A successful long-term outcome for a new kidney transplant recipient depends on the early perioperative management and course after surgery. Important factors affecting long-term outcome include the occurrence of delayed graft function (DGF); episodes of acute rejection; early surgical complications, such as urinary obstruction, urine leak, or vascular complications; and sepsis. Toxicity from calcineurin inhibitors (CNIs) can lead to chronic transplant damage later in the posttransplantation course. Donor and recipient factors affect long-term outcome, particularly the use of high kidney donor profile index (KDPI) donors or highly sensitized recipients. The early recognition and management of risk factors in the immediate postoperative period may lessen their long-term negative effect and improve outcome.
A patient’s journey to a successful kidney transplant begins long before the patient meets the surgical and anesthesiology teams, at the time of diagnosis of chronic kidney disease where the patient and his or her nephrologist discuss and initiate the process of waitlist candidacy. Surgical management of the kidney transplant recipient begins in the immediate preoperative period. The initial evaluation includes a careful history and physical examination to determine whether potential contraindications to transplantation exist. For instance, the presence of significant cardiac disease may preclude successful surgery. Characteristics such as tobacco use, diabetes, obesity, hypertension, and dyslipidemia have all been shown to be independent predictors of cardiovascular disease in kidney transplant recipients and should prompt further cardiac evaluation, particularly in the symptomatic preoperative candidate. The Revised Cardiac Risk Index has also been demonstrated to be a useful perioperative tool for evaluating adverse cardiac event risk in kidney transplant recipients, particularly for those older than age 50. In addition, peripheral vascular disease and vascular insufficiency are more common in end-stage renal disease (ESRD) patients and represent a barrier to successful transplantation, with a higher incidence of postoperative renal transplant artery stenosis, graft failure, and mortality. Thus a simple pulse examination before surgery with ankle brachial indices in select patients can help stratify perioperative risks of vascular morbidity in kidney transplant recipients. Assessment of the recipient’s pretransplant fluid status and electrolyte levels to determine the need for dialysis is also important in the perioperative period. However, routine hemodialysis immediately before transplantation is not warranted except in cases of metabolic derangements (e.g., hyperkalemia) or fluid overload because preoperative hemodialysis has been associated with an increased risk of delayed graft function. Knowledge of the donor status is also helpful in the early postoperative management of the transplant recipient. With an ideal deceased donor or a living related donor, the expected outcome is an immediately functioning transplant that may preclude posttransplant dialysis. Kidneys procured from high KDPI donors or donation after circulatory death (DCD) donors have a higher likelihood of DGF, which can lead to volume overload and the need for urgent dialysis. Technical considerations include the need for vascular reconstruction, which may prolong surgery and contribute to postoperative DGF. Recipient factors also affect the early postoperative course. Significant risk factors for early posttransplant dysfunction include pretransplant sensitization, obesity, younger or older age, and anatomic considerations that complicate the surgery.
In the early perioperative period, attention to fluid and electrolyte balance is crucial. Careful monitoring of urine output is essential, and any decrease in urine flow must be evaluated. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend measuring urine volume every 1 to 2 hours for at least 24 hours after transplantation and daily until graft function is stable. In addition, serum creatinine should be measured daily until hospital discharge, and frequently thereafter. For example, creatinine should be measured two to three times per week for a month, and a tapering frequency of measurements in ensuing weeks. A decrease in urine volume may be a result of acute tubular necrosis, hypovolemia, urinary leak, ureteric obstruction or, most significantly, vascular thrombosis or acute rejection. Assessment of the patient’s volume status may help eliminate hypovolemia as a cause of decreasing urine output. DGF can be ascertained further with duplex ultrasonography to assess perfusion of the graft and to exclude renal artery or vein thrombosis. Duplex ultrasonography also allows the diagnosis of a urinary complication such as obstruction or leak.
