David J Reich Cosme Manzarbeitia Radi Zaki Jorge A Ortiz and Sergio Alvarez

19.1. LIVER TRANSPLANTATION

Late complications specific to liver transplantation include technical complications, recurrent liver disease, and chronic hepatic rejection, in addition to the side effects of long-term immunosuppression that affect recipients of any type of organ transplant (discussed in Chapter 18). Evaluation of allograft dysfunction in the liver recipient with long-term follow-up requires screening for hepatic artery thrombosis or stenosis, biliary problems, recurrent disease, rejection, and infection. All of these problems may present with similar findings and laboratory abnormalities. Initial workup routinely includes duplex ultrasound, cholangio-gram, liver biopsy, pan cultures, and serology testing.

19.1.1. Technical Complications

Technical complications that present late posttransplant involve the biliary and hepatic vascular trees.

19.1.1.1. Biliary Complications

After the early posttransplant period, biliary complications involve bile leaks, usually from the T-tube tract, and anastomotic stenosis of the choledocho-choledochostomy or choledochojejunostomy.

19.1.1.1a. Biliary Leak. Spontaneous bile leaks from the anastomosis or elsewhere are unusual late posttransplant because of the scarring process. However, patients may suffer a bile leak from the T-tube exit site, approximately 3 months posttransplant. Most centers that use T tubes to stent the biliary anastomosis bring the long limb of the tube out through the recipient bile duct. This is removed approximately 3 months posttransplant, following a normal cholangio-gram. T tubes used in the nontransplant setting are generally removed long before 3 months. However, transplant recipients do not form a mature tract until several months posttransplant because of heavy immunosuppression. Occasionally, 3 months is still not long enough to form a mature tract, and after T-tube removal, bile that leaks into the abdominal cavity causes peritonitis. Most leaks are self-limited and the only therapy required is hydration and antibiotics. Sometimes, severe peritonitis and even septic shock develop, necessitating emergent endo-scopic retrograde cholangiopancreatography (ERCP) and nasobiliary or internal stenting. Surgery for a T-tube tract leak is only rarely required. This complication is one of the reasons that more and more programs perform the choledochochole-dochostomy without T-tube stenting.

19.1.1.1b. Biliary Stricture The majority of biliary complications that present late posttransplant are related to biliary ischemia from hepatic artery stenosis or thrombosis, or from low flow state related to sepsis. The biliary tree receives blood supply predominantly from the arterial rather than the portal vascular system. The donor duct receives arterial supply via the hepatic artery. In the nontransplant setting, the duct is also supplied by the paraduodenal arcades, but in transplant recipients these arcades are severed during the hepatectomy. Therefore, the allograft distal bile duct is particularly prone to ischemia. Biliary ischemia in the patient with long-term follow-up usually presents aas a stricture of the duct-to-duct or biliary-enteric anastomosis. Patients develop insidious allograft dysfunction or overt jaundice and/or cholangitis. ERCP (in the case of a duct-to-duct anastomosis) or percutaneous transhepatic cholangiography (PTC) (in the case of a biliary-enteric anastomosis) is diagnostic and may allow for stenting and balloon dilatation of the stricture. Failure of balloon stricturoplasty necessitates surgical revision, namely, conversion of a duct-to-duct anastomosis to a Roux-en-Y choledochojejunostomy or revision of a choledochojejunostomy. Sometimes, biliary ischemia affects the more proximal biliary tree. In the most extreme situation, patients develop secondary sclerosing cholangitis, which, if progressive, is an indication for retransplantation. An important point to remember is that a patient who presents with biliary problems posttransplantation requires evaluation of not only the biliary tree but also the hepatic artery.

19.1.1.2. Vascular Complications

Vascular complications that affect liver recipients with long-term follow-up include thrombosis or stenosis of the hepatic artery or portal vein.

