to progression in developing more timely therapeutic interventions to combat AKI. Last, there still is a wide knowledge gap in

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terms of basic pathophysiological mechanisms of renal insufficiency secondary to CVD that links to the clinical manifestations. 1.1. Acute kidney injury biomarkers in patients with cardiovascular disease AKI is simply divided into 2 types: intrinsic and prerenal. Intrinsic AKI is associated with injured renal cells which may abnormally secret cellular substances into the urine [such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule (KIM)-1, interleukin (IL)-18, N-acetylβ-D-glucodaminidase (NAG) and liver fatty acid-binding protein (LFABP)] or lose ability to reabsorb filtered substances such as cystatin C. Urinary concentrations of these substances are therefore potentially being candidate biomarkers for early detecting intrinsic AKI, and may also reflect the degree of renal parenchymal damage. Whilst prerenal AKI is associated with reduced glomerular filtration, mostly contributory to a decompensation response of the kidney to hemodynamic derangements such as reduced renal blood flow and increased venous pressure. Biomarkers for detecting prerenal AKI are usually circulating substances such as creatinine and cystatin C which ideally should be freely filtered through the glomeruli without renal tubular excretion. Increased circulating levels of these substances may reflect renal damage if the degree of damage is high enough to cause defective glomerular filtration. Serum creatinine is a glomerular filtration marker (but not an ideal one as it is also excreted from the renal tubule) traditionally used to evaluate renal function. However, there has been growing evidence that it is not sensitive and specific enough to detect early renal parenchymal damage/injury. Elevation of serum creatinine levels above the "normal range" occurs after a substantial amount of functioning kidney tissue has been lost. Minor effects on renal parenchyma are difficult to detect due to the functional reserve capacity of the kidney. Furthermore, serum creatinine is not an accurate marker of glomerular filtration rate (GFR) in the nonsteady-state condition of AKI.(Thadhani et al., 1996) In most CV studies, an increase in serum creatinine > 0.3 mg/dl is widely used as the criteria for diagnosis of AKI, this increase has been demonstrated to have satisfactory sensitivity (81%) and specificity (62%) to predict mortality in patients hospitalized for HF.(Gottlieb et al., 2002) A study in ADHF patients demonstrated that decline in estimated GFR (eGFR), defined as a > 20% reduction of eGFR calculated by the Modified Diet and Renal Disease equation, and a > 0.3 mg/dl increased serum creatinine level are both predictive of mortality. However, mortality prediction of an increase in creatinine, but not decline in eGFR, is dependent of baseline renal function.(Testani et al., 2010) This study has raised concern in interpretation of change in creatinine levels in heterogenous populations with different baseline renal function. In fact, both serum creatinine and creatinine-based eGFR are affected by many confounding factors such as age, gender, race, sex, protein intake, muscle mass and underlying illness. Serum cystatin C is also a glomerular filtration marker. Cystatin C is produced from all nucleated cells at a constant rate.(Filler et al., 2005) It is solely and freely filtered through the glomeruli without tubular excretion then completely reabsorbed and catabolized by the proximal tubular cells thereby normally not being excreted into the urine and not returning to the circulation. Thus, circulating cystatin C appears to be a more ideal and reliable filtration marker than serum creatinine. Compared to serum creatinine, serum cystatin C has been demonstrated to 6 hour-to-2 day earlier detect AKI in various settings (Herget-Rosenthal et al., 2004; Nejat et al., 2010) including acute MI,(Fouad & Boraie, 2013) and to be more strongly predictive of mortality and CV events in the elderly.(Shlipak et al., 2005) Serum cystatin C levels are associated with left ventricular hypertrophy (LVH) and diastolic dysfunction in patients with known coronary artery disease.(Ix et al., 2006) In addition, cystatin C is less likely to be affected by age, gender, height and muscle mass than creatinine (Filler et al., 2005) but its circulating levels may be altered in inflammatory state.(Keller et al., 2007) Estimating GFR from serum cystatin C has been demonstrated to be at least equally accurate (Tidman et al., 2008) to creatinine-based eGFR but superior in specific patient groups such as children, the elderly, and patients with reduced muscle mass.(Filler et al., 2005) However, measurement of cystatin C level is more expensive and not normally available compared to This article is protected by copyright. All rights reserved. Downloaded from J Physiol (jp.physoc.org) at CLEMSON UNIV on June 12, 2014