Measures to decrease the likelihood of DGF often are used during the operative procedure and in the perioperative period. Maintenance of adequate blood pressure and fluid status may be accomplished with intravenous albumin or crystalloid. There is no evidence for the superiority of one type of fluid during kidney transplant; however, the use of normal saline is associated with a higher incidence of acidosis. Shorter cold ischemia or pulsatile perfusion of the donor organ also may decrease the likelihood of postoperative DGF, and there is ongoing evaluation of normothermic perfusion techniques in this context. Some centers have used intraarterial calcium channel blockers, such as verapamil, to improve renal blood flow. It is common practice to administer mannitol (12.5 g) about 10 minutes before the kidney is reperfused, which helps trigger an osmotic diuresis and might be protective. Loop diuretics are also commonly used at the time of renal reperfusion. Oral calcium channel blockers have been used to decrease the incidence of DGF. There is controversy about the early initiation of CNIs because of the potential for nephrotoxicity. Some centers delay the use of CNIs until there is established diuresis. If additional immunosuppression is desired, polyclonal or monoclonal anti–T-cell antibodies may be used as induction therapy.
Early complications of renal transplantation may be mechanical/surgical or medical. Early medical problems are more common than posttransplant surgical problems ( Table 14.1 ). The most common early posttransplant medical problem is DGF, which occurs in 20% of patients who received kidneys from ideal deceased donors and in nearly 40% of patients in whom the donors were older than age 55 years. After or concomitant with DGF, acute rejection may become a significant clinical problem. Other reasons for early medical complications include acute cyclosporine or tacrolimus nephrotoxicity, prerenal azotemia, other drug toxicity, infection, and early recurrent disease. An uncommon but serious posttransplantation medical problem is thrombotic microangiopathy (discussed later). Thrombotic microangiopathy may be induced by rejection or as a secondary consequence of cyclosporine, tacrolimus, or sirolimus therapy. CNI blood levels should be measured regularly during the immediate postoperative period until target levels are reached, as this measurement may indicate the likelihood of CNI toxicity versus rejection in the diagnosis of graft dysfunction. The level of mammalian target of rapamycin (mTOR) inhibitor should also be measured regularly if this class of drugs is used.
|Ureteral obstruction |
Renal vein thrombosis
|Acute rejection |
Delayed graft function
Acute calcineurin inhibitor nephrotoxicity
Mechanical problems usually are the result of complications of surgery or specific donor factors, such as multiple arteries, that lead to posttransplantation dysfunction. Mechanical/surgical factors include obstruction of the transplant, hematuria, urine leak or urinoma, and vascular problems such as renal artery or vein stenosis or thrombosis. Postoperative bleeding is another potential complication that may cause compression of the transplant because the transplant usually is placed in the retroperitoneal space. Posttransplant lymphoceles are another common cause of early transplant dysfunction. Lymph drainage from transected lymphatic channels accumulates in the perivascular and periureteral space and can cause ureteral obstruction or lower-extremity swelling from iliac vein compression.
After implantation of a living donor kidney transplant, urine output begins immediately or within minutes. (See Chapter 29 for a more complete discussion of urinary problems.) The same is not generally true of deceased donor kidneys, in which urine output may not be apparent for 1 hour or more after implantation and may be sluggish or nonexistent for days if the kidney has been injured (DGF) by donor factors or preservation. If a kidney that was formerly making urine slows down or stops and does not respond to fluid administration, urinary obstruction must be considered in the differential diagnosis. The initial evaluation is to check the patient’s vital signs and physical examination to ensure adequate hydration and to check that the Foley catheter is functioning correctly. Obstruction of the Foley catheter by blood clots easily may occur and can be cleared by gentle irrigation. If these problems are not present, renal transplant ultrasound is the fastest, most accurate, and least expensive method to assess the renal pelvis for obstruction. Pelvicaliceal and/or ureteral dilation seen by ultrasound implies distal obstruction. If the bladder is collapsed rather than full, the problem is likely to be ureteral obstruction. Treatment should be immediate decompression of the renal transplant pelvis by percutaneous insertion of a nephrostomy tube. Subsequently (usually 1 or 2 days later to allow blood and edema to clear after nephrostomy tube placement), a nephrogram can be obtained to evaluate the ureter for stenosis or obstruction. The diagnosis is confirmed by a decline in the serum creatinine level after decompression of the renal pelvis.
