Perioperative considerations in kidney transplantation: An anaesthesiologist’s perspective

Abstract

Kidney transplant is the treatment of choice for patients with end-stage kidney disease. Meticulous anaesthetic management is the cornerstone of good postoperative patient and graft outcomes. Over the decades, the perioperative strategies for preoperative optimization, fluid management, immunosuppression, haemodynamic monitoring, and pain management keep changing with the inclusion of newer studies. The aim of this review is to update anaesthesia colleagues for recent advancements in perioperative care of patients undergoing kidney transplantation.

Key Words: End stage kidney disease; Kidney transplantation; Perioperative care; Immunosuppression; Hemodynamic

Core Tip: Updated knowledge of perioperative anaesthetic management in kidney transplantation is important to adhere with latest advancements in hemodynamic monitoring, fluid management, pain control, and other aspects of anaesthesia care to improve postoperative outcomes. This review comprises the best practices based on recent developments in perioperative care of kidney transplant recipients.

INTRODUCTION

Chronic kidney disease (CKD) is among the top chronic illnesses worldwide, with a prevalence ranging from 11% to 13% and being a leading cause of morbidity and mortality[1]. Kidney transplantation is offered to patients with end-stage kidney disease (ESKD) and has advantages of increasing long-term survival as well as better quality of life. It is the most common solid organ transplant performed worldwide. Kidney transplantation is contraindicated in patients with severe infections, severe medical comorbidities, active malignancy, active drug abuse, and uncontrolled psychiatric disorder[2].

Kidney transplantation is a moderate to high-risk surgery due to multi-system involvement, different perioperative haemodynamic targets, immunosuppression, and increased risk of infection; hence, meticulous perioperative anaesthetic management is desired. In this review, we focused on different aspects of anaesthesia care ranging from preoperative assessment to postoperative care of recipients scheduled for kidney transplantation.

PREOPERATIVE CONSIDERATIONS

Preoperative evaluation

All patients scheduled for kidney transplantation must undergo preoperative evaluation days to weeks before surgery. A detailed history of kidney disease (duration, severity, and possible etiologies), dialysis (type, duration, frequency, and access), daily urine output, blood transfusion, previous transplant or surgery, pregnancy (previous or current), associated comorbidities (diabetes, hypertension, coronary artery disease, chronic obstructive pulmonary disease, etc.), involvement of other systems (neurologic, cardiac, pulmonary, hematologic, endocrine, and gastro-intestinal), medications (antihypertensive, anti-diabetic, cardiac, antiplatelet, diuretics, etc.), and drug abuse (smoking, alcohol, and other illicit drugs) is recorded. Donor details include the donor type (deceased or live), age, relation to the recipient, blood group, co-morbidities, glomerular filtration rate (total and split), side of graft, and the number of vessels to be noted.

Pulmonary hypertension, low ejection fraction, valvular dysfunction, arrhythmias, pleural effusion, pulmonary edema, gastroparesis, electrolyte imbalance, anemia, platelet disorder, and osteodystrophy are common consequences of long-standing CKD. Hence, Recipients must be examined thoroughly to see the involvement of other organ systems and their severity as it has a great impact on perioperative anaesthetic management and postoperative outcomes[3-6]. Complete blood count, renal function tests, liver function tests, serum albumin, blood glucose, serum electrolytes, coagulation profile, viral markers (human immunodeficiency virus, hepatitis B and C, and cytomegalovirus), electrocardiogram (ECG), 2 D echocardiography, X-ray chest, pulmonary function test, and pregnancy test in fertile females are the routine investigations required before proceeding to surgery. Additionally, ABO blood grouping, human leucocyte antigen (HLA) test, and cross match are mandatory to decide transplant candidacy.

Recipients may require further evaluation by a psychiatrist, cardiologist, pulmonologist, and urologist for their fitness for kidney transplant surgery and to investigate further if necessary.

Preoperative optimization

Anemia is one of the most common complications of CKD and has multifactorial etiologies. Preoperative correction of anemia is highly encouraged as it is associated with poor postoperative outcomes. Erythropoietin stimulating agents, iron supplementation, vitamin B12, and folic acid are prescribed to improve haemoglobin levels. Preoperative transfusion of red cells carries the risk of HLA sensitization and is highly discouraged[7]. Preoperative spirometry, weight reduction, nutrition build-up, and exercise are highly encouraged as prehabilitation measures to enhance recovery after surgery. Preoperative dialysis is advised to correct volume overload and hyperkalemia (serum potassium ≥ 5.5 mEq/L).

