Hypertension Journal

Show Contents

Cardiovascular Disease in Patients with Chronic Kidney Disease
  JOHTN
REVIEW ARTICLE
Cardiovascular Disease in Patients with Chronic Kidney Disease
Peter A. McCullough1,2,3, Aaron Y. Kluger3,4
1Department of Internal Medicine, Baylor University Medical Center, Dallas, TX
2Department of Internal Medicine, Baylor Jack and Jane Hamilton Heart andVascular Hospital, Dallas, TX
3Department of Internal Medicine, Baylor Heart and Vascular Institute, Dallas, TX
4Department of Internal Medicine, Baylor Scott and White Research Institute, Dallas, TX
Address for correspondence: Peter A. McCullough, Department of Internal Medicine, Baylor University Medical Center, 621 N Hall St, Ste H030 Dallas TX 75226.
E-mail: peteramccullough@gmail.com
Received: 25-02-18; Accepted: 02-03-18
doi: 10.15713/ins.johtn.0146
 
ABSTRACT
Kidney and cardiovascular diseases are strongly associated due to the connections between the heart and the kidneys; kidneydisease may even be seen as a cardiovascular risk. The Chronic Kidney Disease (CKD) Prognosis Consortium showed that CKDseverity was related to cardiovascular death risk, among other factors. When reduced estimated glomerular filtration rate andalbuminuria - both biomarkers for declining renal function - are present in a patient, the rate of cardiovascular events increasessignificantly. Kidney and heart diseases are linked with regard to coronary atherosclerosis, myocardial disease, valvular calcification,and atrial and ventricular arrhythmias. CKD and end-stage renal disease (ESRD) patients with coronary atherosclerosis frequentlyhave accentuated calcification; many CKD-related factors accelerate the calcification process. These may include traditional riskfactors such as hypertension or diabetes, as well as non-traditional risk factors such as uremia, anemia, and increased coagulationproteins. This is also associated with more stable lesions, often leading to episodes of silent and symptomatic coronary ischemiain these patients. CKD is linked to heart failure by accentuating pressure overload, volume overload, and cardiomyopathy, thethree major pathophysiologic mechanisms causing left ventricle failure. Hemodialysis itself may lead to myocardial disease through"myocardial stunning," in which episodes of hypotension during hemodialysis cause transient wall motion abnormalities, worseningsurvival overtime. Short daily hemodialysis in the home setting may be associated with improved outcomes. CKD and ESRDpatients often experience accelerated aortic valvular and mitral annular calcification and fibrosis. These patients should receiveechocardiography during care, to evaluate for valve disease severity as well as the left ventricular systolic and diastolic function.Finally, CKD patients have many of the myocardial and hemodynamic factors of arrhythmia. 62% of cardiac deaths in the UnitedStates Renal Data System database are due to arrhythmias. CKD and ESRD patients should receive individualized treatment andfrequent monitoring due to the increased risk of adverse events and iatrogenic death in this patient population. One option is toform hybrid "cardionephrology" teams comprised cardiologists and nephrologists. This will optimize care for cardiorenal patientsand boost interest in the nephrology field, which is presently lagging.
Keywords: Chronic kidney disease, atherosclerosis, heart failure, aortic valve, mitral valve, arrhythmia, sudden death
How to cite this article: McCullough PA, Kluger AY.Cardiovascular Disease in Patients with Chronic KidneyDisease. Hypertens 2019;5(1): 25-31.
Source of support: Nil
Conflict of interest: None
 
 

Introduction

The heart and the kidneys are inextricably linked throughvascular, neurological, hormonal, and cellular signaling systems.The kidneys are the most vascular organ in the body, receivinga quarter of cardiac output at rest. Thus, kidney disease isstrongly associated with cardiovascular illness and, in fact, maybe considered as a cardiovascular risk state. In addition, wheneither organ sustains injury or begins to fail, there appears to bea consequential effect on the other organs in either an adaptiveor maladaptive response that we now recognize as a "cardiorenalsyndrome(s)."[1] This chapter will review the connectionsbetween the heart and the kidneys from epidemiological,biological, and clinical perspectives with the aim of gaininggreater appreciation for this important interface in both acuteand chronic care.

 
Hypertension Journal, January-March, Vol 5, 2019 25

McCullough and Kluger Cardiovascular disease in patients with chronic kidney disease

Why Does Ckd Convey Increased Cardiovascular Risk?

