© Springer Science+Business Media New York 2017Kathirvel Subramaniam and Tetsuro Sakai (eds.)Anesthesia and Perioperative Care for Organ Transplantation10.1007/978-1-4939-6377-5_22
22. Anesthesia and Intraoperative Management of Renal Transplantation
Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305-5649, USA
KeywordsChronic kidney diseaseEnd-stage renal diseaseRenal transplantationDonation after cardiac death (DCD)HypertensionDiabetes
The global epidemic of diabetes and hypertension has resulted in a dramatic increase of chronic kidney disease. Currently, the prevalence of chronic kidney disease varies between 8 and 16 % among different populations in the world . For patients with end-stage renal disease (ESRD), a transplant provides better survival and health-related quality of life than dialysis [2–4]. In addition, transplantation is less resource intensive and more cost effective than dialysis [5, 6].
Renal transplantation is the most commonly performed organ transplantation in the world. In the USA alone approximately 18,000 kidney transplants are done each year. Unfortunately, because of organ shortages the number of transplants is not significantly increasing. The transplant waiting list however continuous to grow with about 4 % per year and has reached 55,371 active status patients on December 31, 2011. The median waiting time for transplantation has now increased to more than 4 years. Consequently, most patients requiring a renal transplant will not receive one.
In an attempt to alleviate the organ shortage expanded criteria donors and donation after cardiac death (DCD) are alternative strategies to increase the cadaveric donor pool. The long-term survival of single- or dual-kidney grafts from expanded criteria donors older than 60 years of age are excellent, provided that the grafts are evaluated histologically before implantation . With respect to DCD kidneys, initial reports showed higher primary non-function rates. However, in a recent retrospective comparison of post-transplant kidney function there was no difference between DCD kidneys and donation after brain-death kidneys .
Ideally, renal transplantation should precede long-term dialysis . The success of transplantation is negatively affected by lengthy pre-transplantation dialysis dependence . Early transplantation however can only be achieved with living donor transplants. The addition of paired kidney exchanges, altruistic donation, and altruistic donor chains to classic direct donation has significantly expanded the number of live donations. Although transplantation between compatible donor recipient combinations remains preferable, in experienced transplant centers HLA- and ABO-incompatible transplantations have become a reasonable alternative for end-stage kidney disease patients with an incompatible live donor.
Preoperative Considerations Relevant to Intraoperative Management
Coronary Artery Disease
Chronic kidney disease is an independent risk factor for coronary artery disease. A cardiovascular event is the most common cause of death in the perioperative period of renal transplantation. Therefore, screening for coronary artery disease is an essential part of the preoperative evaluation for kidney transplant candidates. Knowledge of the severity of cardiac disease will dictate the perioperative management plan. Recently guidelines for the cardiac disease evaluation and management among kidney transplantation candidates have been endorsed and published by the American Society of Transplant Surgeons, American Society of Transplantation, and National Kidney Foundation . The guidelines recommend a thorough history and physical examination in every patient to identify active cardiac conditions. In patients without known cardiovascular disease a resting 12-lead ECG followed by annual ECGs while on the waiting list is recommended. In patients with no active cardiac condition, but with multiple coronary artery disease risk factors, noninvasive stress testing should be considered regardless of functional status. Risk factors are 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 three or more is considered reasonable. In those patients it is also reasonable to perform preoperative assessment of left ventricular function by echocardiography.
Patients with active cardiac disease such as a left ventricular ejection fraction less than 50 %, left ventricular dilation, exercise-induced hypotension, angina, or symptoms of myocardial ischemia should be referred to a cardiologist for evaluation and long-term management according to American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the general population.
For patients who need coronary artery bypass grafting (CABG) a multidisciplinary team on a case-by-case basis must weigh the risk of CABG before renal transplantation, since the CABG procedure may outweigh the risk of transplantation. For patients with multi-vessel coronary artery disease (CAD) plus diabetes mellitus the guidelines state that CABG is preferable to percutaneous coronary intervention (PCI). For patients with significant (>50 %) left main stenosis or significant (≥70 %) stenosis in three major vessels or in the proximal left anterior descending artery plus one other major vessel CABG to improve survival and/or to relieve angina may be reasonable.
