Management of Patients after Kidney, Kidney-Pancreas, or Pancreas Transplantation

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196 Management of Patients after Kidney, Kidney-Pancreas, or Pancreas Transplantation

The first successful long-term functioning kidney transplant was performed by Joseph Murray in 1954 between two monozygotic twins, avoiding the problem of rejection. The recipient lived 8 years, dying of a cause unrelated to her renal failure. Critical care practitioners played an important role in the development of transplantation, with the development of brain death criteria and the ability to care for patients after brain death, allowing recovery of viable organs to be used for transplantation. The success of organ transplantation has improved with the development of more effective preservation solutions, such as the University of Wisconsin solution in the late 1980s, and with the availability of more effective immunosuppressive agents.

image Background

Kidney Transplants

Kidneys are the most frequently transplanted organ; more than 285,000 transplants have been performed through 2007, with over 16,000 transplants performed per year in the United States1 (Table 196-1). Numerous causes of chronic renal failure result in the need for transplantation, the most common being diabetes mellitus and glomerular disorders (Box 196-1). The source of donors for renal transplantation are both cadavers and living donors. In 2009, there were 10,442 cadaveric donor transplants and 6387 living donor transplants performed.1,2 The living donor pool consists of both living related donors, who have a higher likelihood for a favorable crossmatch, and living unrelated donors. Recent surgical innovations such as using laparoscopy to obtain the donor kidney have decreased morbidity for donors and decreased costs.3 The living donor pool may be expanded through the use of programs to utilize nonrelated donors (e.g., kidney paired donations, non-directed donation).

Box 196-1

Common Indications for Kidney Transplant*

2008 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: transplant data 1998-2007. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD; United Network for Organ Sharing, Richmond, VA; University Renal Research and Education Association, Ann Arbor, MI. Available at:

In most cases, the renal transplant operation is done through a retroperitoneal flank incision. An anastomosis is created between the recipient’s iliac artery and the donor kidney’s renal artery. Another anastomosis is fashioned between the iliac vein and the renal vein. The donor ureter is connected either to the recipient’s bladder using a ureteroneocystostomy or to the recipient’s ureter via ureteropyelostomy.

Pancreas Transplants

Pancreas transplantation for control of diabetes was first successfully reported by Lillehei and colleagues in 1970.4 The major indication for transplantation of this organ is diabetes mellitus. Because of the significant morbidity associated with immunosuppression, transplantation of this organ in isolation is uncommon; most pancreatic transplants are carried out in conjunction with a simultaneous or previous kidney transplant. In 2009, there were 854 simultaneous kidney-pancreas transplants and 379 pancreas-after-kidney transplants or solitary pancreas transplants.2 Isolated pancreatic islet cell transplantation (autotransplantation) has been utilized as an adjunct to total pancreatectomy for patients with intractable pain due to chronic pancreatitis and is an active area of research using human and genetically modified animal islet cells to produce insulin while minimizing the risks of immunosuppression.5 However, these techniques are difficult to apply outside of specialized centers.

The surgical technique for pancreas transplantation involves anastomosis of the pancreatic vascular supply to the iliac artery and vein. A major issue in pancreatic transplantation is ensuring safe drainage of exocrine secretions. The two options employed are drainage of the pancreatic duct into the bladder and drainage of the duct into the small intestine. Bladder drainage has a lower infection rate, but it is associated with metabolic acidosis due to bicarbonate losses in the urine, as well as cystitis, urethral stricture, and hematuria. This has led to a recent increase in the use of enteric drainage.

Compared with other solid-organ transplant operations, rejection is more difficult to diagnose in pancreas transplantation for a number of reasons. Hyperglycemia is not manifested until a significant portion of the graft is lost. For grafts drained into the bladder, decreases in urinary amylase concentrations sometimes suggest that rejection is occurring, although this test is not very sensitive. Needle core biopsies under ultrasound guidance using 18- or 20-gauge needles have reduced complications associated with biopsies to 2% to 3%.6 The problem of detecting rejection of pancreatic grafts has prompted efforts to carry out simultaneous pancreatic and kidney transplants, using the kidney as a “canary” to detect rejection of both organs. This indicator of rejection is not as effective in pancreas-after-kidney transplants, because the two organs are immunologically distinct, as evidenced by higher pancreas graft loss rates after pancreas-after-kidney procedures as compared with simultaneous transplants (22% versus 15%).7 The advantage of early identification of rejection must be balanced against the increased risk of perioperative complications as a consequence of the more challenging simultaneous operation.

image Ethical Issues

A number of ethical issues are related to transplantation. Unstated (and/or unintended) coercion to donate can be overwhelming for the family members or loved ones of a patient with renal failure. The physician must act as an advisor, not only for the recipient but also for potential donors. The risk of mortality for donors is low (0%-0.03%), but there is a complication rate of 18%.8 There is some evidence that renal donors are at slightly increased risk for late renal failure after donation.9,10 These issues mandate a frank and open discussion prior to donation.