Preoperative instructions

Preoperative advice includes fasting instructions as per standard fasting guidelines before surgery except prolonged fasting in patients with gastroparesis, diabetes, and ascites to hasten the risk of aspiration of gastric contents. Additionally, oral proton pump inhibitors or H₂ receptor blockers are prescribed to reduce gastric pH[8]. Preoperative antihypertensives, antianginals, beta-blockers, and other cardiac medications should be continued while oral hypoglycemics, anticoagulants, and antiplatelets must be stopped before surgery. Low-dose aspirin may continue in patients with an increased risk of coronary stent thrombosis. All patients should undergo haemodialysis (excluding preemptive transplant) the day before surgery and dry weight is measured. Coagulation profile and serum electrolytes are repeated on the day of surgery to see the residual effect of heparin or electrolyte disturbances. Kidney transplant is vascular surgery, associated with increased risk of major bleeding, hence two units of packed red cells should be reserved. Preoperative considerations for kidney transplantation are tabulated in Table 1.

Table 1 Preoperative considerations for kidney transplantation.

Area of management	Anaesthesia considerations
Preoperative evaluation	Detailed history of kidney disease, dialysis, urine output, blood transfusion, previous transplant or surgery, pregnancy, comorbidities, multisystem involvement, medications, and drug abuse
	Detailed donor evaluation
	Physical assessment of the recipient for fitness of surgery
	Routine investigations for surgery
	Special testing to decide transplant candidacy
	Secondary evaluation by other specialists, if needed
	Correction of anemia
Preoperative optimization	Weight reduction, exercise, and nutritional build-up
	Smoking and alcohol cessation at least 4-6 weeks before surgery
	Incentive spirometry
	Preoperative haemodialysis
	Repeat electrolytes and coagulation profile on the day of surgery
Preoperative advice	Continue antihypertensive, antianginals, beta-blockers
	Discontinue oral hypoglycemics, anticoagulants, and antiplatelets
	Fasting: As per standard fasting guidelines, prolonged in patients with gastroparesis, diabetes, and ascites
	Anti-anxiety: Short-acting benzodiazepine
	Oral antacid: H2 receptor blockers or proton pump inhibitors

INTRAOPERATIVE CONSIDERATIONS

Anaesthesia technique

General anaesthesia with intubation is a preferred technique by most transplant anaesthesiologist while some others use neuraxial anaesthesia. Living donor kidney transplantation is an elective procedure and patients fast at the time of surgery while deceased donor kidney transplant is an urgency, hence oral non-particulate antacids (10-20 milliliters of 0.3 M sodium citrate) 15-20 minutes before induction of anaesthesia should be considered to decrease the risk of aspiration. Formation of spinal or epidural hematoma, although rare may occur after neuraxial block due to bleeding related to uremia-induced platelet aggregation and adhesion defect or residual effect of heparin used in dialysis[9]. Metabolic acidosis in CKD enhances the absorption of local anaesthetic agents (LA) at the site of injection due to relative alkalization. Also, there is enhanced distribution of LA due to hyperdynamic circulation, and impaired kidney function reduces clearance of metabolites. Dose of local anaesthetic agents should be reduced to minimize the risk of LA toxicity[10].

Induction and maintenance of anaesthesia

Short-acting benzodiazepine, a small dose of midazolam or remimazolam may be administered intravenously to allay anxiety. Repeated boluses or long-acting benzodiazepines (diazepam or lorazepam) should be avoided as there is an increased risk of prolonged postoperative sedation by active metabolites due to their longer half-life in kidney failure[11]. Among opioids, short-acting agents (remifentanil, fentanyl, or alfentanil) are considered safe as these are metabolized by the liver into inactive compounds and their excretion is unaffected in ESKD. Remifentanil is used as a continuous infusion while fentanyl can be used in small boluses for intraoperative analgesia. Long-acting opioids (e.g., morphine) should be avoided as it has active metabolites (morphine-3-glucuronides and morphine-6-glucoronide) and associated risk of prolonged postoperative sedation and respiratory depression[11-14]. Propofol, in the usual dose of 1-1.5 mg/kg, is a widely accepted induction agent with largely unaffected pharmacokinetic and pharmacodynamic properties in chronic kidney disease[15]. Etomidate provides haemodynamic stability and is selectively indicated in recipients with a risk of haemodynamic compromise at induction of anaesthesia (e.g., ischemic heart disease or low ejection fraction) but the reported incidence of myoclonus is higher in kidney failure[16,17]. Ketamine increases heart rate and blood pressure and may be hazardous in recipients with hypertension and ischemic heart disease. Cisatracurium and atracurium are short-acting non-depolarizing muscle relaxants and metabolize by esterase hydrolysis and non-enzymatic degradation (Hoffman elimination) into inactive metabolite. These are considered muscle relaxants of the choice for both tracheal intubation and surgical relaxation during intraoperative periods. For rapid sequence intubation, succinylcholine can be safely administered provided the serum potassium level is < 5.5 mEq/L, otherwise rocuronium should be used and can be completely reversed with sugammadex when needed[18]. Among volatile inhalational agents, isoflurane, desflurane, and sevoflurane can be used safely for the maintenance of anaesthesia. Isoflurane is usually preferred as a volatile agent with better safety in kidney failure. Prolonged use of sevoflurane has a theoretical risk of nephrotoxicity due to accumulation of fluoride ions and compound A[19]. On completion of surgery, the residual effect of muscle relaxants is terminated with IV neostigmine or sugammadex in usual doses without any risk of postoperative paralysis[18,20].

