Transplantation of the Kidney

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Table 40.1. Causes of end-stage renal disease (ESRD): United States Renal Data System (USRDS) Annual Data Report.

Data from www.USRDS.org. Web site of United States Renal Data System.

Hemodialysis is the most common technique for the treatment of ESRD throughout the United States, although transplantation has proven to be the most effective solution to renal failure. The two most common causes of renal failure (Table 40.1), hypertension and diabetes mellitus, are significant risk factors for cardiovascular disease. The combination of underlying medical conditions leading to renal failure and dialysis itself creates an inverse relationship between time on dialysis and success with a renal transplant. Unfortunately, patients often have to wait years before receiving a transplant and have to suffer the debilitating consequences of long-term dialysis.

Prior to renal transplantation or to placement on a list for a cadaveric renal transplant, the potential recipient undergoes a thorough history and a thorough physical exam. Routinely, a complete blood count (CBC), chemistries, prothrombin time, partial thromboplastin time, chest x-ray, electrocardiogram (ECG), and blood type are obtained. In view of the significant effect the antirejection medications have on infectious agents, hepatitis B surface antigen and surface antibody (HBsAg, HBsAB), hepatitis B core antibody (HBcAB), hepatitis C antibody (HepCAb), VOR2, human immunodeficiency virus (HIV), herpes simplex virus (HSV), purified protein derivative (PPD), and cytomegalovirus (CMV) routinely are obtained. In women over 18, a Papanicolaou (Pap) smear from within the past year is required. A mammogram is required in women over 40. Last, blood routinely is sent to the tissue-typing lab for human leukocyte antigen (HLA) typing and for identification of preformed antibodies against a panel of known HLAs. This is called a panel reactive antibody test (PRA). Future workup is directed by the individual’s underlying medical condition. Many patients undergo an echocardiogram, a cardiac stress test, a noninvasive vascular exam, and duplex ultrasound of the carotid arteries, since cardiovascular disease is pervasive through the renal failure population.

The contraindications to renal transplantation (Table 40.2) fall into two large categories. The first category is related to the general effect immunosuppressants have on infections and on cancer and to the patient’s ability to take these drugs. The second category relates to the patient’s overall medical condition, with a focus on cardiovascular status, and his or her ability to undergo a substantial operation.

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Table 40.2. Contraindication to renal transplant.

Recent malignancy Active infection

Active tuberculosis Active AIDS

Hepatitis (with grade 2 cirrhosis or greater) Pregnancy

Active illicit drug use Active alcohol abuse Noncompliance

Uncontrolled psychiatric disorders Severe cardiovascular disease

Other end-stage organ disease (cardiac, pulmonary, hepatic)

How Organs Are Allocated Once a Patient Has Been

Placed on a Cadaveric Waiting List

The goal of the renal allocation scheme is to balance the benefit of matching HLA against waiting time (Table 40.3). Patients steadily accumulate points for each year for which they wait for an organ, and therefore waiting time eventually serves as the driving force behind allocation. Patients cannot start accumulating waiting time until their glomerular filtration rate is less than 20 cc/min. Various numbers of points are given to different degrees of HLA matching, and so a patient’s total points fluctuate with each potential transplant. Finally, points are given to individuals with PRAs greater than or equal to 80%. A PRA of 80% means that the recipient has antibodies against 80% of the antigens against which he/she is tested. The HLAs used are those commonly found in the local population. Patients become sensitized to HLAs and develop antibodies through exposure to human tissue through pregnancy, blood transfusions, and previous transplants of any time (except corneal). Overall, the higher the PRA becomes, the more difficult it is to find a compatible transplant. In the clinical case

Table 40.3. United System for Organ Sharing (UNOS) cadaver kidney allocation system.a

Kidneys allocated locally first, then regionally, then nationally to patients ranked highest, as determined by the following criteria:

Antigen mismatch (0–2 points) Time waiting (<1 + 1 point per year)

Panel reactive antibody >80% (4 points)

Pediatric points (3–4 points) Previous living donation (4 points)

Patients are eligible for marginal donors if specifically consented prior to listing

The individual with the highest cumulative point total is awarded the organ

a Individuals are placed on the waiting list only when their creatinine clearance or glomerular filtration rate (GFR) is less than or equal to 20 mL/min.

