History

Patients with familial renal amyloidosis (FRA) typically present with proteinuria and/or hypertension followed by progressive kidney failure. The latter may evolve extremely slowly, and patients with hereditary apolipoprotein AI and lysozyme amyloidosis may not develop end-stage renal disease (ESRD) for several decades. In contrast to AL amyloidosis, orthostatic hypotension is unusual, probably because autonomic involvement and amyloid cardiomyopathy are rare in FRA.^{[30, 31]}

Many patients give a clear autosomal dominant family history of kidney disease, but penetrance is variable. Individuals with the most common form of fibrinogen A alpha-chain amyloidosis, associated with the Glu526Val variant, frequently (or perhaps even typically) are not aware of any such disease in their family. Patients with FRA who do not give a family history are readily misdiagnosed as having acquired AL amyloidosis.

With variant lysozyme amyloidosis, presentation may involve the following:

This type of FRA usually results in substantial gastrointestinal (GI)( amyloid deposits that may cause poor gastric emptying, but these patients often remain asymptomatic until an acute crisis occurs
The upper GI tract is perforated easily and has a tendency to bleed profusely should gastric erosions or peptic ulceration occur
At presentation, most patients with this type of FRA have substantial amounts of amyloid in the kidneys, spleen, and liver, but the course of the disease tends to be remarkably slow.
Even in the presence of massive hepatosplenomegaly, liver failure rarely occurs; however, spontaneous hepatic rupture has been reported in several cases.
Cardiac amyloid and neuropathy are not features of lysozyme amyloidosis, but petechial rashes starting in childhood are associated with the lysozyme Ile56Thr variant.

The features of hereditary apolipoprotein AI amyloidosis vary significantly with different mutations, as follows:

Patients with the most common amyloidogenic Gly26Arg variant usually present with hypertension and proteinuria and develop progressive kidney disease.
Many mutations are associated with extensive but clinically silent amyloid deposits in the liver and spleen.
Amyloid cardiomyopathy, gut involvement, and skin and laryngeal deposits occur occasionally, and a few patients with variant apolipoprotein AI Glu26Arg and Leu178His develop a progressive neuropathy resembling familial amyloid polyneuropathy, a disease that is usually associated with transthyretin mutations.

Hereditary apolipoprotein AII amyloidosis appears to predominantly cause kidney disease. Progression to ESRD occurs, and at least two patients have kidney transplants that have functioned for more than a decade. There is one report of a patient with long-standing kidney failure who subsequently developed evidence of amyloid cardiomyopathy.^[32]

Most patients diagnosed with fibrinogen A alpha-chain Glu526Val amyloidosis present in late middle age with proteinuria or hypertension and progress to ESRD during the following 5-10 years. Amyloid deposition occurs predominantly in the kidneys and also variably in the spleen, liver, and adrenal glands.^[33]Clinically significant neuropathy or cardiac amyloid deposition does not seem to occur in patients with the Glu526Val variant, and liver failure is very rare.

The other three mutations that cause fibrinogen A alpha-chain amyloidosis have been identified in too few families to make generalizations, other than that these mutations are predominantly associated with kidney disease.

Physical Examination

Clinical features and their association with particular mutations are described in Pathophysiology. Physical examination findings include the following:

Hypertension and edema occur in most patients diagnosed with FRA.
Hepatosplenomegaly is quite common and is probably most common in patients with the apolipoprotein AI type.
Heart failure resulting from restrictive amyloid cardiomyopathy occurs in some patients with variant apolipoprotein AI Leu60Arg and is the predominant feature in patients with the variants Arg173Pro and Leu174Ser.
A symmetrical sensorimotor polyneuropathy occurs in some patients with the apolipoprotein AI Gly26Arg and Leu178His variants.
Laryngeal and cutaneous deposits producing hoarseness, infiltrative plaques, and petechial rashes are associated with the apolipoprotein AI Arg173Pro, Ala175Pro, Leu90Pro, and Leu178His variants, and petechial rashes also occur in patients with lysozyme Ile56Thr.