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creatinine; it is crucial to standardize the test and to validate the cystatin C-based eGFR equation before it becomes widely used.(Tidman et al., 2008) It is noteworthy that use of serum cystatin C for detecting AKI in the setting of CRS needs special attention because high cystatin C levels have been significantly observed in atherosclerosis-associated CVD, independently of GFR.(Salgado et al., 2013) Urinary concentrations of biomarkers directly released from injured renal cells into the urine are likely to be more sensitive and specific for early detection of intrinsic AKI as well as quantitative to the degree of kidney injury, mainly specific to tubular damage, compared to the filtration markers. Most are enzymes or intracellular or transmembrane proteins. Potential biomarkers include NGAL, KIM-1, IL-18, NAG and LFABP. Given that filtered cystatin C is not normally present in the urine, urinary cystatin C may be also considered as a biomarker for early renal (proximal tubule) dysfunction/injury. Elevated urinary cystatin C levels have been demonstrated to differentiate intrinsic AKI from prerenal AKI and have a graded association with AKI severity,(Park et al., 2013b) whilst serum cystatin C can better distinguish between AKI and non-AKI.(Soto et al., 2010) Among biomarkers of intrinsic AKI, KIM-1 appears to be an only biomarker originating from renal proximal tubular cells whilst cystatin C is from all nucleated cells but filtered cystatin C is reabsorbed by tubular cells as previously mentioned. NGAL, NAG and LFABP are also produced from other specific sources than renal tubular cells such as leukocytes (NGAL), liver cells (NAG, LFABP) and brain (NAG).(Vanmassenhove et al., 2013) IL-18 is mainly derived from monocytes/macrophages but can be secreted by epithelial cells including renal proximal tubular cells.(Charlton et al., 2014) Study of these novel AKI biomarkers, predominantly utilizing their urinary concentrations, in CRS is usually conducted in specific CV conditions as the following. Cardiac surgery: Post-cardiac surgery appears to be the most common CV setting that biomarkers of AKI have been investigated. The incidence of post-op AKI defined by the RIFLE criteria is 15-23% in adults and 35-49% in children undergoing cardiac surgery.(Haase et al., 2011) NGAL and KIM-1 are the two biomarkers which perform best as an AKI diagnosis after cardiac surgery compared to cystatin C, interleukin (IL)-18, N-acetyl-β-D-glucodaminidase (NAG) and liver fatty acidbinding protein,(Thurman & Parikh, 2008; McIlroy et al., 2010) where AKI is defined by a 50% increase in serum creatinine. Urinary, and serum to a lesser extent, NGAL has high accuracy early post-cardiac surgery especially at 2-4 hours, and sharply declines after 12 hours, whilst urinary KIM-1 has high accuracy after 12 hours. NGAL is particularly advantageous to pediatric cardiac surgery patients for highly accurate prediction of AKI. A better performance of urinary than serum NGAL has also been demonstrated in most studies,(Mishra et al., 2005; Koyner et al., 2008; Tuladhar et al., 2009; Parikh et al., 2011b) but less pronounced (Parikh et al., 2011a) or reverse (Koyner et al., 2012) in some studies. Interestingly, elevated urine and/or plasma NGAL levels in the absence of AKI diagnosed by RIFLE criteria, the so-called subclinical AKI, is associated with a 16.4-time higher risk than normal NGAL levels for subsequent renal replacement therapy in a study of 2,322 critically ill patients with predominantly cardiac surgery patients (63%).(Haase et al., 2011) Whether a vivid increase in circulating NGAL concentration post-cardiac surgery is mainly back-leakage from renal tubular reabsorption of urinary NGAL is not known. To our knowledge, none of studies investigating both circulating and urinary NGAL concentrations in cardiac surgery population report a correlation between both parameters.(Mishra et al., 2005; Koyner et al., 2008; Tuladhar et al., 2009; Krawczeski et al., 2011; Parikh et al., 2011a; Koyner et al., 2012) Interestingly, the duration on cardiopulmonary bypass during cardiac surgery is not only a risk factor of post-op AKI (Mishra et al., 2005; Parikh et al., 2011a; Parikh et al., 2011b; Koyner et al., 2012) but also induces leukocyte activation.(Edmunds, 1998) Activated leukocytes can be a source of massive NGAL release into the circulation which may have effects (still unknown) on the performance of serum NGAL on post-cardiac surgery AKI prediction. ADHF: Unlike cardiac surgery patients, performance of urinary NGAL in early detection of AKI does not appear to be very promising in patients with ADHF. One study reported that both urine


