Snyder

CRS Objectives

Definitions & classification Pathophysiology Biomarkers Management Fluid management Emerging therapies

Tower of Babel

CRS Defined

Condition characterized by kidney failure and heart failure; the failing organ precipitates failure in the other; the bidirectional interaction of these organs can create a nexus of deterioration of both

CRS Classification

Type 1: Acute worsening of heart function leading to kidney injury

Type 2: Type 3: Type 4: Type 5:

Ronco C et al. Eur Heart J. 2010;31:703-11.

Cardiorenal Syndromes Update 2012

Samuel Snyder, D.O. [email protected]

Cardiorenal Syndrome Update 2012

Samuel Snyder, D.O. [email protected]

CRS Type 1 Ronco et al. JACC, 4 Nov 2008.52(19):1527-39.

CRS Classification


Type 2: Chronic abnormalities of heart function leading to kidney injuries or dysfunction

Type 3: Type 4: Type 5:


CRS Classification



Type 3: Acute worsening of kidney function leading to heart injury or dysfunction

Type 4: Type 5:


CRS Classification



Type 3: Acute worsening of kidney function leading to heart injury or dysfunction

Type 4: Chronic kidney disease leading to heart injury, disease or dysfunction

Type 5:


CRS Classification Type 1: Acute worsening of heart function leading

to kidney injury Type 2: Chronic abnormalities of heart function

leading to kidney injuries or dysfunction Type 3: Acute worsening of kidney function

leading to heart injury or dysfunction Type 4: Chronic kidney disease leading to heart

injury, disease or dysfunction Type 5: Systemic conditions leading to

simultaneous injury or dysfunction of heart and kidney


Type 1 CRS Update

Ronco C, JACC.2012.01.077.

Serum Creatinine as Biomarker in CRS

versus

Dont we measure renal function with Serum Creatinine?

PresenterPresentation NotesGFR is more predictive than LV dysfunction in patients with HF, however, no single test accurately reflects renal function.

Association between S Cr and other renal biomarkers

Iyngkaran P et al, Semin Nephrol. Jan 2012,32:3-17.

PresenterPresentation NotesChronologic association of SCr and novel biomarkers in predicting renal insufficiency. (A) Time-course of decrease in GFR as compared with increase in SCr. (B) Comparison of traditional late approach versus proposed biomarker early approach in the diagnosis of post-cardiac surgery AKI.Modified from Herget-Rosenthal et al64 and Hudson et al.172

Biomarkers in CRS

Goodsaid FM et al, Clin Pharm & Ther. Nov 2009, 86:490-496.

Cystatin C

Cysteine protease inhibitor produced by all cell nuclei Measured in blood and urine Appears sooner, superior diagnostic accuracy

compared to S Cr, sensitive to lesser degrees of AKI or CIN, also in AHF

Predicted readmission and mortality in AHF (1 yr all cause, sens 75%, spec 68%) even with mild AKI

KIM-1

Transmembrane glycoprotein belonging to immunoglobulin gene superfamily

Expessed on proximal tubule apical membrane cilia with injury, found in urine

Detectable within 2-6 hr after AKI, where S Cr is up in 72 hr (CABG)

Best predictive value compared with NGAL, NAG, cystatin C post CABG; little data in CIN; increased risk of death or hospitalization in AHF regardless of GFR

NGAL

Human neutrophil gelatinase associated lipcalin, expressed by neutrophils and epithelial cells, involved in ishemic injury and repair, and in iron trafficking Measured in blood and urine Low sensitivity but high specificity (81%) for AKI after

CPB, elevated as early as 2 hours; plasma appears superior to urinary values; good sens and spec for early dx in CIN; in AHF, associated with very high spec (87%) and sens (100%) for CRS; also correlated with NYHA class and BNP in chronic CHF

NAG

Lysosomal enzyme from proximal convoluted tubule

Enhances predictive power when used with KIM-1 & NGAL

Correlates with GFR, RPF, BNP Associated with increased risk

of death or hospitalization in HF, regardless of GFR

Natriuretic Peptides

Released in response to ventricuar wall stress, volume expansion, pressure overload in HF

Increase GFR & Na+ & water excreation, vasodilation, inhibit RAAS

Expanding role in diagnosis & prognosis of HF & CRS

Biomarkers in CRS Biomarker Associated Injury NHE3 Ischemia, pre-renal, post-renal AKI Cytokines (IL-6, IL-8, IL-18) Toxic, delayed graft function Actin-actin depolymerizing F Ischemia and delayed graft function -GST Proximal T injury, acute rejection -GST Distal tubule injury, acute rejection L-FABP Ischemia and nephrotoxins Netrin-1 Ischemia and nephrotoxins, sepsis Keratin-derived chemokine Ischemia and delayed graft function

Adapted from Cruz DN et al, Seminars in Nephrol, Jan 2012.32(1):79-92.

