Familial Renal Amyloidosis Clinical Presentation

Updated: Nov 10, 2022
  • Author: Helen J Lachmann, MD, MRCP; Chief Editor: Vecihi Batuman, MD, FASN  more...
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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.