Familial Renal Amyloidosis Treatment & Management

  • Author: Helen J Lachmann, MB, MA, MD, MRCP; Chief Editor: Vecihi Batuman, MD, FACP, FASN   more...
 
Updated: Jan 12, 2012
 

Medical Care

  • Organs that are extensively infiltrated by amyloid may fail precipitously, with little or no warning and seemingly without provocation, even when results from routine tests of organ function have previously been entirely normal.
  • Scrupulous attention must be paid to blood pressure control, salt and water balance, maintenance of the circulating volume, and prompt treatment of sepsis to reduce the risk of acute organ failure. Elective surgery and general anesthesia are best avoided in patients with systemic amyloidosis, unless compelling indications are present.[6]
  • Inexorably progressive organ failure is inevitable, particularly in the case of amyloidotic kidneys, once a certain level of organ dysfunction has occurred. Managing this with hemodialysis or peritoneal dialysis is feasible until a transplant becomes available.
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Surgical Care

  • Transplantation
    • Solid organ transplantation has been used in patients with FRA, chiefly to replace failing renal function, although liver and heart transplants have also been performed.[4]
    • Limited worldwide experience suggests that the vast majority of patients with hereditary renal amyloidosis fare remarkably well with transplantation, and despite continued production of the variant amyloidogenic protein, amyloid deposition within renal grafts is usually slow.
  • Kidney transplantation
    • This offers most patients with FRA a much improved quality of life and prolonged survival.
    • Some patients with variant apolipoprotein AI amyloidosis have had renal grafts for longer than 20 years without any reduction in graft function.
    • Isolated renal transplantation alone has been performed for end-stage renal failure in several patients with fibrinogen alpha-chain amyloidosis and probably remains the treatment of choice in older patients with significant co-morbidity. However, clinically significant renal graft amyloid accumulation occurs within a decade in patients with the most common fibrinogen A alpha-chain variant, Glu526Val, and younger patients benefit from combined liver and renal transplantation.
    • Few examples have been reported, but renal transplantation may be justified in patients with lysozyme amyloidosis because of its exceptionally slow course and the relative lack of clinical involvement of other organs in patients with this type of FRA.
  • Liver transplantation
    • This has occasionally been performed for liver failure or acute liver rupture in patients with extensive hepatic amyloidosis. However, clinically significant hepatic amyloidosis is always associated with substantial amyloid deposition in other systems, and transplantation for liver failure, therefore, is palliative unless the production of the respective amyloid fibril precursor protein is reduced.
    • Orthotopic liver transplantation has been used widely and successfully as a form of surgical gene therapy in patients with transthyretin-related familial amyloid polyneuropathy (FAP)[7, 8] because the variant amyloidogenic protein is produced mainly in the liver.
    • Successful liver transplantation has now been reported in hundreds of patients with FAP, and, although the peripheral neuropathy usually only stabilizes, autonomic function can improve substantially and the associated visceral amyloid deposits have been shown to regress in many cases.
    • Fibrinogen is synthesized solely by the liver, and orthotopic hepatic transplantation, therefore, is potentially curative in patients with fibrinogen A alpha-chain amyloidosis. Simultaneous renal transplantation is usually required.
    • Approximately half of the apolipoprotein AI in the circulation is synthesized in the liver, but among the few patients with hereditary apolipoprotein AI amyloidosis who have undergone liver transplantation, it appears that a reduction in the plasma concentration of variant apolipoprotein AI of 50% is sufficient to facilitate overall regression of systemic amyloid deposits.
    • Lysozyme is a ubiquitous protein that is produced diffusely within the body, and this type of amyloidosis cannot be ameliorated by liver transplantation.
  • Heart transplantation: Two patients with apolipoprotein AI amyloidosis have had successful cardiac transplants.
    • One had cardiac amyloidosis associated with apolipoprotein AI Leu174Ser.
    • The other presented with severe renal and cardiac involvement resulting from apolipoprotein AI Leu60Arg. This patient was aged 35 years and had a combined cardiac and renal transplant. Ten years later, she had normal functional status with no evidence of amyloid deposition in her grafts.
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Consultations

  • If significant extrarenal disease is present, advice should be sought from a gastroenterologist and hepatologist.
  • In the very few patients with cardiac or neurological involvement, the relevant specialists should be consulted.
  • Clinical geneticists can provide counseling and advice to family members undergoing screening.
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Contributor Information and Disclosures
Author

Helen J Lachmann, MB, MA, MD, MRCP  Senior Lecturer, Department of Medicine, National Amyloidosis Centre, Royal Free and University College Medical School, UK

Helen J Lachmann, MB, MA, MD, MRCP is a member of the following medical societies: Royal College of Physicians

Disclosure: Nothing to disclose.