PresenterPresentation NotesCystatin C: endogenous cysteine protease inhibitor produced by all cell nuclei; blood and urine, much faster with superior diagnostic accuracy compared to S Cr, sensitive to lesser degrees of AKI or CIN, also in AHF; predicted readmission and mortality in AHF (1 yr all cause, sens 75%, spec 68%) even with mild AKI

KIM-1: Kidney injury Molecule 1, transmembrane glycoprotein belonging to immunoglobulin gene superfamily, expessed on prox tubule apical membrane cilia with injury; found in urine; detectable within 2-6 hr after AKI, where S Cr is up in 72 hr (CABG); best predictive value compared with NGAL, NAG, cystatin C post CABG; little data in CIN; increased risk of death or hospitalization in AHF regardless of GFR

NGAL: human neutrophil gelatinase-associated lipcalin belongs to lipocalin superfamily, expressed by neutrophils and epithelial cells, involved in ishemic injury and repair, and in iron trafficking, measured in blood and urine; low sens but high spec (81%) for AKI after CPB, elevated as early as 2 hours; plasma appears superior to urinary values; good sens and spec for early dx in CIN; in AHF, associated with very high spec (87%) and sens (100%) for CRS; also correlated with NYHA class and BNP in chronic CHF

Inflammatory Mediators in CRS TNF- IL-6, IL-18 Other cytokines C-reactive protein Adhesion molecules

Leading to: Cachexia Anemia Endothelial dysfunction Oxidative stress Distant organ dysfunction

Source: Seminars in Nephrology 2012; 32:70-78 (DOI:10.1016/j.semnephrol.2011.11.010 )

Copyright 2012 Elsevier Inc. Terms and Conditions

Inflammation in CRS

PresenterPresentation Notes

The role of inflammation in HF. Acute or chronic HF leads to concomitant activation of both neurohormonal and inflammatory pathways that result in deleterious effects on left ventricular function and structure. Inflammatory pathway activation also leads to important systemic effects that increase the morbidity and mortality associated with HF. AVP, arginine vasopressin; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system.

Pathways of Immune Mediated Inflammation

Direct antigenic stimulation, e.g., viral myocarditis or cardiac allograft rejection

New antigenic peptides present on myocardium 2 to acute injury trigger immune response

Local or systemic cytokine release Chronic ongoing injury, e.g., chronic HF Activation 2 to hemodynamic overload




Inflammation and AKI. IRI to the kidney initiates a cascade of events after activation of endothelial and dendritic cells of the innate immune system. Leukocyte infiltration leads to inflammation and peritubular capillary obstruction. Ischemia and progressive hypoxia further extends AKI. DAMP, damage-associated molecular pattern.




Danger model of innate immunity. Pathogen-associated molecular patterns (PAMPs), released after infections by bacteria or viruses bind to pattern recognition receptors (PRRs) (ie, Toll-like receptors [TLRs]). Ligation of PAMPs to PRRs leads to activation of the innate immunity and downstream inflammation. In the danger model, dying cells release DAMPs, which bind to PRRs to elicit an immune response. Proinflammatory chemokines and cytokines recruit immune cells to the site of injury, leading to a marked inflammatory response. APC, antigen-presenting cell; DAMP, damage-associated molecular pattern; M, macrophage; PMN, polymorphonuclear leukocyte.

Cardiorenal Anemia Syndrome

The cardiorenal anemia syndrome. Congestive heart failure (CHF) is a cause and consequence of CKD. First, CHF inflames the heart, liver, and vasculature, creating an influx of circulating cytokines that depress erythropoiesis and perturb iron metabolism [44]. Second, CHF directly induces kidney damage, in which GFR can deteriorate by as much as one mL/min/month [4547]. In response to reduced cardiac output, blood pressure (and renal perfusion) is maintained by activation of the renin-angiotensin-aldosterone system. Angiotensin II-mediated renal vasoconstriction and increased metabolic demands of the kidney result in renal ischemia and ultimately tubular cell death [1]. Renal cell death in turn hastens anemia through loss of endocrine function. In addition, aldosterone-induced salt and water retention leads to an increased pre-load on the heart, which increases its rate in an attempt to increase output. Schmidt and Dalton Osteopathic Medicine and Primary Care 2007 1:14 doi:10.1186/1750-4732-1-14



Vitamin D Receptor Activators in CRS

Pathophysiology of BMD in CKD


Pathogenesis of SHPT in CKD. In CKD patients, both increased serum phosphate levels and reduced plasma 1,25-vitamin D levels lead to a decrease of serum calcium levels. All these factors result in enhancement of PTH synthesis and secretion.