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and serum NGAL levels are predictive of AKI defined as a serum creatinine increase > 0.3 mg/dl within 5 monitoring days in hospitalized ADHF patients (n=93).(Shrestha et al., 2012) A modest correlation between urinary and serum NGAL levels have been demonstrated and high urinary NGAL levels are associated with impaired natriuresis and diuresis during the 24-hour period after initiation of diuretic therapy reflecting distal tubular injury/dysfunction in ADHF patients.(Shrestha et al., 2012) Another study (n=141) demonstrated a significant difference in urinary NGAL levels between ADHF patients with and without AKI only on day 3 which is later than AKI detected by the AKIN criteria, increased serum creatinine > 0.3 mg/dl within 48 hours.(Dupont et al., 2012) However, a marginal rise in urinary NGAL preceding AKI was observed. No association between urinary NGAL and KIM-1 concentrations and recovery from AKI has been recently reported.(Park et al., 2013a) A further study in 83 patients hospitalized for ADHF showed that all urinary NGAL, KIM-1 and IL-18 are inadequately sensitive/specific to predict AKI when AKI in this study is defined as a ≥25% decrease in eGFR during days 1-5.(Verbrugge et al., 2013) In contrast, urinary IL-18 is predictive of persistent renal impairment (defined as persistently increased serum creatinine > 0.3 mg/dl for 6 months) and all-cause mortality (average follow-up 7 ± 4 months).(Verbrugge et al., 2013) With the limited number of studies that utilize a variety of referenced AKI criteria and tested biomarkers, currently available data appear not sufficient for pooled analysis of (intrinsic AKI) biomarker performance in ADHF patients. Of note, urine concentrations of NGAL, the most extensively investigated biomarker, seem to be only slightly higher in ADHF patients with AKI than healthy subjects but rather low compared with AKI from other causes such as post-cardiac surgery. Together with the reported performance of intrinsic AKI biomarkers in these patients, it is suggesting that prerenal AKI is likely predominant in ADHF and possibly related to either reduced renal blood flow or increased systemic venous pressure. In addition, baseline NGAL levels of ADHF patients can be increased in association with common comorbidities such as elevated urinary NGAL levels in diabetes and hypertension and increased serum NGAL levels in old age.(Shrestha et al., 2012) Chronic HF: Studies on kidney injury biomarkers in patients with stable chronic HF mainly evaluate their ability to predict clinical outcomes rather than AKI. Urinary NAG, KIM-1 and NGAL concentrations are increased in chronic HF patients.(Damman et al., 2010) A further study (n=2,130) demonstrated an independent association between these biomarkers and the composite of all-cause mortality and HF hospitalization (Damman et al., 2011) while two smaller-scale studies reported this association for urinary KIM-1 and NAG, but not NGAL.(Damman et al., 2010; Jungbauer et al., 2011) High urinary KIM-1 and NAG concentrations are also significantly correlated with decreased LV function and worsened NYHA functional class.(Jungbauer et al., 2011) In addition, one study demonstrated a significant elevation of serum NGAL concentrations in stable HF patients (n=150) with normal serum creatinine levels and an increase in NGAL protein expression within failing myocardial tissue, suggesting that increased serum NGAL concentrations may not only reflect impaired renal function in chronic HF.(Yndestad et al., 2009) Only NAG is correlated with measured GFR ([125I] iothalamate) and effective renal plasma flow.(Damman et al., 2010) MI: To our knowledge, there have been no clinical studies comparing performance on AKI prediction among novel kidney injury biomarkers in patients with acute MI. However, a few studies have examined kidney injury biomarkers in post-MI animal models. An in vivo time-course (3 day and 4, 8 weeks) study in a rat MI model demonstrated a significant increase in serum and urinary NGAL at day 3 and week 2, but not at weeks 4 and 8, post-MI.(Cho et al., 2013) However, a significant increase in circulating activated monocytes observed on day 3 post-MI as well as an inflammatory reaction in infarcted myocardium may be also sources of serum NGAL.(Cho et al., 2013) In a different time-course in vivo (1, 4, 8, 12, 16 weeks) MI study, renal KIM-1 protein expression significantly increased at 1 week post-MI. KIM-1 expression declined at 4 weeks and then gradually increased to reach significance at 12 and 16 weeks in association with development of renal fibrosis.(Lekawanvijit et al., 2012c) An increase in renal tubular KIM-1 protein expression (1 This article is protected by copyright. All rights reserved. Downloaded from J Physiol (jp.physoc.org) at CLEMSON UNIV on June 12, 2014

