Introduction
The enduring techniques of vascular anastomoses described by Alexis Carrel more than a century ago have not changed significantly (see Chapter 1 ). His simple test of satisfactory vascular anastomosis was observation of a viable kidney transplant producing urine within minutes of completion. No matter how many times it has been witnessed before, this observation will always put a smile on the face of everyone in the kidney transplant operating room. However, the progressive improvement in kidney graft survival has focused greater emphasis on surgeon-related causes of kidney graft loss. Surgical misadventure after kidney transplantation, once ranked low as a cause of graft loss in the first 6 months after transplantation, is now three times more likely to occur than graft loss as a result of rejection ( Fig. 28.1 ).
The transplanted kidney is a highly vascular organ. At rest, 10% to 15% of cardiac output, accounting for between 500 and 750 mL/min, passes through the kidney. A graphic example of the magnitude of the renal blood flow is the simple temporary occlusion of the transplant renal vein with a pair of forceps at the time of surgery, described clinically as the Hume test, which results in rapid and pulsatile engorgement of a well-perfused kidney transplant. Equally, a breach in the continuity of the transplanted artery or vein can result in catastrophic blood loss and circulatory failure within minutes, particularly in the presence of a recipient left ventricle already compromised by coexisting coronary artery disease, long-term effects of systemic hypertension, or uremic cardiomyopathy.
The kidney is also unforgiving of interruption of blood flow, with the cortex more sensitive to hypoxia than the medulla. The magnitude of the effect of acute and complete interruption of blood flow during the transplantation procedure depends on the quality of the donor kidney, length of ischemia time, temperature of the kidney, and extent of intrarenal thrombosis that might occur during a period of stasis or reduced renal blood flow. Irreversible cortical necrosis can occur within minutes, and even in the most favorable situations, it is inevitable by the 20-minute mark. Incomplete interruption of blood flow has a more subtle effect. Arterial pressure sensors within the kidney detect pressures capable of triggering a cascade of autoregulatory changes to increase systemic pressures to satisfy the requirements of the kidney, sometimes at the expense of the recipient’s well-being. Impaired venous drainage is probably better tolerated, although sudden occlusion of a previously well-perfused kidney can lead to dramatic rupture of the cortex with uncontrolled bleeding from intrarenal veins.
Technical Complications and Their Prevention
Informed Consent
A description of the possible complications of kidney transplantation given to a patient when obtaining informed consent before surgery can cause alarm. The possibilities should be put into the context of the individual transplant center’s own published results of patient and graft survival at 1 year. Ideally, the individual transplant surgeon’s own results will be peer-reviewed on a regular basis both within and outside the surgeon’s own transplant center.
Kidney transplantation involves placement of a kidney in a heterotopic position. By comparison, cardiothoracic and liver transplant surgeons have an easier task, placing size-matched donor organs into an orthotopic position after removal of the failed recipient organ. In deceased donor kidney transplantation, the surgeon must cope with the computer-allocated pairing of the donor kidney and recipient. Donor kidneys, particularly from an extended criteria deceased donor, are not new engine parts that can be taken off a spare parts shelf. They are preowned and have no regenerative capacity. The good kidney transplant surgeon is one who recognizes the small margin for surgical error and avoids difficult situations by careful preparation and anticipation of the potential pitfalls. The incidence of vascular complications will vary according to the quality of the recipient evaluation, the donor kidney, and surgical technique of implantation. These are discussed in detail in Chapter 11, Chapter 4, Chapter 8 , but some of these points relating to prevention of vascular complications are worth reiterating here. When complications do occur, the surgeon attempts salvage of the situation, balancing risks to both the recipient and the donor kidney.
Preoperative Assessment
An accessible, patent iliac artery and vein with unimpeded proximal blood flow that are able to be sutured are essential, and should be evaluated by a senior member of the transplant surgery team before the patient is placed on the transplant waiting list. Surgical access can be difficult because of a polycystic kidney, obesity, or a failed previous kidney transplant. Extensive mural arterial calcification can make clamping and suturing impossible without disruption of the artery. Placement of a patient on a kidney transplant waitlist without surgical assessment and resolution of identified problems, and lack of systems in place to ensure access to results of the assessment at all times, is considered medically negligent in the event of an avoidable vascular complication.