The CKD Prognosis Consortium (CKD-PC) was establishedin 2009 by the Kidney Disease: Improving Global Outcomes(KDIGO) organization in an attempt to understand the risks ofdeclining renal filtration function represented by the estimatedglomerular filtration rate (eGFR) and the presence of albuminin the urine indexed to the filtered creatinine concentration(urine albumin: creatinine ratio [ACR]). In a series ofmanuscripts, this group used a very large, pooled database(1,555,332 subjects in 45 cohorts) to demonstrate that theseverity of CKD was related to the risks of all-cause mortality,cardiovascular death, acute kidney injury, progressive CKD,and end-stage renal disease (ESRD) as shown in Figure 1.[2]These relationships can also be shown in a "heat map" of riskas demonstrated in Figure 2. It is important to understand thatwhen both eGFR and elevated ACR overlap, there appearsto be magnified risk for all outcomes. Data from the NationalKidney Foundation Kidney Early Evaluation Program (KEEP)and the National Health and Nutrition Examination Surveysuggest that the majority of individuals with CKD in theyounger age groups are identified by albuminuria while thosein the older age strata have reduced eGFR (< 60 ml/min/1.73m2) as the CKD marker [Figure 3].[3] Importantly, the overlapbetween the two markers is less common than one alone inthese large populations. However, when both reduced eGFRand albuminuria are present in the same patient, the predictedand observed rates of cardiovascular events are markedlyincreased over a relatively short (< 5 years) duration. Thus,it is critical that in every patient, the eGFR is calculated fromthe patient's age, gender, race, and serum creatinine usingstandardized equations and the urine ACR is checked ona first morning voided specimen. Structural kidney disease(including polycystic kidney disease) detected by imagingstudies is also characterized as CKD in the absence of eGFRand ACR abnormalities. The CKD-PC was limited in termsof non-fatal cardiovascular outcomes; therefore, we must turnour attention to other sources of information to understand theconnections to coronary atherosclerosis, myocardial disease,valvular disease, and arrhythmias.

 
The term "reverse epidemiology" has been applied topatients with ESRD for many risk factors, particularly bodyweight. This means that in the general population, increasedadiposity, as expressed with the body mass index, is consistentlyassociated with cardiovascular events and reduced survival.However, in ESRD, increased BMI confers improved survival.This suggests that increased adiposity is the inverse of cachexia.That is, as chronic disease progresses, cachexia and reduction inweight are common observations on the pathway towards death.Thus, retention of adiposity is associated with survival. Reverseepidemiology has also been observed with total cholesterol andalbumin which are proxies for nutritional intake which again isinversely related to the degree of cachexia.

Kidney Disease and Coronary Atherosclerotic Calcification

Data from many studies suggest that the CKD milieupromotes the early initiation and accelerated course ofcoronary atherosclerosis. Since CKD is strongly associatedwith traditional coronary risk factors including hypertension,diabetes, dyslipidemia, and smoking, the combination of thesefactors may be reflected by CKD, and thus, its relationship isamplified by positive confounding. However, when adjustingfor these factors, CKD has been consistently associated withnon-fatal myocardial infarction and cardiovascular death.[3] Aprominent feature of coronary atherosclerosis in patients withCKD and ESRD is accentuated calcification which occurs inall cases of atherosclerosis when reviewed at necropsy. Initially,calcium deposits on cholesterol crystals in the subendothelialspace.[4] However, the progression of atherosclerosis involves amultitude of local and systemic factors which stimulate vascularsmooth muscle cells to undergo osteoblastic transformation intoosteocyte-like cells which deposit calcium hydroxyapatite crystalsinto both the subendothelial and medial compartments of bloodvessels. Many factors have been implicated in CKD to acceleratethis process including low-density lipoprotein cholesterol,non-high-density lipoprotein cholesterol, vascular calcificationfactor, osteoprotegerin, and most notably phosphorus.[5] AseGFR falls, there is retention of phosphate which can stimulatethe Pit-1 receptor on vascular smooth muscle cells, therebyfacilitating the osteoblastic transformation.[6] Of note, neitherdietary calcium nor the plasma concentration of calcium hasbeen independently associated with calcific deposits in thecoronary arteries. As CKD progresses, coronary artery disease iscommonly identified on a variety of clinical studies, frequently aslonger lesions and in more proximal vessels.[7] Fortunately, moreextensive calcification - while related to the burden of coronarydisease - is also associated with more stable lesions; thus, CKDpatients often have stable but extensive CAD leading to episodesof both silent and symptomatic coronary ischemia.