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and 12-16 weeks) occurred earlier but was associated with a biphasic pattern of reduced GFR postMI (1-4 weeks and 16 weeks). Interestingly, an obvious increase in renal KIM-1 expression at 1 week post-MI was associated with a significantly decrease in systolic blood pressure and measured GFR, suggesting that KIM-1 may reflect renal tubular injury contributed to by hemodynamic derangements post-acute MI. An association between renal dysfunction and increased renal KIM-1 expression has been confirmed in a further 16-weeks post-MI animal study.(Lekawanvijit et al., 2013) A significant increase in both urinary NGAL and KIM-1 concentrations measured at day 5 postacute MI has been demonstrated in a rat MI model then back to sham level on follow-up day 30.(Entin-Meer et al., 2012) In the same study, a significantly higher-than-sham level of both urinary biomarkers was persistently observed in a rat CKD model until the study endpoint (9 weeks postsubtotal nephrectomy) but significantly less than the level on day 5 post-insult, suggesting that urinary NGAL and KIM-1 may have some role in assessing renal damage in the CKD setting. The currently use criteria for AKI were initially established based on simple markers for the prime purpose of generating a universal consensus despite awareness of their clinical weakness. Increasing evidence of novel early kidney injury biomarkers is promising especially in AKI caused by primary kidney disease. However, use of these kidney injury biomarkers for early detection of AKI in common CV conditions needs to be further validated. 1.2. Pre-clinical study of renal changes following cardiovascular disease Pre-clinical study on mechanisms of renal impairment secondary to CVD is mainly conducted in an experimental model of either cardiac dysfunction alone or combined cardiorenal dysfunction for investigating incipient renal changes and further worsening of the kidney, respectively. Study of incipient renal changes is mostly conducted in a rat MI model induced by left anterior descending coronary artery ligation. Renal interstitial fibrosis with a mild reduction in GFR has been demonstrated in association with systolic dysfunction without changes in BP at 3 weeks post-MI.(Martin et al., 2007) Significant renal gene dysregulation related to cell proliferation, metabolic processes, and cell communication was detected by microarray analysis. The mechanisms underlying such changes, however, were not described. A time-course study of renal changes was systematically investigated at 1, 4, 8, 12 and 16 weeks following MI in a rat MI model.(Lekawanvijit et al., 2012c) Renal dysfunction determined by measured GFR was observed in a biphasic pattern, first at 1 and 4 weeks with a function restored then and again declining at 16 weeks. Reduced GFR at 1 week post-MI was associated with a significant decrease in systolic BP, suggesting a contributing role of hemodynamic disturbance to early renal dysfunction. Inflammatory activation in the kidney was detected at 1 week by an increase in renal macrophage infiltration, IL-6 mRNA expression and transforming growth factor-β (TGF-β) protein expression. Renal interstitial fibrosis, predominantly at the cortex-tocorticomedullary junction area, mediated by the Smad-associated pathway was demonstrated at 4 weeks onward, maximum at 16 weeks when the second decline in GFR was observed, suggesting that progressive renal fibrosis may contribute to late renal dysfunction. Progressively increased albuminuria following MI despite no significant difference from sham levels may reflect intrinsic renal injury. A similar trend of early decline in renal function (3 days post-MI) in association with decreased systolic BP, increased renal expression of pro-inflammatory cytokines (TGF-β, IL-1β and vascular cell adhesion molecule 1) followed by progressive renal fibrosis has been demonstrated in a 3 week MI mouse study.(Lu et al., 2012) A recent time-course (3 days and 4, 8 weeks) MI rat study has demonstrated a significant decrease in systolic BP 1 day post-MI and a significant increase in circulating activated monocytes on day 3 post-MI, accompanied by an increase in renal macrophage infiltration, renal expression of nuclear factor-κB (NF-κB) and renal inflammatory cytokine gene (IL-1, IL-6 and tumor necrosis factorα) expression. Renal interstitial fibrosis, mainly at the corticomedullary junction was observed at 4 and 8 weeks post-MI that was significantly reversed by use of liposomal clodronate to deplete This article is protected by copyright. All rights reserved. Downloaded from J Physiol (jp.physoc.org) at CLEMSON UNIV on June 12, 2014

