40
Transplantation of the Kidney
David A. Laskow
Objectives
1. To discuss the inclusion/exclusion criteria for renal transplantation.
2. To discuss the technical aspect of renal transplantation.
3. To discuss the impact of the source of the kidney donor in relationship to the outcome.
4. To discuss organ allocation.
5. To introduce the basic antirejection medications.
6. To describe the different types of rejection.
7. To discuss the management of a postoperative renal allograft recipient.
Case
A 27-year-old man presents with increasing serum creatinine 2 weeks after a renal allograft transplant. The patient is afebrile, with blood pressure at 155/85, pulse at 84, and respiration at 16. On physical exam, his wound is well healed, and the allograft is palpable and nontender in the right lower quadrant. Urinalysis, laboratory values, and ultra- sound are pending.
Inclusion/Exclusion Criteria for Candidates Seeking Kidney Transplantation
Patients with end-stage renal disease (ESRD) have three options to replace and support their failing renal function: hemodialysis, peri- toneal dialysis, and renal transplantation. All three are viable options in the management of a patient’s renal function. These options are not mutually exclusive, and, in fact, most patients eventually are treated with all three.
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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 cadav- eric 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 anti- body (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 con- dition. 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.
Table 40.1. Causes of end-stage renal disease (ESRD): United States Renal Data System (USRDS) Annual Data Report.
Diabetes Hypertension Glomerulonephritis Cystic kidney disease Interstitial nephritis Obstructive nephropathy Collagen vascular disease
Data from www.USRDS.org. Web site of United States Renal Data System.
Malignancies Metabolic disorders
Congenital/other hereditary disease Sickle cell disease
AIDS related
Unknown
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 sensi- tized 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 40.2. Contraindication to renal trans- plant.
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)
Table 40.3. United System for Organ Sharing (UNOS) cadaver kidney allocation system.
aKidneys 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.
presented, it would be helpful to know what the HLA match was, as well as what the recipient PRA was prior to transplant.
The allocation scheme recognizes and rewards with points the fact that children on dialysis often have a difficult time maintaining good nutrition, which in turn causes poor physical and mental development, and that children derive more benefit from a transplant than adults.
Special status and points are given to patients who have donated a kidney and who go into renal failure themselves. As opposed to liver, heart, and lung transplant allocation schemes, with kidney trans- plants there are no points allocated based on medical need. Kidneys are allocated first locally, then regionally, and, last, nationally, with the exception of mandatory sharing of a zero mismatched kidney.
Usually six HLAs are identified in both the donor and the recipient.
Occasionally, fewer than six HLAs are identified in the donor, making it impossible to have a perfect six antigen match. The benefit seen in these well-matched kidneys is derived from the absence of a mis- matched HLA. Therefore, rather than giving special points for a six- HLA matched kidney, the United Network for Organ Sharing (UNOS) gives primacy to the zero mismatched recipient/donor combination, then a one mismatch, a two mismatch, and so on.
Kidneys donated from family members are much more likely to share common HLAs than those from a live, unrelated donor or from a cadaver donor. Among siblings, there is a 25% chance of a six-antigen match, a 50% chance of a three-antigen match, and a 25% chance of no match at all. Parent to child donations or vice versa always are at a minimum of a three-antigen match. Living, related recipient/donor match also occurs with minor HLAs that are not tested for. It is for this reason that recipients of a living, related allograft enjoy excellent long- term renal allograft function.
Who Can Serve as a Cadaveric Donor?
Cadaveric renal organ donation has come full circle. Initially, patient kidneys were harvested after cardiac death. After transplantation, these kidneys had a high incidence of acute tubular necrosis. The Harvard brain death criteria (Table 40.4) established in 1968 and modified by Mohandas and Chow helped set the guidelines for brain death determination.
1Note that an electroencephalogram (EEG) is not required to make the diagnosis of brain death. The determination of brain death is a clinical diagnosis made after excluding agents such as hypothermia, drugs, and ethyl alcohol (ETOH), all of which can cause reversible brainstem depression. Once the diagnosis of brain death is determined, the Organ Placement Organization (OPO) is contacted, and the suitability of the various organs for donation is determined.
1
Mohandas A, Chow SN. Brain death: a clinical and pathological study. J Neurosurg
1971;35:211; 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 physi- cian 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 deter- mining the overall health of the individual and his/her renal func- tion. This type of donation often is spousal, but it has occurred between distant relatives, friends, and community members. The lack of cadav- eric 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” indi- viduals who provide live donations to ensure that organ donation is as 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.
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, respec- tively. 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 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.
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. Occa- sionally, the recipient’s internal iliac vein is divided to enable the exter- nal 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 steno- sis may be reduced by the uses of an aortic punch biopsy. More com- monly, 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 thrombo- sis occurs less than 2%.
Posttransplant Period
The differential of an increasing serum creatinine is influenced sig- nificantly 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, com- plete blood count (CBC), and blood chemistry routinely are obtained in the workup for this problem. Duplex ultrasound identifies fluid col- lection 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 deteriora- tion in renal function, based on time from transplant to change in func- tion, 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 diag-
nosis can be broken down into immunologic causes, technical causes,
nephrologic causes, infectious causes, and drug toxicity. The recipi- ent 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. Hyper- acute 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 imme- diate 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 trans- fusions. Patients, while waiting for a transplant, have their blood
Rising serum creatinine
Early Day 0–7
Intermediate Day 8–3 months
Late
>3 months–years
Immunologic Hyperacute
Vascular
Acute tubular necrosis (ATN) Recurrent disease
Immunologic
Technical
Nephrologic Nephrologic Nephrologic
Infectious Infectious
Infectious
Drugs Drugs Drugs
Technical Technical
Immunologic Acute cellular rejection
Chronic rejection
Chronic rejection Acute cellular rejection
Vascular: rare RAS Ureteral: strictures Vascular: rare artery stenosis
Ureteral: leaks/strictures Vascular: arterial/venous
Ureteral: bladder leak
Bleeding: retroperitoneal hematoma
ATN
Recurrent disease De novo renal disease
Recurrent disease De novo renal disease
UTI CMV
Other opportunistic infections UTI
CMV infection
Tacrolimus/cyclosporine Rapamune
Drugs that alter the metabolism of cyclo/tacro Urinary tract infection (UTI)
Nonimmunosuppression drug ACE inhibitor, Bactrim Immunosuppression drug:
OKT3, RATG, cyclosporine, tacrolimus