19.1.1.2a. Hepatic Artery Thrombosis and Stenosis. Approximately 4% of transplant recipients develop hepatic artery thrombosis, and half the time this occurs in patients with long-term follow-up. Risk factors for hepatic artery thrombosis include pediatric cases (because of small vessel size), vascular reconstructions (such as for a donor accessory right hepatic artery originating from the superior mesenteric artery), anastomotic technical imperfections, intimal injuries (such as from clamping, traction, or long cold ischemia), poor inflow, and high outflow resistance (such as during rejection or other forms of allograft dysfunction). Recently, more attention is being paid to the role of hypercoagulable states predisposing to hepatic artery thrombosis. Hepatic artery thrombosis presents with a spectrum of manifestations ranging from insidious allograft dysfunction to overt hepatic necrosis with fulminant liver failure. The most common presentation involves biliary complications, including Gram-negative sepsis, anastomotic stricture, or intrahepatic bile lakes. Unlike hepatic artery thrombosis in the early posttransplant period, which is often diagnosed shortly after onset and is therefore amenable to repair, late hepatic artery thrombosis is usually diagnosed after a delay and is not amenable to repair; even if revascularization is possible, it is not safe to reperfuse chronically necrotic tissue. Some recipients tolerate hepatic artery thrombosis, whereas others require biliary interventions (such as stric-turoplasties or biloma drainages), and approximately half require retransplantation. Many programs perform periodic surveillance ultrasonography, even long-term, after transplantation, to screen for hepatic artery stenosis. Hepatic artery stenosis is amenable to angioplasty, or surgical revision, prior to development of full-blown hepatic artery thrombosis.

19.1.1.2b. Portal Vein Thrombosis and Stenosis. Portal vein thrombosis and stenosis are rare, occurring in less than 1% of liver transplant recipients. Acute thrombosis may cause fulminant liver failure. In other cases, patients present insidiously with manifestations of portal hypertension, including ascites or var-iceal hemorrhage. Acute thrombosis may be amenable to emergent thrombec-tomy. The cases that present insidiously often require portosystemic shunting, either surgically or with transjugular intrahepatic portosystemic shunt (TIPS). Risk factors for portal vein thrombosis include pretransplant portal vein thrombosis, hypercoagulable states, low flow states, and recurrent hepatic fibrosis or cirrhosis.

19.1.2. Chronic Hepatic Rejection

The hallmark of chronic rejection in liver recipients is biliary ductular necrosis, termed "ductopenia" and "vanishing bile duct syndrome," which results in progressive jaundice. The ducts suffer direct lymphocytotoxic injury as well as ischemia from the obliterative vasculopathy caused by antibody-mediated intimal damage of hepatic arterioles. In the late phase of chronic rejection there is diffuse hepatic fibrosis. Allograft function deteriorates, marked by cholestasis and ultimately, loss of synthetic function and portal hypertension. Putative risk factors include human leukocyte antigen (HLA) mismatching and nonimmunologic factors such as ischemia reperfusion injury and cytomegalovirus infection. Heavy immunosuppression with tacrolimus, mycophenolate mofetil, and/or sirolimus may reverse chronic rejection in the early phases. Advanced chronic rejection is an indication for retransplantation.

19.1.3. Recurrent Disease after Liver Transplantation

Many diseases may recur after liver transplantation; in some cases, these may recur after liver transplantation; in others, there may be no immediate impact on patient or graft function, at least in the short term.

19.1.3.1. Metabolic Liver Disease

When the metabolic abnormality is primarily within the liver, transplantation will be curative for metabolic disease; transplantation, at present, is indicated only where there is also significant liver disease (e.g., hemophilia with end-stage hepatitic C virus [HCV] infection). Such indications include alphal-antitrypsin deficiency, antithrombin-III deficiency, protein C deficiency, protein S deficiency, Wilson's disease, tyrosinosis, Byler's disease, galactosemia, hemophilia A and B, and Crigler-Najjar syndrome. Where the disease process is extrahepatic, liver replacement is not always indicated. However, when the disease recurs, transplantation is sometimes indicated, as the effects of disease can be modified, as with genetic hemochromatosis and congenital erythropoietic porphyria. In patients grafted for cystic fibrosis, the disease may affect the graft but medium-term survival is good. In conditions such as the sea-blue histiocyte syndrome or Gaucher's disease, liver replacement is not indicated.