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Table 40.4. Brain death criteria.

Absence of spontaneous movement

Absence of spontaneous respiration over a 4-minute test period Absence of brain reflexes as evidenced by:

Fixed dilated pupils Absent gag reflex

Absent corneal and ciliospinal reflexes Absent doll’s eye movements

Absent response to caloric stimulation Absent tonic neck reflex

Unchanged status for at least 12 hours

Responsible pathologic process deemed irreparable

Hypothermia and the presence of CNS depressants such as barbiturates must be excluded

CNS, central nervous system.

Data from Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. JAMA 1968;205:337.

Currently, the majority of individuals are able to donate multiple organs. Individuals who have severe, nonrecoverable neurologica injuries can donate their organs as well, although this type of donation is somewhat controversial. This less common form of donation usually is determined by the family, and the organ procurement organization is contacted. Life support is withdrawn in an operating room setting, and cardiopulmonary death usually occurs within minutes. A physician other than a member of the transplant team pronounces the patient dead. This type of donation is termed a controlled, non–heart-beating donor. Well-functioning liver and kidney allograft can be harvested in this manner with little effect on immediate function. Uncontrolled, non–heart-beating donations occur when a patient is undergoing a cardiac arrest and resuscitation has failed. This often is a setting in which organ donation already has been discussed, and the patient arrests prior to brain death. Rapid infusion of preservation solution and heparinization are paramount for retrieving usable organs.

Issues that Arise with Live Donation

Since the immunosuppressive agents have become so effective at stopping acute rejection, HLA match has taken on a diminished role. ABO blood type incompatibility remains a significant obstacle to organ donation. As the need for HLA match has diminished, the number of living, unrelated, emotionally attached donors has increased. The focus of the live donor evaluation (Table 40.5) is determining the overall health of the individual and his/her renal function. This type of donation often is spousal, but it has occurred between distant relatives, friends, and community members. The lack of cadaveric donors has resulted in the transplant community exploring the possibility of some financial remuneration for both live and cadaveric donors.

The transplant community has an obligation to these “heroic” individuals who provide live donations to ensure that organ donation is as

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Table 40.5. Live donor evaluation.

Identifying individuals who are willing to serve as live kidney donors Discussion concerning the willingness of the individual to donate isolated

from potential conflicting recipient issues Complete history and physical

Psychosocial evaluation Laboratory test

Urinalysis, complete blood count, complete metabolic profile, and coagulation studies

Blood type

Infectious screening for hepatitis A, B, and C, CMV, EBV, HSV, HIV, toxoplasmosis, and RPR

PSA in men over 50

Pregnancy test, Pap smear, and mammogram in women over 40

If donor and recipient are ABO compatible and there are no medical or psychological contraindications to donation then proceed with remainder of donor workup

24-hour urine collection for protein and creatinine clearance Cardiac evaluation

ECG (if abnormal add echocardiogram) Chest x-ray

MRI/MRA Immunologic studies

HLA typing

Crossmatching with the recipient

CMV, cytomegalovirus; EBV, Epstein-Barr virus; ECG, electrocardiogram; HLA, human leukocyte antigen; HSV, herpes simplex virus; PSA, prostate-specific antigen; RPR, rapid plasma reagent.

safe as possible. It is important to inform the patient that, although the operation is safe, complications and rare deaths have occurred with donation. Currently, donation in this country is based solely on an altruistic basis, and paid donation is prohibited.

Surgical Techniques

The kidney transplant operation is well described in Chapter 65, “Kidney Transplantation and Dialysis Access,” in Surgery: Basic Science and Clinical Evidence, edited by J.A. Norton, R.R. Bollinger, A.E. Chang, et al., published by Springer-Verlag, 2001. Here, several clinically important points will be mentioned. An important point to note is the difference between placing a kidney obtained from a cadaver donor and placing a kidney obtained from a live donor.

During the procurement of a kidney from a cadaveric donor, a cuff of vena cava and aorta can be left on the renal vein and artery, respectively. The renal vein anastomosis actually is sewn between the cuff of the vena cava and recipient’s external iliac vein in an end-to-side fashion. This anastomosis can be done without the worry of tearing the thin wall of the right renal vein. Large hemostatic bites of the vena cava may be taken without concern for narrowing the anastomosis. Having a cuff of aorta allows for a single anastomosis even in the presence of multiple renal arteries. The cuff of aorta is sewn in an end-to-side

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fashion to the external iliac artery. Once again, with a large cuff, the surgeon need not be concerned with narrowing the renal artery anastomosis.

