Cardiovascular Disease Assessment Prior to Kidney Transplantation

TRADITIONAL FACTORS	CKD/ESKD FACTORS	NONTRADITIONAL POSTTRANSPLANT FACTORS
Age	Anemia	Allograft dysfunction
Diabetes mellitus	Bone mineral metabolism	Chronic inflammation/oxidative stress
Dyslipidemia	Hypervolemia: LV hypertrophy and pulmonary hypertension	Hyperhomocysteinemia
Hypertension	Proteinuria	Metabolic consequence of immunosuppression
Physical inactivity	Uremic toxins	Posttansplant diabetes mellitus
Tobacco use	Vascular calcification	Obesity

Table 2

Screening guidelines for cardiovascular disease in kidney transplant candidates based on recommendations from the 2012 American College of Cardiology/American Heart Association (ACC/AHA) Statement on Cardiac Disease Evaluation and Management among Kidney and Liver Transplantation Candidates, American Society of Transplantation-Kidney Pancreas Community of Practice (AST-KPCOP) Cardiovascular Disease Work Group, and Kidney Disease Improving Global Outcomes (KDIGO) 2020 Guidelines for the Evaluation of the Kidney Transplant Candidate.^6,7,8 EKG: electrocardiogram; CVD: cardiovascular disease; CAD: coronary artery disease; LVEF: left ventricular ejection fraction; CT: computed tomography; CABG: coronary artery bypass grafting; PCI: percutaneous coronary intervention; ESRD: end-stage renal disease; RHC: right heart catheterization; OSA: obstructive sleep apnea; PAH: pulmonary artery hypertension; KT: kidney transplant; TAVR: transcatheter aortic valve replacement; NYHA: New York Heart Association

Relevant risk factors among transplantation candidates include diabetes mellitus, prior cardiovascular disease, more than 1 year on dialysis, left ventricular hypertrophy, age greater than 60 years, smoking, hypertension, and dyslipidemia. The specific number of risk factors that should be used to prompt testing remains to be determined, but the committee considers three or more as reasonable.
Significant pulmonary hypertension is defined as right ventricular systolic pressure more than 45 mm Hg on echocardiogram, or ancillary evidence of right ventricular pressure overload.
Significant pulmonary arterial hypertension is defined by mean pulmonary artery pressure ≥ 25 mm Hg, pulmonary capillary wedge ≤ 15 mm Hg, and pulmonary vascular resistance of > 3 Wood units in the absence of an identified secondary cause (eg, obstructive sleep apnea, left heart disease).
Risk factors for pulmonary hypertension included portal hypertension, connective tissue disease, congenital heart disease, and chronic obstructive pulmonary disease.