In patients in whom coronary revascularization with PCI is appropriate and who are expected to receive a transplant in the subsequent 12 months, balloon angioplasty or bare-metal stent (BMS) placement followed by 4–12 weeks of dual-antiplatelet therapy is probably the best strategy. In patients who have received a drug-eluting stent (DES) it may be reasonable to perform kidney transplantation surgery without interruption of clopidogrel therapy if the risk of bleeding is low. Transplantation surgery within 3 months of BMS placement and within 12 months of DES placement is not recommended, particularly if the anticipated time of post-stent dual-antiplatelet therapy will be shortened. Transplantation surgery is not recommended within 4 weeks of coronary revascularization with balloon angioplasty.
Among patients being considered for renal transplantation with clinical markers of cardiac risk (diabetes mellitus, prior known coronary heart disease, prior heart failure, extra-cardiac atherosclerosis) and those with unequivocal myocardial ischemia on preoperative stress testing, it is reasonable to initiate beta-blockers preoperatively and to continue them postoperatively provided that dose titration is done carefully to avoid bradycardia and hypotension.
Perioperative initiation of beta-blockers in beta-blocker-naive patients may be considered in kidney transplantation candidates with established coronary heart disease or two or more cardiovascular risk markers to protect against perioperative cardiovascular events if dosing is titrated and monitored. However, initiating beta-blocker therapy in beta-blocker-naive patients the night before and/or the morning of surgery is not recommended.
Hypertension is both a cause and a consequence of chronic kidney disease. In patients with end-stage renal disease the prevalence of hypertension is close to 100 %. Adequate blood pressure control in the perioperative period is particularly important due to the increased risk of cardiovascular disease and stroke. For patients taking beta-adrenergic blockers before renal transplantation, continuing the medication perioperatively and postoperatively is recommended to prevent rebound hypertension and tachycardia.
The prevalence of atrial fibrillation (AF) in ESRD patients is higher than in the general population and is associated with an increased risk of stroke and mortality . Pre-existing AF is associated with poor post-transplant outcomes . The majority of studies do not support a protective effect for warfarin in ESRD patients with AF.
In dialysis patients the prevalence of pulmonary hypertension is 30–60 % . The pathogenesis is unclear and probably multifactorial. Pulmonary hypertension is associated with increased graft failure and mortality after renal transplantation . It is not evident that the decreased success of renal transplantation is a reflection of poor cardiac function. Kidney transplantation candidates with echocardiographic evidence of significant pulmonary hypertension should be evaluated for underlying causes (e.g., obstructive sleep apnea, left heart disease). Echocardiographic evidence of significant pulmonary hypertension in this population is defined by right ventricular systolic pressure more than 45 mmHg or ancillary evidence of right ventricular pressure overload. Right heart catheterization confirming the presence of significant pulmonary arterial hypertension (as defined by mean pulmonary artery pressure ≥25 mmHg, pulmonary capillary wedge ≤15 mmHg, and pulmonary vascular resistance of >3 Wood units) in the absence of an identified secondary cause (e.g., obstructive sleep apnea, left heart disease) requires referral for pulmonary arterial hypertension management and vasodilator therapy to optimize these patients before transplantation. Patients with significant pulmonary hypertension may benefit from monitoring their pressures with a pulmonary artery catheter and intraoperative transesophageal echocardiography (TEE) to monitor right ventricular function. Following renal transplantation pulmonary artery pressures decrease significantly [14–16].
In patients with ESRD under dialysis treatment , heart failure is a relatively common finding. No consensus exists on the level of systolic dysfunction at which patients are at an acceptable risk to undergo renal transplantation. In a retrospective study after transplantation patients with pre-existing left ventricular (LV) dysfunction did have more CHF-related hospitalizations but similar overall survival, graft function, and graft loss when compared with control patients . The vast majority (87 %) of patients with LV dysfunction showed normalization of the left ventricle ejection fraction (LVEF) within 12 months. In another study a cohort of 103 patients with LVEF ≤40 % undergoing renal transplantation showed normalization of LVEF in 69.9 % of the patients within a year . ESRD with significantly depressed ventricular function is not a contraindication to renal transplantation, but it may complicate the anesthetic management. Patients with significant decreased ejection fractions may benefit from intraoperative TEE.