19.1.3.2. Autoimmune Liver Disease

Most autoimmune liver diseases will recur in the allograft but have little impact in the short and medium term. Primary biliary cirrhosis recurs in the allograft in 20% of patients at 5 years and 45% at 51 years. Some have found that recurrence is greater in those on tacrolimus compared with cyclosporine. The role of ursodeoxycholic acid (UDCA) in this situation is unclear. Autoimmune hepatitis, which may recur, especially if corticosteroids are withdrawn, usually responds rapidly to reintroduction of steroids, with no adverse, long-term impact. In primary sclerosing cholangitis (PSC), diagnosing recurrence is difficult since differentiation between recurrent primary disease and de novo secondary disease may be difficult. PSC recurs in about 45% of patients at 5 years and may lead to cirrhosis, requiring retransplantation.

19.1.3.3. Viral Hepatitis

The hepatitis A virus may reinfect the graft, but in the few cases reported, there have been no significant consequences. As for the hepatitis B virus (HBV), until recently, recurrent HBV meant that those who were HBV DNA positive prior to transplantation were contraindicated for transplantation. Those who were DNA negative were treated with hepatitis B immune globulin (HBIg). Now, patients are treated with lamivudine for 6 weeks prior to transplantation, until HBV is reduced to less than 1 million copies/ml or undetectable. Follow-up after transplantation is with both lamivudine and HBIg; the optimal dose and duration of HBIg treatment is uncertain, but some centers aim to maintain levels above 100 units/ml forever or offer vaccination. Development of resistant mutants is an increasing problem. The role of other antiviral therapies, such as gancyclovir, adefovir, or famciclovir, is uncertain at this time. The hepatitis C virus (HCV) almost invariably recurs after transplantation but the extent of the graft damage is variable. Survival in the short term is not significantly affected, but there are concerns regarding long-term recurrence, as cirrhosis at 5 years occurs in 8-25% of patients. Several factors have been variably implicated in recurrence, including genotype (1b), viral load, HLA match, degree of immunosuppression, quasi-species, and recipient age. Patients grafted more recently for HCV appear to develop graft fibrosis more quickly; the reasons for this are uncertain. The roles of interferon and/or ribavirin are uncertain: Concerns about inducing chronic rejection need to be balanced against any therapeutic benefit. Until recently, HIV and AIDS were contraindications for transplantation; the advent of successful control of viral replication has led some centers to transplant HIV patients. Outcomes are variable.

19.1.3.4. Other Indications

A return to alcohol will lead to recurrent alcoholic liver disease in a small proportion of cases, although, overall, 1- and 5-year survival is no different in this cohort of patients. Pretransplant abstinence, often necessary to determine if the liver will recover enough to avoid the need for transplantation, is a relatively poor indicator for future abstinence. Nonalcoholic steatohepatitis (NASH) is occasionally an indication for transplantation. Recurrence of NASH has been identi fied after transplantation and may be associated with progressive fibrosis in the graft. This is more common when the underlying cause of the NASH (such as obesity or jejunal-ileal bypass) has not been altered. Budd-Chiari syndrome, once a major indication for transplantation, is less common now, due to the introduction of other treatments. There is a 30-40% probability of further thrombosis despite the use of anticoagulation. The presence of an underlying disorder will affect the need for transplantation. Post liver transplantation cancer is usually persistence rather than recurrence. For liver cell cancer (HCC), hepatocellular carcinoma, the probability of recurrence is predicted by the size and number of nodules (most imaging modalities underestimate both), the presence of capsular penetration, lymph node involvement, and vascular invasion. Options to treat the cancer prior to or during surgery have had little impact. Cholangiocarcinomas are very difficult to detect prior to transplantation and are rarely cured, although aggressive approaches with chemo- and brachytherapy have been associated with a good outcome in selected patients at the Mayo Clinic. The only secondary cancers that may be indications for liver transplantation are the symptomatic endocrine tumors in which worthwhile palliation can be achieved.

19.2. KIDNEY TRANSPLANTATION

Most technical complications in the kidney transplant recipient occur during the early postoperative period (i.e., within the first month after transplant). A few of these, however, may be seen later on in the course of treatment and are briefly described here. By and large, the major cause of morbidity and kidney graft loss in the late postoperative period is the development of chronic, irreversible rejection. Finally, many of the long-term complications of immunosuppression have already been described in Chapter 18 and are not repeated here.