	ACC/AHA⁶	AST-KPCOP⁷	KDIGO⁸
Coronary Artery Disease	Preoperative 12-lead EKG in patients with known CVD or any cardiovascular symptoms (Class I, Level of Evidence C)		Evaluate all candidates for the presence and severity of cardiac disease with history, physical examination, and EKG (not graded).
	Preoperative 12-lead EKG in patients without known CVD or without any cardiovascular symptoms (Class IIa, Level of Evidence C)
	Annual 12-lead EKG after listing (Class IIb, Level of Evidence C)
	Noninvasive stress testing in candidates with no active cardiac conditions on the basis of multiple CAD risk factors^a regardless of functional status (Class IIb, Level of Evidence C)	Noninvasive testing is the preferred initial screening modality for CAD, including dobutamine stress echocardiography and myocardial perfusion imaging, although the predictive value of a positive noninvasive test for immediate posttransplant cardiovascular outcomes is unclear. Coronary angiography is a better predictor of posttransplant CVD-associated mortality, but the use of angiography is limited due to concerns about adverse events, especially renal injury in those not yet on dialysis.	Suggested that asymptomatic candidates at high risk for CAD (eg, diabetes, previous CAD), or with poor functional capacity undergo noninvasive CAD screening (2C).
	LVEF < 50%, evidence of ventricular chamber enlargement, exercise-induced hypotension, angina, or known ischemia should prompt referral to a cardiologist for management of ischemic heart disease (Class I, Level of Evidence B)		If any signs or symptoms of active cardiac disease, should undergo assessment by a cardiologist for further management prior to transplant (not graded).
	Uncertain role of noncontrast CT calcium scoring and/or cardiac CT angiography in pre-transplant risk stratification (Class IIb, Level of Evidence B)		Perform cardiac imaging in patients with systemic amyloidosis. If significant cardiac amyloid confirmed, recommend excluding such patients (not graded).
	Uncertain role of periodic screening for myocardial ischemia in asymptomatic listed candidates (Class IIb, Level of Evidence C)	Once evidence of ischemic heart disease (typically by noninvasive cardiac stress testing) is found in the potential kidney transplant candidate, careful serial cardiovascular assessment must continue during wait-list time.	Suggested that candidates with myocardial infarction be assessed by a cardiologist to determine whether further testing is warranted and when to safely proceed with kidney transplant (2B). Suggest that transplant be delayed an appropriate amount of time after placement of a coronary stent based on cardiologist recommendation (2B).
	CABG is preferred to PCI in kidney transplant candidates with multivessel CAD and diabetes mellitus (Class IIa, Level of Evidence B).	Large prospective randomized studies will be needed to determine the efficacy of preoperative coronary revascularization on posttransplant cardiovascular outcomes.	Suggested that patients with asymptomatic, advanced triple-vessel CAD be excluded from kidney transplant unless they have an acceptable estimated survival (2D).
	Prophylactic revascularization in patients with stable CAD that will not improve symptoms or survival is not recommended prior to transplant surgery (Class III, Level of Evidence B).	It remains to be determined if preoperative risk stratification and ultimately revascularization, when indicated, will improve cardiovascular outcomes following kidney transplant.	Recommend that asymptomatic candidates with known CAD not be revascularized exclusively to reduce perioperative cardiac events (1B).
Heart failure	Reasonable to perform preoperative echocardiographic assessment of LV function in potential kidney transplant candidates (Class IIa, Level of Evidence B).	Larger studies are needed to define the incremental predictive value of clinical and echocardiographic parameters (including global longitudinal strain) for adverse CVD events in kidney transplants.	Suggested that patients with uncorrectable, symptomatic NYHA Class III/IV heart disease be excluded from kidney transplant unless there are mitigating factors that give the patient an acceptable estimated survival (2D). Assess with cardiologist and consider combined/simultaneous heart and kidney transplant.
Valvular disease	Consider yearly echocardiogram in ESRD patients with moderate aortic stenosis (Class IIb, Level of Evidence C).	Outcomes among patients with KT undergoing TAVR versus open surgical replacement have only been examined in retrospective analyses, with variable outcomes reported. Larger studies will be needed to identify more reliable estimates of outcomes following TAVR in KT recipients.	Patients with severe valvular heart disease should be evaluated and managed by a cardiologist according to local cardiac guidelines (Not graded)
Pulmonary hypertension^b	Reasonable to evaluate for secondary causes (OSA, left heart disease)(Class IIa, Level of Evidence C).	While RHC is the gold standard for the diagnosis of PH, transthoracic echocardiography is the most commonly used technique to assess pulmonary pressures in practice, given the expensive and invasive nature of RHC.	Suggested that asymptomatic candidates who have been on dialysis for at least 2 years or have risk factors for pulmonary hypertension^d undergo echocardiography (2D).
	Consider RHC to confirm echocardiographic evidence of elevated PA pressures (Class IIb, Level of Evidence C).		Recommend not excluding candidates with uncorrectable pulmonary artery systolic pressure > 60 mm Hg by RHC, but consider the risks of sudden deterioration or progression after transplant, and patient should have an acceptable estimated survival (1C).
	If RHC confirms significant PAH,^c consider referral to a pulmonary vascular disease specialist (Class IIa, Level of Evidence C).	There is demonstrated importance in closely managing pulmonary hypertension preoperatively.	Patients with estimated pulmonary systolic pressure > 45 mm Hg by echo should be assessed by a cardiologist (not graded).

Table 3

Major trials of patients with ischemic heart disease treated with percutaneous coronary intervention (PCI), revascularization with coronary artery bypass graft (CABG), and/or conservative optimal medical therapy (OMT).^{11,12,13,14,15,16,17} COURAGE: Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; DIAD: Detection of Ischemia in Asymptomatic Diabetics; BARI-2D: Bypass Angioplasty Revascularization Investigation 2 Diabetes; FAME 2: Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 Trial; ISCHEMIA: International Study of Comparative Health Effectiveness with Medical and Invasive Approaches; ISCHEMIA-CKD: International Study of Comparative Health Effectiveness with Medical and Invasive Approaches-Chronic Kidney Disease; CAD: coronary artery disease; DM: diabetes mellitus; CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate; PCI: percutaneous coronary intervention; OMT: optimal medical therapy; CABG: coronary artery bypass graft; FFR: fractional flow reserve; MI: myocardial infarction: CV: cardiovascular