Right or Left Donor Kidney
In general, transplant surgeons always prefer the left donor kidney because of its longer renal vein and shorter artery. When given the choice of a living left donor kidney with two arteries or a right kidney with one artery, most surgeons choose the former. The longer left renal vein is less fragile and more easily sutured to the more deeply situated external iliac vein than the short right renal vein. Equally, the right renal artery anastomosis is more difficult to site because of its propensity to kink. Objective evidence to support the greater ease of transplantation of the left kidney is found in Australian registry data that compared outcomes of left and right deceased donor kidney pairs. The data of paired kidneys from 2396 heart-beating brain-dead donors showed that recipients of right-sided kidneys were at significantly greater risk of developing delayed graft function and had inferior graft function because of greater risk of graft loss in the 3 months after transplantation, but principally because of surgical misadventure. Recent registry data from the Netherlands, however, refute these findings, suggesting that although the risk of technical complications for deceased donor implants is not different for right or left kidneys, technical graft failure rate is higher with the right kidney from a living donor.
Anastomosis of the deceased donor right renal vein can be facilitated by vein elongation using the adjacent donor inferior vena cava ( Fig. 28.2 ) or a donor iliac vein extension graft. Alternatively, as is frequently the need in living donor right kidneys, the recipient external iliac vein can be mobilized by dividing the internal iliac veins. Creation of a vein extension using the gonadal vein in the live donor kidney has also been described, but in practice is rarely necessary.
Back Table Preparation
All donor kidneys require back table preparation, and failure of the surgeon to examine the deceased donor kidney before starting the recipient procedure can create problems if the kidney is not “as advertised” by the retrieval surgeon. Accessory arteries may have been missed or divided ( Fig. 28.3 ). Atheromatous plaque, clot, or an intimal flap may be impinging on the lumen of the renal artery. Inadvertent traction or a donor surgeon’s wayward scissor may have torn or injured the donor renal vein. If problems are identified and corrected before surgery, operating and anastomosis times are kept to a minimum and surgical options are retained, such as preservation of the inferior epigastric artery for anastomosis to a lower-pole artery. For living donor kidneys, a missed accessory artery in the living donor kidney is apparent at the time of initial cold perfusion at the back table. This is not the case for the in situ, cold-perfused, deceased donor kidney. Donor artery and vein are mobilized as necessary, with perirenal adipose tissue trimmed, the gonadal vein ligated and removed and, in the case of a deceased donor kidney, the adrenal gland removed. Hemostasis after revascularization of the transplanted kidney is easier if vein tributaries and small hilar vessels associated with trimmed tissue are ligated.
Repeat flushing of a deceased donor kidney with a small volume of preservation solution has several advantages. Residual venous blood, if present, can be cleared. Leaking vessels can be identified and ligated before revascularization. There is also clinical evidence that the subsequently “freshened” deceased donor kidney is more likely to avoid graft dysfunction. Finally, the kidney vasculature is accurately oriented. The superior and inferior margins of the artery and vein can be marked to reduce the risk of twisting the vessels at the time of anastomosis ( Fig. 28.4 ). To reduce handling of the donor kidney during the surgical procedure and for ease of surgery, the kidney can be placed in a temporary stocking, or a surgical glove surrounded by ice slush. The back table with ice slush and preservation fluid should be available until the fascia is closed, in the event that it is necessary to cool the kidney again.
Transplant Renal Vein Anastomosis
The technical details of the anastomosis have been described in Chapter 11 , but one or two points are worth reiterating. Unless there is a recipient history of factors predisposing to venous thrombosis, systemic heparinization for the vascular anastomoses is unnecessary in a dialysis-dependent patient, even in the era of widespread use of synthetic erythropoietin agents. The site of the iliac vein anastomosis can be marked with a sterile surgical marking pen before applying the venous clamps to reduce the risk of vein rotation during clamp application. Accurate sizing of the venotomy length prevents stretching of the end of the transplant renal vein to accommodate a venotomy that is too long. Stretching leads to a long, stenosed anastomosis. After opening the vein, the surgeon searches for pairs of valve cusps and disrupts them if they are adjacent to the anastomosis. A stay suture is applied to the midpoint of at least one of the sides of the venotomy to reduce the risk of catching the opposite wall of the anastomosis with the continuous running vein suture.
