Initial Hospitalization Care

Mary Ann Cameron

Ruben L. Velez^*

Karl R. Brinker^†

University of Texas Southwestern Medical Center, Dallas, Texas 75390; ^* Dallas Nephrology Associates, Dallas, Texas 75235; and ^†Dallas Nephrology Associates, Dallas, Texas 75208

INTRODUCTION

The initial transplant hospitalization follows a prior careful pretransplant evaluation, transplant selection committee decisions, and continued updates of the recipient medical status (1, 2, 3). The recipient is then admitted for a final evaluation before a planned transplant from a living donor or a much more hurried evaluation of suitability for a deceased donor (cadaveric) transplant. Risk factors for long-term renal transplant outcome include prior recipient sensitization (high preformed antibodies), acute rejection episodes, donor age, human leukocyte antigen (HLA) mismatching, delayed graft function (DGF), and loss of a prior renal transplant (4). The expanded use of marginal donors (5,6) and increased acceptance of higher risk recipients make early management posttransplant even more challenging. Initial immunosuppression, antimicrobial prophylaxis, intraoperative volume loading, postoperative handling of early graft dysfunction and other complications have a profound impact on long-term outcome. This chapter is intended to address these issues occurring during the first hospitalization.

PATIENT SELECTION

Initial Screening for Deceased Donor Recipients

Although the practice varies from institution to institution, initial notification regarding a kidney donor organ is typically via an organ procurement specialist from the local organ
procurement organization (OPO) to the reference HLA laboratory. After notification, the organ donor material will be delivered. The samples received will be tested to determine ABO type and at least HLA class I (A, B) and class II (DR) antigen type. Derivation of HLA type may be performed by serologic, molecular, or a combination of the two techniques. ABO and HLA typing results are reported to the organ procurement coordinator and are entered into the United Network for Organ Sharing (UNOS) database, which is a national organ and potential recipient registry. Patients having no mismatches for HLA-A, HLA-B, or HLA-DR normally receive first consideration for an offer of the donor organ. If there are no such potential candidates, then the organ(s) will be offered to the patient(s) having the highest point score, which is determined by time on the waiting list, degree of HLA-DR antigen matching, and level and specificity of HLA antibody sensitization. Other factors, including the location of the organ(s), are also taken into consideration.

Once the ABO type is determined, a screening antiglobulinenhanced crossmatch will be performed on ABO compatible potential organ recipients who are located in a particular region. This crossmatch consists of incubating potential recipient serum with donor lymphocytes and assessing compatibility of patient serum with donor T- and B-cell antigen targets. In theory, the patient who has a negative screening antiglobulin crossmatch will be contacted to come in for a final crossmatch using fresh serum. In reality, more than one patient may be called in for final crossmatching for a single organ if the patient at the top of the list is sensitized to HLA antigens. This is done to minimize selection time for each donor kidney.

Final Crossmatching for Both Deceased and Living Donor Transplants

At the time of final crossmatching, many centers perform an additional determination of the donor-recipient ABO compatibility assessment. In addition, another lymphocyte crossmatch using current serum is performed and may include basic cytotoxic testing for T and B cells, antihuman globulin-enhanced complement-dependent cytotoxicity (AHG CDC) technique for T cells and/or a more sensitive technique using flow cytometric crossmatching (FCXM) for T and B cells. The goal is for crossmatches to show compatibility with T- and B-cell targets by the crossmatch methods utilized.

After all testing is performed, the most important information for the transplant nephrologist and surgeon is (a) whether the patient is a first transplant or a regraft candidate or has other known sensitizing events (including pregnancy and blood transfusion), (b) whether the patient has a history of HLA antibodies as determined by a panel reactive antibody (PRA) test, which may be performed by cytotoxic, enzyme-linked immunosorbent assays (ELISA), flow cytometric bead or cell analysis or, most recently, by using a microsphere bead-based methodology leading to antibody identification, (c) the T- and B-cell crossmatch results. The crossmatch results should be interpreted in light of the patient’s clinical history of HLA sensitization, PRA level, and antibody identification. A primary transplant patient without foreign HLA exposure is expected to be negative by all crossmatch tests. If not, then a query about clinical conditions (i.e., lupus, rheumatoid arthritis, etc.) and medications associated may be instigated. Autoantibodies have been shown to provide little to no acute risk to organ recipients.

In the highly sensitized potential recipient, whether primary or regraft, the risk of graft loss is high if a crossmatch against T or B cells is positive. Historically, incompatible crossmatches with AHG CDC technique can result in immediate or accelerated rejection with organ loss. The scenario in which the AHG CDC crossmatch is negative and flow cytometry is positive is thought to have a lower risk of hyperacute rejection. However, this situation may be associated with increased risk of acute rejection episodes, which may lead to decreased overall kidney allograft survival (7,8).

