Perioperative anesthesia care for the pediatric patient undergoing a kidney transplantation: An educational review

Abstract Living‐donor kidney transplantation is the first choice therapy for children with end‐stage renal disease and shows good long‐term outcome. Etiology of renal failure, co‐morbidities, and hemodynamic effects, due to donor‐recipient size mismatch, differs significantly from those in adult patients. Despite the complexities related to both patient and surgery, there is a lack of evidence‐based anesthesia guidelines for pediatric kidney transplantation. This educational review summarizes the pathophysiological changes to consider and suggests recommendations for perioperative anesthesia care, based on recent research papers.


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VOET ET al. disease prevalence, etiology, and registration differ worldwide, so comparison between regions is difficult.
The etiology of ESRD in children, and therefore, the pathophysiological changes to consider, differ significantly from those in adults.
In young children, common causes are congenital disorders such as dysplastic kidneys and obstructive uropathy. In older children, glomerulopathies such as focal segmental glomerulosclerosis are more prevalent.
Renal replacement therapies include hemodialysis, peritoneal dialysis, and kidney transplantation from a deceased or living donor.
Timing and type of renal replacement therapy vary between countries, depending on cultural and economic factors. For example, in North America and Europe, transplantation is the ultimate renal replacement therapy. In some European countries, up to 50% of transplantations are performed using living donors, and in several countries, children are given priority on the waiting list. In contrast, Middle East and African countries have the lowest organ donation rates of any source. 4 Most donor kidneys come from adult donors, but kidneys of small deceased pediatric donors (<20 kg) can also be transplanted. These small kidneys are often transplanted "en bloc": two kidneys along with a part of the donor aorta and vena cava.
Having the potential to grow along with a growing recipient, small pediatric kidneys show a good long-term outcome when transplanted in older children or adult recipients. 5 However, in small pediatric recipients, this procedure shows a high incidence of vascular complications. Therefore, adult donor kidneys are preferred for small recipients (<20kg).

| Cardiovascular changes in children with endstage renal disease
The pathophysiology of kidney disease affects various components of the hemodynamic system, causing hypertension and structural cardiovascular changes even at a young age.
Sodium homeostasis and blood pressure regulation are closely related through the pressure natriuresis system. In a healthy state, an increased blood pressure at the glomerulus results in decreased sodium reabsorption in the tubules, causing natriuresis and a reduction in circulating volume and blood pressure. 6 In renal disease, this mechanism is impaired, which results in an increased circulating volume and thus increased myocardial preload and stroke volume.
Furthermore, the left ventricular afterload is increased due to a chronically activated sympathetic nervous system (SNS). In the normal state, close interaction between the SNS and the kidneys maintains blood pressure and glomerular filtration rate (GFR). However, in diseased kidneys, the reduced GFR stimulates the renin-angiotensin system and the afferent sympathetic output to the SNS. 7 The increased SNS activity then results not only in hypertension, but also reduced heart rate variability and impaired baroreflex sensitivity. 8 Additionally, uremia and electrolyte imbalances cause endothelial dysfunction and vascular calcifications. This vasculopathy causes increased arterial stiffness and therefore reduced compliance of the vascular tree, further augmenting the cardiac afterload. 9 Consequently, both changes in preload and afterload increase the myocardial workload. Indeed, the majority of pediatric patients with renal failure show myocardial strain and left ventricular hypertrophy on echocardiography. Although systolic function is usually not impaired, diastolic dysfunction is often found. This puts children with ESRD at an increased risk for cardiovascular complications. Early transplantation has been shown to prevent impairment of baroreflex function and improve left ventricular function in children with ESRD and myocardial hypertrophy. Kidney transplantation in an early stage of kidney failure may therefore slow down cardiovascular pathophysiological changes. 10

| Hemodynamic physiology of the donor kidney
Ischemia and subsequent reperfusion render the donor kidney particularly vulnerable to tissue hypoxia and acute kidney injury (AKI). The challenge in kidney transplantation is to minimize kidney tissue hypoxia by balancing oxygen delivery and oxygen consumption ( Figure 1).
At donor nephrectomy, oxygen delivery ceases completely. This is followed by a short warm ischemia period after which the donor kidney is rapidly cooled to minimize oxygen consumption and cell disintegration. This cold ischemia period enables storage of the donor kidney until transplantation. When the vascular anastomosis in the recipient starts, the kidney tissue will gradually warm to body temperature. Cell metabolism will subsequently start up and the warm ischemia period commences. This period ends with unclamping of the vessels after which renal blood flow is restored. Nonetheless, a mismatch between oxygen supply and demand, started in the warm ischemia period, is continued after reperfusion. Supplying oxygen after an ischemic period causes ischemia-reperfusion injury resulting in endothelial damage and reduced autoregulation. This compromises microvascular perfusion and oxygen supply, particularly affecting the donor kidney's medulla with its easily obstructed narrow vasculature. Moreover, cellular damage induced tissue edema increases the oxygen diffusion distance between blood and renal cells, further impairing