Coauthor(s)

Philip N Hawkins, MBBS, PhD, FRCP  Clinical Director of National Amyloidosis Centre, Professor, Department of Medicine, Royal Free and University College Medical School

Disclosure: Nothing to disclose.

Specialty Editor Board

Donald A Feinfeld, MD, FACP, FASN  Consulting Staff, Division of Nephrology & Hypertension, Beth Israel Medical Center

Donald A Feinfeld, MD, FACP, FASN is a member of the following medical societies: American Academy of Clinical Toxicology, American Society of Hypertension, American Society of Nephrology, and National Kidney Foundation

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

George R Aronoff, MD  Director, Professor, Departments of Internal Medicine and Pharmacology, Section of Nephrology, Kidney Disease Program, University of Louisville School of Medicine

George R Aronoff, MD is a member of the following medical societies: American Federation for Medical Research, American Society of Nephrology, Kentucky Medical Association, and National Kidney Foundation

Disclosure: Nothing to disclose.

Rebecca J Schmidt, DO, FACP, FASN  Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine

Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association

Disclosure: Renal Ventures Ownership interest Other

Chief Editor

Vecihi Batuman, MD, FACP, FASN  Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System

Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, and International Society of Nephrology

Disclosure: Nothing to disclose.

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Proposed mechanism for amyloid fibril formation. The drawing depicts a generic amyloid fibril precursor protein (I) in equilibrium with a partially unfolded, molten, globulelike form of the protein (II) and its completely denatured state (III). Autoaggregation through the beta domains initiates fibril formation (IV), providing a template for ongoing deposition of precursor proteins and for the development of the stable, mainly beta-sheet, core structure of the fibril. The amyloidogenic precursor proteins in patients with familial renal amyloidosis are thought to be less stable than their wild-type counterparts, causing them to populate intermediate, molten, globulelike states more readily.
An extended kindred with hereditary amyloidosis associated with fibrinogen A alpha-chain Glu526Val; disease penetrance is high in this particular family.
Partial DNA sequence of the gene associated with fibrinogen A alpha-chain Glu526Val in a patient with familial renal amyloidosis, and a sequence from a healthy control. The mutation, which alters codon 526 from glutamic acid to valine, is marked with an arrow.
Progression of amyloid deposits in a patient with amyloidosis associated with fibrinogen A alpha-chain Glu526Val. These serial posterior, whole-body, scintigraphic images were obtained following intravenous injection of iodine-123 (123I)–labeled human serum amyloid P component into a 48-year-old man with hereditary amyloidosis associated with fibrinogen A alpha-chain Glu526Val in whom asymptomatic proteinuria had been identified. Both parents were alive and well and older than age 80 years. The scan at diagnosis (left) showed modest abnormal uptake into renal amyloid deposits, which increased at follow-up 3 years later (right). The remainder of the image represents a normal distribution of tracer throughout the blood pool.
Regression of amyloidosis associated with fibrinogen A alpha-chain Glu526Val following hepatorenal transplantation. The pictures are serial anterior, whole-body, scintigraphic images obtained following intravenous injection of iodine-123 (123I)–labeled human serum amyloid P component into a patient with amyloidosis associated with fibrinogen A alpha-chain Glu526Val. Prior to hepatorenal transplantation (left), heavy amyloid deposition was present in an enlarged liver and spleen. No amyloid deposits were identified in a follow-up study obtained 42 months after hepatorenal transplantation (right); only a normal distribution of tracer is present throughout the blood pool.
Regression of amyloidosis associated with apolipoprotein AI Gly26Arg following hepatorenal transplantation. These serial anterior, whole-body, scintigraphic images were obtained following intravenous injection of iodine-123 (123I)–labeled human serum amyloid P component into a patient with hereditary amyloidosis associated with apolipoprotein AI Gly26Arg. Prior to hepatorenal transplantation (left), heavy amyloid deposition was present in the liver, obscuring the kidneys. Two years after combined hepatorenal transplantation (right), a follow-up scan was normal, showing tracer distributed evenly throughout the background blood pool, including the transplanted organs. Splenic amyloid deposits that were evident initially in posterior scans had regressed at follow-up.
Table. Recognized Genotypes and Their Associated Phenotypes in Familial Renal Amyloidosis
Amyloid Fibril Precursor ProteinOrgans/Tissues Predominantly Affected by Amyloid and Common Clinical FeaturesEthnic Origin of Affected Kindreds
Lysozyme Ile56ThrRenal - Proteinuria and renal failure