Cardiovascular Disease in Patients with Chronic Kidney Disease
Figure 1: Risks of fatal and non-fatal kidney outcomes from the chronic kidney disease prognosis consortium stratified by baseline urinealbumin: creatinine ratio across a spectrum of eGFR. The red arrows denote an inflection point at eGFR < 60 ml/min/1.73 m2. Adapted fromreference[2]

26 Hypertension Journal, January-March, Vol 5, 2019

Cardiovascular disease in patients with chronic kidney disease McCullough and Kluger

Cardiovascular Disease in Patients with Chronic Kidney Disease
Figure 2: Adjusted risk of outcomes according to eGFR and urine ACR. Adapted from reference[2]

Cardiovascular Disease in Patients with Chronic Kidney Disease
Figure 3: Identification of CKD by eGFR and urine ACR in KEEP, N = 40,013 and NHANES, N = 10,486. Adapted from reference.[3]

Hypertension Journal, January-March, Vol 5, 201927

McCullough and Kluger Cardiovascular disease in patients with chronic kidney disease

It has been suggested that there are both traditional and nontraditionalrisk factors that may contribute to more acceleratedatherosclerosis in persons with CKD. The traditional riskfactors include elevated LDL-C, hypertension, diabetesmellitus, smoking, and family history of premature coronarydisease (first-degree relative female before age 55 and malebefore age 45 years). Non-traditional risk factors in CKDhave been variously mentioned in literature and include bloodmarkers of mineral and bone disorder (hyperphosphatemia,elevated calcium-phosphorus product, osteopontin, andhyperparathyroidism), C-reactive protein, uremia, asymmetricdimethylarginine and reduced nitric oxide availability, anemia,increased unbound iron (catalytic or poorly liganded iron),homocysteine, fibrinogen, and increased coagulation proteins.None of these factors have been sufficiently tested in prospectivestudies to be considered a therapeutic target for prevention inCKD patients with atherosclerosis.

 
Heart Failure in Ckd

CKD promotes the three major pathophysiologic mechanismsby which the left ventricle can fail: Pressure overload, volumeoverload, and cardiomyopathy. Since hypertension is both adeterminant and a consequent of CKD, the vast majority of CKDpatients have longstanding histories of elevated blood pressureand increased cardiac afterload resulting in left ventricularhypertrophy and increased left ventricular mass.[8] Salt andwater retention result in chronic volume overload. Nephroticsyndrome and loss of oncotic forces result in worsened fluidretention and edema. Uremia and retention of many substances(indoxyl sulfate and p-cresol) result in impaired myocytefunction in both systole and diastole. It has become recentlyunderstood that the production of fibroblast growth factor-23from bone in response to CKD phosphate retention has offtargeteffects on the left ventricular myocardium, resulting inincreased left ventricular mass and cardiac fibrosis. The resultantmyocardial tissue has a reduced capillary density comparedto that of persons with normal renal function. Considerableevidence is accumulating that "CKD cardiomyopathy" ismanifest by impaired systole and diastole with biomarkerand imaging evidence of cardiac fibrosis. The observationthat galectin-3 levels correlate with type III aminoterminalpropeptide of procollagen, matrix metalloproteinase-2, andtissue inhibitor of metalloproteinase-1 suggests that myocardialmacrophage infiltration enhances turnover of extracellularmatrix proteins in patients with CKD.[9] Thus, patients withCKD are at very high risk for the development of heart failureassociated with markedly impaired cardiorespiratory functionand the cardinal features of fatigue, effort intolerance, edema,and clinical findings including pulmonary congestion andelevation of B-type natriuretic peptides (BNP and NTproBNP).[10] When acutely decompensated heart failureis present, then a vicious cycle of worsened renal filtrationfunction, venous and renal congestion, and further retention ofsalt and water can occur. This is commonly termed cardiorenalsyndrome type 1 [Figure 4].[11]

Cardiovascular Disease in Patients with Chronic Kidney Disease
Figure 4: Pathophysiology of cardiorenal syndrome type 1. ADHF = acutely decompensated heart failure. AKI = acute kidney injury.Reproduced with permission from reference.[10]

28 Hypertension Journal, January-March, Vol 5, 2019

Cardiovascular disease in patients with chronic kidney disease McCullough and Kluger

Cardiovascular Disease in Patients with Chronic Kidney Disease
Figure 5: Pathophysiologic rationale for myocardial stunning inESRD on hemodialysis