Preoperative Assessment

The assessment of the potential kidney transplant recipient shortly before surgery is crucial to the early transplant course. It begins with a very thorough history and physical examination and review of all available records, recent cardiovascular evaluation, and reports of recent routine screening tests (mammogram, Pap smear, prostate-specific antigen [PSA]). A complete blood count (CBC), blood urea nitrogen (BUN), serum creatinine, glucose, electrolytes, liver function tests, and coagulation studies should be performed. Most serologic tests should have been done in the pretransplant process and should be available for review. A recent chest x-ray and electrocardiogram should be performed and reviewed. Potential contraindications for transplantation need to be assessed. Accepted contraindications to transplantation include active infection, active or recent malignancy, potentially severe cardiovascular disease, active hepatitis, and a positive HLA crossmatch. Other relative contraindications that should be evaluated include HIV status, noncompliance with medical therapy, substance abuse, psychological problems, severe liver disease, severe peripheral vascular disease, gastrointestinal bleeding, and morbid obesity. Most of these should have been resolved during the patient’s pretransplant evaluation and subsequent updates, but unexpected findings often occur. A careful assessment of the volume status of the patient, together with the chemistry reports, can help the transplant physician decide the need for preoperative dialysis. Although some transplant programs may routinely dialyze patients before transplantation, our practice is to decide whether preoperative dialysis is needed on an individual basis. There has been concern about the negative impact of pretransplantation hemodialysis on early graft dysfunction (9). Several factors should be taken into consideration when making this decision. Patient-related issues include the volume status of the
patient, hyperkalemia, hypokalemia, and the degree of azotemia. With the now proven advantage of preemptive transplantation (10), more patients present without a prior history of dialysis. Donor-related factors that should be taken into account include the donor age. For deceased donors the history of hypertension, diabetes, cause of death, presence of brain death, duration of cardiopulmonary resuscitation, vasopressor use, warm ischemia time, and cold ischemia time should also be considered. These are all risk factors for delayed graft function (4, 5, 6). The patient and donor cytomegalovirus (CMV) status should be determined in order to plan a prophylactic regimen.

Following this pretransplant assessment, initial immunosuppression is planned and discussed with members of the transplant team. Once a negative HLA crossmatch has been reported and reviewed, the ABO compatibility between donor and recipient should again be confirmed. The patient is then cleared for operation.

THE INITIAL IMMUNOSUPPRESSIVE REGIMEN

Selection of the initial immunosuppression regimen for patients undergoing renal transplantation has become more complex with the enlarged number of drugs available; each with advantages and disadvantages.

History

In 1978, the accepted regimen was limited largely to corticosteroids and azathioprine with selective use of Minnesota antilymphocyte globulin (MALG) for steroid-resistant acute rejection episodes. Some transplant centers utilized other techniques such as thoracic duct drainage, splenectomy, and irradiation of the graft. In 1982, the use of total lymphoid irradiation (TLI) was described for use in high-risk renal retransplants (11). In 1984, cyclosporine (CsA) was approved for use in solid organ transplantation in the United States after extensive clinical trials. Thereafter, 1-year graft survival in most centers improved dramatically, from 50% to 80% by 1990. Since 1984, the routine armamentarium has expanded with the addition of murine monoclonal antibody to CD3 (OKT3), equine antithymocyte globulin (ATGAM), tacrolimus (FK506), rabbit antithymocyte globulin (rATG), mycophenolate mofetil (MMF), sirolimus (rapamycin), and humanized or chimeric monoclonal antibodies targeting the α-chain (CD25) of the interleukin-2 receptor (anti-IL-2Rα) (Basiliximab and daclizumab). The aim of an initial immunosuppression regimen should always balance two objectives. The first goal is an attempt to maximize short- and long-term graft survival. The second objective is to minimize the adverse effects of the regimen (largely infections, cardiovascular events, and malignancies). In the past, regimens were most often tailored to the type of renal transplant: living donor versus cadaveric donor and first versus retransplants. Today the regimen should be tailored to anticipated or actual initial function of the renal graft (i.e., the presence or absence of DGF) and to the high- or low-risk status of the recipient. High-risk recipients include pediatric patients, black patients, those receiving grafts with prolonged cold ischemia times, and other patients at increased immunologic risk (such as retransplants who have had early loss of a prior transplant for nontechnical reasons) or those with high levels of preformed antibodies.

Induction

Induction therapy refers to the use of polyclonal or monoclonal antibodies to attenuate the immune response at the time of transplant surgery. A related concept has been sequential immunosuppression referring to the use of the same agents for the purpose of delaying or lowering the initial dose of nephrotoxic calcineurin inhibitors (CIN) in patients receiving grafts with greater ischemic or other injury. The benefits of induction, including a decreased incidence and severity of DGF and a reduced incidence of acute rejection, probably extend to all renal transplants (12,13). However, induction also is associated with an increased risk for late death after transplant (but not death with a functioning graft), late malignancy-related death, and with early deaths due to infections and cardiovascular causes (14). It also increases the cost and possibly the length of the initial hospitalization. Renal transplantation does, however, confer a significant survival advantage over maintenance dialysis (15). Therefore, the risks and benefits of induction and the agent used need to be carefully considered for each patient.

The induction agents now used are largely polyclonal (rATG) or monoclonal anti-IL-2Rα. MALG is no longer produced and ATGAM has been shown to be less effective than rATG (16). OKT3 use has decreased dramatically because of the associated cytokine release syndrome as well as the formation of human antimouse antibodies (HAMA).

