Solid Organ Transplantation in AL Amyloidosis
Solid Organ Transplantation in AL Amyloidosis
Vital organ failure remains common in AL amyloidosis. Solid organ transplantation is contentious because of the multisystem nature of this disease and risk of recurrence in the graft. We report outcome among all AL patients evaluated at the UK National Amyloidosis Centre who received solid organ transplants between 1984 and 2009. Renal, cardiac and liver transplants were performed in 22, 14 and 9 patients respectively, representing <2% of all AL patients assessed during the period. One and 5-year patient survival was 95% and 67% among kidney recipients, 86% and 45% among heart recipients and 33% and 22% among liver recipients. No renal graft failed due to recurrent amyloid during median (range) follow up of 4.8 (0.2–13.3) years. Median patient survival was 9.7 years among 8/14 cardiac transplant recipients who underwent subsequent stem cell transplantation (SCT) and 3.4 years in six patients who did not undergo SCT (p = 0.01). Amyloid was widespread in all liver transplant recipients. Solid organ transplantation has rarely been performed in AL amyloidosis, but these findings demonstrate feasibility and support a role in selected patients.
Amyloidosis is a multisystem disorder characterized by deposition of protein as insoluble fibrils, which disrupt tissue structure and function. Despite the heterogeneity of the precursor proteins which form amyloid fibrils in vivo, the structure and properties of all amyloid fibrils are remarkably similar. Classification of amyloidosis is based upon the precursor protein from which the fibrils are derived. In AL amyloidosis, which has an age-adjusted incidence in the United States of 5.1–12.8 million patients per year and is the commonest type of acquired amyloidosis, the fibrils are derived from monoclonal immunoglobulin light chains produced by clonal dyscrasias which are usually of a subtle nature.
AL amyloid can deposit in almost any organ. Systemic AL amyloidosis may present with dysfunction of a single organ or alternatively, there may be amyloid deposition and dysfunction of multiple organ systems concomitantly. Untreated, it is a progressive and almost universally fatal disease. Deposition of amyloid in the kidneys presents with varying degrees of proteinuric chronic kidney disease (CKD) and may lead to end-stage renal disease (ESRD). In a recent study, 42% of patients presenting with renal AL amyloidosis required renal replacement therapy (RRT) during the course of their disease. AL amyloid deposits in the heart typically cause a restrictive cardiomyopathy characterized by concentric ventricular wall thickening and diastolic dysfunction resulting in congestive heart failure (CHF). Once CHF has supervened in AL amyloidosis, prognosis is poor with a median survival of 4–6 months. Hepatic AL amyloid can present indolently with hepatomegaly or deranged liver function tests or occasionally with liver failure or hepatic rupture, and is usually associated with presence of extensive extrahepatic deposits. Hyperbilirubinemia in the context of hepatic AL amyloid confers a particularly poor prognosis of <4 months.
In the absence of available treatment to disperse existing amyloid deposits, therapy of AL amyloidosis revolves around attempting to reduce the abundance of amyloidogenic monoclonal serum free light chains with myeloma-type chemotherapy to slow or halt ongoing amyloid deposition. Despite considerable advances in chemotherapy in recent years leading to improved median survival times, a significant proportion of patients have advanced, unsalvageable organ dysfunction by the time they are diagnosed with systemic AL amyloidosis, and the majority of patients continue to die from their disease. Furthermore, patients with advanced cardiac and hepatic involvement are usually too unwell at presentation to tolerate the doses of chemotherapy that are required to successfully suppress their underlying clonal disease.
The role of solid organ transplantation in AL amyloidosis is contentious due to shortage of donor organs. Previous small series have shown inferior outcomes with heart and kidney transplantation among patients with AL amyloidosis compared to those with other causes of cardiac and renal failure, respectively. Deaths have been associated with both recurrence of amyloid in the graft or progressive deposition of amyloid in nontransplanted organs. We present here the clinical management and outcome in 45 patients with AL amyloidosis attending a single national center over a 25-year period who were selected to receive solid organ transplants, and highlight in particular, the disease- and treatment-related factors that are likely to influence outcome with solid organ transplantation during the modern era of effective chemotherapy.