19.2.1. Surgical Complications 19.2.1.1. Lymphocele

Lymphoceles are collections of lymphatic fluid in the preperitoneal and retroperitoneal space, and their incidence ranges from 10% to 15%. They are caused by disruption of the lymphatics lying along the course of the iliac vessels during preparation for implantation of the allograft in the retroperitoneal space; this complication is not seen with intra-abdominal placement of the allograft. Prevention centers on meticulous ligation of the lymphatics around the iliac vessels versus sharp dissection around the lymphatics. Lymphoceles may cause allograft dysfunction by creating venous obstruction, ureteric obstruction, infection, and lower extremity pain and swelling. The clinical presentation is of swelling and tenderness over the graft, lower extremity swelling, a rise in serum creatinine and a decrease in urine output, and are usually seen within the first 3 to 6 months after transplantation. Diagnosis can be made by ultrasound revealing a perinephric collection. The collection should be sampled for creatinine and protein content. Compared to serum, the fluid has a higher protein content and an equal creatinine. Treatment is indicated in large, symptomatic, or complicated lymphoceles. No surgical treatment is indicated for small asymptomatic lympho-celes. The first line of therapy is percutaneous drainage with a closed suction system. Once the drainage decreases, the drain may be removed. If the drainage does not decrease, sclerosing agents in the form of alcohol or betadine can be used. If the lymphocele recurs, surgical management is indicated. Surgical management consists of internal drainage, which can be performed by an open technique in which the lymphocele is drained into the peritoneal cavity and omentum is placed in the lymphocele cavity. This can also be achieved laparoscopically to create a peritoneal window.

19.2.1.2. Ureteric Stenosis

The ureteric anastomosis is the Achilles' heel of kidney transplantation. There is a high risk of ischemic injury, a result of the segmental blood supply to the ureters. Vascular disruption of the ureters is dependent on the technique of the harvesting surgeon to maintain a significant amount of tissue around the ureters during extraction. Ureters are more vulnerable to ischemic injury during living related or living unrelated versus cadaveric extractions. Ureteric leaks have been discussed previously. Ureteric stenosis may be a manifestation of ischemia or rejection, or secondary to extrinsic obstruction. Examples of extrinsic obstruction are lymphocele or ureteric kinking. Common clinical presentations may be asymptomatic allograft dysfunction presenting with proteinuria, increasing cre-atinine, and proteinuria. The cause of this dysfunction will be identified on ultrasound as hydronephrosis. The diagnostic gold standard is an antegrade neph-rogram via percutaneous nephrostomy or a retrograde pyelogram. Retrograde pyelograms can be extremely difficult to complete due to an obscure ureteric orifice as a result of implantation. Therapeutically, the stricture can be dilated and a double-J stent can be passed. The stent can subsequently be removed in 2 weeks to a month. This is very effective treatment for strictures less than 2 cm in length. For strictures greater than 2 cm in length, surgical intervention is required. For strictures due to extrinsic obstruction, the cause should be treated.

19.2.1.3. Renal Artery Stenosis

This is the most common late vascular complication, most often associated with living related or living unrelated kidney transplants, and has been described in detail in Chapter 15.

19.2.2. Chronic Rejection

Chronic rejection is the major cause of graft loss in renal transplantation. The term "chronic rejection" is a misnomer; the proper term should be "chronic allograft nephropathy." Histological findings of chronic rejection are interstitial fibrosis, tubular atrophy, glomerular proliferation, and sclerosis, as well as arterial intimal thickening (see Chapter 21). The etiology is multifactorial. Immunologic factors contributing to chronic rejection are repeated episodes of acute rejection, which occur several months after transplantation, inadequate immunosuppression (iatrogenic or due to noncompliance), and HLA mismatching. The nonim-munologic factors are hypertension, delayed graft function, cold ischemic time, donor age > 55 years, and hyperlipidemia. Chronic allograft nephropathy is neither prevented nor treated with current, available immunologic medications. An important factor for managing a patient with chronic allograft nephropathy is to rule out other causes of allograft dysfunction, including acute rejection, cal-cineurin inhibitor toxicity, and recurrence of preexisting diseases. Chronic al-lograft nephropathy presents as a slow, insidious process of deteriorating cre-atinine clearance, proteinuria, and hypertension. However, the secondary causes of allograft dysfunction usually have an acute onset, presenting with more rapid allograft deterioration.