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circulating activated monocytes.(Cho et al., 2013) Interestingly, post-MI (3 and 9 weeks) renal inflammation and tubular necrosis and fibrosis in association with increased blood cystatin C levels are all attenuated by angiotensin II type 1 receptor blocker losartan.(Wen et al., 2013) Whether infarct size, usually determined by a fraction of the infarcted and non-infarcted endocardial and epicardial lengths at mid-left ventricular cross section and expressed as a percentage, has effects on timing of incipient renal changes is not clear. With an equal average MI size of 34%, Windt et al (Windt et al., 2008) did not see any renal structural pathology while Bongartz et al (Bongartz et al., 2012) reported mild glomerulosclerosis at 6 weeks post-MI. The above 1, 4, 8, 12 and 16 weeks time-course study with larger average MI sizes of 46, 44, 45, 42 and 41, respectively, reported significant tubulointerstitial inflammation or fibrosis in all time points post-MI.(Lekawanvijit et al., 2012c) By contrast, 12 weeks post-MI rats with a large average MI size of 54.2% demonstrated significant renal dysfunction without significant renal structural changes in both glomeruli and tubulointerstitium,(Bauersachs et al., 2000) whereas only renal structural change without renal dysfunction was observed in 12 and 14 weeks MI rats with smaller infarct sizes (42% and 35%).(Lekawanvijit et al., 2012c; Liu et al., 2013) One study with a modest MI size (18.1%) however showed a significant renal dysfunction at 16 weeks post-MI rats, despite using plasma creatinine levels for assessment, in association with significantly renal interstitial damage and increased number of glomerular macrophage infiltration.(van Dokkum et al., 2004) Method of renal structural assessment varies across studies from mainly semiquantitative assessment by human,(Bauersachs et al., 2000; Windt et al., 2008; Bongartz et al., 2012) to quantitative assessment by human and digital image analysis program.(van Dokkum et al., 2004; Lekawanvijit et al., 2012c; Liu et al., 2013) Renal changes following MI are generally minimal therefore likely more sensitive to be detected by quantitative methods. In summary, early renal dysfunction post-MI can be reversible due at least in part to transient hemodynamic derangement (decreased systolic BP). Whilst this transient functional impairment is likely a reflection of prerenal AKI, the process of intrinsic renal damage associated with inflammatory activation occurs simultaneously and tends to be persistent and progressive to fibrogenesis process. Renal structural changes following acute MI are predominantly located around the corticomedullary junction, the region most vulnerable to ischemic injury due to reduced renal blood flow. Renal fibrosis tends to progress over time, ultimately contributing to late renal dysfunction. Renal inflammation and fibrosis might be mediated via the TGF-β/Smad/NF-κB pathway in association with activation of the renin-angiotensin-aldosterone system (RAAS). Thus, interventions with an anti-inflammatory effect or RAAS blockade may prevent progression of renal fibrosis and late renal dysfunction. Study of further renal changes by superimposed CV events in the setting of CKD has also been investigated in combined cardiorenal dysfunction models mostly induced by either unilateral or 5/6-subtotal nephrectomy (5/6-STNx) followed by left anterior descending coronary artery ligation. These models represent all stages of CKD patients who are considered at high risk for CV death irrespective of the severity of renal dysfunction.(Levey, 1998) In unilateral nephrectomized rats, MI further impairs renal function determined by plasma creatinine and proteinuria as well as renal structural changes including glomerular inflammation, sclerosis and interstitial damage compared with unilateral nephrectomized rats without MI.(van Dokkum et al., 2004) Larger infarct size is associated with a higher degree of additional proteinuria and sclerotic glomeruli. Another study demonstrated that rapidly progressive proteinuria and striking renal interstitial injury (mainly confined in the cortex and outer medulla) observed in unilateral nephrectomy plus MI rats is mediated via angiotensin II type 1a receptor and alleviated by blockade of this receptor.(Homma et al., 2012) In a more severe renal failure model of 5/6-STNx, superimposed MI results in a significant decrease in systolic BP from 2 weeks post-MI onward but does not further reduce creatinine


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clearance.(Bongartz et al., 2012) Compared with 5/6-STNx alone, only worsened glomerulosclerosis in association with a lower urinary excretion of nitric oxide metabolites was significantly lower in 5/6-STNx+MI rats.(Bongartz et al., 2012) By contrast, another study showed further decline in creatinine clearance without further renal damage (proteinuria and glomerulosclerosis), and the renoprotective effects of angiotensin converting enzyme inhibitor observed in 5/6-STNx rats do not have additional beneficial renal effects in 5/6-STNx+MI animals.(Windt et al., 2008) Combined 5/6STNx+MI animals in these two studies, Bongartz et al.(Bongartz et al., 2012) and Windt et al.(Windt et al., 2008), have comparable follow-up period (6 weeks post-MI) and infarct size (34% vs 39%), and renal structural assessment is both mainly based on semiquantitative methods. Only obvious difference is an interval period between 5/6-STNx and MI surgery. Renal damage from 5/6-STNx may not fully develop that possibly obscures smaller renal changes secondary to superimposed MI performed at 2 weeks after 5/6-STNx in the former study but may fully develop in the latter performing 9 week interval between the two insults.