The external iliac veins in an obese recipient or a short, muscular male patient with a deep pelvis and almost vertically disposed external iliac vein can be challenging, particularly for right-sided donor kidneys placed in the left iliac fossa. For ease of access, it is tempting to place the venous anastomosis close to the inguinal ligament, but there is a risk of compression of the renal vein during wound closure. Options include lengthening of the donor renal vein or the sometimes difficult task of mobilization of the external iliac vein by dividing the internal iliac vein and its tributaries. The surgeon should ensure that there are long stumps on the ligated veins. Lost ligatures can result in massive blood loss within minutes from the large and thin-walled labyrinth of pelvic and presacral veins that are prone to retracting into the depths of the surgical wound. In such instances, bleeding is best managed by carefully packing the depths of the wound and applying pressure, a request for blood products, and systematic control of venous bleeding by application of metal clips or polypropylene (Prolene) sutures.
A thrombosed or stenosed external iliac vein is preferably identified by color Doppler ultrasound scanning (CDUS) before surgery and should be considered in patients with a history of deep vein thrombosis (DVT), previous transplant surgery, unilateral leg swelling, or emergency dialysis access via the femoral vein ( Fig. 28.5 ). When encountered at the time of surgery, the common iliac vein often has a preserved lumen and can be used for the transplant renal vein anastomosis. Alternatively, the surgeon can close the wound and transplant the kidney into the opposite iliac fossa.
Transplant Renal Artery Anastomosis
The extent of dissection of the iliac artery should be limited to diminish the risk of disruption of adjacent lymphatic channels. If the internal iliac artery is to be used, the surgeon fully mobilizes the bifurcation of the common iliac artery and carefully examines the origin for an atheromatous plaque. Use of the internal iliac artery is avoided if the opposite side artery has been involved in a previous transplant ( Fig. 28.6 ). The bifurcation or trifurcation of the internal iliac artery should be preserved to reduce the risk of buttock claudication. If both internal iliac arteries have been used for transplantation, claudication is inevitable as is impotence.
Arterial clamps are applied with care to avoid damage or rupturing plaques. Endarterectomy can often be avoided by carefully selecting a soft segment of artery. To avoid kinking during wound closure, the renal artery length can be adjusted by resecting the donor aortic patch and implanting as in a live donor kidney. Equally, the shortened artery of the right kidney can be anastomosed to the end of the internal iliac artery. This has the added advantage of deeper placement of the transplant anastomoses, less tension on the short right renal vein, and easy positioning of the kidney after revascularization.
Multiple renal arteries are encountered more commonly with the increasing popularity of laparoscopic living kidney donation and the preference for the left kidney. At least 20% of left kidneys have more than one artery after living donation. Small accessory renal arteries, particularly at the upper pole, can be ligated without problem, but not lower-pole arteries that often contribute blood supply to the donor ureter. Anastomosis of two arteries close together on an aortic patch of a left-sided deceased donor kidney is comparatively straightforward but dual arteries to a right-sided kidney make positioning of the kidney difficult without kinking one or the other artery.
Individual transplant surgeons will have their own views about how best to manage multiple arteries of a living kidney donor. Multiple arteries can be pantalooned on the back table to create a single arterial orifice, minimizing anastomosis time. Alternatively, separate anastomoses can be formed, although warm ischemic time will inevitably be longer. Although vascular multiplicity leads to longer warm ischemic times and higher rates of delayed graft function, no difference in longer-term outcomes is seen, and this should not discourage the use of such kidneys.
Reperfusion
Reperfusion is the high point of the transplant procedure—there is no turning back. Before completing the arterial anastomosis, air is excluded from the clamped vessels by injecting heparinized saline. Fixed retractors that might compress proximal iliac vessels are reviewed and individual anastomoses are tested before revascularization of the transplanted kidney. Imperfect anastomoses are managed more easily beforehand ( Fig. 28.7 ). The proximal arterial clamp and venous clamps are released first. The last clamp removed is the distal iliac artery clamp after systemic blood pressure has stabilized after reperfusion of the kidney. Observation of urine within a couple of minutes is a reassuring sight—a pink, firm, and well-perfused kidney is the next best thing. If neither is observed, the surgeon should actively look for problems. Kidneys from marginal donors or with long renal ischemia times may have a “blotchy” or mottled appearance with dark, less well-perfused areas. An encouraging sign is the gradual reduction in extent of the dark areas until the kidney is uniformly pink ( Fig. 28.8 ).