YEAR/TRIAL	PATIENT CHARACTERISTICS	RENAL FUNCTION			INTERVENTION	FOLLOW-UP PERIOD	PRIMARY OUTCOME	OVERALL EFFECT
YEAR/TRIAL	PATIENT CHARACTERISTICS	eGFR <60	eGFR <30	DIALYSIS	INTERVENTION	FOLLOW-UP PERIOD	PRIMARY OUTCOME	OVERALL EFFECT
2007/COURAGE^11,12	2,287 patients, stable CAD	320 (14%)	16 (0.7%)	None, excluded from the study	PCI + OMT vs OMT alone	4.6 years	All-cause death; nonfatal MI	No difference in primary outcome
2009/DIAD¹⁷	1,123 patients, Type 2 DM, no symptoms of CAD	None	None	None, excluded from the study	561 patients with adenosine sestamibi MPI vs 562 patients no screening	4.8 years	All-cause death; nonfatal MI	No difference in primary outcome in those screened
2009/BARI-2D¹³	2,368 patients, type 2 diabetes & stable CAD	494 (21%)	None, excluded from study	None, excluded from study	PCI+ OMT or CABG + OMT vs OMT alone	4.4 years	All-cause death, MI, or stroke	No difference in primary outcome
2012/FAME 2¹⁴	888 patients	22 (2%)	None, excluded from study	None, excluded from study	FFR (< 0.8)-guided PCI + OMT vs OMT alone	5.04 years	All-cause death, MI or urgent revascularization	No difference for FFR > 0.8 on OMT
2020/ISCHEMIA¹⁵	5,179 patients, stable CAD and moderate or severe ischemia	568 (11%)	None, excluded from study	None, excluded from study	Initial invasive PCI or CABG + OMT vs conservative OMT + revascularization as needed	3.2 years	CV death, nonfatal MI, hospitalization for unstable angina, heart failure, cardiac arrest with resuscitation	No difference in primary outcome
2020/ISCHEMIA-CKD¹⁶	777 patients, advanced CKD and moderate to severe ischemia on stress	None	362 (47%)	415 (53%)	Initial invasive PCI or CABG + OMT vs conservative OMT + revascularization as needed	2.2 years	All-cause death or nonfatal MI, hospitalization for unstable angina, heart failure or cardiac arrest with resuscitation	No difference in primary outcome; increased incidence of new onset dialysis and stroke

Table 4

Guideline recommendations for optimal medical therapy to address major CVD risk factors in patients with advanced kidney disease.^{23,24,25,26,27,28} BP: blood pressure; Hb: hemoglobin; HD: hemodialysis; HTN: hypertension; CKD: chronic kidney disease; DASH: Dietary Approaches to Stop Hypertension; PD: peritoneal dialysis; T2DM: type 2 diabetes mellitus; eGFR: estimated glomerular filtration rate; MI: myocardial infarction; SGLT2i: sodium/glucose cotransporter-2 inhibitors; ESAs: erythropoiesis-stimulating agents; HD: hemodialysis; PD: peritoneal dialysis; PTH: parathyroid hormone