Another ethical issue that arises relates to transplanting a pancreas without performing a kidney transplant in a patient with diabetes mellitus without renal insufficiency. In most patients with normal renal function, the benefits of being insulin free do not outweigh the long-term risks of immunosuppression. It is reasonable to consider pancreas transplant alone in diabetics without end-stage renal failure if there is evidence of early diabetic nephropathy or problems related to blood glucose control are disabling (e.g., lack of awareness of hypoglycemia) or in patients when two or more secondary diabetic complications are present.

A third ethical issue frequently encountered by critical care physicians relates to the decision to reduce temporarily or to discontinue immunosuppression when a transplant recipient presents with a proven or suspected infection. Tension can exist among the critical care team, the transplant team, and the patient surrounding this issue. On the one hand is the possibility of death from uncontrolled infection, and on the other hand is the loss of a kidney or pancreas graft that would provide considerable improvement in the quality of life.

image Current Immunosuppressive Agents/Regimens

The field of immunosuppression has undergone many changes over the past decade, driven by a much better understanding of the immune system, allowing the development of targeted therapies. Most patients will receive a combination of agents to prevent rejection. These agents include calcineurin antagonists (cyclosporine, tacrolimus), proliferation signal inhibitors (sirolimus, rapamycin, or everolimus), proliferation inhibitors (azathioprine, mycophenolate mofetil), and corticosteroids. Other agents frequently used to combat rejection include antilymphocyte antibodies and interleukin (IL)-2 receptor antagonists. Induction therapy with anti-T-cell antibodies or IL-2 receptor antibodies are commonly utilized in pancreas transplantation. A summary of these agents and mechanisms of action is provided in Table 196-2.

TABLE 196-2 Immunosuppressive Agents and Mechanism of Action

Class of Agent Uses Mechanism of Action
Corticosteroids (methylprednisolone, prednisone) Induction, maintenance, rejection Redistribution of lymphocytes
Block T-cell proliferation, IL-2 synthesis
Antilymphocyte antibodies (antithymocyte globulin, OKT-3) Induction, rejection Lymphocyte depletion
Humanized antibodies (basiliximab, daclizumab) Induction, rejection Specific targets: IL-2 receptor
Calcineurin inhibitors (cyclosporine, tacrolimus) Maintenance, rejection Inhibit IL-2 production
Inhibit expansion and differentiation of T cells
Proliferation signal inhibitors (sirolimus [rapamycin], everolimus) Maintenance Block cytokine-driven cell cycle progression
Antimetabolites/antiproliferative agents (azathioprine, mycophenolate mofetil) Maintenance Inhibit RNA/DNA synthesis

IL-2, interleukin-2.

Most of the immunosuppressants have significant side effects and toxicities and significant drug interactions. For a complete discussion of this issue, please see Chapter 176. Common side effects of immunosuppressive agents are summarized in Table 196-3.

TABLE 196-3 Side Effects of Common Immunosuppressive Agents

Antithymocyte globulin Fever, leukopenia, thrombocytopenia, serum sickness
Azathioprine, mycophenolate mofetil Leukopenia, thrombocytopenia, anemia, diarrhea, abdominal pain, hepatotoxicity, pancreatitis
Basiliximab, daclizumab Hypersensitivity (anaphylaxis), fever
Corticosteroids Hyperglycemia, osteoporosis, impaired wound healing, hypertension, Cushingoid facies, Addisonian crisis (from rapid withdrawal)
Cyclosporine Nephrotoxicity, neurotoxicity, drug interactions, hypertension, hyperkalemia, hirsutism, gingival hyperplasia
Sirolimus, everolimus Hyperlipidemia, myelosuppression, impaired wound healing, diarrhea, arthralgia, pneumonitis
Tacrolimus Nephrotoxicity, neurotoxicity, drug interactions, hypertension, hyperkalemia, diarrhea, diabetes, tremor
OKT-3 Pulmonary edema, fever, rigors, diarrhea, headache, bronchospasm, increased cytomegalovirus infection, risk of posttransplant lymphoproliferative disorder

