Critical Care Medicine

Abdominal Transplantation: Pancreas (incl. Kidney/Pancreas)

ICU Management of the Kidney, Pancreas, and Kidney/Pancreas

Rejection, Allograft dysfunction, Anatomic complications, Infection

1. Description of the problem

What every clinician needs to know

This chapter will cover four conditions related to kidney (cadaver renal transplant [CRT], living-related renal transplant [LRRT]), simultaneous kidney-pancreas (SPKT), pancreas after kidney (PAKT), and pancreas (PTA) transplants: rejection, allograft dysfunction, anatomic complications and infection. The basic principles hold for all of the different transplants. Clinical features may overlap and therefore a high index of suspicion is required. Monitoring of laboratory tests (blood urea nitrogen/creatinine [BUN/Cr], amylase, lipase, glucose), ultrasound, biopsy, and a close relationship with the transplant surgeon and/or transplant nephrologist is paramount.

Rejection

Kidney and pancreas rejection can be either acute or chronic, with acute rejection being more common. Acute rejection generally can occur in the first few weeks to several months after transplant. Chronic rejection is usually a result of several episodes of acute rejection and presents as progressive deterioration of the allograft. Hyperacute rejection is rare with blood group (ABO) and antibody testing of donors and recipients; however, when it occurs it does so upon reperfusion in the operating room and the graft must be removed.

Acute rejection of the renal allograft can manifest with fever, tachycardia, pain over the allograft site (usually lower quadrants) or increasing or plateaued Cr values; it can also be asymptomatic. Acute rejection of the pancreas allograft has similar symptoms, but a rising amylase and lipase level (or decreasing urine amylase in bladder-drained pancreas transplants). Hyperglycemia is usually a late sign of rejection/thrombosis.

Chronic rejection patients usually present to clinic or physician offices with laboratory derangements, decreasing urine output, malaise or uremic symptoms. Chronic renal or pancreas transplant patients rarely need the intensive care unit (ICU).

Clinical features of rejection can overlap with ischemia/reperfusion injury, allograft dysfunction, or ureteral obstruction and therefore other conditions need to be ruled out at the same time. The transplant surgeon should be the decision maker on whether a biopsy is needed.

Allograft dysfunction

Renal allograft dysfunction presents early after transplant and is determined after anatomic and rejection complications are ruled out. Often the allograft never begins functioning from the start (no to minimal urine output, failure of creatinine and phosphorus clearance, electrolyte imbalances—primary nonfunction), or the function plateaus after several days and does not continue to improve (delayed allograft function or acute tubular necrosis [ATN]).

Occasionally the allograft will improve with time as the ischemia/reperfusion injury recovers, but the patient may need hemodialysis during this time. However, if there is no improvement in the first 3 months, the patient should be considered for relisting to regain all the waiting time.

Pancreas allograft dysfunction is similar in presentation. Usually the patient cannot be liberated from insulin requirements, although sometimes enough function is preserved to lower the amount of insulin the patient needs. Severity of reperfusion injury can be estimated by the postoperative amylase/lipase levels. Often the pancreas allograft will continue along with a slow decline of any residual function and a slow increase in insulin requirements.

Anatomic complications

Renal transplantation requires anastamosis of the donor renal artery and vein to the recipient external iliac artery and vein (usually), and the ureter to the bladder dome. Complications are separated into vascular and ureteral complications. Vascular complications include postoperative bleeding (rare), vessel thrombosis, vessel stricture and aneurysms. Ureteral complications include urine leak, hematuria, obstruction and ureteral stricture.

Pancreatic transplantation requires anastamosis of the donor superior mesenteric artery (SMA)/splenic Y-graft and the portal vein to the recipient external iliac artery and vein, as in renal transplants. The portion of duodenum containing the pancreatic duct is anastomosed more commonly to the distal jejunum, or occasionally to the bladder. Vascular complications are similar to renal transplants. The bowel anastomosis can leak and rarely can develop strictures. Other considerations include infections, bowel obstructions and allograft pancreatitis.