The choice of rATG versus anti-IL-2Rα depends upon recipient risk. Acute rejection rarely occurs during rATG use. This allows for temporary withdrawal or decreasing the dose of CIN in patients with delayed graft function. However, acute side effects including rare anaphylaxis, frequent high fever with initial doses, leukopenia, thrombocytopenia, and serum sickness do occur. Increased risk for early and late mortality have already been described. Anti-IL-2Rα agents have many fewer side effects although several episodes of severe acute hypersensitivity have been reported with basiliximab but not daclizumab (17). However, rejection can occur during anti-IL-2Rα use, and delay in the use of a maintenance CIN should be avoided. In terms of effectiveness, one French multicenter trial comparing basiliximab to rATG found a similar incidence of acute rejection and overall short-term outcome. There were fewer adverse events including infections with basiliximab (18). Conversely, a multicenter trial with both US and European centers compared rATG with basiliximab in transplants involving high-risk donors or recipients. It was stopped early by the safety monitoring board because acute rejection was significantly increased
in the basiliximab group (19). The choice between basiliximab and daclizumab has been influenced by the simpler and less expensive basiliximab regimen of two postoperative doses (on day 0 and 4) compared with the five-dose regimen given at 2-week intervals for daclizumab. The effectiveness of a two-dose regimen of daclizumab has been suggested but awaits a prospective randomized trial.

In summary, induction therapy should be based on individual donor and recipient risk factors. If used, anti-IL-2Rα is safer than rATG. In high-risk patients such as patients with high PRA, sensitized retransplants, or black recipients with, or anticipated to develop, DGF, rATG appears more effective. We have generally used a 5-day course of polyclonal induction but a recent report of 3-day induction with rATG (20) or interim dosing of rATG based on CD3 lymphocyte counts (21) suggests three doses could be equally effective. Organ Procurement and Transplantation Network, and Scientific Renal Transplant Registry data show the frequency of use of these agents in the United States for 2001 as follows: 26% basiliximab, 15% daclizumab, and 18% rATG (22). This suggests an approximate overall incidence of induction of 59% in US renal transplants.

Initial Maintenance Immunosuppression

The initial maintenance immunosuppressive regimen generally utilizes three drugs: a CIN, a corticosteroid, and an antimetabolite (azathioprine or MMF). Corticosteroids usually are begun in high doses (prednisone, prednisolone, or methylprednisolone 100 to 200 mg/day) just before transplant then rapidly tapered to 20 mg/day in the first week postoperative and to 0.1 to 0.15 mg/day by day 90. In the United States, attempts to avoid steroids initially are often followed by unacceptable rates of acute rejection.

Azathioprine has largely been replaced by MMF since the three pivotal studies in the early 1990s showed a clear reduction in the first-year incidence of acute rejection with MMF (23, 24, 25). The usual dose is 2 grams per day in nonblack and 3 grams in black recipients given in divided doses. The initial dose is given pretransplant. MMF doses remain at the initial levels unless reduction is necessary to lessen what are most often gastrointestinal side effects. Unfortunately, drug levels of MMF still are not widely available in the clinical setting. The drug can be given orally or intravenously in equivalent dosage.

A CIN is a component of the initial immunosuppressive regimen in nearly all renal transplants. The initial dose is generally given on the first postoperative day. In instances of DGF, however, the initial dose may either be reduced or postponed until the serum creatinine falls to 25% of its preoperative baseline value with an established urine output above 1500 cc per 24 hours (see induction above). CsA was the CIN of choice in 1992, being used in 94% of US patients at initial hospital discharge. However, CsA use fell to only 39% in 2001 when the use of tacrolimus at initial discharge rose dramatically to 55% (22). These changes in CIN use reflect prospective clinical trials such as the Phase III US Multicenter Trial of FK506 which showed decreased frequency and severity of acute rejection in tacrolimus-treated patients compared with cyclosporine gel caps. In this study, the CINs were used in combination with azathioprine, prednisone, and OKT3 induction (26). In a later report, long-term (5-year) graft survival based on intent-to-treat analysis was equivalent (27). However, when crossover from cyclosporine to tacrolimus for acute rejection was counted as a cyclosporine graft failure, significant improvement in 5-year graft survival could be shown for tacrolimus. When used with MMF instead of azathioprine, a reduced rate of steroid resistant rejection has been shown for tacrolimus compared with CsA microemulsion (28). A recent single center report of black recipient outcome has confirmed a reduced rate of first-year acute rejection (9% versus 36%) and showed improved 5-year graft survival (79% versus 60%) with tacrolimus versus cyclosporine (all patients on MMF) (29). This supports and extends a prior multicenter study (30).

The use of sirolimus in initial immunosuppressive regimens for renal transplant has been primarily with CIN-based regimens and in place of MMF. Two trials have shown improved 1-year graft function without an apparent significant increase in first-year acute rejection. In these studies, concentration-based sirolimus was used with an initial reduced dose with withdrawal of cyclosporine 6 months posttransplant (31,32). However, a randomized trial of tacrolimus and sirolimus versus tacrolimus plus MMF showed better graft function at 6 months posttransplant for the MMF arm. MMF-treated patients did better with respect to lipid levels and diastolic blood pressure, whereas those on sirolimus had less leukopenia and gastrointestinal adverse events (33). More concerning are recent reports of sirolimus-associated impaired recovery from DGF (34) and possible potentiation of CIN-induced endothelial damage resulting in an increased incidence of thrombotic microangiopathy (35).