Diabetes mellitus is not only the most significant risk factor for the development of ERSD but is also associated with significantly higher rate of graft loss and mortality after transplantation . Cardiovascular events are the cause of mortality in over 60 % of patients. After renal transplantation patients with diabetes have an increased risk of infection. Compared with renal transplant recipients without diabetes infection-related mortality is increased . End-stage renal disease patients with diabetes have a compromised immune system due to impaired neutrophil and monocyte function . Immunosuppression after transplantation further decreases the immunological response. In retrospective studies perioperative hyperglycemia in diabetics and non-diabetics is associated with an increased likelihood of delayed graft function [22, 23]. The usefulness of strict control of blood glucose concentration during the perioperative period is uncertain in patients with diabetes mellitus undergoing kidney transplantation. Tight perioperative glycemic control with intravenous insulin did not decrease the incidence of delayed graft function in diabetics when compared to standard subcutaneous insulin therapy .
The use of erythropoietin has virtually eliminated the problem of anemia in those with ESRD. The number of blood transfusions has dramatically decreased, and quality of life, cognitive function, exercise tolerance, cardiac function, and, most importantly, survival have increased . In diabetics, maintaining the hematocrit at greater than 30 % is associated with a 24 % reduction in cardiac events in the first 6 months after transplant .
Chronic kidney disease is associated with a prothrombotic tendency in the early stages of the disease. After progression to ESRD, bleeding diathesis by inhibited platelet adhesion to injured vessels is added to the picture . Platelet adhesion to the injured vessel wall is impaired by dysfunction of von Willebrand factor (vWF) , enhanced production of nitric oxide (vasodilator and platelet function inhibitor), and anemia. Correction of anemia in ESRD disease decreases bleeding tendency. The therapeutic effect of anemia correction is explained by enhancing platelet contact to the vessel wall. The increased number of red blood cells distributes more platelets from the center of the blood vessel toward the periphery, increasing platelet contact with and adhesion to injured vessel walls. In addition, the release of ADP (a platelet aggregation inducer) from red blood cells and the scavenging effect exerted by hemoglobin on nitric oxide exert a therapeutic effect .
Desmopressin (DDAVP) can be used to promote platelet aggregation by increasing plasma vWF and factor VIII levels. DDAVP can be administered either intravenously or subcutaneously at a dose of 0.3 mg/kg in a single dose. Cryoprecipitate rich in factor VIII and vWF also has a rapid onset of action and its effect is short lived (4–12 h).
Estrogen administration can achieve more prolonged correction of bleeding tendency. Estrogen can either be administered intravenously at a dose of 0.6 mg/kg daily for 5 days or it can be administered transdermally in the form of estradiol, 50–100 mg, twice a week.
The elderly are the fastest growing population with chronic kidney disease. Kidney transplantation can result in improved life expectancy and quality of life in the elderly. Age is no longer considered an absolute contraindication to transplantation. In carefully selected elderly patients the overall outcome after transplantation is excellent .
The prevalence of obesity (body mass index (BMI) ≥30 kg/m2) at the time of transplantation among kidney transplant recipients continues to increase inexorably. Although controversial, obesity is considered a predictor of acute rejection and other adverse outcomes after kidney transplantation . Cutoff BMI values above which patients will not be transplanted differ among centers.
Patients with diabetes mellitus and BMI >30 have an increased infection risk and a trend towards decreased survival after transplantation . Total body weight dosing of IV anesthetics in the obese will result in overdosing and ideal body weight dosing will result in underdosing. Lean body weight is the preferred dosing scalar for most IV anesthetic agents in the obese population.
Human Immunodeficiency Virus
Kidney transplantation in human immunodeficiency virus (HIV)-infected recipients is being performed and investigated in select centers. A high incidence of early post-transplant complications such as acute rejection has been observed. The high rejection rates are of serious concern .
Adequate venous access should be established because there is a potential for rapid blood loss. Before induction of anesthesia the fluid status of the patient undergoing renal transplant surgery needs to be assessed. Fluid status can range from significant hypovolemia to fluid overload. The patient’s volume status can be estimated by the frequency of dialysis and when it was last performed.
Hyperkalemia is a feature of chronic renal insufficiency and probably is an adaptive response that reflects a new set point for potassium hemostasis and excretion . Recognition that mild-to-moderate hyperkalemia is an adaptive response should lead to tolerance of steady-state serum potassium levels of 5.0–5.5 mmol/L. Therefore, serum potassium levels in the 5.0–5.5 mmol/L range should not be a reason to delay surgery. Higher levels or acute increases must be treated.