After the Foley catheter is removed, the most common cause of urinary obstruction is not ureteral stenosis, but rather bladder dysfunction. This problem is particularly common in diabetic patients with neurogenic bladders. Initial management is replacement of the Foley catheter and a trial of an alpha-blocker, such as tamsulosin, doxazosin, or terazosin. If bladder dysfunction persists after one or two such trials, it may be necessary to start intermittent self-catheterization. In rare instances in which bladder dysmotility is severe and urinary tract infections are common, it may be preferable to drain the transplant ureter into an ileal conduit to the anterior abdominal wall. Ideally, a patient with a neurogenic bladder should have been evaluated before transplantation with urodynamic studies, and a decision should have been made about management at that time (see Chapter 12, Chapter 4 ).
During the first 1 or 2 weeks after transplantation, obstruction usually is caused by a technical problem related to surgery (see Chapter 29 ). If a ureteral stent was placed at the time of surgery, it is highly unusual to have obstruction. Indeed, the incidence of major urologic complications after kidney transplant in patients who had a prophylactic stent placed during surgery is significantly lower compared with those who did not have a ureteral stent placed during the transplant. However, placement of ureteral stents during transplant carries a higher risk of infection so it is recommended that a sulfa-based antibiotic prophylaxis be administered to these patients. Possible explanations for obstruction are a twisted ureter or anastomotic narrowing. Generally, obstructions appear several weeks postoperatively, after the stent has been removed, and occur most frequently at the anastomosis between ureter and bladder. Usually, these obstructions can be crossed by a guidewire and dilated percutaneously by an interventional radiologist ( Fig. 14.1 ). If the nephrostogram shows a long (>2 cm) stricture, especially a proximal or midureteral stricture, it is likely to be a result of ischemia and is not usually amenable to balloon dilation, necessitating surgical repair ( Fig. 14.2 ). The operation of choice for a long stricture or one that has failed balloon dilation is ureteroureterostomy or ureteropyelostomy using the ipsilateral native ureter. The spatulated ends of the transplant and native ureters are anastomosed using running 5-0 absorbable suture. This anastomosis can be done over a 7 French double-J stent, which is left in place for 4 to 6 weeks. If no ipsilateral ureter is available, it may be necessary to use the contralateral ureter. If neither the ipsilateral ureter nor the contralateral ureter is available, alternatives include bringing the bladder closer to the kidney using a psoas hitch or fashioning a Boari flap, but these measures are seldom necessary. Another method is endoureterotomy; experience with this method is growing. Even if urinary obstruction is clinically silent (i.e., the patient is asymptomatic with a normal creatinine value), urinary obstruction manifested by dilation of the pelvis and calices on ultrasound should be treated because it ultimately leads to thinning of the renal cortex and loss of renal function. Urinary obstruction should be treated immediately to minimize damage to the transplanted kidney.
Bleeding Into the Urinary System
Gross hematuria is common immediately postoperatively because of surgical manipulation of the bladder. The Leadbetter–Politano procedure for ureteroneocystostomy is associated with more hematuria compared with the extravesical approach typified by the Lich-Gregoir technique or the technique described by us (see Chapter 11 ). The advantage of the latter technique is that it effectively prevents reflux and can be done with excellent long-term results. Occasionally, continuous bladder irrigation is necessary if gross hematuria is associated with clots, although intermittent manual irrigation usually is adequate. Bladder outlet obstruction by a blood clot is an emergency; vigilant nursing care is required to ensure that it does not occur. It is preferable not to distend the bladder in the immediate postoperative period to avoid disrupting the bladder sutures or causing a leak, and continuous bladder irrigation and cystoscopy ideally are avoided. Minor hematuria without clots is common in the first 1 or 2 days regardless of the surgical method of ureteroneocystostomy and does not require treatment; it resolves over time without specific treatment.