 
It has become increasingly recognized that hemodialysis itselfmay contribute to myocardial disease through the process of"myocardial stunning," in which there are transient wall motionabnormalities that are related to episodes of hypotension duringhemodialysis. The greater the number of segmental wall motionabnormalities, the worse the survival overtime [Figure 5]. Recentanalyses suggest that short daily hemodialysis in the home settingis associated with fewer episodes of intradialytic hypotension,regression of left ventricular hypertrophy, and a 41*#37; lower riskof heart failure, fluid overload, and cardiomyopathy.[12]

Valvular Calcification

Accelerated aortic valvular and mitral annular calcificationand fibrosis are common in patients with CKD and nearlyuniversally present in patients with ESRD. The murmur ofaortic valve sclerosis is found in the majority of patients whilethe mitral annular disease is usually silent and detected onlyby echocardiography or other forms of imaging. The aorticvalve sclerosis and calcification can progress to symptomaticaortic stenosis while the mitral annular disease can result invery mild functional stenoses or regurgitation by Doppler butrarely requires surgical attention. Both valvular lesions can bethe substrate for acute infective endocarditis in ESRD patientswith temporary dialysis catheters, which occurs at the rate of6-8% per year. Staphylococcus aureus is the main cause (75%)of vascular access-related bacteremia among patients receivinglong-term hemodialysis. When endocarditis occurs in thissetting, the operative mortality rate can be in excess of 50%.[13]Most patients with CKD should undergo echocardiography atsome point in their care not only to evaluate for the extent ofvalve disease but also to assess the left ventricular systolic anddiastolic function.

Cardiovascular Disease in Patients with Chronic Kidney Disease
Figure 6: Major adverse renal and cardiac events (MARCE) are strongly associated with AKI and raise the possibility of strategies thatreduce AKI, translating into improved clinical outcomes as measured by the time to first MARCE event in clinical trials. Reproduced withpermission from reference[18]

Hypertension Journal, January-March, Vol 5, 201929

McCullough and Kluger Cardiovascular disease in patients with chronic kidney disease

Atrial and Ventricular Arrhythmias

Patients with CKD have the myocardial and hemodynamicdeterminants of all forms of arrhythmias. In the United StatesRenal Data System database, 62% of cardiac deaths (27% of alldeaths) are attributable to lethal arrhythmias.[14] Atrial fibrillationoccurs at an elevated rate in patients with CKD and is associatedwith an increased risk of cardioembolic stroke compared to thosewith normal renal function at all levels of the CHA2DS2-VAScscore. Recent data are supportive of apixaban (either 2.5 mg or5 mg p. o. bid) potentially in place of warfarin for CKD patientswith non-valvular atrial fibrillation at high risk of stroke orsystemic embolism.[15] Due to accelerated myocardial fibrosisand the presences of both macrovascular and microvasculardisease, reentrant ventricular tachycardia is believed to be theprelude to ventricular fibrillation followed by asystole andsudden death. Increased premature atrial and ventricular beats,when seen on monitoring, can be harbingers of atrial fibrillationand ventricular tachycardia, respectively. Electrolyte shifts -particularly changes in potassium concentration that occursin CKD and are accentuated with forms of dialysis - are alsobelieved to play a role in ventricular arrhythmias and suddendeath, most likely due to ventricular fibrillation. The role ofimplantable cardio-defibrillators is controversial at the timeof this writing, given the associated shortened survival and therisks of device and lead infection in ESRD.[16] Each guidelinesbasedapproach in the population of patients with heart diseaseand normal renal function is complicated by increased adverseevents and even iatrogenic death in patients with CKD andESRD. Thus, therapy must be individualized and very frequentmonitoring is required.

Cardionephrology Collaboration

In light of the strong link between kidney disease and heartdisease, there is a great need for collaboration betweencardiologists and nephrologists. This is becoming increasinglyrelevant with the growing use of mechanical devices suchas left ventricular assist devices and novel cardiorenaltherapies.[17] Rangaswami et al. advocated the formationof hybrid "cardionephrology" teams for the treatment ofcardiorenal syndromes.[17] One possibility is a dedicatedcardionephrology training track for fellows, involvingnephrology/cardiology fellow cross rotations.[17,18] This wouldrevive the currently declining interest in the nephrology fieldas well as optimize care for cardiorenal patients [Figure 6].[17]

Summary

The connection between kidney and heart disease can be viewedin four domains: Coronary atherosclerosis, myocardial disease,valvular abnormalities, and arrhythmias. CKD plays a role inthe pathogenesis, presentation, outcomes, and management ofeach manifestation of CVD. Future research is needed to betterunderstand the unique mechanisms at work in patients with CKDthat promotes and worsens CVD outcomes. Practical strategies,such as the formation of dedicated cardionephrology teams, areneeded to guide clinicians in the appropriate management of thishigh-risk population.