19.2.3. Disease Recurrence

Recurrence of the primary kidney disease is rare, accounting for only 1% of cases of late allograft dysfunction. In general, kidney recipients may develop recurrence of diabetic nephropathy, focal segmental glomerulosclerosis, mem-branoproliferative glomerulonephritis, immunoglobin A (IgA) nephropathy, he-molytic uremic syndrome, or systemic lupus erythematosus (see Chapter 21).

19.3. PANCREAS TRANSPLANTATION 19.3.1. Rejection

Acute rejection in simultaneous kidney-pancreas (SPK) transplantation is usually diagnosed by a rapid increase in serum creatinine, along with a decrease in urinary amylase (25% from the baseline) fall in urinary pH, and, finally, a rise in plasma glucose. Exocrine function is impaired well before endocrine manifestations are noted. Other monitoring tests include magnetic resonance angiography, pancreas-specific protein, and interleukin-10. However, the gold standard for the diagnosis of rejection is biopsy, though it is not commonly performed.

The incidence of acute pancreas rejection episodes is significantly lower in SPK compared with pancreas after kidney (PAK) transplant and pancreas transplant alone (PTA). Nowadays the incidence of rejection has decreased secondary to the use of new immunosuppressive drugs (tacrolimus, mycophenolate, anti-IL-2 antibodies, etc.). Graft failure rates secondary to immunologic reasons for SPK at 1, 2, and 3 years are 2%, 3%, and 5%, respectively; for PAK, 9%, 14%, and 20%, respectively; and for PTA, 16%, 18%, and 30%, respectively.

Chronic rejection is characterized by a progressive increase of blood glucose levels or increased insulin requirements, with a continued decline in urinary amylase and C-peptide concentration in patients with multiple previous acute rejection episodes. Data from the University of Wisconsin (Ann Surg 1998;22S, 3) demonstrate that minimizing HLA mismatches improves the long-term survival in SPK recipients by decreasing the incidence of chronic rejection.

19.3.2. Urologic Complications

The most frequent late complications in kidney-pancreas transplantation are urologic in nature. These are usually seen in pancreata drained into the bladder, and management of complications frequently involves conversion to enteric drainage. The conversion rate for severe urologic complications ranges between 15% and 20%.

19.3.2.1. Hematuria

Early hematuria is due to suture line bleeding and has an incidence rate of 17%. Chronic hematuria is usually the result of ulcerations in the duodenal segment or from bladder stone formation in the suture or staple line. It can also be related to the granulation tissue observed in the area of the anastomosis. It requires intervention in approximately 30% of cases. Treatment is with Foley catheter placement, irrigation, and/or cystoscopy for evacuation of clots and fulguration of bleeders.

19.3.2.2. Duodenal-Bladder Leaks

Commonly observed in the first 6 months posttransplant, duodenal-bladder leaks can be seen in up to 15% of cases and can result from technical anastomotic breakdown, acute or chronic rejection, and cytomegalovirus (CMV) infection.

19.3.2.3. Urethral Strictures

This complication usually results from urethritis and is seen in 2.8% of cases. It is usually observed months to years postsurgery. Enteric conversion is necessary if short-term therapy with Foley catheterization fails.

19.3.2.4. Chronic Urinary Tract Infections (UTIs)

This is the most frequent complication (62.5%) of patients induced by the irritant effect of exocrine secretions on the bladder mucosa. The treatment is antibiotic therapy (sometimes long-term) aimed at the offending organism.

19.3.2.5. Metabolic Complications

Without enough patient fluid intake, acidosis and dehydration can occur from loss of salt (bicarbonate) in the urine. Treatment is with salt supplementation (bicarbonate tablets) and the administration of mineralocorticoids.

19.3.2.6. Reflux Pancreatitis

This complication presents with elevations of serum amylase and lipase. Treatment is with long-term catheterization and alpha blockade.

19.3.2.7. Bladder Mucosal Neoplasia

There are anecdotal reports of the development of neoplasia in bladder mucosa bathed with nonphysiologic pancreatic exocrine secretions.

19.3.3. Other Complications

Hypoglycemia after pancreas transplantation may occur secondary to antiinsulin antibodies or continued gastric enteropathy. In terms of surgical complications, the incidence of incisional hernias is the same as for other solid organ transplants.

Mortality after the initial postoperative period is most commonly secondary to myocardial infarction. In a recent 3-year follow-up study, half of the deaths occurred in the first 6 months.

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