A flaccid, poorly perfused kidney is reason for concern. Modern tissue typing and crossmatching techniques have essentially excluded hyperacute rejection as a cause (see Chapter 10 ). The surgeon starts with inspection of the renal artery to exclude kinking or twisting and resolves it if possible by repositioning the kidney. Next is confirmation of pulsatility of the iliac artery proximal to the anastomosis and its continuity into the transplant renal artery to the hilum of the kidney. Interruption of flow can be due to an intimal flap, particularly in recipients with underlying arterial disease and kidneys from older donors. Management is not easy. The most likely site of an intimal flap would be at the anastomosis or the proximal clamp site.
The decision to revise the arterial anastomosis or the “safety-first option” of removing the transplanted kidney and reperfusing with preservation solution can be difficult. If revision is undertaken, the recipient is heparinized, the transplant artery flushed with at least 50 mL of heparinized saline, and the renal vein clamped.
Extrarenal arterial spasm is a not uncommon finding and likely the result of undue traction on the renal artery during donor or implantation surgery. The spasm may be segmental. The kidney is soft but not necessarily discolored. Anecdotal reports suggest that placement of a swab generously soaked in papaverine around the artery and excision of affected artery adventitial tissue may help. Alternatively, and with permission of the anesthetist, the iliac artery distal to the arterial anastomosis is clamped and diluted glycerol trinitrate injected into the proximal iliac artery. Spasm is usually self-limiting but can cause concern and warrant systemic heparinization. If no arterial inflow problem can be identified and systemic blood pressure is satisfactory, the surgeon should be patient, particularly if the kidney swells when the renal vein is temporarily occluded (Hume test). A small incision into the capsule of the kidney followed by evidence of bright arterial bleeding can also be reassuring, as can an on-table ultrasound.
Catastrophic bleeding after removing all vascular clamps is unlikely to occur if the anastomoses have been assessed before revascularization. If present, however, it is usually venous in nature and either from a tributary vein, or worse, from a disrupted venous anastomosis because of traction on a thin-walled and right-sided living donor kidney renal vein. Because of the continuous nature of the suture, simple repair is usually impossible and, if attempted, results in excessive blood loss or anastomotic stenosis, or both. Removal of the kidney, reperfusion with preservation solution, and calmly starting all over is a sensible solution.
The observation of a tense, engorged, and pulsatile kidney with marked capsular bleeding is indicative of venous outflow obstruction. Causes can be a rotated or compressed renal vein, apposition of the sides of the venous anastomosis because of imperfect suturing, or inclusion of external iliac vein valve cusps in the anastomosis. Because of the relatively controlled situation, revision of the anastomosis usually can be undertaken within 10 minutes, after systemic heparinization, clamping the renal artery, and exsanguination of the transplant. This can also be achieved by reclamping the iliac vessels, removing the ligature from the gonadal or adrenal vein stump, and cannulating the iliac artery to flush the kidney. An uncommon cause of venous outflow obstruction is compression of the left common iliac vein as it passes under the right common iliac artery, described as the May-Thurner syndrome. Probably the extra 500 to 750 mL of blood per minute from the transplanted kidney is enough to compromise the narrowed iliac vein at that point. If recognized at time of surgery, a more proximal venous anastomosis can be attempted or the internal iliac artery divided to allow mobilization of the right common iliac artery. If recognized after transplantation, endovascular stenting of the iliac vein may be an option.
A disappointing observation on completion of the vascular anastomoses is the finding of a well-perfused transplant but with the ureter pointing in the wrong direction, away from the bladder. The kidney has been transplanted upside down, and this is more likely to occur with a living donor kidney in the absence of the full length of renal vein and the aortic patch to assist with orientation. One option is to remove the kidney, reperfuse, and start again. Alternatively, the kidney can be left in place and, provided there is an adequate length of ureter, it can be provided with a more circuitous route to the recipient bladder. The latter option may increase the risk of subsequent ureteric stenosis because of the longer, more tortuous course of the ureter.