 
References
  1. Ronco C, McCullough PA, Anker SD, Anand I, Aspromonte N,Bagshaw SM, et al. Cardiorenal syndromes: An executivesummary from the consensus conference of the acute dialysisquality initiative (ADQI). Contrib Nephrol 2010;165:54-67.
  2. Levey AS, de Jong PE, Coresh J, El Nahas M, Astor BC,Matsushita K, et al. The definition, classification, and prognosisof chronic kidney disease: A KDIGO controversies conferencereport. Kidney Int 2011;80:17-28.
  3. Whaley-Connell AT, Sowers JR, Stevens LA, McFarlane SI,Shlipak MG, Norris KC, et al. CKD in the united states: Kidneyearly evaluation program (KEEP) and national health andnutrition examination survey (NHANES) 1999-2004. Am JKidney Dis 2008;51 4 Suppl 2:S13-20.
  4. McCullough PA, Chinnaiyan KM, Agrawal V, Danielewicz E,Abela GS. Amplification of atherosclerotic calcification and monckeberg's sclerosis: A spectrum of the same disease process.Adv Chronic Kidney Dis 2008;15:396-412.
  5. McCullough PA, Agarwal M, Agrawal V. Review article: Risks ofcoronary artery calcification in chronic kidney disease: Do thesame rules apply? Nephrology (Carlton) 2009;14:428-36.
  6. Li X, Yang HY, Giachelli CM. Role of the sodium-dependentphosphate cotransporter, pit-1, in vascular smooth muscle cellcalcification. Circ Res 2006;98:905-12.
  7. Charytan DM, Kuntz RE, Garshick M, Candia S, Khan MF,Mauri L, et al. Location of acute coronary artery thrombosesin patients with and without chronic kidney disease. Kidney Int2009;75:80-7.
  8. Lubanski MS, McCullough PA. Kidney's role in hypertension.Minerva Cardioangiol 2009;57:743-59.
  9. McCullough PA, Olobatoke A, Vanhecke TE. Galectin-3:A novel blood test for the evaluation and management ofpatients with heart failure. Rev Cardiovasc Med 2011;12:200-10.
  10. Hanson ID, McCullough PA. B-type natriuretic peptide, beyonddiagnostic applications. In: Bakris GL editor. The Kidney inHeart Failure. New York NY: Springer; 2012. p. 67-77.
  11. Ronco C, Cicoira M, McCullough PA. Cardiorenal syndromeType 1: Pathophysiological crosstalk leading to combined heartand kidney dysfunction in the setting of acutely decompensatedheart failure. J Am Coll Cardiol 2012;60:1031-42.
  12. McCullough PA, Chan CT, Weinhandl ED, Burkart JM,Bakris GL. Intensive hemodialysis, left ventricular hypertrophy,and cardiovascular disease. Am J Kidney Dis 2016;68:S5-S14.
  13. Nucifora G, Badano LP, Viale P, Gianfagna P, Allocca G,Montanaro D, et al. Infective endocarditis in chronichaemodialysis patients: An increasing clinical challenge. EurHeart J 2007;28:2307-12.
  14. Herzog CA, Mangrum JM, Passman R. Sudden cardiac deathand dialysis patients. Semin Dial 2008;21:300-7.
  15. McCullough PA, Ball T, Cox KM, Assar MD. Use of oralanticoagulation in the management of atrial fibrillation inpatients with ESRD: Pro. Clin J Am Soc Nephrol 2016;11:2079-84.
  16. Makar MS, Pun PH. Sudden cardiac death among hemodialysispatients. Am J Kidney Dis 2017;69:684-95.

30 Hypertension Journal, January-March, Vol 5, 2019

Cardiovascular disease in patients with chronic kidney disease McCullough and Kluger

  1. Rangaswami J, Mathew RO, McCullough PA. Resuscitation forthe specialty of nephrology: Is cardionephrology the answer?Kidney Int 2017;93:25-6.
  2. Ronco C, Ronco F, McCullough PA. A call to action to developintegrated curricula in cardiorenal medicine. Blood Purif2017;44:251-9.

 
Hypertension Journal, January-March, Vol 5, 201931