image Common Related Diseases and Conditions

The vast majority of patients receiving kidney and/or pancreas transplants do not require admission to the intensive care unit (ICU). For those patients who do require admission, most are admitted because of perioperative difficulties, which are frequently related to an underlying medical disorder (Box 196-2). A number of medical illnesses are more common in patients with chronic renal failure, including atherosclerotic heart disease, hypertension, congestive heart failure, diabetes mellitus, chronic obstructive pulmonary disease, peripheral vascular disease, and cerebrovascular disease. Discussions with the patient or family often will reveal a history of one or more of these illnesses, allowing evaluation and treatment to be tailored appropriately for the patient.

image Routine Perioperative Care: Kidney or Kidney/Pancreas Transplant

For typical kidney transplant recipients without acute tubular necrosis, a brisk diuresis begins within minutes of revascularization of the kidney graft. This diuresis is due to a number of factors including intraoperative administration of diuretics, proximal tubular damage related to allograft ischemia, fluid and electrolyte disturbances as a result of chronic renal failure, and osmotic factors related to uremia. In patients after kidney-pancreas transplantation, the diuresis also can be related to hyperglycemia. Tight control of blood glucose concentration should be achieved using an insulin infusion. Many patients who were euglycemic before transplantation become hyperglycemic after transplantation, owing to the effects of corticosteroids (occasionally administered to prevent rejection) and the stress of surgery. The appropriate target for blood glucose control remains controversial, with recent evidence showing no benefit to tight glucose control.11 Nonetheless, in pancreas transplant patients in particular, insulin infusions around the time of transplant have been associated with improved islet function.12 Our current practice is to maintain blood glucose concentration at 80 to 140 mg/dL. An example of an insulin drip protocol is noted in Figure 196-1. Urinary losses should be corrected with a hypotonic solution; a common prescription is 2.5% dextrose in 0.2% saline infused at a rate of 1 mL per milliliter of urinary output for the first 12 to 24 hours after transplantation. Sodium bicarbonate and potassium chloride should be added as needed, based on frequent measurements of serum electrolyte concentrations. Urine volumes of less than 100 to 200 mL/h within the first 12 hours after renal transplant may represent a problem with the graft, and this finding should be immediately communicated to the transplant service (Box 196-3).

Immunosuppression is typically initiated in the operating room and continued postoperatively. At most transplant centers, the dosing of the immunosuppressive agents is protocol driven and determined by the transplant service. Examples of standard protocols for kidney transplant and simultaneous kidney-pancreas transplant patients are illustrated in Table 196-4.

Prophylactic antibiotics appropriate to cover skin and genitourinary flora should be given for 24 to 48 hours. Potential agents include ampicillin/sulbactam (1.5-3 g intravenously [IV] every 6 hours), ertapenem (1 g IV daily), ceftriaxone (1 g IV daily), and gatifloxacin (40 mg IV daily). There is no evidence to support longer courses of antibiotics in kidney transplant recipients. Trimethoprim/sulfamethoxazole (80 mg trimethoprim/40 mg sulfamethoxazole by mouth [PO] daily) or dapsone (50 mg PO daily for sulfa-allergic patients) is used routinely at most centers for prophylaxis against Pneumocystis jirovecii and Nocardia species. Prophylaxis for cytomegalovirus is given at our center (valganciclovir dosed by renal function) for 3 to 6 months.

Several specific issues should be considered in pancreas transplantation aside from the usual management of kidney transplantation. The first of these is related to the high rate of graft loss in pancreas transplants owing to portal venous thrombosis. Many centers use a low-dose anticoagulation regimen of unfractionated heparin (100-500 units IV hourly as a continuous drip) in an effort to reduce graft loss from this complication. Systemic anticoagulation increases the risk of postoperative hemorrhage. Second, there is a high incidence of wound and intraabdominal infections after pancreas transplantation, being as great as 47% in some centers.13,14 Some centers advocate longer courses of broad-spectrum antibiotics because of concerns about infection, although data to support this practice are lacking.

image Posttransplant Complications

Posttransplant issues requiring ICU admission can be divided into those occurring immediately post transplant and those occurring at some time remote to the perioperative period. Kidney transplant patients are admitted to the ICU at a frequency of 16 per 1000 patient-years and have a mortality rate associated with admission of 40%, significantly higher than the general population.15 Common postoperative complications after kidney and/or pancreas transplantation are listed in Table 196-5.