Anaesthesia monitoring

Standard anaesthesia monitors include non-invasive blood pressure, ECG, capnography, pulse oximetry, and temperature for intraoperative periods. Additionally, the insertion of an arterial cannula may be considered in high-risk cardiac patients for beat-to-beat invasive blood pressure monitoring, to assess fluid responsiveness by observing dynamic indices, and for arterial blood sampling. Blood pressure cuff, intravenous lines, and arterial cannulation should be avoided in the fistula arm due to the risk of damage to the arterial venous fistula[21].

The placement of a central venous catheter in either subclavian or internal jugular vein may be considered for the infusion of anti-thymocyte globulin, vasopressors, and inotropes. Strict aseptic precautions must be sought as there is an increased risk of infection on immunosuppression. Previous multiple-line insertions, venous thrombosis, and distortion of anatomic landmarks can make it difficult to insert a catheter with landmark approach, hence the use of real-time ultrasound for vessel localization and venipuncture is highly encouraged to improve success rate and reduced complications[22].

Fluid management

Fluid management is a crucial part of perioperative care in kidney transplantation as hypovolemia leads to hypotension and poor flow to newly grafted kidneys. It further increases the risk of higher dosages of vasopressors or inotropes, metabolic acidosis, ischemia-reperfusion injury, acute tubular necrosis, acute kidney injury, delayed graft functioning, and rejection. Traditionally, central venous pressure (CVP) monitoring has been considered to assess fluid responsiveness with target CVP ranging from 1-2 kPa, but recent evidence is against its routine use during kidney transplantation. Newer dynamic indices [stroke volume variation (SVV), pulse pressure variation (PPV), cardiac output] have been investigated and found better for intraoperative fluid management with reduced incidences of postoperative complications. The recommended target PPV or SVV during the intraoperative period is 10%-15%. There is loss of autoregulation in the denervated kidney and perfusion of graft is mainly dependent on the recipient’s mean arterial pressure (MAP), hence continuous measurement of MAP is helpful. The recommended target MAP after reperfusion is 12-14.6 kPa. Small boluses of intravenous ephedrine (5-10 mg) or low-dose norepinephrine can be considered to maintain desired MAP after reperfusion of graft[23-25]. Currently, the use of low-dose dopamine to improve urine output is opposed as it is associated with tachycardia, increased length of stay in the intensive care unit, and mortality[26]. Continuous infusion of nitroglycerine or labetalol (bolus or infusion) may be considered to manage perioperative hypertension.

Immediate urine output on the opening of the vascular clamp is a sign of graft function. If there is no urine output within 5 minutes of reperfusion, increasing blood pressure, fluid bolus, and/or IV furosemide (10-40 mg) may be considered. Mannitol, 12.5-25 g, 10-15 minutes before graft reperfusion has been considered an osmotic diuretic, free radical scavenger, and decreases ischemia-reperfusion injury in decreased donor kidney transplantation but routine use is not recommended[27,28].