Infection

Signs of infection can overlap with those for rejection, and immunosuppression blunts traditional signs of infection (fever, white count). There should be a lower threshold for suspecting and empirically treating infection in these patients, and opportunistic infections also need to be considered. Patients with renal transplants additionally are at risk for BK polyomavirus, which can mimic rejection, making diagnosing rejection vs BK infection difficult. A skilled transplant pathologist can help with this diagnostic dilemma.

Clinical Features

Rejection

Clinical features of rejection overlap with ischemia/reperfusion injury, ureteral (and to a lesser extent bowel) obstruction and infection. Other conditions need to be investigated, and biopsy (ultrasound [US}- or CT-guided) is required for diagnosis. The transplant surgeon or transplant nephrologist should decide whether a biopsy is needed.

Allograft dysfunction

Primary nonfunction in renal and pancreas allografts is when the allograft never functions after transplant and hemodialysis is needed in the first 48 hours, and will continue on a regular basis. Less severe ischemia/reperfusion injury presents with a Cr and/or amylase/lipase/glucose value that has reached a plateau.

Anatomic complications

Vascular

Postoperative bleeding with renal transplants is rare, as bleeding should be localized and corrected in the operating room. On occasion, a renal transplant patient develops a postoperative hematoma (from the anastomosis, unligated vessels in the graft hilum or surrounding tissues); often expectant management is adequate. However, if the hematoma is causing vascular compromise or renal function is not improving or stops, operative evacuation is often needed.

Postoperative bleeding with pancreatic transplants is more common owing to the vascularity of the organ, as well as the dissection needed to free the organ from surrounding organs and tissues. Pancreas bleeding often needs operative exploration to correct, and the transplant surgeon should be notified when blood transfusion is required. Delayed gastrointestinal (GI) bleeding can also occur from the enteric anastomosis. This is usually self-limited and presents between postoperative days 6 and 10. A late massive GI bleed can occur due to an arterioenteric fistula and may be due to infection or pseudo-aneurysm formation.

Arterial and venous thrombosis (of either the recipient iliac vessels or donor allograft vessels) are infrequent in renal transplants but more common in pancreatic transplants. Surgical technique is the main etiology for pancreatic thrombosis, which usually occurs in the first 24 to 48 hours. Thrombosis primarily begins with the portal vein and if not caught immediately will quickly expand, and the organ will need to be removed. Vascular strictures usually develop later and can cause worsening graft dysfunction if not caught and treated.

Ureteral/bowel

Ureteral complications range from anastamotic leak to stricture and obstruction. Patients will arrive to the floor or unit with a Foley catheter that must remain in place for 3 to 5 days to avoid overdistention of the bladder and risk of anastomotic disruption. Abrupt cessation of urine output should prompt examination of the Foley's patency, followed by vascular thrombosis and ureteral leak. Minor leaks can be treated with drainage of the urinoma and continued Foley drainage; major leaks need to be repaired operatively.

Bowel leaks often present as an acute abdomen and should be treated as such. Operative repair is needed for bowel leaks. Strictures are less common, as the anastomosis is large enough to allow drainage of the pancreatic duct.

Infection

General principles of infection management in the ICU or floors apply, although immunocompromised patients often have less typical signs and symptoms. Urinary tract infections (UTIs) in renal patients should be treated promptly and appropriately as transplant pyelonephritis can cause scarring and dysfunction.

Differentiation between these four related conditions is important and difficult, due to overlapping presentations. Early suspicion, diagnosis and treatment are key. Daily monitoring of BUN, Cr, amylase/lipase, electrolytes and urine output, liberal use of US and early investigation of abnormalities is recommended.

Supportive care until enhanced immunosuppression, anatomic correction and sepsis care are completed is essential. As immunosuppressed patients often do not mount a febrile or leukocytosis response to infection, more liberal use of cultures and antibiotics is justified versus typical ICU patients. Consultation with an infectious disease physician experienced with transplant patients can be helpful in difficult cases.