2. Cardiovascular complications in patients with kidney disease: uremic toxins as a potential missing link in cardiorenal connection High prevalence of CVD is responsible for approximately half of all deaths in the renal failure population.(USRDS, 2007) CV mortality is 10-30 times higher in dialysis patients than in the general population.(Sarnak et al., 2003) In addition, CKD patients have a greater risk for CV events and mortality than progression to end-stage renal disease (ESRD).(Keith et al., 2004) In the CKD population, HF is the most common clinical presentation of CVD whilst left ventricular hypertrophy (LVH), a surrogate of uremic cardiomyopathy, is predictive of CV mortality. Sudden cardiac death, HF and MI are three most common causes of cardiac death respectively.(USRDS, 2012) Despite the high incidence of accelerated atherosclerosis and MI as well as the high mortality post-acute MI,(Lindner et al., 1974) only 15-25% of cardiac deaths in CKD population are attributable to ischemic heart disease half of which are angiographically negative for significant coronary atherosclerosis.(Rostand et al., 1984) Cardiac interstitial fibrosis (a crucial component of uremic cardiomyopathy) and non-obstructive vascular diseases (such as vascular stiffness, calcification and ossification) are predominant CV pathology in CKD patients; both are hypertension-independent (Amann et al., 1995; Glassock et al., 2009) and may contribute to the high incidence of sudden cardiac death and ischemic heart disease in the absence of significant coronary atherosclerosis. Importantly, traditional CV risk factors are insufficient to explain the extraordinarily high prevalence of CVD in the CKD population. CKD-specific/related risk factors such as anemia, hypertension and abnormal calcium-phosphorus homeostasis have been demonstrated to be closely associated with CV pathology and mortality; however death due to CV complications is still predominant even these risk factors have been corrected. This is highly suggesting that there are still missing links regarding the heart-kidney connection (Figure 1) in the setting of CRS. Despite tremendous advances in the development of dialysis technology, CV mortality is still unacceptably high in dialysis patients compared with renal transplantation patients.(USRDS, 2012) Whilst LVH gradually regresses after transplantation,(Gross & Ritz, 2008) progression of LVH persists in long-term hemodialysis patients (London et al., 2001; Zoccali et al., 2004) even if hypertension and anemia are controlled.(London et al., 2001) Such collective data have drawn attention to nondialyzable uremic toxins as a potential further link in kidney-heart interactions. Protein-bound uremic toxins (PBUTs) are currently the main focus due to recent emerging evidence regarding their causal role in the pathogenesis of CRS (for review, see (Lekawanvijit et al., 2012b)).


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2.1. Role of protein-bound uremic toxins in CRS Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are two most extensively studied PBUTs with regard to their contribution to the pathogenesis and progression of CRS. Both are associated with renal progression as well as increased CV and all-cause mortality.(Barreto et al., 2009; Liabeuf et al., 2010; Wu et al., 2011; Wu et al., 2012) Pre-clinical studies have demonstrated their causative effects on CV and renal pathology which includes renal inflammation and fibrosis, increased cardiac protein and collagen synthesis and endothelial dysfunction.(Dou et al., 2007; Meijers et al., 2009; Lekawanvijit et al., 2012b; Neirynck et al., 2012) IS is implicated in vascular calcification and ossification (Muteliefu et al., 2009; Adijiang et al., 2010) that is commonly found in advanced stage CKD patients and associated with poor CV outcomes.(Aoki et al., 2005; Guerin et al., 2006) In addition, IS also enhances oxidative stress in kidney,(Owada et al., 2008; Tumur & Niwa, 2008) heart(Fujii et al., 2009; Lekawanvijit et al., 2012a) and endothelial cells.(Dou et al., 2007; Yu et al., 2011) Cardiorenal fibrosis induced by IS is potentially mediated via the ROS/NF-κB/TGF-β1 pathway. Recently, serum IS levels have been demonstrated in vivo to be positively correlated with renal KIM1 expression in a chronic MI model with consequent renal dysfunction and fibrosis.(Lekawanvijit et al., 2013) Of note, there still have been no report on direct evidence of renal and/or CV dysfunction induced by PBUTs. Most studies on PBUTs in CRS merely document an association. Serum IS, but not pCS, levels have been recently demonstrated to be independently correlated with serum fibroblast growth factor 23 (FGF23) levels in stages 3-5 CKD patients.(Lin et al., 2013) Elevated serum levels of FGF23 are usually observed in CKD patients. FGF23 normally acts on the kidney and parathyroid gland through FGF receptor in the presence of Klotho coreceptor to enhance phosphaturia, inhibit renal 1-α hydroxylase thereby reducing vitamin D production, and suppress parathyroid hormone secretion. Decline in Klotho expression usually observed with the progression of CKD contributes to an compensatory elevation of FGF23 levels however FGF23 fails to regulate phosphorus, vitamin D and parathyroid hormone without klotho,(Kuro-o, 2012) leading to typical CKD manifestations such as hyperphosphatemia, secondary hyperparathyroidism and bone disease. Elevated serum FGF23 levels are not only associated with progression to ESRD (Isakova et al., 2011) but also increasing risk for new-onset LVH and mortality in predialysis CKD patients.(Faul et al., 2011) Although FGF23-associated CV pathology in the setting of CKD can be explained by cardiovascular toxicity of hyperphosphatemia (Amann et al., 2003) and hyperparathyroidism,(Gross & Ritz, 2008) FGF23 itself has been demonstrated in vivo and in vitro to directly induce LVH through FGF receptor-dependent calcineurin-NFAT signaling pathway which is independent of Klotho coreceptor.(Faul et al., 2011) This indicates that normal mineral regulatory function of FGF23 is shifted to cardiovascular toxicity in the state of Klotho deficiency. Whether IS and FGF23 are mechanistically interrelated in the pathophysiology of CRS is not known. However, recent data indicate that PBUTs are implicated in Klotho deficiency. Exogenous IS and pCS both can directly induce renal fibrosis, suppress renal Klotho protein and mRNA expression, and promote DNA hypermethylation of Klotho gene in association with increased expression of DNA methyltransferase 1 in the absence of a reduction in GFR in a mildly function-compromised CKD model.(Sun et al., 2012a) Reduced Klotho protein expression by IS or pCS is prevented by administration of an oral adsorbent, AST-120.(Adijiang & Niwa, 2010) ROS and NF-κB have been demonstrated to be involved in the mechanism of IS-reduced Klotho protein and mRNA expression in the kidney.(Shimizu et al., 2011) This suggests that Klotho might be involved in PBUT-induced renal fibrosis mediated via the ROS/NF-κB/TGF-β1 pathway. In addition, renal fibrosis induced by IS or pCS is associated with activation of the renal RAAS and epithelial-to-mesenchymal transition of renal tubular cells. Inhibition with losartan significantly reduces renal fibrosis, suppresses activation of the Smad-dependent TFG-β1 pathway and restores the epithelial phenotype of renal tubular cells in unilateral nephrectomy-mice administered with either IS or pCS.(Sun et al., 2012b) Thus, the