Positioning The Kidney and Wound Closure
The ureteroneocystostomy should be the relaxing part of the kidney transplant operation. The kidney is positioned to avoid compression of the vascular pedicle and, all being well, urine is being produced. A suction drain may be placed, although it is not always required and may not have any effect on the risk of wound complications. A drain is perhaps most useful in the patient on peritoneal dialysis where delayed function is expected, because it will allow the drainage of dialysis fluid when an unidentified peritoneal breach is present, or in patients receiving sirolimus for primary immunosuppression. Many patients on peritoneal dialysis will have high volume drainage even in the absence of dialysis or a breach, which may lead to prolonged hospital stay.
During apposition of the abdominal wall muscles, the potential for kinking of the kidney transplant vasculature increases, particularly in thin patients receiving large kidneys, male patients with a narrow deep pelvis, a venous anastomosis too close to the inguinal ligament, or an incision too close to the anterior superior iliac spine. Mobilizing the peritoneum in a medial direction off the undersurface of the anterior abdominal wall may help. Monitoring transplant arterial perfusion during wound closure with ultrasound can be reassuring.
Failing this, a reliable “surgical escape” is to place the kidney into the peritoneal cavity by creating a longitudinal window in the peritoneum, adjacent to the kidney and more anterior to the vascular anastomoses. The kidney is positioned anterolateral to the cecum on the right side and the sigmoid colon on the left side. The greater omentum can be used to separate the bowel from the kidney. Percutaneous biopsy subsequently is still feasible after placement of local anesthetic agent at the level of the peritoneum.
Postoperative Recovery
An experienced member of the surgical team remains with the recipient in the early recovery phase and until there is conclusive evidence of satisfactory perfusion of the transplanted kidney. The careful positioning of the kidney at time of surgery can be undone readily by a restless recipient flexing the hips because of pain, urinary catheter intolerance, and hypoxia, or an unhelpful radiographer who determines that the recipient should sit bolt upright for a mobile chest x-ray. Transplanted kidneys producing urine at the end of the surgical procedure are easier to manage, particularly if urine is being produced in volumes that could not be achieved by residual native kidney function. The better the urine volume, the less likely that clots will form in the bladder.
If no urine has been seen on the operating table or in recovery and the recipient is hemodynamically stable with a central venous pressure of at least 5 cmH 2 O, ultrasound examination is useful before the recipient leaves the operating suite complex, particularly if difficulty was encountered with kidney positioning during wound closure. Out of routine working hours, it helps if the transplant surgeon is adept with the use of an ultrasound machine dedicated to the transplant unit. An inadequate arterial signal and significant collections are indications for an immediate return to the operating room.
The need for an additional arterial anastomosis is also good reason for an early ultrasound in the presence of the operating surgeon with knowledge of the surgical vascular anatomy. Patency of an accessory renal artery is difficult to determine in the early postoperative phase by observation of urine output alone. These smaller vessels are more prone to thrombosis or kinking, and longer-term consequences include poor graft function and hypertension. An avascular segment of kidney can occur, at least initially, without noticeable effect.
Because of the quality of modern ultrasound, indications for formal angiography in the early phase after kidney transplantation are few. They are perhaps limited to the suspicion of proximal iliac artery disease or clamp injury and an obese recipient in whom visualization of the renal artery and iliac vessels is not technically feasible. Computed tomography (CT) angiography is usually easier and faster to obtain.
Drain Tube
Removal of a suction drain, when placed, should be a straightforward task. Without suction it is withdrawn slowly with a twisting motion to dislodge fatty tissue trapped in the small side holes of the drain as a result of the suction. Small pediatric kidneys have been known to undergo torsion of the vascular pedicle on removal of the drain with resultant loss of graft function.
The timing of drain tube removal depends on the volume and nature of the drained fluid. It is not unusual to record 100 to 200 mL of heavily blood-stained drainage in the first few hours of transplantation. Drainage volume can be an unreliable gauge of active bleeding, particularly if brisk. Patient discomfort, tachycardia, hypotension, and abdominal findings of an enlarging mass around the transplant are indicators of a significant bleed requiring urgent surgical exploration. Large-volume drainage of less heavily blood-stained fluid generally indicates residual peritoneal dialysate (if the peritoneum was breached), lymph, or urine. Urine is excluded by biochemical analysis or absence of glucose on dipstick testing.