2. Emergency Management

Rejection

Rejection of either renal or pancreas allografts does not usually require emergent management, but early diagnosis and anti-rejection therapy are key.

Allograft Dysfunction

Supportive care is necessary for primary nonfunction and severe allograft dysfunction. This usually involves initiating hemodialysis for correction of hyperkalemia, uremia, and acidosis in renal allografts and close observation of insulin requirements in pancreas allografts. In pancreas transplants, close monitoring for vascular thrombosis is essential during this time.

Anatomic Complications

Aggressive supportive care for bleeding complications includes serial hemoglobin measurement and correction of coagulopathy. The degree of coagulopathy correction, especially for pancreas transplants, should be discussed with the transplant surgeon to balance the risk of ongoing bleeding versus thrombosis. Risk factors include recipient obesity, antiplatelet agents, and anticoagulation. Urine leaks may be managed expectantly depending on severity and location. Early surgical exploration with ureteral reimplantation may be indicated for very early leak, large leaks, or leaks that do not respond to conservative measures. Supportive care for bowel leaks should include typical support for non-immunocompromised acute abdomen patients, including antibiotics, pain control, and volume resuscitation while waiting for operative repair.

Infection

General principles of infection and sepsis management apply, but given the narrower margin of error in immunocompromised patients, particular attention to detail is warranted. Early lactate measurement can help risk-stratify patients with "normal" blood pressure, early collection of cultures from every potential source is useful, and early empiric antibiotics are typically necessary in this infection-prone population.

3. Diagnosis

Rejection

Biopsy is necessary to confirm this diagnosis, using Banff criteria. Biopsy is usually US-guided, and can be done at the bedside for ICU patients.

Allograft Dysfunction

Renal and/or pancreatic dysfunction in the absence of a correctable cause suggests allograft dysfunction (owing to either ischemia/reperfusion injury or primary nonfunction). This is often a diagnosis of exclusion, after rejection and anatomic considerations are ruled out.

Anatomic Complications

Doppler US is the initial screening tool and is often performed on postoperative day 1 as a baseline study. If US is inconclusive, either computed tompography (CT), magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), or angiography can be performed. These tests are often difficult to use as the patient's Cr level is elevated, and contrast nephropathy will further add to the diagnostic dilemma.

Infection

The traditional diagnostic methods and criteria apply but are less sensitive in the immunocompromised patient. Unique considerations include infected lymphoceles or seromas, BK viremia, transplant pyelonephritis, opportunistic infections, and donor-transmitted infection.

In the early days after renal and/or pancreas transplantation, rejection, allograft dysfunction, and anatomic complications are difficult to distinguish from one another. Laboratory and clinical pictures can overlap. When the specific biochemical markers start to rise or plateau, the first step is to do a Doppler US of the allograft(s). This will tell you if the vessels are patent, and also give you a resistive index (RI), which can help differentiate between vessel stenosis (low RI, usually <0.4 to 0.5) or allograft dysfunction (high RI, usually >0.8 and absence of diastolic flow). If a ureteral or bowel leak is suspected, a non-contrast CT scan may be useful.

Rejection

Rejection needs to be included in the differential with all complications. Often the creatinine or amylase/lipase value either plateaus or begins to rise. Cross-matches should be double-checked, but to proceed with transplant the initial cross-match should have been negative. Donor-specific antibodies (DSA) should also be checked, as minor antigens can mediate a humoral rejection. Biopsy is the gold standard and should be done expeditiously.

Allograft Dysfunction

In allograft dysfunction, the patient may have refractory hyperkalemia, none to minimal urine output, and an acidosis. Hemodialysis may be needed. An US to rule out vascular compromise, and allograft biopsy are needed before allograft dysfunction can be diagnosed.