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potential pathway of PBUT-induced (more specific to IS) renal fibrosis is likely to be the ROS-NF-κBKlotho/Smad-dependent TGF-β1 pathway. It is noteworthy to further investigate effects of RAAS blockade on PBUT-associated CV pathology that could be performed either in cultured cardiac cells stimulated with PBUTs, experimental CRS models, or in CRS patients with established renal dysfunction by analysis of CV endpoints in associated with IS concentrations. Klotho deficiency also plays a role in IS-induced endothelial cell dysfunction. Increased ROS production, reduced nitric oxide (NO) and decreased cell viability observed in endothelial cells stimulated with IS are attenuated by Klotho protein.(Yang et al., 2012) Recently, aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor mediating cellular adaptive and toxic responses, has been demonstrated to be activated by IS.(Schroeder et al., 2010) Stimulation of human umbilical vein endothelial cells with IS results in enhanced oxidative stress and increased expression of AhR target genes and monocyte chemoattractant protein-1 (MCP-1).(Watanabe et al., 2013) Administration of AhR antagonists inhibits the IS-induced increase in MCP-1 expression in a dose dependent manner.(Watanabe et al., 2013) Both IS and pCS are derived from colonic microbiotic metabolism of dietary amino acids tryptophan and tyrosine, respectively.(Aronov et al., 2011) Novel therapy targeting site of the toxin production has opened the prospect for reducing levels of such PBUTs in pre-dialysis CKD (and potentially CVD) patients. Given that CKD patients are at greater risk for CV mortality than progression to dialysis-dependent ESRD,(Keith et al., 2004) such interventions may be beneficial in improving IS/pCS-associated CV pathology and outcomes. Strategies include low protein diet, probiotic and prebiotic treatment and use of oral adsorbents. Trials of probiotic and/or prebiotic treatments to maintain normal colonic microbiotic homeostasis demonstrate promising results in improving renal function and quality of life in predialysis CKD patients.(Ranganathan et al., 2010) However, beneficial CV endpoints have never been studied. A strict low protein diet decreases serum IS level in predialysis CKD patients (Marzocco et al., 2013) but it has raised concerns regarding protein malnutrition in this setting. The therapeutic role of an oral adsorbent, AST-120, in reducing colon-derived PBUTs has been widely investigated. Renoprotective effects of AST-120 are observed at various stages of CKD in both patients with and in experimental models of CKD, mostly demonstrated in association with an IS-lowering effect. A multicenter, randomized, controlled trial has demonstrated a beneficial effect of AST-120 on preservation of renal function in predialysis CKD patients (n=460),(Akizawa et al., 2009) although there was no difference in incipient dialysis or survival between treated and control groups due mainly to infrequent events over the 1-year treatment duration. Preliminary results from two large-scale trials (Evaluating Prevention of Progression In Chronic Kidney Disease, EPPIC) showed no benefits on study endpoints comprising time to initiation of dialysis, doubling serum creatinine levels and death, however a reduction in CKD progression was observed in high risk (proteinuria and hematuria) patients with good compliance.(Schulman et al., 2014) The potential benefit of AST-120 on CV protection has been recently demonstrated, for example, in preventing cardiac fibrosis in CKD rats,(Fujii et al., 2009; Lekawanvijit et al., 2012a) and limiting or stabilizing atherosclerotic plaque in CKD mice with apolipoprotein E-deficiency.(Yamamoto et al., 2011) In predialysis CKD patients, AST-120 improves parameters of endothelial dysfunction,(Yu et al., 2011) vascular stiffness(Nakamura et al., 2004) and calcification,(Goto et al., 2013) and may be beneficial on delaying progression of LVH.(Nakai et al., 2011) Study of AST-120 on both CV and renal endpoints is however very rare.


