**2. Evaluation of risk factors by specific organ system disease**

#### **2.1. Recurrence of glomerular disease of the native kidneys**

Recurrence of glomerular disease is the third most common cause of graft loss after chronic allograft injury and death with a functioning graft. Currently available data on the incidence of recurrent disease and resultant graft loss are heterogeneous due to different study design, follow-up durations, patient samples, and the variable use of surveillance biopsies among centers. The reported incidence of recurrent renal disease after renal transplantation and the risk of graft loss from disease recurrence are shown in table 3. The clinical course and impact on graft survival vary between different types of glomerulonephritis (Colgert et al., 2008; Kasiske et al., 2009). Nonetheless, with the exception of primary focal segmental glomerulo‐ sclerosis (FSGS), recurrent glomerular disease is usually a late complication after transplan‐ tation. FSGS secondary to reflux nephropathy or obesity does not recur after transplantation. In patients with hypertensive renal disease or other causes of chronic kidney disease, focal segmental sclerosis may be found on histologic evaluation and must be differentiated from the primary disorder. Suggested risk factors for recurrence of primary FSGS include history of recurrence in a previous transplant, younger age at diagnosis, rapid progression to end stage renal disease from the time of initial diagnosis ( < 3 years), presence of mesangial proliferation in the native kidneys, older donor kidneys, Caucasian ethnicity, and the collapsing variant. Living donor kidneys (versus deceased donor) have not consistently been demonstrated to be associated with an increased risk of recurrence. Familial and sporadic forms of FSGS with podocin mutation, slow progression to end stage kidney disease (ESKD), and non-nephrotic range proteinuria in the native kidney disease are associated with low risk of recurrence (Ponticelli et al., 2010).

transplant centers as an essential component of the transplant evaluation process. A detailed cardiovascular history not only predicts the operative risk but also helps in postoperative cardiac management to improve short- and long-term cardiac outcomes. Over the years there has been much controversy over the best strategy for pre-transplant assessment and manage‐ ment of coronary artery disease (CAD) to prevent adverse peri-operative cardiac events. Recently, the American Heart Association / American College of Cardiology (AHA/ACC) have developed the 2012 AHA/ACC guidelines for "Cardiac Disease Evaluation and Management Among Kidney and Liver Transplantation Candidates" based on a comprehensive review of the literature pertinent to perioperative cardiac evaluation of potential kidney or liver transplant recipients (Lentine et al., 2012). These guidelines are endorsed by the American Society of Transplant Surgeons, American Society of Transplantation, and the National Kidney Foundation (discussed below). The AHA/ACC classifications of evidence to perform a test or

**Table 3.** Rates of recurrent renal disease after transplantation and risk of graft loss from disease recurrence1

*FSGS*: focal segmental glomerulosclerosis; *MPGN*: membranoproliferative glomerulonephritis; *GN*: glomerulonephrop‐

2Diarrhea (+) HUS usually does not recur; Diarrhea (-) or familial may recur in 21-28%; Factor H or I mutation may recur in 80% to 100%; Patients with mutation membrane cofactor protein does not have recurrence (reference Kasiske et

FSGS 20-50 50 Ig A nephropathy 20-60 10-30 MPGN I 20-50 30-35 MPGN II 80-100 10-20 Membranous GN 3-30 30 HUS2 10-40 10-40 Anti-GBM disease 15-50 < 5 ANCA-associated 7-25 < 5 Vasculitis SLE 3-10 < 5

athy; *HUS*: hemolytic uremic syndrome; *SLE*: systemic lupus erythematosus.

**Recurrence rates (%) Graft loss from disease recurrence (%)**

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**a.** Determining whether the transplant candidate has an active cardiac condition

The primary goal of pre-operative evaluation is to determine whether potential transplant candidates have any active cardiac condition both during the initial evaluation and immedi‐ ately before an anticipated transplantation procedure. "Active" cardiac conditions are defined as unstable coronary syndromes (eg, unstable angina, severe angina, or recent myocardial infarction (MI), decompensated heart failure, significant arrhythmias, and severe valvular disease). The presence of one or more of these conditions is associated with high rates of perioperative cardiovascular morbidity and mortality, hence delay or cancellation of the

therapy is shown in table 4.