Reflective Questions
What is the cardiovascular status of children with kidney failure when they present for surgery? How to prepare for anesthesia care in the child with kidney failure?
How to monitor and support hemodynamics in pediatric kidney transplantation?
What is best practice anesthesia care for the child with kidney failure or a donor kidney? tissue oxygenation. Simultaneously, the restored renal blood flow triggers glomerular filtration and tubular sodium reabsorption, thus increasing kidney oxygen consumption and entailing a further mismatch between oxygen supply and demand. If the oxidative stress persists, interstitial fibrosis and partial loss of kidney function may occur. Kidneys from deceased donors, long ischemia times (>24 h) and increased donor age are known risk factors for this injury to occur, and are related to an increased incidence of acute tubular necrosis and delayed graft function (DGF). 11,12 Hypoxia had been shown to blunt renal autoregulation. Therefore, shortly after reperfusion, donor kidney perfusion pressure is sensitive to changes in systemic blood pressure and flow. 13

| PREOPER ATIVE A SS E SS MENT
An extensive preoperative assessment is of vital importance to acquire a clear picture of potential metabolic changes and end-organ damage. In general, children with ESRD are frail, acidotic, anemic and hypertensive. However, with high-quality supportive care, for example, optimal nutrition, fluid restriction, and prevention of acidosis, children may remain in a relatively good condition. In contrast, unsuccessful care may lead to malnutrition, neurological damage, severe electrolyte imbalances, bones and teeth deformities, hypervolemia, and congestive heart failure. Table 1 summarizes the impact of renal failure on the functioning of various types of organs. Consequences for anesthesia are discussed in detail below.

| Pulmonary function
Fluid overload and leakage of alveolar membranes can cause pulmonary edema and obstructive lung function. Uremia, anemia, and malnutrition also play a role in this pathogenesis. If the edema persists, interstitial fibrosis develops, causing a restrictive lung function.
Therefore, lung function tests in children with ESRD may show a restrictive, obstructive or mixed pattern. A reduced oxygen reserve may be present, even when clinical signs are not manifest. 14

| Cardiovascular function
Cardiac changes and increased SNS activity are associated with a high incidence of hypertension. A preoperative electrocardiogram and echocardiography are required to assess the cardiovascular state and myocardial performance. Hypertension is often treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. These drugs are the therapy of first choice, as they have been shown to slow down progression of chronic kidney disease in children. 15 If necessary, a calcium antagonist is added. Antihypertensive drugs are usually stopped on the day of surgery, as the combination with the vasodilatory effects of anesthetics may cause refractory hypotension.

| Bone mineralization
Reduced renal excretion of phosphates causes hyperphosphatemia, whereas hypocalcemia results from an impaired renal vitamin D production and a decreased intestinal calcium absorption. Both hyperphosphatemia and hypocalcemia cause deficiencies in mineralization and trigger the secretion of parathyroid hormone. This hormone stimulates calcium resorption form bones leading to renal osteodystrophy. Metabolic acidosis accelerates this process. Therefore, children with renal failure may present with brittle bones and teeth. 16 F I G U R E 1 Factors contributing to kidney oxygen delivery and oxygen consumption in kidney transplantation. Oxygen delivery to the kidney is the product of renal blood flow and arterial oxygen content. Arterial oxygen content depends on hemoglobin concentration and arterial oxygen saturation. Renal blood flow is the resultant form cardiac output, intravascular volume, renal artery patency and autoregulation of renal perfusion pressure. When intact, intrarenal autoregulatory mechanisms regulate blood flow and pressure at the glomerulus, within a defined range of arterial blood pressure. Microvascular function, oxygen diffusion gradient and tissue properties play important roles in medullary tissue oxygenation. After kidney ischemia and reperfusion, oxygenation may be hampered due to edema and endothelial damage. Oxygen consumption is mainly determined by basic renal cell metabolism, glomerular filtration rate and sodium reabsorption. The medulla's microvascular structure and high oxygen consumption rate make this region more prone for a disbalance between oxygen delivery and oxygen consumption. Therefore, it is more affected by hypotension and hypoxia compared with the renal cortex [Colour figure can be viewed at wileyonlinelibrary.com]

| Co-morbidities
Specific co-morbidities can be present, depending on the type of renal disease.
Severe types of obstructive uropathies and kidney dysplasia can cause reduced urine formation in utero, resulting in oligohydramnios and abnormal lung development. In these patients, reduced lung capacity may be present and should be assessed with lung function testing.
Kidney dysplasia is associated with congenital cardiac diseases, most frequently being a septal defect. Glomerulonephritis often leads to a rapid decline in kidney function and difficult to manage hypertension. As criteria for dialysis might be quickly reached, a pre-emptive transplantation is therefore often not feasible.