Gastroparesis is another common feature of ERSD. Gastroparesis is not limited to diabetics with ESRD. The prevalence in patients with all-cause ESRD is reported to range between 36 and 62 % [34, 35]. Therefore, it seems prudent to treat ESRD patients as having a full stomach.
Standard intraoperative monitoring as recommended by the American Society of Anesthesiologists is required for all renal transplant patients. In addition, monitoring should reflect relevant comorbidities and volume status changes that can vary with the time since the last dialysis. A central venous catheter (CVC) aids in the assessment of volume status and can be used for rapid central venous fluid and drug administration. Central venous pressures are the most commonly used metric for assessment of static preload . However, the utility of central venous pressure monitoring in patients with myocardial dysfunction and left-heart failure diminishes. Although seldom required, transesophageal echocardiography (TEE) and pulmonary arterial catheters may be indicated for patients with severe left ventricular dysfunction, valvular abnormalities, or pulmonary hypertension.
Invasive, intra-arterial blood pressure monitoring is the gold standard of blood pressure measurement and has a low complication rate. It is especially useful in patients with significant cardiovascular or lung disease. New devices allow continuous cardiac output and stroke volume variation to be monitored using mathematical interpretation of the arterial waveform. These metrics have been shown to accurately reflect fluid responsiveness in surgical patients and may be useful in the absence of TEE or pulmonary arterial catheters .
Pharmacokinetics and Pharmacodynamics
Chronic kidney disease does not affect only drugs excreted by the kidney. Changes in plasma protein binding associated with chronic kidney disease can profoundly affect hepatic metabolism and distribution. Diminished plasma protein binding increases free fraction of the drug. For example, if total (free plus protein-bound) plasma concentrations are considered, many lipophilic drugs such as diazepam, midazolam, and thiopental appear to have an increased drug distribution and clearance; but if the pharmacokinetics are calculated in terms of free unbound drug, both distribution and clearance remain unchanged [38–40]. The net result is an underlying rate and extent of distribution and elimination much the same as in normal patients.
Cardiac output affects the early pharmacokinetics (front end kinetics) of drug distribution and dilution in the first minutes after administration. A decreased cardiac output increases the fraction of drug distributed to brain, reduces the rate of redistribution, and results in higher concentrations and reduced dose requirements.
An increased cardiac output decreases the fraction of drug distributed to the brain and increases the rate of redistribution, which will result in lower concentrations and increased dose requirement. Anemia associated with renal failure patients may result in a higher cardiac output and as a result an increased dose requirement.
In a study evaluating the induction dose of propofol in renal failure patients there was a significant negative correlation of propofol dose with preoperative hemoglobin concentration . End-stage renal disease patients required significantly higher propofol doses to induce loss of (1.42 (0.24) mg/kg versus 0.89 (0.2) mg/kg) in normal renal function patients. Propofol dose required to achieve a BIS of 50 was also higher in ESRD patients (2.03 (0.4) mg/kg versus 1.39 (0.43) mg/kg) in normal renal function patients . The propofol concentration associated with loss of consciousness is similar between healthy subjects and patients with renal failure . In hypovolemic patients or patients with decreased LV function propofol induction dose should be reduced and carefully titrated. There is no difference in the pharmacokinetics for maintenance infusion of propofol between healthy subjects and patients with renal failure [42, 43]. Propofol, a weak acid, is highly bound (98–99 %) to plasma protein, mainly albumin. Protein binding is not different in patients with renal disease .
Etomidate may be a useful induction agent in patients with severely compromised cardiac function. However, in a retrospective study etomidate administration for induction of anesthesia has been associated with increased 30-day mortality and cardiovascular morbidity after non-cardiac surgery . The percentage of unbound (free) plasma etomidate is increased in patients with renal failure (43 % in renal failure patients versus 25 % in healthy subjects) .
Currently thiopental is not commercially available in the USA. In patients with chronic renal failure, the free fraction of thiopental was almost twice that found in healthy subjects . The reduced plasma protein binding of thiopental in renal failure is related partly to hypoalbuminemia and partly to competitive displacement of thiopental from binding sites by substances present in uremic plasma. In one study, the thiopental induction dose in renal failure patients was similar to normal subjects .