1Only selected renal disease are listed.

al., 2009)

Despite the propensity for certain kidney disease to recur, the risk generally does not preclude transplantation and recurrence rarely results in early graft loss. However, systemic primary amyloidosis (AL amyloidosis) and light chain deposition disease are associated with high rates of disease recurrence and increased morbidity and mortality after transplantation and are considered contraindication to transplantation by most centers. In rare selected patients with sustained complete remission of the hematological disorder kidney transplantation can be performed at the discretion of the transplant nephrologist and hematologist/oncologist (Bridoux et al., 2011; Canaud et al., 2012).

#### **2.2. Cardiovascular disease and peripheral vascular disease**

Cardiovascular disease (CVD) is the leading cause of death after renal transplantation. Deaths with a functioning graft occurring within 30 days after transplantation are due to ischemic heart disease in nearly half of the cases. Cardiovascular screening is considered by most


*FSGS*: focal segmental glomerulosclerosis; *MPGN*: membranoproliferative glomerulonephritis; *GN*: glomerulonephrop‐ athy; *HUS*: hemolytic uremic syndrome; *SLE*: systemic lupus erythematosus.

1Only selected renal disease are listed.

The following section describes specific medical and urological issues that should be addressed

Recurrence of glomerular disease is the third most common cause of graft loss after chronic allograft injury and death with a functioning graft. Currently available data on the incidence of recurrent disease and resultant graft loss are heterogeneous due to different study design, follow-up durations, patient samples, and the variable use of surveillance biopsies among centers. The reported incidence of recurrent renal disease after renal transplantation and the risk of graft loss from disease recurrence are shown in table 3. The clinical course and impact on graft survival vary between different types of glomerulonephritis (Colgert et al., 2008; Kasiske et al., 2009). Nonetheless, with the exception of primary focal segmental glomerulo‐ sclerosis (FSGS), recurrent glomerular disease is usually a late complication after transplan‐ tation. FSGS secondary to reflux nephropathy or obesity does not recur after transplantation. In patients with hypertensive renal disease or other causes of chronic kidney disease, focal segmental sclerosis may be found on histologic evaluation and must be differentiated from the primary disorder. Suggested risk factors for recurrence of primary FSGS include history of recurrence in a previous transplant, younger age at diagnosis, rapid progression to end stage renal disease from the time of initial diagnosis ( < 3 years), presence of mesangial proliferation in the native kidneys, older donor kidneys, Caucasian ethnicity, and the collapsing variant. Living donor kidneys (versus deceased donor) have not consistently been demonstrated to be associated with an increased risk of recurrence. Familial and sporadic forms of FSGS with podocin mutation, slow progression to end stage kidney disease (ESKD), and non-nephrotic range proteinuria in the native kidney disease are associated with low risk of recurrence

Despite the propensity for certain kidney disease to recur, the risk generally does not preclude transplantation and recurrence rarely results in early graft loss. However, systemic primary amyloidosis (AL amyloidosis) and light chain deposition disease are associated with high rates of disease recurrence and increased morbidity and mortality after transplantation and are considered contraindication to transplantation by most centers. In rare selected patients with sustained complete remission of the hematological disorder kidney transplantation can be performed at the discretion of the transplant nephrologist and hematologist/oncologist

Cardiovascular disease (CVD) is the leading cause of death after renal transplantation. Deaths with a functioning graft occurring within 30 days after transplantation are due to ischemic heart disease in nearly half of the cases. Cardiovascular screening is considered by most

**2. Evaluation of risk factors by specific organ system disease**

**2.1. Recurrence of glomerular disease of the native kidneys**

during the transplant evaluation process.

6 Current Issues and Future Direction in Kidney Transplantation

(Ponticelli et al., 2010).

(Bridoux et al., 2011; Canaud et al., 2012).