| Timing of transplantation
The timing of transplantation depends on progression of disease, success of conservative therapy and the availability of a suitable donor. A pre-emptive living donor kidney transplantation can be prepared when optimal supportive care is successful and enables the child to grow. Physical growth is favorable, as a larger abdominal space and vasculature reduce the risk of vascular complications.
Moreover, the donor-recipient size mismatch related hemodynamic consequences are probably less pronounced in larger recipients.
When pre-emptive transplantation is not feasible, dialysis is started as a bridge to transplantation. Indications to start dialysis are fluid overload leading to congestion, untreatable hyperkalemia, excessive uremia, and cessation of growth and development due to lack of energy. Peritoneal dialysis is preferred, as it can be practiced at home and preserves veins and arteries. However, it bears the risk of peritonitis, sometimes necessitating a (temporary) switch to hemodialysis.

| INTR AOPER ATIVE C ARE
Kidney transplantation is a combined vascular and urologic surgical procedure. The vascular anastomoses are commonly made to the iliac vein and iliac artery, preferably using the retroperitoneal approach. In small recipients (<20 kg), the donor kidney is frequently placed intraabdominal whereby the vascular anastomoses are made to the descending aorta and inferior vena cava. After reperfusion and apparent adequate perfusion of the graft, the ureter is anastomosed to the bladder. Table 2 summarizes anesthesia management in pediatric kidney transplantation. Specific challenges are discussed in detail in the following paragraphs.

| Mechanical ventilation strategy
Regarding the prevalence of reduced lung function, it seems reason-

| Hemodynamic therapy
Hemodynamic goals can be reached using a balanced mix of fluids and vasoactive drugs. Second, a relatively large adult kidney in a small child has hemodynamic consequences. Considering a blood flow to an adult kidney of approximately 500 ml min −1 and a CO of around 2000 ml min −1 for a two-year-old child, the recipient's CO has to increase 25% to meet the flow demands of the donor kidney. Therefore, optimal perioperative supportive hemodynamic therapy is required to prevent hypoperfusion and early ischemia of the graft. We would recommend to guide this therapy by advanced hemodynamic monitoring to prevent both hypovolemia and fluid overload. 34 Still, despite optimal support, a reduction in graft blood flow  Nonsteroidal anti-inflammatory drugs are contraindicated as they compromise renal capillary blood flow. Epidural analgesia in pediatric kidney transplantation has been reported to have favorable outcome and relatively stable hemodynamics. 28 However, its common practice is probably hampered by the fear for potential hemodynamic instability and epidural hematoma or abscess formation in patients with renal failure.
Late complications after kidney transplantation are hypertension, graft failure or rejection, infections and malignancies.
Hypertension is seen in 50-80% of the recipients, although 75% of them did not have hypertension prior to transplantation. It is most frequently caused by the side effects of immunosuppressive medication, stenosis of the arterial anastomosis or graft rejection.
Post-transplant hypertension is related to a lower GFR at one-year post-transplantation and reduced graft survival rates.
Graft failure is related to several factors. First, the incidence is related to increased ischemia times, postmortem donors and older donor age. These factors are probably associated with more extensive ischemia-reperfusion injury. Second, the immunosuppressive calcineurin inhibitors are nephrotoxic and sometimes dosing adjustments are required to prevent further kidney damage. Third, particularly juvenile recipients show reduced therapy adherence, causing a peak in graft failure rates between 17-25 years of age. 16 A high infection rate is seen in the first-year post-transplantation.
This occurs particularly in preschool recipients due to their immature immune system combined with the immunosuppressive therapy. Hospital admission is often required to guarantee oral intake and prevent hypovolemia and kidney damage.
Malignancies are a late complication of any organ transplantation due to the life-long immunosuppressive therapy. In the North American (NAPRTCS) database 2.3% of pediatric kidney recipients developed a malignant disorder within three years after transplantation, lymphoproliferative disorders having the highest incidence. 1 During anesthesia, surgical stress, hemodynamic changes and fluid shifts are potential risks for kidney hypoperfusion and postoperative reduced graft function. Therefore, fluid status and blood pressure should be cautiously monitored and optimized. Clearly, any medication with a nephrotoxic profile, like NSAID's, nephrotoxic antibiotics or contrast dye, should be withheld in these patients.

| P OS T-TR AN S PL ANT A SS E SS MENT OF RENAL PERFUS I ON AND FUN C TI ON
Last but not least, the anesthesiologist should be aware of the psychological burden and anxiety that is experienced around surgery and anesthesia, both by patient and parents. They have to cope with a history of frequent hospital admissions and interventions and might fear the risk of graft function loss due to surgical or anesthesia procedures. Therefore, care must be taken to detect post-traumatic stress reactions. 52

| SUMMARY
Pediatric kidney transplantations show good long-term outcomes, provided that optimal medical care is delivered. Anesthesia care for pediatric kidney transplantation requires thorough understanding of the pathophysiological processes in the child with ESRD.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analyzed in this study.