In kidneys obtained from live donors, the renal artery may be sewn to the external iliac artery in an end-to-side fashion or to the internal iliac artery in an end-to-end fashion. The left kidney often is the preferred kidney, especially from a live donor, as the left renal vein is considerably longer and thicker-walled than the right renal vein. Occasionally, the recipient’s internal iliac vein is divided to enable the external iliac vein to be moved more anteriorly and out of the pelvis. If the kidney from a live donor has two arteries, they may both be sewn directly into the external iliac artery. The incidence of renal artery stenosis may be reduced by the uses of an aortic punch biopsy. More commonly, the smaller of the two arteries is sewn into the larger main renal artery in an end-to-side fashion under ice on the back table. The kidney is then placed within the recipient, and a single anastomosis between the main renal artery and the recipient iliac artery (external or internal) is performed. Vascular thrombosis of the artery and vein are rare events: arterial thrombosis occurs less than 1%, and venous thrombosis occurs less than 2%.

Posttransplant Period

The differential of an increasing serum creatinine is influenced significantly by the amount of time from the day of the transplant to the increase in serum creatinine (Fig. 40.1). Three different time periods can be created based on the most likely cause for an increasing serum creatinine post–kidney transplant: the early period, the intermediate period, and the late period.

Throughout the posttransplant period, a thorough history and a thorough physical exam help narrow the differential diagnosis of a rising serum creatinine. Drug levels, urine analysis with culture, complete blood count (CBC), and blood chemistry routinely are obtained in the workup for this problem. Duplex ultrasound identifies fluid collection around the kidney and reveals the status of blood flow through the artery and vein. A renal scan often is helpful in identifying changes in renal flow and urinary leaks, and a kidney biopsy is needed to make a definitive diagnosis of rejection. These tests are used routinely in sorting out the correct etiology for the recipient of a renal allograft who presents with a rising serum creatinine.

The following sections describe the most likely causes of deterioration in renal function, based on time from transplant to change in function, and focus the history and physical exam on the most pertinent facts (Fig. 40.1). Algorithm 40.1 illustrates the investigation into a rising serum creatinine level over time.

The Early Period

In the early postoperative period, day 0 to day 7, the differential diagnosis can be broken down into immunologic causes, technical causes,

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Rising serum creatinine

Figure 40.1. Differential for a rising serum creatinine post–renal transplant. ACE, angiotensinconverting enzyme; CMV, cytomegalovirus; RAS, renal artery stenosis; RATG, rabbit antithymocyte globulin.

nephrologic causes, infectious causes, and drug toxicity. The recipient in the case presented has passed this crucial period.

Immunologic Causes

Hyperacute rejection has become a rare event, as the ability to detect preformed antibodies prior to the transplant has improved. Hyperacute rejection derives from antibodies in the recipient’s serum directed against the donor’s antigens. These preformed antibodies bind to the donor tissues, activating the complement cascade, which leads to immediate graft thrombosis. The two methods for screening for donor-specific antibodies are lymphocytic crossmatch and flow cytometric studies.

A variant of hyperacute rejection is accelerated vascular rejection.

The level of preformed antibodies is too low to be detected by the current screening test, but it quickly rises with stimulation by exposure to the new donor antigen. Clinically, the kidney often is functioning; however, urine output acutely falls off, and serum creatinine rises. Patients at risk for hyperacute rejection or early vascular rejection have been exposed previously to antigens. Patients may be exposed to human HLA through previous transplants, pregnancy, and blood transfusions. Patients, while waiting for a transplant, have their blood

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checked on a monthly basis for antibodies against a panel of known human antigens. Patients with a high PRA are at higher risk for immunologic complications. See Algorithm 40.1 and Figure 40.1.