**2.2. Cardiovascular disease and peripheral vascular disease**

2Diarrhea (+) HUS usually does not recur; Diarrhea (-) or familial may recur in 21-28%; Factor H or I mutation may recur in 80% to 100%; Patients with mutation membrane cofactor protein does not have recurrence (reference Kasiske et al., 2009)

**Table 3.** Rates of recurrent renal disease after transplantation and risk of graft loss from disease recurrence1

transplant centers as an essential component of the transplant evaluation process. A detailed cardiovascular history not only predicts the operative risk but also helps in postoperative cardiac management to improve short- and long-term cardiac outcomes. Over the years there has been much controversy over the best strategy for pre-transplant assessment and manage‐ ment of coronary artery disease (CAD) to prevent adverse peri-operative cardiac events. Recently, the American Heart Association / American College of Cardiology (AHA/ACC) have developed the 2012 AHA/ACC guidelines for "Cardiac Disease Evaluation and Management Among Kidney and Liver Transplantation Candidates" based on a comprehensive review of the literature pertinent to perioperative cardiac evaluation of potential kidney or liver transplant recipients (Lentine et al., 2012). These guidelines are endorsed by the American Society of Transplant Surgeons, American Society of Transplantation, and the National Kidney Foundation (discussed below). The AHA/ACC classifications of evidence to perform a test or therapy is shown in table 4.

#### **a.** Determining whether the transplant candidate has an active cardiac condition

The primary goal of pre-operative evaluation is to determine whether potential transplant candidates have any active cardiac condition both during the initial evaluation and immedi‐ ately before an anticipated transplantation procedure. "Active" cardiac conditions are defined as unstable coronary syndromes (eg, unstable angina, severe angina, or recent myocardial infarction (MI), decompensated heart failure, significant arrhythmias, and severe valvular disease). The presence of one or more of these conditions is associated with high rates of perioperative cardiovascular morbidity and mortality, hence delay or cancellation of the


it should also be noted that in ESKD patients both myocardial perfusion study (MPS) and DSE have reduced sensitivity and specificity compared with that of the general population. In the general population, abnormalities on myocardial perfusion study has been suggested to correlate well with the presence of coronary artery disease (CAD) with mean weighted sensitivity of 88% and specificity of 74% (Klocke et al., 2003). In patients with stage 5 CKD (GFR < 15 ml/min or dialysis dependent) DSE and MPS have been reported to have sensitivities ranging from 44% to 89%, and 29% to 92%, respectively, and specificities ranging from 71% to 94% and 67% to 89%, respectively, for identifying ≥ 1 coronary stenosis > 70% (Lentine et al. 2009, Lentine et al, 2012). Furthermore, abnormal MPS and DSE test results have not been consistently shown to be associated with prognostic value for cardiac events and mortality in ESKD patients. In a meta-analysis of 12 studies involving either thallium-201 scintigraphy or DSE, Rabbat *et al*. demonstrated that ESKD patients with inducible ischemia had 6 times higher risk of MI and 4 times higher risk of cardiac death than patients without inducible ischemia (Rabbat et al., 2003). In contrast, in a small prospective study of 106 kidney transplant candi‐ dates clinically classified as moderate (age ≥50 years) or high (diabetes mellitus, extra-cardiac vascular disease, or known CAD) coronary risk who underwent MPS, DSE, and coronary angiography, De Lima *et al.* found that clinical risk stratification and coronary angiographic findings of CAD (defined as ≥70% stenosis in ≥1 epicardial arteries by visual estimation by 2 observers) predicted major adverse cardiac events (MACEs) [defined as sudden death, myocardial infarction, arrhythmia, heart failure, unstable angina, or revascularization] after a median follow-up of 46 months but results of MPS and DSE did not predict MACEs (De Lima

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Given the wide ranges of sensitivities and specificities of the MPS and DSE and the inconsistent associations of angiographically defined CAD with subsequent survival in ESKD patients, the AHA/ACC Writing Committee acknowledges that there are currently no definitive data to sup‐ port or refute screening for myocardial ischemia among potential kidney transplant candidates without active cardiac conditions. However, it is recommended that until further data are avail‐ able, it may be useful to use aggregate CAD risk factors to target screening of patients with the highest pretest probability of having significant CAD. Suggested algorithm for pretransplant

In general, high cardiac risk candidates should undergo a formal evaluation by cardiology. If necessary, percutaneous coronary intervention or coronary bypass surgery and cardiac rehabilitation should be performed prior to transplantation. If coronary intervention is indicated, caution should be made especially if stenting is planned. The 2012 AHA/ACC guidelines do not recommend transplant surgery within 3 months of bare metal stent (BMS) and within 12 months of DES placement, particularly if the anticipated time of poststent dual antiplatelet therapy will be shortened (Class III; level of Evidence B). Transplant surgery is also not advisable in patients within 4 weeks of coronary revascularization with balloon

In patients with established CVD or in those at risk for CV events, aggressive risk factor modification and treatment *per* ACC/AHA guidelines (Pearson et al., 2002) are recommended. The cardioprotective effects of statins, aspirin, ACE inhibitors, and/or β blockers have been

cardiac evaluation based on the 2012 AHA/ACC guidelines is shown in figure 1.

angioplasty (Clas III; Level of Evidence B) (Lentine et al., 2012).

et al., 2003).