A leak of urine from the transplanted kidney in the early postoperative period may be clinically obvious if the patient presents with abdominal pain, an increasing creatinine level, and a decrease in urine output. Urine in the peritoneal cavity causes peritonitis and pain. More commonly, assuming that the kidney was placed in the retroperitoneal position, a urinoma collects around the kidney and bladder and causes a bulge in the wound and pain with direct displacement of adjacent viscera, including the bladder. The diagnosis should be suspected if the serum creatinine level is increasing (or not decreasing appropriately). Adjunctive tests to help make the diagnosis of urine leak, if it is not obvious clinically, include a renal scan, which would show urine in the retroperitoneal space surrounding the bladder or around loops of bowel, or an ultrasound, which would show a fluid collection outside the bladder and when aspirated has a high creatinine level. Urine leak generally is because of a surgical problem with the ureteroneocytostomy or ischemic necrosis of the distal ureter. Other causes include postbiopsy injury and ureteral obstruction. Such a leak should be immediately repaired surgically because the risk of wound infection increases with delay in treatment.
Transplant renal artery stenosis is a relatively common vascular complication after kidney transplant with an incidence of 1% to 23%. It may manifest in the early postoperative period by: (1) fluid retention, (2) elevated creatinine levels, and (3) hypertension. (See Chapter 28, Chapter 30 for a more complete discussion of vascular problems.) Commonly, the patient does not tolerate cyclosporine or tacrolimus because these drugs exacerbate the preexisting ischemia at the glomerular arteriolar level. The aforementioned triad of clinical findings need not all be present, and the diagnosis should be suspected for any one of the three clinical signs. Cytomegalovirus (CMV) infection and DGF have been described as risk factors for transplant renal artery stenosis. If the creatinine level is greater than 2 mg/dL, renal arteriography is best avoided because of the nephrotoxicity of the contrast dye. Magnetic resonance angiography usually can give an accurate delineation of the arterial anatomy. Ultrasound also is safe, but less discriminatory, and may be helpful if jetting of flow beyond a stricture is seen.
As the population of renal transplant recipients has become older and includes more diabetic patients and patients with vascular disease, transplant renal artery pseudostenosis has become increasingly common. Pseudostenosis refers to arterial stenosis in the iliac artery proximal to the implantation of the transplant renal artery. Although the anastomosis and renal artery may be completely normal, a more proximal iliac artery stenosis can lead to hypoperfusion and resulting high renin output by the transplanted kidney.
Treatment of transplant renal artery stenosis and pseudostenosis includes both percutaneous interventions and surgery. Generally, ostial stenosis, long areas of stenosis, and stenosis in tortuous arteries difficult to access radiographically are not treated as successfully with percutaneous interventions (balloon dilation or stenting) as with surgery. Stenoses within smaller branches of the renal artery may be treatable only by angioplasty. Iliac artery disease causing pseudostenosis may be treated by angioplasty, but risks embolization or dissection, leading to thrombosis or further ischemia. A recent systematic review of transplant renal artery stenosis treated with either percutaneous angioplasty or stenting demonstrated equivalent outcomes with success rates ranging from 65% to 94%. Surgical options include bypass of the stenosis using autologous saphenous vein, a prosthetic graft, or an allogeneic arterial graft procured from a deceased donor. The risk of the procedure has to be weighed against the potential benefit of improving renal transplant blood flow. In addition to the serum creatinine determination, a biopsy may be useful to assess the quality of the renal parenchyma. In advanced chronic rejection with an elevated creatinine level for more than 1 month, it may not be prudent to repair such arteries, but this problem is not generally encountered in the early posttransplant course. Fig. 14.3 shows a renal artery stenosis in the lower pole artery that was managed successfully by balloon angioplasty.
Renal transplant arterial thrombosis usually occurs early (within 30 days) in the posttransplant period, but is a rare event and is generally caused by a technical error at the time of surgery. It usually is related to an intimal injury to the donor kidney during procurement or to anastomotic narrowing or iliac artery injury during implantation. The incidence of renal transplant arterial thrombosis is around 1% to 2%. Kidneys from donors younger than 5 years old have been associated with a higher risk of thrombosis. The kidney tolerates only 30 to 60 minutes of warm ischemia before it is irreversibly injured, making it difficult to diagnose and correct this problem before it is too late to salvage the kidney. The diagnosis should be suspected in a patient who has had a transplant hours to days before and has had good urine output but who suddenly has a decrease in urine output. A high degree of suspicion has to be present, and the patient should be returned to the operating room promptly. Although some reports of catheter-based thrombolysis for renal artery thrombosis have been described, the majority of cases require operative intervention and if unsuccessful require transplant nephrectomy. If the patient had urine output preoperatively from the native kidneys, the diagnosis is difficult to make in a timely manner because urine output may continue after the renal transplant has thrombosed. The advantage of diagnostic ultrasound has to be weighed against the disadvantage of delaying a return to the operating room. Almost all kidney transplants with arterial thrombosis are lost because of ischemic injury.