TABLE 196-5 Common Postoperative Complications: Kidney, Kidney-Pancreas, Pancreas Transplant

Early Late
Myocardial infarction Myocardial infarction
Renal failure Renal failure
Hyperglycemia Transplant artery stenosis
Graft thrombosis Respiratory failure
Hemorrhage Posttransplant infection (immune-compromised host)
Wound infection  
Respiratory failure Posttransplant lymphoproliferative disorder
Posttransplant infection (hospital acquired) Graft pancreatitis
Deep venous thrombosis Acute and chronic rejection
Metabolic acidosis  
Graft pancreatitis  
Hyperacute and acute rejection  
Bladder leak  
Pseudomembranous colitis  

Postoperative Respiratory Failure

The majority of kidney and/or pancreas transplant patients admitted with a diagnosis of respiratory failure after surgery have a self-limited form of the condition secondary to the residual effects of general anesthesia. These patients can be extubated when awake, and recovery from the effects of neuromuscular blocking agents is complete or nearly so. Other causes of immediate postoperative respiratory failure include congestive heart failure from perioperative myocardial infarction (MI), pulmonary edema due to intravascular volume overload secondary to acute tubular necrosis, preexisting pneumonia, aspiration pneumonitis, pulmonary embolus, or (rarely) acute respiratory distress syndrome (ARDS) secondary to intraoperative events or posttransplant pancreatitis. In this setting, it is key to perform a rapid and thorough diagnostic workup to determine the etiology of more serious causes of respiratory failure. This evaluation should include electrocardiography (ECG), determination of circulating levels of cardiac enzymes, chest radiography, arterial blood gas analysis, and measurements of serum electrolytes and blood urea nitrogen (BUN)/creatinine concentration. Based on findings from history, physical examination, and the results of these initial tests, the clinician can obtain additional tests as needed to establish a diagnosis. Additional tests that may be helpful include duplex ultrasound scans of the lower extremities for deep venous thrombosis, spiral computed tomography (CT) of the chest to evaluate for pulmonary embolus, cardiac echocardiography, diagnostic bronchoscopy, and transplant ultrasound and/or biopsy.

Respiratory Failure Distant To Transplant

Occasionally, patients are admitted to the ICU with respiratory insufficiency or failure weeks or years after pancreatic and/or renal transplantation. The differential diagnosis is broadened in these patients because of the increased risk of infection associated with immunosuppression. The differential diagnosis for respiratory failure includes infectious causes, cardiogenic causes, and renal failure. It is important to glean from the patient, family, or records any features such as cytomegalovirus (CMV) status of the patient and donor, past history of cardiac disease, and recent changes in transplantation medications. A rapid workup should take place to evaluate the cause of decompensation. It is frequently necessary to intubate the patient, even in the absence of overt respiratory failure, to perform bronchoscopy for diagnostic evaluation. Initial evaluation should include chest radiography; complete blood cell count; determination of serum electrolytes, BUN/creatinine and cardiac enzymes; sputum sampling; and ECG. It is also prudent to include a rapid screen for CMV in this evaluation. Other tests, including diagnostic bronchoscopy, CT of the chest, echocardiography, and lower extremity Doppler examinations, should be carried out as clinically indicated. Typically, the noninfectious causes of respiratory failure, such as renal failure with fluid overload and myocardial dysfunction causing congestive heart failure, are more readily identified and treated, leaving the more subtle causes to sort through over the next several days of the patient’s ICU course. Exclusion of cardiac and renal failure mandates strong consideration for the possibility of an infectious cause of respiratory compromise.

Initial treatment for posttransplant respiratory failure distant to surgery requires broad-spectrum antibacterial, fungal, and viral therapy until a definitive diagnosis is reached. It is not unusual in such circumstances to have patients on agents that will cover common bacterial organisms, Candida and Aspergillus, and CMV (see also Chapter 195). Common regimens include broad-spectrum antibiotic agents with antipseudomonal and antianaerobic activity, an agent with gram-positive activity, a broad-spectrum antifungal agent, and ganciclovir to provide antiviral coverage for cytomegalovirus and other members of the herpesvirus family. Similarly to other work in the ICU care, delay to appropriate antibiotics in transplant patients has been associated with worsened outcomes.16 A number of appropriate agents for this purpose are listed in Table 196-6. In situations where Pseudomonas is strongly suspected, an additional agent should be added to provide double coverage of this organism. In situations where the patient has high risk for or has known vancomycin-resistant Enterococcus faecium

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