In our opinion, the initial maintenance immunosuppressive regimen for standard risk patients should include either cyclosporine at doses to achieve whole blood levels of 250 to 400 ng/mL at discharge, or tacrolimus to achieve levels of 5 to 15 ng/mL. In high-risk patients, including blacks, the CIN should be tacrolimus. Most renal transplant recipients can take these medications orally by the first postoperative day. Cyclosporine can be given intravenously at 25% to 33% of the oral dose. We avoid the use of IV tacrolimus because of neurotoxicity. MMF is given at 2 g/day for nonblack and 3 g/day for black patients. Gastrointestinal side effects will reduce these doses in some patients. It is our impression that divided doses given three or even four times daily occasionally alleviate these symptoms. Corticosteroids remain an important part of our initial immunosuppressive regimen. Use of steroid-free initial immunosuppression should at present be limited to the individual case with severe toxicity or in a clinical trial. Similarly, the use of sirolimus in initial immunosuppression should be limited to clinical trials. However, future initial immunosuppressive regimens may
be quite different. Drug minimization strategies targeting corticosteroids and CINs and have recently been reviewed (36). The goal always should be to maximize graft and patient outcomes while minimizing the side effects of immunosuppression.

INTRAOPERATIVE AND THE INITIAL 48 HOURS POSTOPERATIVE MANAGEMENT OF VOLUME AND ELECTROLYTE ISSUES

After preoperative assessment and management, the transplant physician’s next encounter with the renal transplant recipient generally occurs postoperatively in the recovery room or intensive care unit. In the great majority of cases, our initial 12 to 24 hours of postrenal transplant care has occurred in these hospital areas. It begins with a careful review of the operative record, discussion with the surgeon regarding intraoperative findings or unusual events, followed by a careful examination of the patient.

CBC, electrolytes, BUN, creatinine, glucose, and a chest x-ray are immediately obtained. The exam includes a clinical determination of volume status and initial urine output. We utilize central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP) only in circumstances of clinical uncertainty or significant cardiac dysfunction.

Usually, the recipient of a living donor transplant exhibits euvolemia and excellent urine output (greater than 200 cc/h). If not, urgent assessment is required for a transplant perfusion defect secondary to technical intraoperative problems with either the donor or recipient. The recipient of a deceased donor transplant, however, receives a kidney that is damaged to a varying degree due to ischemia/reperfusion injury. The sources of ischemic injury occur in the multiple settings of preoperative donor management, procurement surgery, kidney storage, the recipient surgery, and the early postoperative course (37). The molecular and cellular bases of reperfusion injury (oxygen-centered free radical injury) have been reviewed recently for the clinician (38). Our approach to this problem has derived from the studies of Davidson (39,40,41). The intraoperative administration of 25% albumin in doses of 1.2 to 1.6 g/kg compared with less than 0.4 g/kg resulted in significant improvement in urine output within 30 minutes, 24-hour urine volume, serum creatinine at 1 week, iothalamate clearance at 1 and 7 days, reduction of DGF and primary nonfunction, and improved 1-year graft and patient survival (39). Further, the relative risk of DGF in patients receiving less than 0.8 g/kg albumin intraoperatively versus greater than 0.8 g/kg was 2.064. The value of albumin was preserved when stratified for cold ischemia time, length of surgery, recipient age, furosemide dose, mannitol dose, and volume of crystalloid administered. An earlier study in cadaver recipients assessed the effect of oral verapamil begun 2 days postoperatively. Cyclosporine was begun on day 5 when a course of MALG induction was completed (40). The group receiving verapamil had increased renal parenchymal blood flow which did not decrease when cyclosporine was given. Although cyclosporine blood levels were higher in the verapamil group, day 7 creatinine was lower and the incidence of acute rejection in the first month decreased. A follow-up study utilized an experimental group receiving intraoperative renal artery verapamil plus a 14-day course of oral verapamil. Both groups received 1.3 g/kg of intraoperative albumin. Again cyclosporine levels were higher in the verapamil group but the incidence of DGF function was lower, early renal function better, and actuarial graft survival improved. The two approaches, albumin volume expansion and the use of a calcium channel blocker thus appear to be additive. More recent experimental studies have shown ischemia-induced cellular calcium influx promotes oxygen-free radical accumulation and subsequent cellular injury all of which can be blocked by calcium channel blockers. These agents may also decrease cyclosporine nephrotoxicity or inhibit calcium dependent endothelin-induced vasoconstriction (38).

Our approach therefore has been to give intraoperative albumin, intraoperative renal artery verapamil, and oral verapamil beginning on the first postoperative day. Only one case of volume overload requiring postoperative urgent ultrafiltration has occurred. Our goal is mild plasma volume expansion immediately postoperatively. If there is no immediate urine output, 200 mg of furosemide with or without 12.5 g of mannitol is given. Thereafter, we monitor urine output every hour for 24 hours. We replace 100% of urine output with 0.9% NaCl for the first 8 hours and then decrease to 75%. Upon transfer to the regular transplant floor we measure urine output every 2 hours and replace at a rate of 75%. We use 0.45% NaCl only if the patient develops hypernatremia, or 0.45% NaCl plus added NaHCO₃ if significant hyperchloremic metabolic acidosis develops. The physician is notified of urine output less than 50 cc/h. In this case, we generally give 500 cc of 0.9% NaCl over 1 hour if no clinical evidence of volume overload exists. If urine output does not increase, a further dose of furosemide is given assuming vital signs are appropriate for the patient. Using this approach, our incidence of DGF in cadaver donor recipients during the years of 2000 to 2002 has been 22%. Primary nonfunction has been 4%. Concurrent mean cold ischemia time was 19.3 hours. Hyperkalemia has been unusual unless the patient is oliguric and significant preoperative hyperkalemia (potassium greater than 5.5 mEq/L) was not corrected before surgery. Hypokalemia occurs most often in living donor transplants who may have large urine outputs on this protocol. It has been our impression that hypokalemia is rarely severe despite brisk diuresis and responds to small amounts of supplemental potassium plus a decreased rate of urine replacement.