**Table 4.** Evidence Grading

surgical procedure may be required. The 2012 AHA/ACC guidelines recommend that a thorough history and physical examination be performed in all patients preoperatively to identify any active cardiac conditions (Class I; Level of Evidence C). In prospective transplant candidates with chronic cardiac conditions, re-assessment of their cardiac status before surgery may be necessary. The former is defined as chronic limiting angina, an MI that is < 30 days old but without symptoms of unstable angina, prior history of coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI), decompensated heart failure, moderate valvular disease or prior valve surgey, or stable arrhythmias.

**b.** Noninvasive stress testing in kidney transplant candidates without active cardiac conditions

The AHA/ACC recommend noninvasive stress testing in kidney transplant candidates with no active cardiac conditions based on the presence of multiple CAD risk factors regardless of functional status. Eight relevant risk factors among transplant candidates –as defined in the Lisbon Conference report include: diabetes, prior cardiovascular disease, dialysis duration of greater than 12 months, left ventricular hypertrophy, age > 60 years, smoking, hypertension, and dyslipidemia (Abbud-Filho et al., 2007). Although the exact number of risk factors required to initiate noninvasive stress testing has not been well defined, the AHA/ACC Committee suggests that the presence of 3 or more risk factors should prompt further evaluation with noninvasive stress testing (Class IIb; Level of Evidence C) (Lentine et al., 2012)

Noninvasive stress testing for CAD may be performed with exercise or with a pharmacological agent, and gauged by electrocardiography (EKG) changes (exercise stress test), myocardial perfusion distribution (myocardial perfusion imaging), or left ventricular wall motion (stress echocardiogram). Myocardial perfusion studies (MPS) and dobutamine stress echocardiogram (DSE) are more commonly used due to the frequent abnormalities detected on baseline EKGs in patients with ESKD. In addition, dialysis patients may not be able to achieve an adequate level of exercise during an exercise stress test because of their sedentary lifestyles. However, it should also be noted that in ESKD patients both myocardial perfusion study (MPS) and DSE have reduced sensitivity and specificity compared with that of the general population. In the general population, abnormalities on myocardial perfusion study has been suggested to correlate well with the presence of coronary artery disease (CAD) with mean weighted sensitivity of 88% and specificity of 74% (Klocke et al., 2003). In patients with stage 5 CKD (GFR < 15 ml/min or dialysis dependent) DSE and MPS have been reported to have sensitivities ranging from 44% to 89%, and 29% to 92%, respectively, and specificities ranging from 71% to 94% and 67% to 89%, respectively, for identifying ≥ 1 coronary stenosis > 70% (Lentine et al. 2009, Lentine et al, 2012). Furthermore, abnormal MPS and DSE test results have not been consistently shown to be associated with prognostic value for cardiac events and mortality in ESKD patients. In a meta-analysis of 12 studies involving either thallium-201 scintigraphy or DSE, Rabbat *et al*. demonstrated that ESKD patients with inducible ischemia had 6 times higher risk of MI and 4 times higher risk of cardiac death than patients without inducible ischemia (Rabbat et al., 2003). In contrast, in a small prospective study of 106 kidney transplant candi‐ dates clinically classified as moderate (age ≥50 years) or high (diabetes mellitus, extra-cardiac vascular disease, or known CAD) coronary risk who underwent MPS, DSE, and coronary angiography, De Lima *et al.* found that clinical risk stratification and coronary angiographic findings of CAD (defined as ≥70% stenosis in ≥1 epicardial arteries by visual estimation by 2 observers) predicted major adverse cardiac events (MACEs) [defined as sudden death, myocardial infarction, arrhythmia, heart failure, unstable angina, or revascularization] after a median follow-up of 46 months but results of MPS and DSE did not predict MACEs (De Lima et al., 2003).