Role of Selective VDRA in CKD


The role of the selective VDR activator, paricalcitol, in CKD. The selective VDR activator, paricalcitol, may reduce several cardiovascular risk factors commonly associated with CKD, such as CKD-MBD, left ventricular hypertrophy (LVH), hypertension, vascular calcification (VC), and proteinuria.



Impact of VDRA on markers of CV disease


Impact of VDRA on different markers of CV disease. VDR activation in a wide range of tissues leads to different positive effects. In fact, VDR activation results in increased fractional shortening, vascular relaxation, and thrombomodulin levels. On the other hand, VDRA administration improves blood pressure control, heart weight, left ventricular hypertrophy, posterior wall thickness, left ventricular end-diastolic pressure, and decreases renin and angiotensin levels, atrial natriuretic factor, brain natriuretic protein, plasminogen activator inhibitor-1, and vascular endothelial growth factor.

Diagnosis & Management of Volume Overload in CRS

Wet or Dry? Nephrologist Cardiologist

PresenterPresentation NotesAlthough early therapy conferred a 248% improved survival rate, in patients erroneously diagnosed with HF, improper HF therapy increased mortality by 165% compared with no therapy at all (13.6% versus 8.2%). These findings support the fact that both early and accurate volume assessment is critical.Tuy T, Peacock WF, Semin Nephrol, Jan 2012, 32:112-120.

Table 1. Common Clinical Features of Fluid Overload in ADHF Presentation, % Symptoms Dyspnea 87-93 Exertional 86-97 Orthopnea 10-59 Paroxysmal nocturnal dyspnea 13-39 At rest 1-6 Weight gain 5-15 Signs Jugular venous distention 5-54 Abdominal jugular reflex 6 Edema 35-70 Gallop 1-26 Rales 25-45 Ascites 3-17

Tuy T, Semin Nephrol. Jan 2012,32:112-120.

Ronco C, JACC.2012.01.077.



Bioimpedance Vectorial Analysis


Description of the simple and easy-to-use technology for bioimpedance vector analysis in patients with heart failure. The machine is small and light and it can be carried and moved easily. The results offered by the measurements are reactance, resistance, and phase angle, allowing the construction of a vector perfectly describing the status of hydration and the nutritional condition of the patient. For easy interpretation a hydration scale is reported by the printed module. Repeated measurement can offer a trend owing to vector migration usable to assess effects of therapy or even to guide fluid management strategies.



BIVA

Transthoracic Intrathoracic


Placement of transthoracic impedance cardiography.



BIVA Tolerance Ellipses


Bioimpedance vector analysis tolerance ellipses. BIVA tolerance ellipses corresponding to the 50th percentile (smallest oval), 75th percentile (middle oval), and 95th percentile (largest oval) of the impedance vector distribution. The short vector is indicative of fluid overload whereas the long vector is indicative of volume depletion.

PresenterPresentation NotesGraphic representation of the hydration state in the visual scale for BIVA.

Typical example of migration in response to fluid depletion therapy. Arrow A indicates the hydration status of a patient with moderate-severe overhydration. Arrow B indicates a patient in a euvolemic state.



BNP in relation to Hydration Status


BNP levels (pg/mL) on admission, clinical stability, and discharge, in relation to hydration status.

Acute Volume Management

Volume overloaded hypertensive patients Volume overloaded normotensive patients Volume overloaded hypotensive patients Preload reduction Afterload reduction

Diuretics

Mainstay of pharmacologic therapy No clear evidence of improved long-term

mortality Rapidly efficacious in volume reduction Increase activation of RAAS & SNS Compromise renal perfusion, renal

underfilling

How to Diurese?

Low dose v. high dose High dose: longer LOS, higher mortality,more

azotemia, more ICU admissions in ADHF registry

Continuous infusion Combination with nitrates, nesiritide

Fluid Removal by RRT

Intermittent: IHD

CRRT CVVH, SCUF CVVHD, CVVHDF SLEDD PD: APD, CCPD




Recent equipment specifically designed for SCUF (Aquadex System 100, CHF Solutions, Inc, and Dedyca, Bellco). The third machine is called CARPEDIEM (Cardio-Renal Pediatric Dialysis Emergency Machine) and it has been designed by the International Renal Research Institute of Vicenza for neonates and small children (Bellco).