Technical Complications

Technical complications of the vasculature leading to vascular thrombosis of the artery or vein usually occur within the first 48 to 72 hours posttransplant. The overall incidence of vascular complications is reported to be between 0.5% and 3%. The clinical hallmark of vascular thrombosis is a rapid fall in urine output with an increase in serum creatinine and change in the color of the urine from yellow to a brick red. Thrombosis of the renal allograft often is associated with thrombocytopenia and hyperkalemia. If vascular thrombosis is suspected after a live donor, the recipient should be returned to the operating room immediately, since there is only a narrow window of time before the ischemic damage to the kidney becomes irreversible. Bleeding in the retroperitoneum space often presents with a decline in renal function and a drop in platelets. As the retroperitoneum hematoma expands, platelets are consumed, and the hematoma compresses the renal vein, resulting in a sharp drop in urine production.

Urine leaks rarely are caused by poor anastomosis. The vascular supply of a ureter in its normal anatomic position is rich in collaterals. The transplanted ureter is dependent on the blood from the renal artery traveling the length of the ureter. If the transplanted ureter has been skeletonized or is of excessive length, the distal aspect of the ureter may become necrotic, leading to a urinary leak. If the distal aspect of the ureter is ischemic, the physician needs to continue to monitor the recipient for a late developing ureteric stricture.

Nephrologic Causes

The most common cause of a rising serum creatinine in the early postoperative period is acute tubular necrosis (ATN). Many factors can influence the incidence of ATN, the most important of which are the length of warm ischemic time, the length of cold ischemic time, the method of preservation, and the age of the donor; ATN also may be exacerbated by hypovolemia and dialysis.

Focal glomerulosclerosis is the only clinical entity that is seen with any frequency recurring in the immediate postoperative period. The hallmark of recurrent disease is proteinuria in the nephrotic range.

Infectious Causes

Any infection can alter the renal transplant function in the early postoperative period. The most common infections in the early postoperative period are the same that are found in the general population: urinary tract infections, wound infections, and pulmonary infections.

Immunosuppressive Drugs and Their Toxicities

Immunosuppression regimens often are a cocktail of multiple drugs. Calcinurin inhibitors are the mainstay of the majority of immunosuppressive regimens. They are known to inhibit the transcription of interleukin-2 (IL-2), a major mediation of cellular acute rejection. Calcinurin inhibitors have a profound effect on renal hemodynamics,

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causing afferent arterial vasoconstriction, a decrease in AFR, a decrease in renal plasma flow, and an increase in renal vascular resistance. Subsequently, the calcinurin inhibitor cyclosporine and tacrolimus are known for their nephrotoxicity. Many of the side effects of the calcinurin inhibitors parallel the nephrotoxicity. In addition, rapamycin has been shown to be nephrotoxic when combined with cyclosporine. Less appreciated is the cytokine release that occurs with OKT3 and occasionally with rabbit antithymocyte globulin (RATG) that also alters renal function. There are multiple drugs that alter the metabolism and absorption of calcinurin inhibitors; they alter the serum levels of the inhibitors, resulting in either toxicities or rejections.

Drugs that alter the renal flow, like angiotensin-converting enzyme (ACE) inhibitors, also may potentiate the nephrotoxic effect of the calcinurin inhibitors. Last, drugs that usually are mildly nephrotoxic may cause significant deterioration when given with a calcinurin inhibitor. Patients and physicians often are unaware of the significant nephrotoxicity seen when nonsteroidals are taken in combination with a calcinurin inhibitor.

The Intermediate Period

During the intermediate period, drug toxicity in the form of calcinurin inhibitors and acute cellular rejection are the most common causes of decrease in renal function. (See the case presented.) Acute rejection is a T-cell–mediated process that occurs most commonly between day 8 and day 90. The T-cell response to transplanted alloantigens is expressed either directly on donor tissue or indirectly by professional self-antigen presenting cells that have phagocytosed the donor alloantigens and presented them again. Once T-cell activation occurs, multiple cytokines are released, which are responsible for promoting the acute agent response. The cytokine IL-2, elaborated by T cells, plays a central role in acute rejection and has served as the focus to antirejection therapy. The details of T-cell–mediated agents are described in Chapter 62, “Immunology of Transplantation,” of Surgery: Basic Science and Clinical Evidence, edited by J.A. Norton, R.R. Bollinger, A.E. Chang, et al., published by Springer-Verlag, 2001. The incidence of acute rejection has decreased steadily with changes in the immunosuppressive protocols. It is uncommon to lose a kidney immediately to acute rejection, although the presence of acute rejection, the number of acute rejections, the time to acute rejection (late rejection has a worse prognosis than early), and the severity of the rejection episode are strong predictors of late graft loss.

