The concept of replacing a diseased human organ with tissue from a living or deceased person has existed since ancient times. The different kinds of transplanted tissue include an autograft (tissue from the recipient), an isograft (tissue from an individual with the same genotype, such as a monozygotic twin), an allograft (tissue from a genetically disparate individual from the same species), and a xenograft (tissue from a different species).
As early as 1916, Little and Tyzzer articulated the important differences between these graft types, stating “isografts succeed; allografts are rejected.” A century later, the clinical practice of transplantation remains subject to these laws. Nonetheless, the introduction of modern immunosuppression drugs has led to dramatic improvements in allograft outcomes. As a result, kidney transplantation has become a common intervention.
RECIPIENT OPERATION IN KIDNEY TRANSPLANTATION
Unfortunately, only a small minority of the patients that would beneﬁt from a kidney transplant ever receive one. There is an ever-growing waiting list 84,355 patients in the United States in 2010 that far exceeds the number of annual procedures. In 2009, 16,830 kidney transplants were performed: 10,442 from a deceased donor, and 6388 from a living donor.
Despite the growing need for organs, the number of deceased organ donors per year has been stagnant. Nonetheless, the annual number of kidney transplants continues to rise. Much of this growth has been fueled by an increase in live donors, in large part because of substantial improvements in the organ harvesting process, such as the introduction of minimally invasive techniques.
INDICATIONS, DONOR MATCHING, AND PREOPERATIVE EVALUATION
All patients with either end-stage renal disease or advanced chronic kidney disease (stage 4 or 5) should be considered for renal transplantation. Those who can tolerate the surgical and anesthetic risks, and who can safely be immunosuppressed after the transplant, are potential candidates. Relative contraindications include uncorrectable advanced cardiopulmonary disease, cirrhosis, active malignancies, active infections, active substance abuse, and inadequate social support.
Before transplantation, the donor and recipient must be conﬁrmed to have compatible blood types. In addition, precautions must be taken to ensure immune compatibility. Recipient serum must be tested against donor lymphocytes to ensure the recipient does not have preformed antibodies to donor proteins. The problematic alloantibodies are most commonly directed against donor major histocompatibility complex (MHC) class I and class II antigens. MHC class I antigens are expressed on most nucleated cells, albeit at variable levels, whereas MHC class II antigens are expressed mainly on antigen presenting cells (B lymphocytes, dendritic cells, and some endothelial cells). Thus recipient serum is tested against donor lymphocytes, which contain both MHC antigens. A positive crossmatch predicts a high likelihood of hyperacute or early rejection.
In the past, the human leukocyte antigen genes (HLA) of both donor and recipient, which encode the MHC genes, were also examined to determine the risk of later alloantibody production and delayed graft rejection. Because of the efﬁcacy of current immunosuppressive therapies, however, there is a reduced need to ensure HLA matching between the donor and recipient. Moreover, acute rejection episodes that do occur can usually be effectively treated. Nonetheless, transplants between HLA-identical siblings continue to yield the best long-term outcomes.
Kidney transplants from living donors result in superior outcomes compared with those where the kidney has been obtained from a deceased donor. Proinﬂammatory and proapoptotic physiologic perturbations associated with death, as well as the increased cold ischemic times associated with deceased donor transplantation, account for this difference in outcome.
MECHANISM OF ACTION OF IMMUNOSUPPRESSIVE MEDICATIONS IN KIDNEY TRANSPLANTATION
Whether procured from a living or deceased donor, kidneys for transplantation are ﬂushed with cold (4° C) preservation solution until asanguinous. The use of cold organ preservation allows for successful trans- plantation even with extended ischemic times, which may exceed 48 hours. As a result, kidneys may be shipped over long distances to reach the recipient. Nonetheless, it is preferable to minimize ischemic times. Deceased donor kidneys may also be placed on a specialized mechanical perfusion apparatus that has been shown to decrease the incidence of delayed allograft function.