The Candidates

Azotemia, baseline or progressive CKD or AKI Oliguria, absolute or relative Diuretic resistance CRS class?

Figure 3




Typical hemodynamic behavior of a patient undergoing extracorporeal ultrafiltration is reported. Blood pressure instability may be owing to two main causes: (1) the occurrence of an angle in the blood volume trajectory caused by rapid UF exceeding refilling capacity and a sudden decrease in circulating blood volume (this is managed with a reduced speed of fluid removal), and (2) the occurrence of an 1 angle in the trajectory depending on excessive UF and patient dehydration beyond adequate levels. This can be documented by sequential BIVA measurements (lower panels). ECFV, extracellular fluid volume.

Figure 4




Didactic representation of a time course of BNP, UF volume, and creatinine over several days after hospitalization for ADHF and the beginning of extracorporeal UF.

Figure 5




Didactic representation of a time course of BNP, UF volume, and creatinine over several days after hospitalization for ADHF and the beginning of extracorporeal UF. The management is modified based on the NGAL curve.

Effects of CRRT in CRS

Substantial weight loss Improvement in pulmonary congestion Increased diuresis at lower diuretic doses

However Conversion of nonoliguria to oliguria Increased neurohumoral activation Reduced renal perfusion pressure

Agostoni PG, et al. J Am Coll Cardiol. 1993;21:424-31.

Hemofiltration might

Reduced lung water, improvement in dyspnea, cardiac funciton, gas exchange, edema, ascites, effusions, cardiac filling pressures, heart rate, BP, SVR

Preserved effective circulating volume Reduced NE, PRA, aldosterone, increased

renal perfusion and diuresis

Marenzi G, et al. Am J Med. 1993:94;49-56.

Lack of Standardized

Definitions Patient populations Therapies Trials

Lack of Standardized

Definitions Patient populations Therapies Trials Results

What about PD?

5B Approach to Management

Balance of fluids Blood pressure Biomarkers Bioimpedance Blood volume

Ronco C, et al. Semin Nephrol, Jan 2012.32(1):129-141.



Innovations


A wearable/portable UF system for the treatment of overhydration in patients with oliguria refractory to diuretics, AKI, CKD, and congestive heart failure. The system consists of a vest in which a complete extracorporeal circuit, blood and UF pumps, batteries, and fluid waste bags are integrated. This prototype has been created in the International Renal Research Institute of Vicenza and in the laboratories of Rand (Mirandola Modena) and Dainese (Vicenza, Italy). The system is intended to be used for ambulatory UF from a few hours to continuous use 24 h/d.

Unifying Hypothesis?

Ronco C, JACC.2012.01.077.

Iatrogenesis and CRS

Ronco C, JACC.2012.01.077.

CRS ObjectivesTower of BabelCRS DefinedCRS ClassificationCardiorenal SyndromesUpdate 2012Slide Number 6CRS ClassificationSlide Number 8CRS ClassificationSlide Number 10CRS ClassificationSlide Number 12CRS ClassificationSlide Number 14Slide Number 15Type 1 CRS UpdateSerum Creatinine as Biomarker in CRSDont we measure renal function withSerum Creatinine?Association between S Cr and other renal biomarkersBiomarkers in CRSCystatin CKIM-1NGALNAGNatriuretic PeptidesBiomarkers in CRSInflammatory Mediators in CRSInflammation in CRSPathways of Immune Mediated InflammationSlide Number 30Slide Number 31Cardiorenal Anemia SyndromeVitamin D Receptor Activators in CRSRole of Selective VDRA in CKDImpact of VDRA on markers of CV diseaseDiagnosis & Management of Volume Overload in CRSSlide Number 37Slide Number 38Bioimpedance Vectorial AnalysisBIVABIVA Tolerance EllipsesSlide Number 42BNP in relation to Hydration StatusAcute Volume ManagementDiureticsHow to Diurese?Fluid Removal by RRTSlide Number 48Slide Number 49The CandidatesSlide Number 51Slide Number 52Slide Number 53Effects of CRRT in CRSHemofiltration might Lack of Standardized Lack of Standardized What about PD?5B Approach to ManagementInnovationsSlide Number 61Unifying Hypothesis?Slide Number 63Iatrogenesis and CRS

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