Anatomic Complications

Laboratory abnormalities for renal allografts include rising BUN/Cr, possible hyperkalemia, and metabolic acidosis. Renal artery thrombosis presents with a sudden cessation of urine output; renal vein thrombosis (usually occurs early within the first 10 days) presents with a tender swollen graft and hematuria. In pancreas allografts, increasing serum amylase and lipase values, a decreasing urinary amylase level for bladder-drained grafts, and graft tenderness are present. Persistent hyperglycemia is a late finding of vascular thrombosis, and it may be too late to salvage the graft at that time. Increasing glucose levels should prompt immediate Doppler US.

Infection

A high degree of suspicion is needed to diagnose infections in the immunosuppressed patient, as fever and elevated white blood cell count may not be present. Empiric cultures and antibiotics, and often an infectious disease consult, may be necessary.

4. Specific Treatment

Rejection

Usually increasing immunosuppression is the first line of therapy for acute rejection. This is decided by the transplant surgeon and varies by center. Intensivists need to know the immunosuppression side effects. High-dose corticosteroids are usually the first-line treatment when increasing immunosuppression is not helpful. Common side effects are hyperglycemia, GI bleed, and possibly altered mental status.

Allograft Dysfunction

Primary nonfunction and severe allograft dysfunction usually require hemodialysis within the first 24 to 48 hours after renal transplant. In pancreas transplants, an insulin sliding scale or infusion may be necessary. Expectant management is used for less severe forms of allograft dysfunction, including following BUN/Cr and potassium levels.

Anatomic Complications

Vessel stricture may be amenable to angiographic intervention, but graft thrombosis requires operative treatment for any hope of graft salvage, especially pancreas transplants, where allograft pancreatectomy is often the end result. The anastomotic site is usually the most common location for strictures. Risk factors include recipient atherosclerotic disease, improper suturing technique, and donor artery trauma. Recipients may present later with poorly controlled hypertension, allograft dysfunction, and peripheral edema.

Recipient vascular complications are much less common, but can be devastating. Early events like iliac artery thrombosis are graft- and limb-threatening and should be managed like any ischemic extremity. Ureteral strictures may be able to be dilated or stented or nephrostomy tubes may need to be placed for adequate drainage. Presentation is usually an elevated serum Cr value.

Graft US to assess for hydronephrosis is a good screening tool. Urine leaks most commonly occur early from the anastomotic site. Common causes include ischemia of the ureter, tension on the anastomosis, and direct surgical trauma to the ureter. Symptoms include fever, pain, swelling at the graft site, increased creatinine level, decreased urine output, and cutaneous urinary drainage. Early exploration with ureteral reimplantations is indicated for large or refractory leaks. Drain placement to evacuate a urinoma and stenting can manage most urine leaks postoperatively.

Infection

Empiric antibiotics should be chosen based on previous use, local antibiograms, and suspected source.

5. Disease monitoring, follow-up and disposition

Rejection

Renal rejection can often be difficult to treat, and several rounds of high-dose corticosteroids may be given over several months. An adequate biopsy should contain several glomeruli. Often BK virus makes diagnosis of rejection difficult, and consultation with a transplant pathology department may be necessary. If the rejection is still not adequately treated, Campath and thymoglobulin may be needed. Close follow-up in a transplant center is of paramount importance. Often along with high-dose corticosteroids, the calcineurin inhibitors are increased and a second agent is added (Myfortic [mycophenolate mofetil]). Intravenous immunoglobulin (IVIG) and plasmapheresis are used for humoral (antibody-mediated) rejection.In refractory or severe rejection cases, OKT3 and thymoglobulin are used.

Allograft Dysfunction

Again, primary nonfunction often requires early re-initiation of hemodialysis. Less severe dysfunction may allow enough function to avoid hemodialysis while controlling fluid status and electrolytes, although longevity of the graft may not be as long. Allografts do not necessarily need to be removed when no longer functioning if there is no hematuria, fevers of unknown origin, or tenderness over the allograft site. If no significant graft function is restored, a patient can be relisted within 3 months to regain his/her waiting time for renal transplants. Otherwise, after 3 months or pancreas transplants, relisting for another transplant is the only option.