Abstract and Introduction
Abstract
Vital organ failure remains common in AL amyloidosis. Solid organ transplantation is contentious because of the multisystem nature of this disease and risk of recurrence in the graft. We report outcome among all AL patients evaluated at the UK National Amyloidosis Centre who received solid organ transplants between 1984 and 2009. Renal, cardiac and liver transplants were performed in 22, 14 and 9 patients respectively, representing <2% of all AL patients assessed during the period. One and 5-year patient survival was 95% and 67% among kidney recipients, 86% and 45% among heart recipients and 33% and 22% among liver recipients. No renal graft failed due to recurrent amyloid during median (range) follow up of 4.8 (0.2–13.3) years. Median patient survival was 9.7 years among 8/14 cardiac transplant recipients who underwent subsequent stem cell transplantation (SCT) and 3.4 years in six patients who did not undergo SCT (p = 0.01). Amyloid was widespread in all liver transplant recipients. Solid organ transplantation has rarely been performed in AL amyloidosis, but these findings demonstrate feasibility and support a role in selected patients.
Introduction
Amyloidosis is a multisystem disorder characterized by deposition of protein as insoluble fibrils, which disrupt tissue structure and function. Despite the heterogeneity of the precursor proteins which form amyloid fibrils in vivo, the structure and properties of all amyloid fibrils are remarkably similar. Classification of amyloidosis is based upon the precursor protein from which the fibrils are derived. In AL amyloidosis, which has an age-adjusted incidence in the United States of 5.1–12.8 million patients per year and is the commonest type of acquired amyloidosis, the fibrils are derived from monoclonal immunoglobulin light chains produced by clonal dyscrasias which are usually of a subtle nature.
AL amyloid can deposit in almost any organ. Systemic AL amyloidosis may present with dysfunction of a single organ or alternatively, there may be amyloid deposition and dysfunction of multiple organ systems concomitantly. Untreated, it is a progressive and almost universally fatal disease. Deposition of amyloid in the kidneys presents with varying degrees of proteinuric chronic kidney disease (CKD) and may lead to end-stage renal disease (ESRD). In a recent study, 42% of patients presenting with renal AL amyloidosis required renal replacement therapy (RRT) during the course of their disease. AL amyloid deposits in the heart typically cause a restrictive cardiomyopathy characterized by concentric ventricular wall thickening and diastolic dysfunction resulting in congestive heart failure (CHF). Once CHF has supervened in AL amyloidosis, prognosis is poor with a median survival of 4–6 months. Hepatic AL amyloid can present indolently with hepatomegaly or deranged liver function tests or occasionally with liver failure or hepatic rupture, and is usually associated with presence of extensive extrahepatic deposits. Hyperbilirubinemia in the context of hepatic AL amyloid confers a particularly poor prognosis of <4 months.
In the absence of available treatment to disperse existing amyloid deposits, therapy of AL amyloidosis revolves around attempting to reduce the abundance of amyloidogenic monoclonal serum free light chains with myeloma-type chemotherapy to slow or halt ongoing amyloid deposition. Despite considerable advances in chemotherapy in recent years leading to improved median survival times, a significant proportion of patients have advanced, unsalvageable organ dysfunction by the time they are diagnosed with systemic AL amyloidosis, and the majority of patients continue to die from their disease. Furthermore, patients with advanced cardiac and hepatic involvement are usually too unwell at presentation to tolerate the doses of chemotherapy that are required to successfully suppress their underlying clonal disease.
The role of solid organ transplantation in AL amyloidosis is contentious due to shortage of donor organs. Previous small series have shown inferior outcomes with heart and kidney transplantation among patients with AL amyloidosis compared to those with other causes of cardiac and renal failure, respectively. Deaths have been associated with both recurrence of amyloid in the graft or progressive deposition of amyloid in nontransplanted organs. We present here the clinical management and outcome in 45 patients with AL amyloidosis attending a single national center over a 25-year period who were selected to receive solid organ transplants, and highlight in particular, the disease- and treatment-related factors that are likely to influence outcome with solid organ transplantation during the modern era of effective chemotherapy.
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