When sevoflurane is administered the US Food and Drug Administration recommends not to use fresh gas flows <1 L/min and not to exceed 2 MAC hours at fresh gas flow rates between 1 and 2 L/min. For exposures greater than 2 MAC hours fresh gas flows of 2 L/min are required. The safety of sevoflurane in patients with chronic kidney disease has not been established due to remaining concerns about compound A and inorganic fluoride-induced renal toxicity. Degradation of sevoflurane to compound A (fluoromethyl-2,2-difluoro-1-[trifluoromethyl] vinyl ether) occurs by a reaction with strong bases such as barium hydroxide lime or to a lesser extent soda lime which are present in carbon dioxide absorbers of the anesthesia apparatus breathing circuit. Low fresh gas flows and higher temperatures in the breathing circuit increase compound A concentrations. Compound A causes renal injury in rats and is cytotoxic to human kidney-derived HD-2 cells [48–50]. The mechanism of compound A renal toxicity is unclear but is probably related to the renal cysteine conjugate beta-lyase pathway in the biotransformation of compound A. In human studies with compound A exposure as high as 428 ppm/h no evidence of renal toxicity could be demonstrated [51–56]. However, other studies at exposure greater than 160 ppm/h demonstrate renal dysfunction as measured by albuminuria, glucosuria, and enzymuria [57–59]. Fluoride ions are produced by oxidative defluorination of sevoflurane by the cytochrome P450 system in the liver. Deterioration in renal function as demonstrated by increased serum urea nitrogen and creatinine levels at 24 h was detected after peak serum inorganic fluoride concentrations greater than 50 mmol/L . Inorganic fluoride is excreted in the urine at approximately half the glomerular filtration rate. In renal failure patients the half life of fluoride is prolonged , thereby increasing the risk for nephrotoxicity. The few studies in patients with renal insufficiency indicate no further worsening of renal function after sevoflurane anesthetics [61–63]. Recognizing the limited safety data in patients with chronic kidney disease it is prudent to use sevoflurane with caution in renal transplant patients.
Isoflurane is not nephrotoxic. Similarly desflurane biodegradation does not increase fluoride concentration and worsening renal function has not been observed in patients with or without renal disease [55, 57, 64, 65].
Succinylcholine can be used safely in patients with chronic renal failure, assuming that the potassium concentration is less than 5.5 mEq/L . The hyperkalemic response after succinylcholine administration is not exaggerated and just as in healthy patients a transient potassium increase of approximately 0.5–1.0 mEq/L is observed. In the presence of conditions that increase the risk of an exaggerated hyperkalemic response (e.g., burns, trauma, tissue ischemia, infections, and neuromuscular disorders including neuropathies), succinylcholine should be avoided. Renal failure can be associated with reduced plasma cholinesterase activity and succinylcholine can cause a prolonged neuromuscular block .
Patients with chronic renal failure may require a reduced dose of mivacurium . Recovery from mivacurium-induced neuromuscular blockade is slower and correlates with the reduced plasma cholinesterase activity . The clearance of the cis–cis isomer, an isomer contributing minimally to the neuromuscular block, is significantly reduced.
In patients with renal failure there is large between-patient variability in pharmacodynamic and pharmacokinetic parameters of rocuronium . The major route of rocuronium elimination is by direct liver uptake and excretion in the bile. The liver metabolizes a small portion of rocuronium and some is excreted renally. In renal failure patients the clearance of rocuronium is reduced by 33–39 %, with a 66–84 % increase in the mean residence time. The decreased or absent renal clearance explains the prolonged mean residence time and possible prolongation of effect. When endotracheal intubation and neuromuscular block for a short period of time are needed rocuronium 0.3 mg/kg can provide adequate intubating conditions 4–5 min after administration. Mean recovery times after this dose in patients with and without renal failure are not different. However, there was a significant difference in the variability of the total duration of the block. In the renal failure group the time to spontaneous recovery of the TOF to 70 % ranged from 11 to 95 min . Rocuronium, 1.2 mg/kg, can be used for rapid sequence-induction tracheal intubation but anticipate prolonged recovery from neuromuscular blockade.
The majority of vecuronium is excreted in the bile. In a meta-analysis of eight studies it was shown that the duration of action of vecuronium is longer in patients with renal failure . The plasma clearance and elimination half-life are decreased. These findings can be explained by the fact that 20–30 % of administered vecuronium in healthy subjects is excreted by the kidneys. The pharmacokinetics and dynamics of vecuronium are also highly variable in renal failure patients.