In cases of more than one renal transplant artery in which arterial reconstruction is performed at implantation, there may be increased risk of thrombosis of one or more arteries. This increased risk is a particular concern if there is a small accessory renal artery supplying the lower pole of the kidney and providing the ureteral blood supply. Thrombosis of a branch artery may manifest as an increase in serum creatinine levels associated with hypertension. Angiography shows partial thrombosis and loss of perfusion of a wedge-shaped section of renal parenchyma. The risk of this situation, in addition to potential long-term hypertension, is caliceal infarction and urine leak in the early postoperative period. Such kidneys, with partial infarction, generally can be salvaged. Urine leaks occurring through the outer cortex of the kidney after partial infarction may be managed by nephrostomy tube placement for urinary drainage and placement of another drain adjacent to the kidney to prevent urinoma. When the transplant ureter necroses as a result of arterial ischemia, alternative urinary drainage needs to be provided surgically; this would be managed most often by ureteropyelostomy using the ipsilateral native ureter.
Renal Vein Thrombosis
Renal vein thrombosis occurs in between 0.1% and 4.2% of recipients and is more common in deceased donor transplants. Thrombosis may occur as a technical complication when the donor renal vein was narrowed by repair of an injury or when the vein was twisted or compressed externally, but it may occur in the absence of a technical complication. Risk factors for renal vein thrombosis include use of the right donor kidney, prolonged ischemic time, older donors, older recipients, use of peritoneal dialysis pretransplant, hypercoagulable states in the recipient, and perioperative hypotension in the recipient. The diagnosis is indicated by sudden onset of gross hematuria and decrease in urine output, associated with pain and swelling over the graft. Ultrasound shows absence of flow in the renal vein, diastolic reversal of flow in the renal artery ( Fig. 14.4 ), and an enlarged kidney, often with surrounding blood. Ultrasound can point to this diagnosis definitively. Only if it is immediately recognized and repaired can this problem be reversed. Immediate surgical repair of the vein and control of bleeding are required, and it is generally necessary to remove the kidney and revise the venous anastomosis. However, some instances of catheter-directed thrombolytic therapy or thrombectomy have been successfully reported in the setting of early postoperative renal vein thrombosis. Bleeding from the swollen and cracked kidney surface usually can be controlled with hemostatic agents.
As with all surgery, postoperative bleeding may complicate renal transplant outcomes. Bleeding generally occurs during the first 24 to 48 hours after transplantation and is diagnosed by a decreasing hematocrit, swelling over the graft with a bulging incision, or significant blood seepage from the incision. Postoperative bleeding occurs in roughly 12% of kidney transplant recipients and is more likely to occur in those with calcified iliac vessels who receive higher doses of heparin as prophylactic anticoagulation and in patients taking anticoagulation agents for other medical problems such as coronary artery or cerebrovascular disease. Patients treated with clopidogrel for underlying cardiac disease are at significant risk for postoperative bleeding; this class of medications should be avoided or discontinued 1 week before renal transplantation if acceptable from a cardiac perspective. If the hematoma is not clinically obvious, an ultrasound or computed tomography (CT) scan can define its size and help determine whether or not surgical evacuation is appropriate. Treatment includes immediate surgery and blood transfusions as necessary.