Primary nonfunction of pancreas allografts often involves restarting home dosages of insulin. Occasionally less severe dysfunction may allow some endocrine function of the organ where less insulin is needed. Allograft pancreatectomy is not needed unless there are fevers or tenderness over the allograft.

Anatomic Complications

For vascular strictures not amenable to angiographic interventions and continued or worsened function, relisting the patient is the option. In ureteral strictures, operative repair with resection and bypass of the stenotic ureter is often needed when other methods have failed. Prognosis depends on the severity of allograft damage resulting from the vascular or ureteral complication, and the reversibility of the complication.

Infection

With proper resuscitation, antibiotics, and source control, most acute infection episodes can be successfully treated, with the exception of multi-drug-resistant organisms. The difficulty is keeping these patients infection-free after resolution of the acute episode. Recurrent UTIs are especially difficult to treat and often require ongoing evaluation by transplant ID. In worsening or not improving infectious situations, consult transplant ID, and consider further imaging and antifungal and antiviral therapies.

The key for diagnosis is an adequate biopsy specimen. An inadequate sample is often nondiagnostic. BK virus also makes reading rejection difficult, and consulting a transplant pathology department may be necessary. US does have false negatives; high indexes of suspicion for vascular issues may require CT angiography, invasive angiography, or MRA, depending on graft function. Severe sepsis and septic shock can have up to a 50% culture-negative rate, but a poor response to empiric antibiotics should lead to other possible sources/opportunistic pathogens.

Close follow-up in a transplant center with either the transplant surgeon or transplant nephrologist is mandatory for all renal and/or pancreas recipients who recover and leave the ICU.

Pathophysiology

Rejection

Mechanisms of renal rejection are complex and can be either cellular or humoral. Cellular includes T-cell native immunity, and characteristically infiltrate tubules and arterial endothelium. Humoral rejection includes a mismatch between the human leukocyte antigen (HLA) loci of the donor and recipient. Cross-matching prior to transplant should eliminate this; however, minor antigen incompatibilities (donor-specific antibodies [DSA]) can also mediate humoral rejection. Alloantibodies preferentially attack the peritubular and glomerular capillaries.

Allograft Dysfunction

The main mechanism for primary nonfunction is felt to be ischemia/reperfusion or preservation injury. Certain donor conditions can affect the incidence of primary nonfunction or allograft dysfunction (eg, premorbid pressor requirements, donor age, cold ischemic time).

Anatomic Complications

Thrombosis of the artery or vein in the immediate postoperative period is most commonly a technical issue such as intimal dissection, kinking, compression by hematomas or lymphoceles, torsion of vessels, or donor artery trauma. This can present with sudden cessation of urine, tender swollen graft, hematuria, or hyperkalemia (for renal transplants) or sudden hyperglycemia, elevation in serum amylase and lipase, and allograft tenderness (for pancreas transplants). Stenosis can be from an anastomotic stricture or "kinking" of the artery or vein during closing, donor artery trauma, and recipient atherosclerotic disease. Recipients may present with poorly controlled hypertension, allograft dysfunction, and peripheral edema.

Ureteral leak is often technical (causes include ischemia, anastomotic tension, and direct surgical trauma to the ureter) and may present with fever, pain, swelling at graft site, increased creatinine level, decreased urine output; ureteral stricture can be either technical (edema, hematoma, kinking) or from ischemia of the ureter ("stripping" of the distal ureteral blood supply). An early bowel leak is technical, while a late leak can be due to rejection, cytomegalovirus infection, and blunt abdominal trauma.

Infection

Immunosuppression, invasive line, intubation, and postoperative hematomas all can render these patients more prone to infections.

Epidemiology

Rejection

Acute rejection occurs within the first 60 days and can occur in up to 40% of transplants, although with improved immunosuppression this figure is decreasing. Antibody-mediated rejection (AMR) can occur in up to 20% to 30% of all acute rejection episodes and can co-exist with cellular rejection. For pancreas transplants, rejection rates are 5% to 25% depending on the combination of immunosuppression that is used.