Intravenous crystalloids are preferred over colloids in the perioperative period. Infusion of normal saline in large doses (> two liters) has a risk of hyperchloremic metabolic acidosis, hyperkalemia, renal afferent vasoconstriction, reduced GFR, urine production, and delayed graft function (DGF). A lactated ringer is a hypotonic solution and may cause lactic acidosis and hyperkalemia. Balanced low chloride solutions (e.g., plasmalyte-A) are isotonic, contain acetate as a buffer, and significantly decrease the risk of DGF with better perioperative acid base and electrolyte control and are considered the crystalloid of choice in kidney transplantation[29,30]. Colloids containing starches are not recommended in kidney transplantation due to the inherent risk of coagulopathy, kidney injury, and postoperative graft dysfunction[31,32]. Albumin increases plasma oncotic pressure, has antioxidants and anti-inflammatory properties, and decreases the risk of ischemia reperfusion injury but has a potential risk of immunogenicity, disease transmission, and increased cost. Routine use is not recommended to improve early graft function and should be considered in selected patients with low serum albumin (< 30 g/L) or when there is an excessive requirement of intraoperative fluids or vasopressors[33].

Transfusion management

Delivery of oxygen is unaffected in ESKD patients as the oxygen dissociation curve is shifted to the right due to chronic anemia. Blood loss during kidney transplantation is usually 100-200 mL and does not necessitate blood transfusion. The intraoperative threshold for blood transfusion is serum haemoglobin level < 70-80 g/L[34]. Leukoreduced red blood cells decrease the risk of HLA alloimmunization and transfusion-related reactions. Alteration in coagulation system in ESKD is multifactorial (platelet dysfunction, anemia, thrombocytopenia, uremia, endothelial dysfunction, and inflammation) and associated with increased risk of both thrombosis and bleeding. Perioperative transfusion of blood products (fresh frozen plasma, cryoprecipitate, or platelets) and antithrombotic agents (e.g., heparin) must be individualized and considered carefully. Use of point of care coagulation testing with viscoelastic devices (e.g., thromboelastography) proves helpful in reducing transfusions and related complications[35-37].

Immunosuppression

During the intraoperative period, induction therapy with anti-thymocyte globulin, a polyclonal antibody, 1-1.5 mg/kg, or basiliximab, a monoclonal antibody, 20 mg IV is given to prevent acute rejection. The selection of induction agent is based on donor (live/decreased, ischemia time, elderly, and HLA match) and recipient (re-transplant, HLA sensitization) characteristics and is decided by the transplant nephrologist. Antithymocyte globulin infusion should be given slowly through a central venous catheter over 4-6 h and should be preceded by injection of paracetamol 0.5-1 g, hydrocortisone 100 mg, and pheniramine maleate 45.5 mg to prevent infusion-related reactions. IV methylprednisolone 10 mg/kg is given 10-15 minutes before graft reperfusion to prevent acute graft rejection[38].

Pain management

Pain during kidney transplantation is usually mild to moderate and adequate pain control can be achieved by multimodal analgesia including IV paracetamol, IV opioids (remifentanil or fentanyl), intrathecal morphine, epidural analgesia, skin infiltration by local anaesthetic agents, and/or fascial plane blocks (erector spinae, quadratus lumborum or tranversus abdominis plane)[39]. Analgesia modalities are to be individualized based on patient characteristics, renal function, anaesthesia technique, and patient tolerance to pain. Intrathecal morphine has shown an added advantage of reducing catheter-related bladder discomfort in the postoperative period. Fascial plane blocks are effective in perioperative pain control, has the advantages of decreased consumption of IV analgesics and opioids are devoid of pharmacological interaction with other drugs, and are safely performed under ultrasonic guidance[40,41]. Nonsteroidal anti-inflammatory drugs induced afferent vasoconstriction and impairment of renal blood flow may cause acute kidney injury in transplanted kidney and to be avoided in kidney transplant recipients[42,43].

Other intraoperative measures

Temperature is monitored every half an hour and body warmers (forced air warmers, warming blankets, fluid warmers) should be used to prevent hypothermia. Close blood glucose monitoring is recommended especially in diabetics, and the target blood glucose during the perioperative period is 6-10 mmol/L[44]. To minimize the risk of surgical site infection, first-generation cephalosporin (e.g., cefazolin) 2 g IV, is administered 30-60 minutes before skin incision, although practice may vary at different transplant centers[45]. For prevention of postoperative nausea and vomiting, IV palanosetron 0.075 mg is preferably given as it does not carry a risk of QT prolongation. Intraoperative considerations for kidney transplantation are tabulated in Table 2.

Table 2 Intraoperative considerations for kidney transplantation.