Differential Diagnoses

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Media Gallery

Familial renal amyloidosis. Proposed mechanism for amyloid fibril formation. The drawing depicts a generic amyloid fibril precursor protein (1) in equilibrium with a partially unfolded, molten, globulelike form of the protein (2) and its completely denatured state (3). Autoaggregation through the beta domains initiates fibril formation (4), providing a template for ongoing deposition of precursor proteins and for the development of the stable, mainly beta-sheet, core structure of the fibril (5). 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.
Familial renal amyloidosis. An extended kindred with hereditary amyloidosis associated with fibrinogen A alpha-chain Glu526Val; disease penetrance is high in this particular family.
Familial renal amyloidosis. 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.
Familial renal amyloidosis. 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.
Familial renal amyloidosis. 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.
Familial renal amyloidosis. 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.

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Table. Recognized Genotypes and Their Associated Phenotypes in Familial Renal Amyloidosis

Table. Recognized Genotypes and Their Associated Phenotypes in Familial Renal Amyloidosis

Amyloid Fibril Precursor Protein	Organs/Tissues Predominantly Affected by Amyloid and Common Clinical Features	Ethnic Origin of Affected Kindreds
Lysozyme Ile56Thr	Renal - Proteinuria and kidney failure Skin - Petechial rashes Liver and spleen - Organomegaly (usually well-preserved function)	2 British families (possibly related)
Lysozyme Asp67His	Renal - Proteinuria and kidney failure GI tract - Bleeding and perforation Liver and spleen - Organomegaly and hepatic hemorrhage Salivary glands – Sicca syndrome	Single British family
Lysozyme Try64Arg	Renal - Proteinuria and kidney failure GI tract - Bleeding and perforation Salivary glands – Sicca syndrome	Single French family
Lysozyme Trp82Arg	Renal - Proteinuria and kidney failure	Single Chinese family
Apolipoprotein AI wild type	Amyloid deposits in aortic atherosclerotic plaques	20-30% of elderly individuals at autopsy
Apolipoprotein AI Gly26Arg	Renal - Proteinuria and kidney 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 kidney failure Liver and spleen - Organomegaly and liver failure	Single Ashkenazi family
Apolipoprotein AI Leu60Arg	Renal - Proteinuria and kidney 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 failure	Single Spanish family
Apolipoprotein AI Leu64Pro	Renal - Proteinuria and kidney failure Liver and spleen - Organomegaly	Single Canadian-Italian family
Apolipoprotein AI deletion 70-72	Renal - Proteinuria and kidney failure Liver and spleen - Organomegaly (usually well-preserved function) Retina - Central scotoma	Single family of British origin
Apolipoprotein AI Leu75Pro	Renal - Proteinuria and kidney 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 disease	Single 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 failure	Single Italian family
Apolipoprotein AI Ala175Pro	Larynx - Dysphonia Testicular - Infertility	Single British family
Apolipoprotein AILeu178His	Cardiac - Heart failure Larynx – Dysphonia Skin - Infiltrated plaques Peripheral nerves – Neuropathy	Single French family
Apolipoprotein AII Stop78Gly	Renal - Proteinuria and kidney failure	American family
Apolipoprotein AIIStop78Ser	Renal - Proteinuria and kidney failure	American family
Apolipoprotein AIIStop78Arg	Renal - Proteinuria and kidney failure	Russian family, Spanish family (different nucleotide substitutions in the two kindreds)
Fibrinogen A alpha-chain Arg554Leu	Renal - Proteinuria and kidney failure	Peruvian, African American and French families
Fibrinogen A alpha-chain frame shift at codon 522	Renal - Proteinuria and kidney failure	Single French family
Fibrinogen A alpha-chain frame shift at codon 524	Renal - Proteinuria and kidney failure	Single American family
Fibrinogen A alpha-chain Glu526Val	Renal - Proteinuria and kidney failure Late-onset liver (rarely) - Organomegaly and liver failure	Multiple families (northern European extraction, variable penetrance)
Fibrinogen A alpha-chain Gly540Val	Renal - Proteinuria and kidney failure	Single German family
Fibrinogen A alpha-chain Indel 517-522	Renal - Proteinuria and kidney failure	Single Korean child

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Familial Renal Amyloidosis Clinical Presentation

History

Physical Examination

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