Compartment Syndrome
All can be well with a transplanted kidney while the recipient is in a supine or near-supine position. Ultrasound is also performed with the recipient in a supine position. However, when the patient is placed in a sitting or standing position, downward movement of abdominal contents can cause external compression of the transplanted kidney or change its position. Contributing factors include a large native polycystic kidney, heavy fat-laden small-bowel mesentery, and greater omentum in a patient with truncal obesity. Size of the transplanted kidney may also play a role. Hematoma, urinoma, lymphocele, or paralytic ileus can do likewise, even with the patient in a supine position. The contribution of the compartment syndrome to initial poor kidney transplant function should not be underestimated ( Fig. 28.9 ). Reversible factors should be resolved without delay. A paralytic ileus or pseudoobstruction of the large bowel can be frustrating to manage in the first week after transplantation. The latter may require a rectal tube to deflate the large bowel under supervision of the colorectal surgery team. Surgical decompression with insertion of a mesh to relieve pressure may be required.
Hematoma
Hematoma formation is a not uncommon finding after kidney transplantation during the initial inpatient period, particularly in anticoagulated recipients or those receiving antiplatelet agents, thymoglobulin, or plasmapheresis. Most hematomas are small and insignificant ultrasound findings that resolve spontaneously. Those associated with discomfort, hypotension, transplant dysfunction, and falling hemoglobin are not. Extreme examples are surgical emergencies after rupture of the kidney cortex or arterial anastomosis disruption ( Fig. 28.10 ). Others expand progressively within the retroperitoneal space with inevitable external pressure on the transplant and adverse effect on arterial blood inflow or venous outflow. The extent of the hematoma by CT scanning is best shown as a heterogeneous crescentic peritransplant collection ( Fig. 28.11 ). CT findings change with time after the bleeding event, with evidence of recent bleeding of more concern. Ultrasound examination is appropriate to assess transplant perfusion but because of surrounding bowel gas is unreliable for assessment of hematoma size.
Percutaneous drainage of the hematoma is unlikely to be successful. Indications for surgical exploration of the transplanted kidney include symptoms, progression of size, ongoing blood loss, and transplant dysfunction. The original wound is reopened and care taken to remove the hematoma, always being alert to the possibility of dislodging the clot that is providing tenuous hemostasis at the site of bleeding. Surgical exploration in the first day or so after transplantation for hematoma evacuation might locate active bleeding from a hilar vessel, a retroperitoneal vein, or divided abdominal wall muscle. Thereafter, a more common finding is a stable hematoma without obvious cause. Invariably, transplant perfusion and function improve after hematoma evacuation. Bruising in dependent subcutaneous areas lateral to and below the transplant, such as the labia or the scrotum, is often seen several days later. The risk of hematoma formation is increased by the use of anticoagulants, particularly in patients receiving heparin by infusion for prophylaxis against vascular thrombosis. Careful titration of heparin infusion rate to maintain an activated partial thromboplastin time of 60 seconds is not easy. The reported risk of need for surgical intervention in patients heparinized after transplantation is 30% to 60%. Heparinized patients positive for lupus anticoagulant are especially difficult to manage with heparin. Greater safety can be achieved with the use of thromboelastography to direct judicious use of heparin, during and after transplant surgery in patients at risk. Anecdotally at least, hematoma formation is more common in the presence of antiplatelet agents such as aspirin and/or clopidogrel. They are prescribed increasingly on a long-term basis by cardiologists and nephrologists in patients with significant cardiovascular disease or in attempts to improve fistula patency. Their use is not a contraindication to transplantation. However, they do reduce the margin for surgical error and dictate the need for meticulous hemostasis at time of surgery.
Vascular Thrombosis and Thrombophilia
Early kidney transplant loss as a result of thrombosis of artery or vein is a devastating complication, with a 2% incidence (see Fig. 28.1 ). Compared with other forms of vascular surgery, the incidence of thrombosis is low, perhaps because of the highly vascular nature of the kidney. The low incidence may also support the traditional view that renal failure is associated with a bleeding tendency secondary to platelet and clotting factor dysfunction. Arterial thrombosis or infarction of a denervated kidney is often painless and heralded only by loss of graft function. By the time the diagnosis is confirmed by imaging, kidney salvage is not a practical option ( Fig. 28.12 ). Interruption of the venous drainage can be spectacular with graft rupture and bleeding. It has an equally disappointing prospect for kidney salvage because of the rapidity of the process after occlusion of the renal vein has occurred. Thrombotic complications are minimized by identification and management of risk at the time of transplantation.