IMPAIRED RENAL GRAFT FUNCTION DURING THE FIRST HOSPITALIZATION

DGF is one of the early risk factors that affects long-term graft function (4,42, 43, 44). Review of 17,937 cadaveric kidney transplants by Peters et al (42) concluded that DGF was a
significant factor affecting long-term graft function, but cold ischemia time could not be shown to have a significant negative impact in long-term allograft survival. Gjertson (44) reported a 21% incidence of DGF in deceased donor transplants based upon UNOS data. He found that DGF significantly increased the chance of early (less than 6 months) but not late acute rejections, suggesting that it may increase the immunogenicity of the kidney. The definition of DGF has varied in the past, but usually includes oliguria, poor clearance, and the need for dialysis in the first week posttransplantation. Less than 5% of the kidneys may never function (primary nonfunction [PNF]). DGF may be seen in 5% to 50% of grafts from deceased donors. In transplants from living donors, DGF or PNF is rare. The procedure of laparoscopic nephrectomy in donors was initially associated with an increased incidence of DGF. With increased experience by transplant teams, the incidence has decreased (45,46). Table 7.1 lists the most common risk factors associated with DGF. Table 7.2 lists the most common causes of impaired graft function in the early posttransplant period.

Acute Tubular Necrosis

Acute tubular necrosis (ATN) is the most common cause for DGF. It has been estimated that 70% to 90% of DGF may be secondary to ATN. Nevertheless, we must stress the importance of early diagnosis (see below) and use of kidney biopsies in view of the incidence of acute rejection complicating the clinical picture of ATN (47). This has raised the issue of the immunologic and nonimmunologic factors that contribute to DGF in this early period. It has been postulated by Shoskes and Halloran (37) that ischemia may induce expression of HLA antigens on some cells in the allograft and promote release of cytokines. Up-regulation of the immune system and adhesion molecules has also been noted. Nonimmunologic factors were found to be a significant risk for poor outcome by Matas et al (43), only in deceased donor transplants. Conversely, immunologic factors were significant in both living and deceased donor transplants irrespective of DGF (43). Lechevallier et al (48) identified several risk factors for ATN. They observed that donor and recipient vascular backgrounds, donor age, cold ischemia time, preservation solution, and the use of “right” kidneys were related to a higher incidence of ATN. ATN accounted for 92.1% of their cases of DGF. These investigators also stressed the importance of kidney biopsy in the diagnosis and management of these patients. Others have noted additional predisposing factors, including relationship between donor and recipient body mass, female to male donors, and cause of death of the donor.

TABLE 7.1. Risk factors for delayed graft function

Age of donor

Donor history

Comorbid conditions
Cause of death
Brain death
ICU donor management

Injury at procurement

Organ preservation methods

Warm ischemia time

Cold ischemia time

Inadequate nephron mass

Reduced donor kidney mass versus recipient body size

Prior recipient sensitization

ICU, intensive care unit.

The diagnosis of ATN is made on clinical grounds and biopsy. Early oliguria should lead to the differential diagnosis and diagnostic approach as outlined in Table 7.2 and Figure 7.1. The recipient’s volume status should be assessed by examination and with chest x-ray. Color flow Doppler ultrasound and isotope scan help evaluate perfusion of the graft. CIN levels should be measured. Renal biopsy is indicated when there is no clinical improvement. In particular, high-risk patients should be considered for an earlier biopsy (3 to 5 days), compared to lower risk patients (5 to 7 days). Follow-up biopsies should thereafter be performed every 7 to 10 days until good graft function is established.

The value of early dialysis in these patients has not been well studied. The use of biocompatible membranes to improve outcomes in acute renal failure has been reported (49,50), but the benefit in DGF is less certain (51). If dialysis is required in this early period, prevention of hypotension and further ischemic insult to the kidney should be a priority. Kidneys with ATN have impaired autoregulation, making them more sensitive to diminished perfusion. Clinical indications for dialysis in the early posttransplant period fall into three main categories: severe volume overload not responding to diuretics, electrolyte abnormalities, and uremic symptoms. We consider dialysis for hyperkalemia (potassium greater than 6.0mEq/L) that does not respond to usual medical management. Significant metabolic acidosis that cannot be controlled medically may also require dialysis. Patients previously on peritoneal dialysis who still have their catheters in place may be able to tolerate peritoneal
dialysis, with smaller volumes that may cause less insult to the newly transplanted kidney.

TABLE 7.2. Differential diagnosis of graft dysfunction during the early posttransplant period

Acute tubular necrosis

Surgical complication causing early graft dysfunction

Bleeding at the graft site
Graft thrombosis
Renal artery stenosis
Urine leaks
Ureteral obstruction
Lymphoceles

Acute rejection

Thrombotic microangiopathy

Acute medication toxicities (CINs)

Recurrent disease

CINs, calcineurin inhibitors.

FIG. 7.1. Algorithm for early graft dysfunction.

Surgical Complications Leading to Graft Dysfunction

When determining the cause of renal graft dysfunction, surgical causes (vascular and urologic) should be ruled out before the physician concludes that the event has a medical cause (52). Surgical issues of renal transplant are reviewed in detail in Chapter 8. Here we list surgical complications causing early graft dysfunction. The discussion will be limited to incidence, presentation and diagnoses of bleeding, graft thrombosis, renal artery stenosis, urine leaks, ureteral obstruction, and lymphoceles.