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Conclusions Renal impairment is a strong independent risk factor associated with poor prognosis in CVD patients. Renal dysfunction is likely contributed by progressive renal structural damage. Accurate detection of kidney injury in a timely manner as well as increased knowledge of the pathophysiology and mechanisms underlying this injury is of great importance in developing therapeutic interventions for combating renal complications at an early stage. Regarding the role of uremic solutes in the pathophysiology of CRS, a number of further studies are warranted. There may be uremic solutes discovered from proteomics not yet chemically identified or tested for biological activity. Beyond PBUTs, uremic solutes in other classes (according to the European Uraemic Toxin Work Group (EUTox) classification) (Vanholder et al., 2003) may have adverse cardiorenal effects. Although, most small water-soluble solutes and middle molecules can be satisfactorily removed by either conventional or newly-developed dialysis strategies, targeting uremic toxins with cardiorenal toxicity at predialysis stage CKD may retard or prevent incident dialysis as well as the initiation/progression of CRS.

Completing interests There are no competing interests.

Funding This work was supported by National Health and Medical Research Council of Australia (Program Grants 334008 and 546272) and Thailand Research Fund (MRG568079).


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Figure 1 Pathophysiology of cardiorenal syndrome

CRS, cardiorenal syndrome; CVD, cardiovascular disease; HF, heart failure; GFR, glomerular filtration rate; Ca-P, calcium and phosphorus; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system.


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Uraemic toxins and cardiovascular disease across the chronic kidney disease spectrum: an observational study.

Cardiorenal syndrome: role of protein-bound uremic toxins.

Cardiorenal syndrome in chronic kidney disease.

The Influence of Acute Kidney Injury on Acute Cardiovascular Disease.

Hyperuricemia and acute kidney injury secondary to spontaneous tumor lysis syndrome in low risk myelodysplastic syndrome.

The Role of Acute Kidney Injury in Chronic Kidney Disease.

When cardiac failure, kidney dysfunction, and kidney injury intersect in acute conditions: the case of cardiorenal syndrome.

The acute cardiorenal syndrome: burden and mechanisms of disease.

Role of Bile Acid-Regulated Nuclear Receptor FXR and G Protein-Coupled Receptor TGR5 in Regulation of Cardiorenal Syndrome (Cardiovascular Disease and Chronic Kidney Disease).

Acute kidney injury and chronic kidney disease.

Pseudo-acute kidney injury secondary to intravenous dexamethasone.

Eculizumab in secondary atypical haemolytic uraemic syndrome.

Acute kidney injury: gateway to chronic kidney disease.

Cardiovascular complications in atypical haemolytic uraemic syndrome.

Acute coronary syndrome and acute kidney injury: role of inflammation in worsening renal function.

Diabetic kidney disease and the cardiorenal syndrome: old disease, new perspectives.

Acute Kidney Injury and Cardiorenal Syndromes in Pediatric Cardiac Intensive Care.

The Role of M2 Macrophages in the Progression of Chronic Kidney Disease following Acute Kidney Injury.

Pathophysiology of cardiorenal syndrome in decompensated heart failure: role of lung-right heart-kidney interaction.

Acute kidney injury and chronic kidney disease as interconnected syndromes.

The link between acute kidney injury and chronic kidney disease.

Obstructive sleep apnea syndrome and chronic kidney disease: a new cardiorenal risk factor.

Cardiorenal syndrome and vitamin D receptor activation in chronic kidney disease.

PROGRESSION OF CHRONIC KIDNEY DISEASE AFTER ACUTE KIDNEY INJURY.