Area of management	Anaesthesia considerations
Anaesthesia technique	General anaesthesia with intubation: Preferred
	Neuraxial blocks: Risk of spinal or epidural hematoma
	Dose of LA should be reduced
Anaesthesia monitoring	Monitoring: Standard ASA monitors (NIBP, SPO2, ECG, ETCO2, temperature)
	Arterial line: For beat-to-beat blood pressure monitoring and arterial blood gas analysis, avoided in fistula arm
	Central venous catheter: For infusion of induction therapy and vasopressors/inotropes
Fluid management	Fluid responsiveness by dynamic indices (SVV or PPV): Target 10%-15%
	Crystalloids: Low chloride solutions – preferred to avoid normal saline large doses, risk of hyperkalemia and lactic acidosis with ringer lactate
	Colloids: Avoid starches: Risk of coagulopathy, renal injury, routine use of albumin is not recommended
Transfusion management	Red cell transfusions: Transfusion trigger is haemoglobin < 70-80 g/L, Leukoreduced red cell preferred
	Fresh frozen plasma/ cryoprecipitate/ platelet: Avoided routinely, if required point of care coagulation monitoring guide suggested
Pain management	Multimodal analgesia and individualized approach: IV paracetamol, fascial plane block, intrathecal morphine, epidural analgesia, skin infiltration with local anaesthetic Avoid NSAIDS
Immunosuppression	Induction therapy: Antithymocyte globulin, 1-1.5 mg/kg or basiliximab, 20 mg
	IV methylprednisolone (10 mg/kg): 10-15 min before reperfusion of graft
Other interventions	Blood glucose: Target blood sugar 6-10 mmol/L
	Temperature: > 35.5 °C, forced air warming device or blankets, fluid warmers
	Antibiotic prophylaxis: Cefazolin 2 g IV, 30-60 min before surgical incision
	PONV prophylaxis: IV palanosetron 0.075 mg

LA: Local anaesthetic agents; ASA: American Society of Anaesthesiologists; NIBP: Noninvasive MAP; SPO2: Oxygen saturation; ECG: Electrocardiogram; ETCO2: End-tidal carbon dioxide; SVV: Stroke volume variation; PPV: Pulse pressure variation; IV: Intravenous; NSAIDS: Nonsteroidal anti-inflammatory drugs; PONV: Postoperative nausea and vomiting.

SPECIAL CONSIDERATIONS

ABO incompatible transplantation

ABO incompatibility has been considered a contraindication to kidney transplantation, but recent advancements in immunosuppression and desensitization protocols made it possible with excellent results. Anaesthesia management in ABO incompatible kidney transplantation is challenging and needs special attention. In preoperative periods, these patients require intense immunosuppression and multiple sessions of plasmapheresis as a desensitization (removal of donor-specific antibodies) protocol that causes hypoalbuminemia, depletion of fibrinogen and other clotting factors, removal of protective antibodies and need volume replacement with fresh frozen plasma. Hence, higher standards of aseptic precautions must be sought to minimize the risk of infections and intraoperative infusion of albumin should be considered to reduce the need for fluids and vasopressors. Coagulation abnormalities may preclude regional blocks for both anaesthesia and analgesia due to the inherent risk of hematoma formation. Also, viscoelastic coagulation tests may be used to rule out pre-existing coagulation abnormalities and reduce transfusions[46]. Transfusion practice in ABO incompatible kidney transplant requires special considerations. Red blood cells of recipient’s own blood group while plasma and platelets of donor blood group (unidirectional transplant) or AB blood group (bidirectional transplant) must be planned if needed[47].

Paired kidney transplant

Kidney-paired donation (KPD) is indicated in HLA incompatibility, where antibodies against donor HLA are present in the recipient. In the past, it was considered a contraindication to kidney transplants but nowadays availability of better immunosuppression and desensitization techniques made it feasible but higher cost, increased risk of infections, and suboptimal outcomes make KPD as a preferred option in patients with HLA incompatibility[48]. Special attention must be sought while planning for anaesthesia care including a detailed evaluation of medical records of both donor and recipient (blood group, relation, crossmatch) and legal documents related to paired donations as per national laws. Multidisciplinary approach including transplant surgeon, nephrologist, anaesthesiologist, and intensivist must be planned from preoperative optimization, and intraoperative management, to postoperative care of patients. Availability of extra resources (operation theater, personnel, emergency equipment and drugs) must be ready beforehand as the surgeries undergo simultaneously. Also, ensure availability of 24/7 rapid response team and access to specialized medical services including cardiologists, radiologists, and blood banks for emergency backup[49].

CONCLUSION

In conclusion, recently, a significant change in perioperative anaesthesia management in kidney transplantation has occurred. Inclusion of goal-directed fluid therapy, ultrasound-guided regional blocks for analgesia, availability of advanced haemodynamic monitoring, and better immunosuppression improved the postoperative outcomes after kidney transplantation.