Calcinurin inhibitors are the most likely cause of renal dysfunction during this period. The transplanted kidney often is just recovering from ATN or is extremely susceptible to the nephrotoxic effects of these drugs. See Algorithm 40.1 and Figure 40.1.

The Late Period

Last, chronic rejection, intrinsic renal allograft disease, and drug toxicity are predominant causes of a rise in the serum creatinine after

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3 months. Chronic rejection is a term describing a renal allograft recipient who presents clinically with a steady rise in serum creatinine, hypertension, proteinuria, and histologically with interstitial fibrosis, subintimal thickening, and glomerular sclerosis. Chronic rejection is believed to have multiple etiologies, both immunologic and nonimmunologic. Unfortunately, there are no current immunosuppression agents that stop or reverse chronic rejection. Renal dysfunction secondary to recurrent disease is most commonly caused by diabetic nephropathy, focal glomerulosclerosis, and membranoproliferative glomerulonephritis types I and II, although graft loss secondary to diabetic nephropathy is uncommon, since the deterioration of renal function is slow while the patient’s risk of cardiovascular death is high. The most common cause of graft loss in all renal recipients over the age of 50 is death with a functioning allograft. See Algorithm 40.1 and

Figure 40.1.

Summary

It is convenient to examine the problem of deteriorating renal function over time, since the differential and focus of the workup change from the early period (days 0–7), through the intermediate period (day 8 to 3 months), and the late period (over 3 months). Throughout this time course, rejection of some kind is always a consideration; the early period is associated with antibody mediated rejection (hyperacute rejection and accelerated rejection), and the intermediate period is dominated by cellular-mediated rejection, and the late period is associated with chronic rejection. Rejection as a cause for graft loss has been minimized by the present-day armamentarium of immunosuppressive drugs. The penalty that is paid for this benefit, however, is that, as time progresses, the nephrotoxicities associated with the immunosuppressive drugs play a dominant role in allograft dysfunction. In addition, drugs that alter the metabolism of these immunosuppressive agents, as well as medications that act synergistically with them to cause nephrotoxicity, need to be monitored closely once the patient leaves the acute care setting. Finally, in the late period, the cause of renal dysfunction is further complicated by the possibility of recurrent renal disease as well as de novo renal disease. The investigation into renal allograft dysfunction often is aided by routine laboratory tests, urinalysis, complete metabolic panel, complete blood count, and immunosuppressive drug levels; ultimately, however, a renal biopsy often is required for the definitive answer.

Selected Readings

Bowen RA, Ljungman P, Carlos PV. Transplant Infections. Philadelphia: Lippincott-Raven, 1998.

Danovitch GM. Handbook of Kidney Transplantation, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2001.

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Epstein AM, Ayanian JZ, Koegh JH, et al. Racial disparities in access to renal transplantation—clinically appropriate or due to underuse or overuse? N Engl J Med 2000;343(21):1537–1544, and two pages preceding 1537.

Flye MW. Principles of Organ Transplantation. Philadelphia: WB Saunders, 2000.

Ginns LC, Cosimi AB, Morris PJ. Transplantation. Malden, MA: Blackwell Science, 1999.

Kirk AD. Immunology of transplantation. In: Norton JA, Bollinger RR, Chang AE, et al, eds. Surgery: Basic Science and Clinical Evidence. New York: Springer-Verlag, 2001.

Knechtle SJ. Kidney transplantation and dialysis access. In: Norton JA, Bollinger RR, Chang AE, et al, eds. Surgery: Basic Science and Clinical Evidence. New York: Springer-Verlag, 2001.

Levinsky NG. Quality and equity in dialysis and renal transplantation. N Engl J Med 1999;341(22):1591–1593.

Stuart FP, Abecassis MM, Kaufman DB. Organ Transplantation. Georgetown, TX: Landes BioScience, 2000.

Thistlethwaite JR, Bruce D. Rejection. In: Norton JA, Bollinger RR, Chang AE, et al, eds. Surgery: Basic Science and Clinical Evidence. New York: SpringerVerlag, 2001.