TRADITIONAL CVD RISK FACTORS
Hypertension^23,25	Ambulatory BP monitoring should be used to complement standardized office BP readings (2B) Target sodium intake < 2 g daily in patients with HTN and CKD (2C); use caution in recommending DASH diet to CKD patients given risk of hyperkalemia Advise at least 150 minutes per week of moderate-intensity physical activity (2C) Target systolic blood pressure (SBP) of < 120 mm Hg when tolerated (2B) Recommend starting renin-angiotensin-system inhibitors (angiotensin-converting enzyme inhibitor [ACEI] or angiotensin II receptor blocker [ARB]) for patients with HTN, CKD, and moderate-to-severe albuminuria, with or without diabetes (grade varies based on degree of albuminuria and presence or absence of diabetes) Recommend avoiding any combination of ACEI, ARB, and direct renin inhibitor in patients with CKD (1B)
Dyslipidemia²⁶	In adults with newly identified CKD (including those treated with chronic dialysis or kidney transplantation), recommend evaluation with a lipid profile (1C); follow-up measurement of lipid levels is not needed for majority of patients In adults aged ≥ 50 years with CKD and eGFR ≥ 60 mL/min/1.73m² (stage 1-2), recommend treatment with a statin (1B) In adults aged ≥ 50 years with eGFR < 60 mL/min/1.73m² (stage 3a-5) but not treated with chronic dialysis or kidney transplantation, recommend treatment with a statin or statin/ezetimibe combination (1A) In adults aged 18-49 years with CKD but not treated with chronic dialysis or kidney transplantation, statin therapy is suggested in people with one or more of the following: known coronary disease (MI or coronary revascularization), diabetes mellitus, prior ischemic stroke, estimated 10-year incidence of coronary death or nonfatal MI > 10% (2A) In adults with dialysis-dependent CKD, it is suggested that statins or statin/ezetimibe combination not be initiated (2A) but can be continued if the patient was already receiving statin or statin/ezetimibe combination at the time of dialysis initiation (2C) In adults with hypertriglyceridemia and CKD (including those on chronic dialysis and kidney transplant), suggested to advise therapeutic lifestyle changes (2D)
Diabetes mellitus²⁴	Recommended to use hemoglobin A1c (HbA1c) to monitor glycemic control in patients with diabetes and CKD (1C) Recommend an individualized HbA1c target ranging from < 6.5% to < 8.0% in patients with diabetes and CKD not treated with dialysis (1C) Recommend lifestyle modifications including a well-balanced diet and moderate-intensity physical activity (1D) Suggested to maintain a protein intake of 0.8 g protein/kg/day for those with diabetes and CKD not treated with dialysis (2C); suggested to limit sodium intake to < 2 g per day (2C) Recommend treating patients with T2DM and CKD with eGFR ≥ 30 mL/min/1.73m² with metformin (1B) and a sodium-glucose cotransporter-2-inhibitor (SGLT2i) (1A) If glycemic target not achieved with metformin and SGLT2i, or if unable to use those medications, recommended to treat with a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) (1B) and additional drug therapy as needed Recommend treatment with an ACEi or ARB be initiated in patients with diabetes, HTN, and albuminuria and titrated to the highest approved tolerated dose (1B)
CKD / ESKD FACTORS
Anemia²⁷	Anemia in adults with CKD is defined as Hb < 13 g/dL in men and < 12 g/dL in women Guidelines provide specific recommendations on iron supplementation and ESAs in this population Goal should be to maintain Hb level between 10-12 g/dL as many studies have consistently shown better outcomes in HD, PD, and pre-dialysis patients, without an increase in adverse reactions
Hypervolemia	Dry weight reduction in hypertensive hemodialysis patients is associated with improved BP control Per the DRIP trial, a post-dialysis weight reduction of 0.9 kg after 4 weeks was associated with a systolic BP reduction of -6.9 mm Hg (95% CI, -12.4 to -1.3 mm Hg; P = .016), and diastolic BP reduction of -3.1 mm Hg (95% CI, -6.2 to -0.02 mm Hg; P = .048)²⁶ Reducing dry weight was generally well tolerated, but did result in an increase in intradialytic signs and symptoms of hypotension Lung ultrasound-guided strategy may predict which patients can safely benefit from dry weight reduction to target reduced ambulatory blood pressure levels ²⁷
Disorders of mineral metabolism²⁸	Patients with CKD 3a-5D should undergo serial assessments of phosphate, calcium, and PTH levels In patients with CKD 3a-5D, it is suggested to lower elevated phosphate levels toward the normal range (2C) and avoid hypercalcemia (2C) In patients with CKD 3a-5D with hyperphosphatemia, it is suggested to limit dietary phosphate intake alone or in combination with other treatments (2D). If receiving phosphate-lowering treatment, it is suggested to restrict the dose of calcium-based phosphate binders (2B) In patients with CKD 3a-5 not on dialysis, optimal PTH level is not known; it is suggested that patients with persistently high or progressively rising intact PTH levels should be evaluated for modifiable factors of hyperphosphatemia, hypocalcemia, high phosphate intake, and vitamin D deficiency (2C) In patients with CKD 4-5 calcitriol and vitamin D analogs should be used for progressive hyperparathyroidism (2C) In dialysis patients requiring PTH-lowering therapy, it is suggested to use calcimimetics, calcitriol, or vitamin D analogs, or a combination (2B)

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DOI: https://doi.org/10.14797/mdcvj.1117 | Journal eISSN: 1947-6108

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Language: English

Page range: 50 - 61

Submitted on: Apr 16, 2022

Accepted on: Jun 20, 2022

Published on: Sep 6, 2022

Published by: Houston Methodist DeBakey Heart & Vascular Center

In partnership with: Paradigm Publishing Services

Keywords:

cardiovascular screening,

kidney transplantation,

chronic kidney disease,

end stage kidney disease

© 2022 Angelina R. Edwards, Elise C. Ewing, published by Houston Methodist DeBakey Heart & Vascular Center
This work is licensed under the Creative Commons Attribution-NonCommercial 4.0 License.

Volume 18 (2022): Issue 4