Before the harvested organ can be transplanted, surgeons must perform a functional assessment of the allograft and review the anatomic report of the procuring surgeon to determine if there are any tumors, vascular or ureteral anomalies, or traumatic injuries to the kidney that could preclude successful transplantation.
The recipient operation is usually a heterotopic transplant, meaning the recipient’s kidneys are left in place and the transplanted kidney is placed in the iliac fossa, away from its normal anatomic position. The procedure is performed through a Gibson or “hockey stick” incision in one of the lower quadrants of the abdomen. A renal allograft can be implanted on either side, although many surgeons recommend implanting a left kidney in the right iliac fossa and vice versa. The advantage of this approach is that it positions the renal pelvis and ureter at the most anterior aspect of the renal hilum, which facilitates access if reconstruction is required at a later date.
The fascia and muscle layers of the obliques and transversus are divided just lateral to the edge of the rectus abdominis sheath. The superﬁcial epigastric artery can be either ligated and divided, or spared and mobilized medially. In females, the round ligament is divided to mobilize the peritoneum, which is moved superiorly and medially to uncover the external iliac artery and vein. In males, the spermatic cord structures are preserved and mobilized medially to allow retraction of the peritoneum from the abdominal wall.
Anastomosis is performed between the renal allograft vein and external iliac vein, then between the renal allograft artery and external iliac artery. The ends of the allograft vessels are sewn into the sides of the iliac vessels. After the vascular reconstruction is complete, the graft is immediately reperfused. The donor ureter is then anastomosed to the recipient’s bladder. The abdomen is then closed, typically with no drains required.
The fate of the graft depends on the response of the recipient’s immune system. Thus immunosuppression is critical. A combination of azathioprine and corticosteroids was the ﬁrst successful immunosuppression regimen, but the relative inefﬁcacy of this regimen, combined with the adverse effects of high-dose steroids, led to poor outcomes in many patients. The introduction of cyclosporine in the 1980s brought about a dramatic improvement in outcomes and allowed for a signiﬁcant expansion of kidney transplantation.
In the modern setting, there are several combinations of drugs that can be used to maintain immunosuppression in renal transplant recipients. The most common regimen includes a calcineurin inhibitor (tacrolimus, cyclosporine) and an antimetabolite (mycophenolate, azathioprine) or sirolimus. Many centers also include low-dose corticosteroids.
A delicate balance must be maintained between avoidance of allograft rejection and side effects, including opportunistic infections and malignancies. Infections in the ﬁrst month after transplant typically include postoperative surgical infections, urinary tract infections, and pneumonias. At 1 to 6 months, opportunistic infections such as Pneumocystis pneumonia and CMV infection dominate. Further along, BK virus, human papilloma virus, CMV, and EBV-associated lympho- proliferative disease can appear.
CAUSES OF GRAFT DYSFUNCTION IN IMMEDIATE POST-TRANSPLANT PERIOD
Several complications, both surgical and immunologic, may cause delayed graft function (DGF) or failure of a previously functional graft. Therefore, it is essential that patients undergo regular monitoring with measurement of serum creatinine concentration. At some centers, surveillance biopsies are also performed either on a routine basis or in select patients at high risk for rejection.
The most probable causes of graft dysfunction depend on the amount of time that has passed since the transplantation.
Immediate Postoperative Period. After a live donor transplant, the kidney begins functioning right away in roughly 95% of cases. After a deceased donor trans- plant, however, there may be some degree of DGF, which may last for days, weeks, or even months.
Hyperacute rejection occurs minutes to hours after transplantation, and it is often diagnosed in the operating room immediately after revascularization of the allograft. Such rejection reﬂects the presence of preformed antibodies that target antigens on the allograft, such as HLA class I proteins, HLA class II proteins, or ABO blood group antigens. A patient may become HLA-sensitized by previous blood transfusions, pregnancies, or prior transplants. No matter the cause, the presence of preformed antibodies leads to rapid immune complex formation, complement-mediated inﬂammation, and activation of the coagulation cascade with subsequent allograft thrombosis. The allograft is rapidly lost and must be removed. This complication is rarely seen in current transplantation due to preoperative crossmatch testing performed between the recipient serum and donor cells, as described previously.