Skin - Petechial rashes



Liver and spleen - Organomegaly (usually well-preserved function)



2 British families



(possibly related)



Lysozyme Asp67HisRenal - Proteinuria and renal failure



GI tract - Bleeding and perforation



Liver and spleen - Organomegaly and hepatic hemorrhage



Salivary glands – Sicca syndrome



Single British family
Lysozyme Try64ArgRenal - Proteinuria and renal failure



GI tract - Bleeding and perforation



Salivary glands – Sicca syndrome



Single French family
Apolipoprotein AI



wild type



Amyloid deposits in human aortic atherosclerotic plaques20-30% of elderly individuals at autopsy
Apolipoprotein AI



Gly26Arg



Renal - Proteinuria and renal failure



Gastric mucosa - Peptic ulcers



Peripheral nerves - Progressive neuropathy



Liver and spleen - Organomegaly (usually well-preserved function)



Multiple families



(mostly of northern European extraction)



Apolipoprotein AI



Trp50Arg



Renal - Proteinuria and renal failure



Liver and spleen - Organomegaly and liver failure



Single Ashkenazi family
Apolipoprotein AI



Leu60Arg



Renal - Proteinuria and renal failure



Liver and spleen - Organomegaly (usually well-preserved function)



Cardiac (rarely) - Heart failure



British and



Irish kindreds



Apolipoprotein AI



deletion 60-71



insertion 60-61



Liver - Liver failureSingle Spanish family
Apolipoprotein AI



Leu64Pro



Renal - Proteinuria and renal failure



Liver and spleen - Organomegaly



Single Canadian-Italian family
Apolipoprotein AI



deletion 70-72



Renal - Proteinuria and renal failure



Liver and spleen - Organomegaly (usually well-preserved function)



Retina - Central scotoma



Single family of British origin
Apolipoprotein AI



Leu75Pro



Renal - Proteinuria and



renal failure



Liver and spleen - Organomegaly



Italy – Variable penetrance
Apolipoprotein AI



Leu90Pro



Cardiac - Heart failure



Larynx - Dysphonia



Skin – Infiltrated yellowish plaques



Single French family
Apolipoprotein AI



deletion Lys107



Aortic intima - Aggressive early-onset ischemic heart diseaseSingle Swedish patient at autopsy
Apolipoprotein AI



Arg173Pro



Cardiac - Heart failure



Larynx - Dysphonia



Skin - Acanthosis nigricans-like plaques



British and American families
Apolipoprotein AI



Leu174Ser



Cardiac - Heart failureSingle Italian family
Apolipoprotein AI



Ala175Pro



Larynx - Dysphonia



Testicular - Infertility



Single British family
Apolipoprotein AILeu178HisCardiac - Heart failure



Larynx – Dysphonia



Skin - Infiltrated plaques



Peripheral nerves – Neuropathy



Single French family
Apolipoprotein AII



Stop78Gly



Renal - Proteinuria and renal failureAmerican family
Apolipoprotein AIIStop78SerRenal - Proteinuria and renal failureAmerican family
Apolipoprotein AIIStop78ArgRenal - Proteinuria and renal failureRussian family, Spanish family(different nucleotide substitutions in the two kindreds)
Fibrinogen A alpha-chain Arg554LeuRenal - Proteinuria and renal failurePeruvian,



African American and



French families



Fibrinogen A alpha-chain



frame shift at codon 522



Renal - Proteinuria and renal failureSingle French family
Fibrinogen A alpha-chain



frame shift at codon 524



Renal - Proteinuria and renal failureSingle American family
Fibrinogen A alpha-chain Glu526ValRenal - Proteinuria and renal failure



Late-onset liver (rarely) - Organomegaly and liver failure



Multiple families



(northern European extraction,



variable penetrance)



Fibrinogen A alpha-chain Gly540ValRenal - Proteinuria and renal failureSingle German family
Fibrinogen A alpha-chain Indel 517-522Renal - Proteinuria and renal failureSingle Korean child
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