surgical procedure may be required. The 2012 AHA/ACC guidelines recommend that a thorough history and physical examination be performed in all patients preoperatively to identify any active cardiac conditions (Class I; Level of Evidence C). In prospective transplant candidates with chronic cardiac conditions, re-assessment of their cardiac status before surgery may be necessary. The former is defined as chronic limiting angina, an MI that is < 30 days old but without symptoms of unstable angina, prior history of coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI), decompensated heart failure, moderate

I Conditions for which there is evidence for and/or general agreement that the procedure/therapy is useful

II Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/

III Conditions for which there is evidence and/or general agreement that the procedure/therapy is not useful/

B Consistent retrospective cohort, exploratory cohort, ecological, outcome research, or case-control studies, or

**b.** Noninvasive stress testing in kidney transplant candidates without active cardiac

The AHA/ACC recommend noninvasive stress testing in kidney transplant candidates with no active cardiac conditions based on the presence of multiple CAD risk factors regardless of functional status. Eight relevant risk factors among transplant candidates –as defined in the Lisbon Conference report include: diabetes, prior cardiovascular disease, dialysis duration of greater than 12 months, left ventricular hypertrophy, age > 60 years, smoking, hypertension, and dyslipidemia (Abbud-Filho et al., 2007). Although the exact number of risk factors required to initiate noninvasive stress testing has not been well defined, the AHA/ACC Committee suggests that the presence of 3 or more risk factors should prompt further evaluation with

Noninvasive stress testing for CAD may be performed with exercise or with a pharmacological agent, and gauged by electrocardiography (EKG) changes (exercise stress test), myocardial perfusion distribution (myocardial perfusion imaging), or left ventricular wall motion (stress echocardiogram). Myocardial perfusion studies (MPS) and dobutamine stress echocardiogram (DSE) are more commonly used due to the frequent abnormalities detected on baseline EKGs in patients with ESKD. In addition, dialysis patients may not be able to achieve an adequate level of exercise during an exercise stress test because of their sedentary lifestyles. However,

noninvasive stress testing (Class IIb; Level of Evidence C) (Lentine et al., 2012)

valvular disease or prior valve surgey, or stable arrhythmias.

**Evidence Class: Magnitude of procedure/treatment effect**

8 Current Issues and Future Direction in Kidney Transplantation

efficacy of performing the procedure/therapy

effective and in some cases may be harmful

extrapolation from level A studies

IIa Weight of evidence/opinion is in favor of usefulness/efficacy IIb Usefulness/efficacy is less well established by evidence/opinion

C Case-series studies or extrapolations from level B studies

**Evidence Level: Estimate of certainty (precision) of procedure/treatment effect**

A Consistent direction and magnitude of effect from multiple randomized controlled trials

and effective

**Table 4.** Evidence Grading

conditions

Given the wide ranges of sensitivities and specificities of the MPS and DSE and the inconsistent associations of angiographically defined CAD with subsequent survival in ESKD patients, the AHA/ACC Writing Committee acknowledges that there are currently no definitive data to sup‐ port or refute screening for myocardial ischemia among potential kidney transplant candidates without active cardiac conditions. However, it is recommended that until further data are avail‐ able, it may be useful to use aggregate CAD risk factors to target screening of patients with the highest pretest probability of having significant CAD. Suggested algorithm for pretransplant cardiac evaluation based on the 2012 AHA/ACC guidelines is shown in figure 1.

In general, high cardiac risk candidates should undergo a formal evaluation by cardiology. If necessary, percutaneous coronary intervention or coronary bypass surgery and cardiac rehabilitation should be performed prior to transplantation. If coronary intervention is indicated, caution should be made especially if stenting is planned. The 2012 AHA/ACC guidelines do not recommend transplant surgery within 3 months of bare metal stent (BMS) and within 12 months of DES placement, particularly if the anticipated time of poststent dual antiplatelet therapy will be shortened (Class III; level of Evidence B). Transplant surgery is also not advisable in patients within 4 weeks of coronary revascularization with balloon angioplasty (Clas III; Level of Evidence B) (Lentine et al., 2012).