In the immediate postoperative period, acute tubular necrosis (ATN) is the most frequent cause of DGF. Risk factors include prolonged cold ischemia times and older age of the donor. Patients with ATN are offered supportive care because spontaneous resolution after 1 or more weeks is common. ATN is a diagnosis of exclusion, however, and thus other potential causes of DGF must be ruled out, including prerenal state, thrombosis of the renal vessels, anatomic or functional obstruction of the urine collecting system, and urine leak.
Prerenal state, in which there is inadequate perfusion pressure in the allograft, may occur secondary to volume depletion or vasodilation. To avert this complication, patients should receive several liters of ﬂuid in the operating room, which will help offset the vasodilation associated with anesthesia. If DGF occurs, the response to further ﬂuid resuscitation should be included as part of the routine evaluation. Rarely, patients may experience volume depletion secondary to hemorrhage, possibly of the vascular anastomoses. If major postoperative bleeding is suspected, immediate surgical reexploration should be performed.
CAUSES OF GRAFT DYSFUNCTION IN EARLY POST-TRANSPLANT PERIOD
Primary thromboses of the renal vessels (i.e., not secondary to rejection) may occur secondary to surgical technique or, more often, a hypercoagulable state (e.g., antiphospholipid antibody). Both arterial and venous thromboses may cause sudden anuria; venous thromboses are also associated with pain around the allograft. Both kinds of thromboses can only be treated with immediate surgical reexploration, which usually reveals an infarcted graft that must be removed. Thromboses can be diagnosed with color Doppler ultrasound, which will reveal an absence of arterial and/or venous ﬂow.
Obstruction of the urinary collecting system is another possible cause of delayed graft function. There are numerous possible causes, including benign prostatic hypertrophy, neurogenic bladder, blood clots in the ureter, tight ureterovesical anastomosis, and mal-positioning/obstruction of a urinary catheter.
Finally, urine leak may present similarly to delayed renal function because it causes low urine output and, as a result of urine reabsorption, an elevation in serum creatinine and urea concentrations. Possible causes include ureteral infarction or failure of the ureterovesical anastomosis. Urine leaks can usually be diagnosed using ultrasonography or isotope renography. Stenting across the defect may be attempted, although surgical reconstruction may be necessary in some cases.
Early Post-transplant Period (1 Week to 6 Months). Many of the pathologies that cause DGF may also cause renal dysfunction in the early post-transplant period. Prerenal state, for example, may occur secondary to inadequate ﬂuid intake, diarrhea, or use of drugs that impair tubuloglomerular feedback, such as ACE inhibitors or NSAIDs. In addition, renal vessel thromboses may not occur until several weeks post-transplantation.
Postrenal disease, such as urinary tract obstructions and urine leaks, may also occur during this period. In addition to the obstructions that may be seen immediately following the transplantation, patients may also develop lymphoceles, which occur secondary to disruption of lymphatic channels around the iliac arteries. Lymphoceles can cause thigh swelling and urinary frequency secondary to bladder compression. If very large, they may compress the allograft ureter and cause renal dysfunction. The diagnosis can be established using ultrasound or, as needed, analysis of a ﬂuid aspirate. Symptomatic lymphoceles may be treated with a combination of ultrasound-guided drainage, followed by injection of sclerosing agents or, as needed, surgical marsupialization.
The other causes of early post-transplant graft dysfunction include various types of intrarenal disease, including acute allograft rejection (either cellular or antibody-mediated), calcineurin inhibitor nephrotoxicity, medication or contrast-associated nephrotoxic ATN, acute pyelonephritis, and recurrence of the primary renal disease.