Bleeding

Early postoperative bleeding may occur from small vessels in the renal hilum and lacerations of the renal artery distal to the anastomosis unrecognized during procurement, bleeding rarely from the anastomosis. Days later, bleeding from a mycotic aneurysm or perianastomotic infection can occur.
Presentation generally includes intense pain over the graft site and/or back pain, a falling hematocrit, and signs of tachycardia and hypotension (53). Serial hematocrits should be routine for the first 24 hours posttransplant. An ultrasound can confirm a perigraft hematoma, but immediate surgical reexploration is usually indicated. Coagulation tests should be checked.

Graft Thrombosis

Graft thrombosis may be due to either renal artery thrombosis or renal vein thrombosis. The overall incidence of these complications has varied from 0.5% to 8% of renal transplants. The majority of cases occur in the first 48 hours postoperatively and most within 7 days (54). Renal artery thrombosis usually presents as a sudden cessation of urine output, sometimes with graft site pain and a subsequent rise of serum creatinine. However, if the recipient has significant residual native renal function and urine output, the only sign may be a rise or plateau of the serum creatinine. Renal vein thrombosis generally presents with severe graft tenderness, swelling, and hematuria. The diagnosis can be suggested by a Doppler ultrasound or isotope flow scan but may require a confirming renal arteriogram. Renal vein thrombosis is frequently diagnosed only at surgical exploration. Predisposing factors include pediatric donors, technical surgical problems, episodes of hypotension, and a past history of venous thrombosis (55). Additionally, renal vein thrombosis can follow local compression from a hematoma or lymphocele as well as ascending phlebitis from the ipsilateral iliac vein.

Renal Artery Stenosis

Renal artery stenosis is generally felt to be caused by either technical surgical problems or possibly acute rejection (56). Ten percent of cases are found during the first hospitalization but the median time of diagnosis in one series was 5 months (57). Cases have presented as late as 22 months posttransplant (52). Presentation is most often new or increasingly severe hypertension, loss of renal function, and a new bruit (or one with changed intensity) over the graft. Diagnoses can be suggested by Doppler ultrasound and/or a captopril-isotope scan. A renal arteriogram is usually required which should show a greater than 50% stenosis. Despite documentation of a stenosis, if no renal dysfunction exists, the native kidneys should be suspected as the cause of the hypertension.

Urine Leaks

Urine leaks occur at the level of the renal pelvis, ureter, or bladder. They are due to either ureteral ischemia (secondary to disrupted blood supply at the time of procurement or bench preparation) or to technical problems with the ureterovesical anastomosis (58). The incidence varies from 3% to 10% of renal transplants (52). Presentation includes severe pain and swelling at the graft site or a marked increase in cutaneous drainage. They usually occur during the first hospitalization or shortly after discharge. Diagnosis can be made by an ultrasound showing a perinephric fluid collection which can be aspirated and sent for a creatinine level (as can cutaneous drainage fluid). A fluid creatinine level higher than serum confirms the diagnosis. We also frequently use the isotope scan to demonstrate an extravesical collection of radionucleotide.

Ureteral Obstruction

Ureteral obstruction complicates 1% to 6% of renal transplants (58). It can occur early during the first hospitalization due to blood clots, ureteral edema, a technically poor ureterovesical anastomosis, a hematoma of the ureteral wall, and ureteral kinking. Later posttransplant causes include ureteral fibrosis secondary to ischemia, and more recently described, ureteral obstruction in the setting of BK virus infection (59). Presentation most often is a rising serum creatinine, change in urine output, or occasional discomfort of the graft. Diagnosis can be suggested by ultrasound although low-grade hydronephrosis is not unusual posttransplant. An isotope scan with furosemide is also a helpful screening test. For more anatomic detail our service has had frequent success with retrograde pyelograms. In the past all of our ureterovesical anastomoses were performed by our urology service and they had a high percentage of success in catheterization of the ureteral orifice. On most transplant services, however, a percutaneous nephrostomy followed by an antegrade pyelogram is often performed.

Although we have not had a case of a perinephric abscess occurring in the first hospitalization posttransplant, we have been told of such occurrences (60). The early incidence of perinephric abscess may be increased in patients treated with peritoneal dialysis pretransplant. As yet, there is no published series of cases in transplanted kidneys; although a recent review has appeared for native kidneys (61). Early recognition, parenteral antibiotics, and percutaneous drainage of abscesses greater than 3 cm in size appear crucial to successful outcome in native kidneys.

Lymphoceles

Lymphoceles are collections of lymphatic fluid that lack an epithelial lining. They are felt to be caused by severed lymphatics overlying recipient iliac vessels and injury to lymphatics in the hilum of the donor kidney. They have been reported to be more common following retransplantation (62). Recently, they have been found more commonly in patients begun on sirolimus-containing immunosuppressive regimens (63). The reported incidence of symptomatic lymphoceles has varied from 0.6% to 18% (52,58,60). Many are small and of no clinical consequence. They can, however, become symptomatic due to compression of contiguous anatomy such as the transplant ureter causing obstruction,
the bladder causing urinary incontinence, the iliac vein causing ipsilateral leg swelling, or thrombosis and rarely the transplant renal vein causing thrombosis. Scrotal masses secondary to lymphocele drainage into the scrotum occasionally occur. Lymphoceles can also become infected (usually after percutaneous drainage procedures). Aspiration of lymphoceles will differentiate them from urinomas because the creatinine will be similar to serum values. The fluid also has a high protein content. To rule out infection it should also be sent for gram stain and cultures.