Graft Loss and Transplant Nephrectomy
During the early posttransplant period, if a renal transplant loses perfusion because of thrombosis or because of hyperacute, acute, or accelerated vascular rejection, it must be removed. Otherwise, the systemic toxicity of a necrotic kidney may cause fever, graft swelling or tenderness, and generalized malaise. Loss of perfusion can be assessed by nuclear scan or duplex ultrasound. The technically easiest way to perform a transplant nephrectomy depends on how long the kidney has been in place. If nephrectomy is performed within 4 weeks, there are minimal adhesions, and the vessels are exposed easily for ligation and transplant nephrectomy. At later times, it is usually easiest to reopen the transplant incision and enter the subcapsular plane around the kidney. The kidney is dissected free in the subcapsular space, and a large vascular clamp is placed across the hilum. The kidney is amputated above the clamp, and 3-0 polypropylene (Prolene) is used to oversew the hilar vessels. The ureter also is oversewn (see Chapter 11 ).
Rejection During the Early Postoperative Period
Hyperacute rejection is the immediate rejection of the donor kidney upon reperfusion and is mediated by preformed antibodies against the donor. The risk of hyperacute rejection or of antibody-mediated rejection (AMR) is increased when a renal transplant is performed in the setting of ABO mismatch or a positive lymphocytotoxic crossmatch (see Chapter 22 ). Hyperacute rejection is now a rare event because of our understanding of transplant immunology and the implementation of more stringent immunologic testing of donors and recipients to prevent such occurrences. Current guidelines recommend molecular human leukocyte antigen (HLA) typing both the recipient and donor before kidney transplant because HLA matching for HLA-A, HLA-B, and HLA-DR, with an emphasis on HLA-DR matching, has been shown to improve kidney transplant outcomes. For nonsensitized patients with no preformed antibodies, it is reasonable to proceed with transplantation with no prospective crossmatch and this strategy of “virtual crossmatching” has been developed to minimize cold ischemic time. For sensitized patients that have preformed anti-HLA antibodies, the selection of donors toward whom the patient has no preformed antibodies is critical for the success of the transplant. Therefore highly sensitized patients should undergo further serologic typing of the donor and high-resolution HLA typing of both the donor and recipient. In addition, sensitized kidney transplant candidates should undergo a complement dependent cytotoxicity crossmatch and a flow cytometric crossmatch with the putative donor to prevent hyperacute and acute rejection. Although this rigorous immunologic testing of donor and recipient has drastically reduced the incidence of hyperacute rejection, there are reports of hyperacute rejection occurring even in the setting of negative crossmatch results. A hyperacutely rejected kidney has no perfusion on renal scan because of microvascular thrombosis and should be removed. The introduction of solid-phase assays based on the Luminex platform may help identify those with donor-specific antibody (DSA) that may cause a problem in the absence of positive crossmatch results, but these assays require more rigorous validation and standardization. The incidence of hyperacute rejection is not 100% in those with preformed antibodies, presumably because some antibodies have lower affinity, lower density, do not bind complement, or cause accommodation. In some cases, blood type A2 donors may be transplanted successfully to type O recipients because type A2 expresses less of the putative antigen, but this strategy also has increased risk of graft loss. Desensitization is a strategy to remove preformed antibody before transplantation to prevent hyperacute and antibody-mediated rejection. Desensitization regimens include the use of plasmapheresis combined with intravenous immunoglobulin and/or rituximab and are a growing area of research. If at all possible, a crossmatch-negative, ABO-compatible recipient should be identified for the transplant candidate or the kidney can be shipped to a center that has such a patient awaiting a kidney, potentially in exchange for a kidney to which the intended recipient has a negative crossmatch. A strategy such as this will maximize outcomes and utility for the kidney transplant community.
Despite a negative T-cell crossmatch test preoperatively, some patients may develop an early aggressive form of rejection, termed antibody-mediated rejection (AMR). The incidence of AMR is greater than 20% in sensitized patients. The diagnosis of AMR is based on the presence of DSA in recipient serum and biopsy of the transplanted kidney demonstrating microvascular inflammation (glomerulitis or peritubular capillaritis), immune cell infiltration, and usually evidence of complement activation by C4d staining of peritubular capillaries.