In patients with established CVD or in those at risk for CV events, aggressive risk factor modification and treatment *per* ACC/AHA guidelines (Pearson et al., 2002) are recommended. The cardioprotective effects of statins, aspirin, ACE inhibitors, and/or β blockers have been

Figure 1. Suggested algorithm for pretransplant cardiac evaluation

well-described. Omega-3 fatty acid consumption from fish or fish oil has also been suggested to confer a cardioprotective effect. If feasible, β1 cardioselective agents should be given several weeks prior to a planned living donor renal transplant. This allows time to maximize the efficacy of beta blockers and time to slowly titrate beta blockers, avoiding bradycardia and hypotension. Avoidance of these adverse effects may decrease the risk of stroke and all-cause mortality, leading to a positive net clinical benefit (Deveraeaux et al., 2008, Harte et al. 2008).

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In recent years, cardiac troponin T (cTnT) has been suggested to provide prognostic informa‐ tion in the cardiac evaluation of patients with ESKD. Independent investigators have demon‐ strated an association between increased levels of cardiac toponin T isoforms and all-cause and cardiac death risk in asymptomatic patients with ESKD (Lentine et al., 2009, Khan et al., 2005). In a study consisting of 644 wait-listed renal transplant candidates, Hickson *et al.* demonstrated that increasing cTnT levels were associated with progressively reduced survival independent of low serum albumin and history of stroke. The survival of patients with cTnT levels between 0.01 and 0.03 ng/mL did not differ from that of patients with levels < 0.01 ng/mL. In contrast, cTnT levels between 0.03 and 0.09 ng/mL were associated with significantly increased mortality (hazard ratio, HR=3.01, p=0.040). Notably, mortality was further increased in patients with cTnT levels >0.1 ng/mL (HR=4.085, p=0.009) whereas in patients with normal cTnT, excellent survival was achieved independent of other risk factors (Hickson et al., 2008). The 2012 AHA/ACA guidelines support the use of cTnT level at the time of evaluation for kidney transplantation as an additional prognostic marker (Class IIb; Level of Evidence B) (Lentine et al., 2012). However, the routine use of cTnT as adjunctive tools in cardiac risk

Patients with CKD frequently suffer from nonischemic cardiac abnormalities including left ventricular hypertrophy (LVH), left ventricular dilatation, left ventricular systolic and/or diastolic dysfunction. Renal transplantation has variably been shown to improve left ventric‐ ular dysfunction and ameliorate LVH (Zolty et al., 2008). Hence, the presence of such abnor‐ malities does not necessarily preclude transplantation. Nonetheless, patients with an ejection fraction of 40% are considered moderate to high risk candidates and warrant a formal Cardiology consultation. An ejection fraction below 40% generally precludes transplantation. It is our practice to refer these patients to Cardiomyopathy Center for further diagnostic and therapeutic interventions. The presence of advanced irreversible cardiomyopathy is a contra‐ indication to solitary kidney transplantation and patients should be referred for possible

Patients with a history of transient ischemic attacks or cerebrovascular accidents should under‐ go carotid Doppler studies. Duplex ultrasonography may be considered in asymptomatic pa‐ tients with symptomatic peripheral arterial disease (PAD), CAD, or atherosclerotic aortic

*2.2.1. Biomarkers for cardiac risk assessment*

**2.3. Nonischemic cardiomyopathy**

combined kidney-heart transplantation.

**2.4. Peripheral vascular disease**

assessment in renal transplant candidates remains to be studied.

1Unstable coronary syndromes: unstable angina, severe angina, recent myocardial infarction 1Unstable coronary syndromes: unstable angina, severe angina, recent myocardial infarction 2Myocardial perfusion study or dobutamine stress echocardiogram (center specific).

2Myocardial perfusion study or dobutamine stress echocardiogram (center specific).

**Figure 1.** Suggested algorithm for pretransplant cardiac evaluation

well-described. Omega-3 fatty acid consumption from fish or fish oil has also been suggested to confer a cardioprotective effect. If feasible, β1 cardioselective agents should be given several weeks prior to a planned living donor renal transplant. This allows time to maximize the efficacy of beta blockers and time to slowly titrate beta blockers, avoiding bradycardia and hypotension. Avoidance of these adverse effects may decrease the risk of stroke and all-cause mortality, leading to a positive net clinical benefit (Deveraeaux et al., 2008, Harte et al. 2008).