Acute Rejection

Acute rejection threatens immediate allograft survival as well as long-term function. Strict attention to renal function is required from the initial postoperative period until at least 6 months posttransplantation in order to quickly identify evidence of rejection. Despite successful salvage of the allograft, the rejection episode may compromise graft outcome. In 1995, the predicted half-life for an allograft with no history of acute rejection was 27.1 years. However, for one that underwent rejection, estimated graft survival was 11.9 years (64). With the continued introduction of new immunosuppressive regimens and improvements in clinical care, current rejection rates are less than 20%.

Until the introduction of cyclosporine, acute rejection manifested with symptoms of inflammation such as fever, graft tenderness, and pain. With improved immunosuppressive medications the main indicators of rejection are those associated with graft dysfunction, namely an elevated creatinine and decrease in urine output. Unfortunately, these findings usually occur late in the process, and at the point renal insufficiency is diagnosed, much damage may have already occurred. Additionally, the severity of the clinical presentation may not correlate with the degree of inflammation seen on pathology. Therefore, the only means by which to definitively and accurately assess the presence and extent of disease is by a renal biopsy. Alternative, noninvasive mechanisms are under investigation although none are in clinical use at this time. Other diagnoses require consideration, including surgical complications or medication-related toxicities, and appropriate evaluation for these would be recommended prior to performing a biopsy.

Review of the renal biopsy provides guidance for therapy by revealing the severity of the inflammatory response. The current pathologic classification of rejection is based upon the 97 Banff criteria, which provide descriptions for changes seen in acute and chronic rejection (65). The categories pertinent in the postoperative period are segregated into normal, borderline, acute/active, and antibody-mediated rejection (Table 7.3). Care must be taken in the interpretation of the biopsy, as rejection is not a diffuse process and some areas may be severely affected whereas others are spared leading to potential sampling error.

Acute cellular rejection is the most common form of rejection in the early posttransplantation period, although usually it does not occur until after the first postoperative week. The histology will reveal inflammation of the interstitium with lymphocytic invasion of the tubules. These cells cross the basement membrane and may be seen in between tubular epithelial cells. Involvement of atrophic tubules does not qualify as tubulitis, as such lesions are seen in normal kidneys and thus their significance is unclear (65). Neutrophils are not commonly a part of this response, and their presence should raise consideration for an infectious process or different form of rejection (see below).

TABLE 7.3. Acute rejection per the Banff classification

Grade	Criteria
Normal
Antibody-Mediated Rejection	I ATN-like
Antibody-Mediated Rejection	II Capillary-glomerulitis, PMNs, and/or mononuclear cells in peritubular capillaries
	III Arterial-transmural inflammation/fibrinoid change
Borderline	Mild tubulitis (1-4 mononuclear cells per tubular cross section)
	Interstitial inflammation involving 10% to 25% of the parenchyma
IA	Moderate tubulitis (> 4 mononuclear cells per tubular cross section)
	Interstitial inflammation (> 25% of the parenchyma)
IB	Severe tubulitis (> 10 mononuclear cells per tubular cross section)
	Interstitial inflammation (> 25% of the parenchyma)
IIA	Mild to moderate arteritis
IIB	Severe arteritis: loss of > 25% of the lumen
III	Transmural arteritis and/or arterial fibrinoid necrosis
ATN, acute tubular necrosis; PMNs, polymorphonuclear leukocytes.

The first line of treatment is usually a short course, 3 to 5 days, of methylprednisolone. Doses range from 5 to 10 mg/kg/day although the most effective dose has not been clearly established and a greater quantity of steroids is not associated with better outcomes (66,67). The response rate to a course of steroids is approximately 60% to 70%, and steroid resistance is usually described when clinical improvement is absent after 5 days of therapy (68). In this situation, more aggressive immunotherapy, such as antilymphocyte antibodies, is often the next step. In some centers these medications are used as primary therapy.

The antilymphocyte antibodies include the monoclonal antibody OKT3 and the polyclonal antithymocyte globulins, now largely rATG. These medications are associated with more severe toxicities but also with greater allograft salvage, with particular benefit in steroid resistant rejection. For reasons stated earlier, rATG is now the agent of choice, and OKT3 is used less often. When the antilymphocyte antibodies are used as primary therapy in acute rejection, reversal rates are in excess of 90% and for steroid-resistant rejection 81% to 96% (69,70). Concern for allergic reactions prompts
most clinicians to premedicate patients with high doses of steroids, antipyretic agents, and antihistamines. With the greater degree of immunosuppression, prophylactic regimens to prevent CMV, herpes simplex viruses (HSV I and II) varicella zoster virus (VSV) and Pneumocystis carinii are initiated or continued (see later discussion). Adjustments are made in the maintenance immunosuppressive regimen during their use.

Severe acute cellular rejection is characterized by vascular inflammation that may affect the endothelium only or extend further to result in transmural fibrinoid necrosis. Because of the more dismal prognosis in these cases, immediate aggressive immunosuppression is usually employed using antilymphocyte preparations (71).