Thrombosis of the kidney vasculature is the end result of stasis, endothelial changes, and procoagulant factors and can be multifactorial. Causes of stasis are largely technical in nature and readily identifiable at the time of transplant exploration. They include poorly constructed anastomoses, malpositioning of the transplant, rotation of the kidney, or external compression. Recipient hypovolemia and inadequate cardiac output, for whatever reason, are contributory but not causal factors. The contribution of intrarenal causes, such as acute vascular rejection and acute tubular necrosis (ATN), is less quantifiable, but can be diagnosed by histologic examination provided viable cortical tissue can be obtained. Because this is often not the case, intrarenal causes are probably underestimated and underdiagnosed.
Epidemiologic studies have attempted to identify other risk factors, particularly those amenable to preventive strategies. Those that cannot be modified are recipient and donor age, recipient and donor vascular pathology, diabetes mellitus and, at least in the view of some recipients, morbid obesity. A large registry-based and case-matched study has shown that half of all cases of kidney transplant vascular thrombosis occur in repeat transplant recipients. The implication is that transplanted kidneys in the setting of retransplantation are more likely to have endothelial inflammation and development of microthrombi after exposure to the recipient immune system. Strategies exist to minimize this risk in selected, highly sensitized recipients with a negative donor lymphocytotoxicity crossmatch (see Chapter 10 ). ATN attributable to the reperfusion injury is also associated with endothelial changes, and, together with hydronephrosis, is associated with increased intrarenal pressures, making perfusion of the transplanted kidney more difficult. Recipients dependent on peritoneal dialysis before transplantation are more likely to have thrombotic complications, likely due to intravascular hypovolemia.
The introduction of recombinant human erythropoietin (rEPO) has revolutionized the treatment of anemia associated with end-stage kidney disease, reducing the need for routine blood transfusion and improving quality of life and patient survival. The rEPO dose is titrated to provide recipient hemoglobin in the range of 100 to 120 g/L. With higher hemoglobin values, there is an increased risk of adverse cardiac events. Nevertheless, the current widespread use of rEPO in patients presenting for kidney transplantation has not resulted in an increased risk of vascular thrombosis.
Erythrocytosis, defined as hematocrit greater than 51% or hemoglobin greater than 160 g/L, occurs in 10% to 15% of recipients 6 months to 2 years after kidney transplantation. About one-quarter regress spontaneously, with the remainder persisting for several years and remitting as graft function diminishes. Thromboembolic events and symptoms of lethargy, malaise, and headache necessitate repeated venipuncture and may be necessary in up to 30% of these patients. The problem is more common in male patients, smokers, and patients with a rejection-free course. Erythropoietin levels are usually in the normal range. By chance, patients introduced to small doses of an angiotensin-converting enzyme inhibitor for the management of hypertension were noted to have progressive reduction of hematocrit to more normal levels. The suggestion is that angiotensin II is a growth factor for red blood cells.
Thrombophilic Factors
After exclusion of technical causes in a hemodynamically stable kidney transplant recipient, thrombosis may be explained by one of the numerous hypercoagulable or thrombophilic states. Many are inherited, but they are more frequently acquired. These include deficiencies of antithrombin III, protein C, and protein S, each occurring in less than 1% of the dialysis patients. When a thrombotic event of any kind occurs in a patient older than 45 years and in the absence of a family history, these deficiencies are unlikely.
Inheritance of factor V Leiden (FVL) or prothrombin G20210A mutations can increase the risk of thrombosis, usually venous, of the transplant vasculature by at least threefold. FVL mutation is present in 2% to 5% of the normal population and is not more common in patients with kidney disease. It is found, however, in 15% to 20% of patients with venous thromboembolism and 60% of patients with a family history of thromboembolism. When these mutations are present in kidney transplant recipients, the risk of major thrombotic events, particularly renal vein thrombosis (RVT), is 40%. The presence of FVL or prothrombin G20210A mutations is also associated with shorter graft survival, probably as a result of greater microvascular thrombosis in renal vessels affected by rejection or intimal thickening. A case could therefore be made for routine genetic screening for these polymorphisms in patients awaiting a renal transplant. It should be mandatory if there is a history of thromboembolism.