PATHOLOGIC FINDINGS IN ACUTE REJECTION OF KIDNEY ALLOGRAFT
Acute allograft rejection can be either cellular or antibody-mediated. It is the most frequent type of rejection, occurring in 10% to 15% of patients during the ﬁrst year after transplant. Manifestations include a rapid loss in renal function, sometimes accompanied by low-grade fever and pain over the graft. More systemic signs of illness, such as nausea or myalgias, have become uncommon with the use of modern immunosuppression regimens. Acute rejection may occur as little as 1 week after transplantation but is typically seen after 1 to 3 months. It should be strongly suspected in a patient with declining renal function but reasonable plasma calcineurin inhibitor levels and no evidence of recurrent primary disease (i.e., no proteinuria or evidence of glomerular bleeding). Because the treatment strategies for cellular and antibody-mediated acute rejection are different, a renal biopsy is essential for making the distinction.
Acute cellular rejection results from an interaction between recipient antigen-presenting cells (APCs), recipient T cells, and MHC antigens on donor cells. The T cells become activated, resulting in the transcription of genes for cytokines and cytokine receptors, leading to inﬂammation in the allograft. Histopathologic ﬁndings include interstitial inﬂammation, predominantly by T lymphocytes, accompanied by tubulitis, which occurs when T cells cross tubular basement membranes and inﬁltrate tubular epithelium. Inﬂammation of arteries (endarteritis) may also be noted. It usually begins as endotheliitis, characterized by swelling and detachment of endothelial cells, as well as lymphocyte inﬁltration of the endothelial layer. In severe cases, transmural vasculitis may occur, in which lymphocytes inﬁltrate and inﬂame the entire thickness of the vessel wall. Acute cellular rejection can usually be treated with a pulse of high-dose corticosteroids or, in cases of steroid resistance, antilymphocyte antibodies.
Acute antibody-mediated rejection is less common than acute cellular rejection, and it may result from a previous exposure to a speciﬁc antigen, or from de novo reactivity and clonal expansion of reactive B cells. It typically occurs within 2 weeks of transplantation, and the presentation is similar to acute cellular rejection. Patients are found to have antibodies that target donor HLA or ABO-group antigens. Histopathologic ﬁndings can range from a subtle form of tubular injury, similar to what is seen in ATN, to dramatic occlusion of glomerular capillaries by neutrophils and ﬁbrin-rich thrombi. One of the most common histologic manifestations of acute antibody-mediated rejection is peritubular capillaritis, characterized by dilation of the interstitial capillaries and margination of leukocytes, most often a combination of neutrophils and lymphocytes. A helpful marker of acute antibody-mediated rejection is the presence of C4d within peritubular capillaries. C4d is a degradation product of complement factor C4 and can be detected using either immunoﬂuorescence or immunohistochemistry. Acute antibody-mediated rejection can be treated with plasmapheresis to remove the antibodies and infusion of intravenous immunoglobulin.
HISTOPATHOLOGIC FINDINGS IN CALCINEURIN INHIBITOR NEPHROTOXICITY
Calcineurin inhibitor (CNI) nephrotoxicity may also occur in the early postoperative period, often secondary to drug-induced constriction of afferent arterioles. The diagnosis should be suspected in a patient with a supra- therapeutic serum calcineurin inhibitor concentration in whom renal function improves after dose reduction. A lack of response to dose reduction, however, does not necessarily exclude CNI-related disease. Thus a biopsy is often required to make the distinction from acute rejection. If no signiﬁcant pathologic changes are seen at biopsy, the CNI toxicity is assumed to be a predominantly hemodynamic effect. Several pathologic changes, however, are sometimes seen. CNI toxicity can affect tubules, where it causes isometric vacuolization of the epithelial cytoplasm. CNI toxicity can also affect vessels, where it causes hyalinosis of medial myocytes. These changes are best appreciated in afferent arterioles. Rarely, CNI toxicity can cause severe endothelial cell damage that results in thrombotic microangiopathy, characterized by ﬁbrin thrombus formation in small arterioles and glomerular capillaries.