The role of alloantibodies in rejection was quickly observed in ABO incompatible transplants when severe graft necrosis immediately occurred in the operating room. Only recently has their significance throughout the posttransplantation course gained appreciation as more advanced technology allowed for their greater recognition. It is now recognized that antibody-mediated disease also encompasses a form of rejection that may resemble acute tubular necrosis and plays a part, the extent of which is as of yet undetermined, in the development of chronic allograft nephropathy. The underlying mechanism in these responses is the presence of cytotoxic antibodies, either because of ABO incompatibility or from antibodies to donor HLA antigens.

A recent amendment to the Banff classification divides antibody-mediated disease into three categories: (a) a presentation akin to acute tubular necrosis, (b) capillary glomerulitis with infiltration of neutrophils or monocytes, and (c) transmural inflammation of the artery (72). Diagnosis rests upon typical findings on biopsy as well as identification of humoral activity, now possible with the development of more sophisticated techniques. The biopsy may reveal signs of tubular damage and arteritis, or there may be more discrete inflammation consisting of neutrophil and mononuclear cell infiltration of glomeruli and peritubular capillaries (72). Immunofluorescent staining for C4d in the peritubular capillary basement membrane and the presence of antidonor antibodies provide further diagnostic evidence. Successful management of these patients has been obtained with plasmapheresis, intravenous immune globulin, and adjustment of maintenance immunosuppression to include tacrolimus and MMF (73, 74, 75).

The incidence of hyperacute rejection declined with the improvement in routine HLA crossmatch testing. Hyperacute rejection refers to an immediate complication due to high levels of cytotoxic antibody usually recognized at the time of vascular anastomosis when the allograft becomes cyanotic and anuric. Regardless of the intensive immunosuppressive therapy given, outcomes are usually grim, and in most cases nephrectomy is necessary.

The understanding of the pathophysiology involved in rejection processes continues to expand and shape improving therapy. As this comprehension grows, rejection rates will decrease further and more challenging forms of transplantation may become common.

Thrombotic Microangiopathy

The thrombotic microangiopathies (TMA), whether as de novo or recurrent disease, can significantly compromise renal allograft function and survival. These disorders, which include the hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), are characterized by platelet aggregation and the formation of thrombi. Intravascular thrombi damage erythrocytes, causing hemolytic anemia, and the consumption of platelets in the thrombi results in thrombocytopenia. Typically, renal disease occurs more frequently and to a greater degree in HUS, but there may not always be a clear distinction. HUS is not uncommon in the transplant population and must be considered when there is a decline in allograft function.

In the transplant population, HUS usually occurs within the first 3 months posttransplantation, although cases have been described after 21 months of treatment (76). One series described 12 cases of HUS that occurred in 408 transplantations. All 12 presented within the first 2 weeks after surgery (77). Suspicion for TMA occurs when renal function deteriorates in association with a decline in the platelet count and the hematocrit. Platelet counts may still be within the normal range but with a downward trend. Systemic symptoms, if present, are mild and are not diagnostic. Further evidence includes the peripheral smear, which will reveal schistocytes and perhaps a diminished number of platelets. The LD (lactate dehydrogenase) is often elevated, not from hemolysis, but from thrombotic occlusion of the microcirculation resulting in tissue ischemia (78).

In children, the hemolytic uremic syndrome is most commonly precipitated by an episode of gastroenteritis, usually due to E. coli 0157:H7. However, in the transplant population a broader differential diagnosis should be considered. Most importantly, one must distinguish HUS from acute vascular rejection. Both conditions may present with similar clinical findings, therefore a renal biopsy is mandatory to differentiate the two. Histologically, both may reveal subendothelial cell thickening with capillary thrombi and an inflammatory infiltrate. In vascular rejection there is often a neutrophilic infiltration of peritubular capillaries and C4d immunofluorescent staining of their basement membranes not seen in HUS. The characteristic findings in HUS include glomerular and arteriolar thrombi associated with endothelial cell swelling. Tubular and interstitial infiltrates also occur, causing interstitial edema that further compromises renal function. With time, the glomeruli become ischemic and global sclerosis is seen. Immunofluorescence is usually unremarkable although granular staining for immunoglobulin A and C3 may be seen. Electron microscopy reveals the accumulation of subendothelial electron dense material.

Once the diagnosis of TMA is established, an investigation into the inciting cause is necessary. In a patient with a
history of HUS, recurrence of idiopathic or hereditary disease would be the greatest concern. Without such a history, medications are the most probable cause. The most common culprit agents include the calcineurin inhibitors, cyclosporine, and tacrolimus. OKT3 has been associated with HUS, and there are reports that sirolimus may potentiate CIN-induced endothelial injury leading to TMA. Other than the immunosuppressive medications, chemotherapeutic agents, oral contraceptives, and clopidogrel can all trigger TMA (79). It is important to recognize this possible role of antiplatelet agents as they become increasingly indicated in the treatment of cardiovascular disease, especially prevalent in the transplant population. Infections may precipitate HUS, including viral infections, such as CMV and influenza, or sepsis. Pregnancy, systemic lupus erythematosus, malignant hypertension, and malignancy are also possible causes but much less likely in this clinical setting (Table 7.4).

The patients at risk for posttransplant HUS include those who are more predisposed to rejection. The risks include retransplantation, allografts from non-heart-beating donors, and high levels of cytotoxic antibodies (80). Women and patients who receive combined kidney-pancreas transplants also seem to have an increased incidence of TMA (81). The patient whose renal failure was the result of HUS is at particularly high risk for recurrent disease. The immunosuppressive regimen in this situation requires careful consideration and probable avoidance of CINs.

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