AMR is seen most often in sensitized patients with DSA of high mean channel fluorescence by flow crossmatch. Often such patients have had a previous transplant. The time course of this type of rejection is typically within days to weeks of the transplant, although it may occur at any time; it tends to be poorly responsive to steroids and occasionally resistant to all forms of antirejection therapy. Indeed, renal transplant patients who develop DSA have 60% 5-year graft survival compared with 80% graft survival in those who do not develop DSA. Although successful prophylaxis of rejection has been described using intravenous immunoglobulin, rituximab, plasmapheresis, or thymoglobulin in highly sensitized patients, when this form of rejection has started there is no standard treatment. The KDIGO guidelines recommend that such rejection be treated with one or more of the following, with or without steroids: plasmapheresis, intravenous immunoglobulin, anti-CD20 antibody, or other lymphocyte-depleting antibody. Other novel strategies to treat AMR include targeting complement, targeting plasma cells with proteasome inhibitors, targeting the germinal center reaction with anticytokine or cytokine receptor antibodies or costimulatory blockade (belatacept), or directly targeting antibodies by enzymatic cleavage. Randomized controlled trials are needed to determine which of these therapies (or combination of therapies) is most effective in treating AMR.
The most common form of immunologic rejection in the early posttransplant period is acute cellular rejection, mediated predominantly by host T lymphocytes responding to the allogeneic major histocompatibility complex (MHC) antigens on the donor kidney. Without adequate immunosuppression, acute rejection typically occurs 5 to 7 days after transplantation, but it can occur at virtually any later time. The highest incidence of acute rejection is within the first 3 months, and overall rates of rejection vary from 5% to 25% within the first 6 months, depending on HLA matching and the immunosuppressive protocol. The clinical harbingers of acute rejection include an increasing creatinine level, weight gain, and graft tenderness. Often, there are no physical signs or symptoms, making the diagnosis largely dependent on laboratory assessment of renal function. Better diagnostics based on urine or blood molecular analysis have been developed but are at early stages of clinical application. The current diagnosis of acute rejection is based on kidney transplant biopsy and histopathologic changes, including tubulitis (invasion of tubules by lymphocytes), glomerulitis, and arteritis, which are classified according to the Banff Classification System. The importance of biopsy confirmation of rejection relates to the risk of increasing immunosuppression in patients whose graft dysfunction is not caused by rejection but perhaps infection or other causes that might be exacerbated by increased immunosuppression.
First-line treatment of acute cellular rejection is bolus steroid therapy with methylprednisolone sodium succinate (Solu-Medrol). Many regimens are used successfully, but typical dose and duration are 10 mg/kg intravenously daily for 3 days (up to a maximum single dose of 500 mg/day). About 85% to 90% of acute cellular rejection episodes are steroid-responsive. If the patient’s serum creatinine level has not begun to decrease by day 4 of therapy, alternative treatment must be considered, such as antilymphocytic globulin, alemtuzumab (Campath-1H), or rituximab (anti-CD20) as lymphocytotoxic therapy. Many centers use antibody-depleting therapy first line for all severe vascular rejections (Banff 2A and 3), particularly if anti-IL-2 induction was used. However, antibody-depleting therapies may be associated with an increase in infectious complications when used to treat rejection compared with when used for induction. A recent systematic review of randomized trials in treating acute rejection demonstrated that antilymphocyte antibody therapies are likely superior to steroids in the initial treatment of acute cellular rejection in terms of reversing rejection and preventing graft loss, but there was no difference in subsequent rejection episodes or patient survival, and the antibody therapies carry a higher rate of adverse events compared with steroid treatment. Rejection that does not respond to treatment with steroids or antibody therapy occurs in less than 5% of patients, although more frequently in sensitized patients or repeat transplants with significant DSA present.
The effect of acute cellular rejection on graft survival depends on the response to treatment, with minimal effect if treatment results in return to baseline function but negative effect with incomplete response or repeated rejection episodes. Whether or not an early rejection episode predisposes the kidney to chronic rejection is controversial but likely depends on the complete resolution of the rejection and associated DSA.
The entity of borderline rejection on kidney transplant biopsy is of uncertain significance. Whereas some studies demonstrate that treatment of borderline rejection with an increase in the patient’s immunosuppression can improve graft function, others have found little benefit in treating those with borderline rejection on biopsy results. Therefore if a kidney biopsy is interpreted as “borderline” by Banff criteria, we suggest the decision to treat be made on an individual basis according to the clinical picture of the recipient.