The presence of acquired antiphospholipid antibodies (APAs), including anticardiolipin antibody and lupus anticoagulant, is common in patients awaiting transplantation. Although present in about 10% of patients, related clinical events are less common. When associated with a history of thrombotic events, these patients, often with systemic lupus erythematosus, are labeled as having APA syndrome. They have a universal incidence of graft loss to thrombosis when prophylaxis is not employed. Equally, anticoagulation after transplantation offers protection against graft loss. The presence of APAs without a history of thrombosis is seemingly not a problem.
Contribution of Immunosuppressive Agents
The introduction of cyclosporine, usually at doses of 15 mg/kg or more, was associated with an increased incidence of graft thrombosis, particularly RVT, in the first week after transplantation. Cyclosporine was subsequently shown to have procoagulant properties, increasing factor VIII and causing release of tissue factors from monocytes and von Willebrand factor and P-selectin from endothelium. This is likely a dose–response effect, for in recent years meticulous cyclosporine drug dosing based on drug level monitoring has resulted in fewer reports of RVT. Mammalian target of rapamycin (mTOR) inhibitors are not thought to contribute to thromboembolic events after kidney transplantation.
Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura is an infrequent but well-described complication of cyclosporine use. The diagnosis, seen soon after transplantation, is based on deteriorating renal function, decreasing platelet count, and characteristic glomerular thrombi seen in core biopsy specimens. Most resolve with discontinuation of cyclosporine and conversion to tacrolimus. Reports also describe the same presentation with tacrolimus, which responds with conversion to cyclosporine. The alternative would be to introduce an mTOR inhibitor.
Prolonged use of heparin can lead to the development of measurable antibodies against platelet factor 4 (PF4) in up to 20% of patients. Heparin-induced thrombocytopenic syndrome (HITS) is an immune-mediated thrombocytopenia together with thrombotic complications occurring within 24 hours of a patient’s reexposure to heparin during the transplant procedure. The subsequent immune complex activates platelets, predisposes the patient to clotting of veins and arteries, and causes the platelets to be consumed. The diagnosis of HITS for the first time in a transplant recipient is uncommon, but is likely underreported, particularly in preemptive live donor kidney recipients and patients treated by peritoneal dialysis. A proven past diagnosis of HITS (involving measurable PF4 antibody) mandates absolute avoidance of any form of heparin during the transplant procedure. Anticoagulation can be provided with direct thrombin inhibitors such as lepirudin, argatroban, or bivalirudin.
Renal Vein Thrombosis
Occlusion of the renal vein by thrombus soon after transplantation is now an unusual event and invariably associated with a technical problem. However, in the era of high cyclosporine dosing, the incidence of the seemingly spontaneous RVT was as high as 6% and occurred classically toward the end of the first week of transplantation in an otherwise uncomplicated transplant kidney. Witnessing the dramatic presentation over a couple of hours is an unforgettable experience. Rapid onset of oliguria and hematuria is accompanied by graft enlargement and rupture associated with extreme patient discomfort and life-threatening bleeding. RVT can happen during the course of a morning ward round. The Oxford Transplant Unit response almost 2 decades ago was to introduce daily aspirin from the time of surgery, the effect of which was to decrease the incidence of RVT from 5.6% to 1.2%.
The ultrasound findings are of a swollen graft with a crescent of clot along the convex margin of the kidney and covering a longitudinal rupture of the cortex. In this setting, reverse diastolic flow of the arterial waveform is diagnostic ( Fig. 28.13A ). Potentially, the transplant can be saved after early diagnosis if the patient is taken directly to the operating room by the surgical team ( Fig. 28.13B ). The operative findings will match the ultrasound description along with active arterial bleeding from the ruptured cortex. The presentation, apart from evidence of reverse diastolic flow, is similar to the description of graft rupture seen with severe ATN in the era before brain death legislation. Some surgeons of that era performed prophylactic division of the kidney capsule to allow the kidney to cope better with the inevitable parenchymal swelling associated with tubular necrosis.
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