Numerous medications may cause nephrotoxic ATN in allografts, as they do in native kidneys (see Plate 4-3). Certain drugs, such as erythromycin, are especially nephrotoxic when administered along with calcineuinhibitors because of their effects on hepatic metabolism.
Pyelonephritis may occur secondary to immunosuppression and frequent catheterization. Like acute rejection, it may present as fever and allograft pain. Urine dipstick and culture should be performed to assess for the presence of this complication.
Recurrence of a primary renal disease, such as focal segmental glomerulosclerosis, may also occur. Although glomerular disease may sometimes be distinguished from rejection based on the presence of heavy proteinuria or glomerular bleeding (i.e., red blood cell casts or dysmorphic red blood cells) on urine sediment, biopsy is often required to make the distinction.
Late Post-Transplant Period (After 6 Months). Many of the problems that can occur in the early post-transplant period may also occur in the late post- transplant period, including prerenal state, CNI nephrotoxicity, nephrotoxic ATN, pyelonephritis, recurrence of primary disease, and urinary tract obstruction. Late acute rejection may also occur in patients with inadequate immunosuppression or medication non-compliance. The other causes of late post-transplant graft dysfunction include chronic allograft nephropathy, BK virus infection, and renal artery stenosis.
Chronic allograft nephropathy, the most important cause of late allograft loss, is a poorly characterized phenomenon. Most pathologists use the term to encompass a myriad of structural and functional alterations related to chronic rejection that develop over the course of months and generally cause loss of the graft over a period of years. The major histologic ﬁndings include interstitial ﬁbrosis, tubular atrophy, chronic arterial and arteriolar inﬂammation with luminal narrowing, and transplant glomerulopathy (which features doubling of the glomerular basement membrane, as in membranoproliferative glomerulonephritis).
BK virus is a polyomavirus that infects many adults but only appears to cause disease in those who are immunosuppressed. It has a particular tropism for the urinary tract, where it can cause interstitial nephritis or ureteral stenosis. Urine microscopy reveals “decoy cells,” which are tubular epithelial and urothelial cells infected with the BK virus. Since anti-BK antibodies are found in many individuals without BK-related disease, polymerase chain reaction (PCR) testing is performed to detect the virus itself in urine and blood, sometimes on a screening basis. A renal biopsy is performed if PCR is positive in the setting of renal dysfunction. Characteristic histopathologic ﬁndings include intranuclear inclusions within tubular epithelial cells, tubular injury, tubulitis, and interstitial inﬂammation. Anti-SV40 immunohistochemistry is performed to conﬁrm the presence of viral antigen. Treatment usually consists of reducing the dosage of immunosuppressive therapies.
CAUSES OF GRAFT DYSFUNCTION IN LATE POST-TRANSPLANT PERIOD IN KIDNEY TRANSPLATION
Renal artery stenosis (see Plate 4-36) may occur secondary to disease in either the donor or recipient vasculature. Possible causes include vascular trauma and atherosclerosis. Suggestive clinical features include hypertension, renal dysfunction that is worsened upon provision of ACE inhibitors, weakened femoral pulses, and a new bruit over the allograft. Percutaneous transluminal angioplasty may be required for severe cases (see Plate 10-17).
Prognosis. Despite the risks associated with the transplantation procedure and allograft rejection, the overall prognosis for patients who receive renal transplants is excellent. The graft survival rates for deceased donor kidneys are 89%, 78%, and 67% at 1, 3, and 5 years, respectively; meanwhile, the graft survival rates for living donor kidneys are 95%, 88%, and 80% at 1, 3, and 5 years, respectively.
Because of these positive outcomes, kidney trans- plantation is becoming widely practiced around the world. Improvements in organ access, donation, preservation techniques, immunosuppression, and management of disease progression will further improve outcomes and access to transplantation in the future.