Allograft Dysfunction

Primary nonfunction is not common. Acute tubular necrosis or allograft dysfunction is fairly common in the postoperative period, and recorded as anywhere from 20% to 30% with cadaveric organs up to 84% with non–heart-beating donor organs. Delayed function is related to ischemic time and reperfusion injury as well as other categories, including donor characteristics, recipient characteristics, graft procurement (brain-dead vs non–heart-beating donors), and immunologic variables.

Anatomic Complications

The overall incidence of surgical complications with kidney transplant is often reported in the 5% to 10% range. Renal artery thrombosis usually occurs early after transplant but is an uncommon event, with an incidence of less than 1%. Renal artery stenosis/stricture has a reported incidence of 1% to 10%. The incidence of deep vein thrombosis (DVT) is around 5%, and the incidence of pulmonary embolism (PE) is 1%. Renal vein thrombosis complicates approximately 2% of transplants. The rate of urine leaks ranges from 0% to 9%. Lymphoceles occur in up to 22% of renal transplants.

Vascular graft thrombosis is the most common non-immunologic cause of pancreas transplant failure, with loss rates ranging from 2.7% in SPK to 8% in pancreas transplant alone (PTA). Enteric leaks are reported with an incidence of 2% to 10%.

Infection

Due to rejection complications and increased immunosuppression for treatment, kidney and pancreas transplant patients are susceptible to infections, with UTIs and wound infections (both superficial and deep) being the most common.

Prognosis

Rejection

Acute rejection episodes often lead to chronic allograft changes that can significantly decrease the length of graft survival. Increased incidences of acute rejection are often associated with delayed graft function, donor age, and immunologic mechanisms.

Allograft Dysfunction

Delayed function is often associated with decreased graft survival. Risk factors for allograft dysfunction include donor age, living versus cadaveric donor, hypotension, and cerebrovascular accident (CVA); recipient factors include age, body mass index (BMI) greater than 30, and a history of blood transfusions. Other risk factors include the cold ischemic time, HLA match/mismatch, and panel reactive antibody (PRA) titers.

Anatomic Complications

Vascular thrombosis usually necessitates graft removal, as the organs do not tolerate warm ischemia well and are often picked up too late for salvage. Vascular stenosis/stricture salvage depends on several factors, including donor factors, location and length of stenosis, graft dysfunction, and successful interventions. Ureteral salvage depends also on the location and length of stricture.

Infection

Overall prognosis varies with the severity of infection (ie, uncomplicated infection to septic shock). With proper resuscitation, antibiotics, and source control, most acute infection episodes can be successfully treated, with the exception of multi-drug-resistant organisms. The difficulty is keeping these patients infection-free after resolution of the acute episode.

Special considerations for nursing and allied health professionals.

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What's the evidence?

Humar, A, Matas, A. "Surgical complications after kidney transplantation". Seminars Dialysis . vol. 18. 2005. pp. 505-10.

Goodman, J, Tai Becker, Y. "Pancreas surgical complications". Curr Opin Organ Transplant . vol. 14. 2009. pp. 85-9.

Lucas, J. "Antibody-mediated rejection in kidney transplantation: an update". Expert Opin Pharmacother . vol. 12. 2001. pp. 579-92.

Richter, A, Lerner, S, Schroppel, B. "Current state of combined kidney and pancreas transplantation". Blood Purification . vol. 31. 2011. pp. 96-101.

Sutherland, T, Temple, F, Chang, S, Hennessy, O, Lee, W-K. "Sonographic valuation of renal transplant complications". J Med Imaging Radiation Oncol . vol. 54. 2010. pp. 211-8.

White, S, Shaw, J, Sutherland, D. "Pancreas transplantation". Lancet . vol. 373. 2009. pp. 1808-17.

Yarlagadda, S, Klein, C, Jani, A. "Long-term renal outcomes after delayed graft function". Adv Chronic Kidney Dis . vol. 15. 2008. pp. 248-56.

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