Familial Renal Amyloidosis 

Updated: Nov 21, 2018
Author: Helen J Lachmann, MD, MRCP; Chief Editor: Vecihi Batuman, MD, FASN 

Overview

Background

Amyloidosis is a disorder of protein folding in which normally soluble proteins undergo a conformational change and are deposited in the extracellular space in an abnormal fibrillar form.[1] Accumulation of these fibrils causes progressive disruption of the structure and function of tissues and organs, and the systemic (generalized) forms of amyloidosis are frequently fatal. The conditions that underlie amyloid deposition may be either acquired or hereditary, and at least 20 different proteins can form amyloid fibrils in vivo. See the image below.

Proposed mechanism for amyloid fibril formation. T 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.

Renal dysfunction is one of the most common presenting features of patients with systemic amyloidosis, and amyloid accumulation is the major pathological finding in approximately 2.5% of all native renal biopsies. Most such patients have either reactive systemic (AA) amyloidosis or monoclonal immunoglobulin light-chain (AL) amyloidosis, but in the few remaining cases, the disease is hereditary.

The syndrome of familial systemic amyloidosis with predominant nephropathy is inherited in an autosomal dominant manner and was first described in a German family by Ostertag in 1932.[2] Research has shown that almost all patients with familial renal amyloidoses (FRA) are heterozygous for mutations in the genes for lysozyme, apolipoprotein AI, apolipoprotein AII, or fibrinogen A alpha-chain and that the amyloid fibrils in this condition are derived from the respective variant proteins. Both penetrance and the clinical phenotype can vary substantially among different families with the same mutation, and even within individual kindreds.

Pathophysiology

The pathogenesis of amyloid centers around off-pathway folding of the various amyloid fibril precursor proteins. These proteins can exist as two radically different stable structures: the normal soluble form and a highly abnormal fibrillar conformation.

All amyloid fibrils share a common core structure in which the subunit proteins are arranged in a stack of twisted, antiparallel, beta-pleated sheets lying with their long axes perpendicular to the fibril long axis. Proteins that can form amyloid transiently populate partly unfolded intermediate molecular states that expose the beta-sheet domain, enabling them to interact with similar molecules in a highly ordered fashion.

Propagation of the resulting low molecular weight aggregates into mature amyloid fibrils is probably a self-perpetuating process that depends only on a sustained supply of the fibril precursor protein. In some cases, the precursors undergo partial proteolytic cleavage; however, whether this occurs before, during, or after the formation of amyloid fibrils remains unknown.

Studies on hereditary amyloidosis have provided unique and valuable insights into the general pathogenesis of amyloid. Most of the variant proteins associated with hereditary amyloidosis differ from their wild-type counterparts by just a single amino acid substitution, although deletions and insertions also occur (see the Table).

 

Table. Recognized Genotypes and Their Associated Phenotypes in Familial Renal Amyloidosis (Open Table in a new window)

Amyloid Fibril Precursor Protein

Organs/Tissues Predominantly Affected by Amyloid and Common Clinical Features

Ethnic Origin of Affected Kindreds

Lysozyme Ile56Thr

Renal - Proteinuria and renal failure

Skin - Petechial rashes

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

2 British families

(possibly related)

Lysozyme Asp67His

Renal - Proteinuria and renal 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 renal failure

GI tract - Bleeding and perforation

Salivary glands – Sicca syndrome

Single French family

Apolipoprotein AI

wild type

Amyloid deposits in human aortic atherosclerotic plaques

20-30% 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 failure

Single 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 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 renal failure

American family

Apolipoprotein AIIStop78Ser

Renal - Proteinuria and renal failure

American family

Apolipoprotein AIIStop78Arg

Renal - Proteinuria and renal failure

Russian family, Spanish family(different nucleotide substitutions in the two kindreds)

Fibrinogen A alpha-chain Arg554Leu

Renal - Proteinuria and renal failure

Peruvian,

African American and

French families

Fibrinogen A alpha-chain

frame shift at codon 522

Renal - Proteinuria and renal failure

Single French family

Fibrinogen A alpha-chain

frame shift at codon 524

Renal - Proteinuria and renal failure

Single American family

Fibrinogen A alpha-chain Glu526Val

Renal - Proteinuria and renal failure

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

Multiple families

(northern European extraction,

variable penetrance)

Fibrinogen A alpha-chain Gly540Val

Renal - Proteinuria and renal failure

Single German family

Fibrinogen A alpha-chain Indel 517-522

Renal - Proteinuria and renal failure

Single Korean child

Investigation of the variant amyloidogenic forms of lysozyme has been exceptionally informative because wild-type lysozyme is not associated with amyloidosis and has been thoroughly characterized. The amyloidogenic mutations give rise to amino acid substitutions that subtly destabilize the native fold so that, under physiological conditions, these variants readily visit partly unfolded states, promoting their spontaneous aggregation into amyloid fibrils.

The whole process of lysozyme amyloid fibril formation can be reversed. A soluble functional variant lysozyme has been recovered in vitro from preparations of isolated ex vivo amyloid fibrils that had been denatured and permitted to refold in the normal conformation. Wild-type apolipoprotein AI is inherently moderately amyloidogenic, and small amyloid deposits derived from it occur in aortic atherosclerotic plaques in 20-30% of middle-aged and elderly individuals.

Amyloid deposits in all different forms of the disease, both in humans and in nonhuman animals, contain the nonfibrillar glycoprotein amyloid P component (AP). AP is identical to and derived from the normal circulating plasma protein, serum amyloid P component (SAP), a member of the pentraxin protein family that includes C-reactive protein.

SAP consists of five identical subunits, each with a molecular mass of 25.462 d, which are noncovalently associated in a pentameric disklike ring. The SAP molecule is highly resistant to proteolysis, and, although not itself a proteinase inhibitor, its reversible binding to amyloid fibrils in vitro protects them against proteolysis. In contrast to its normal rapid clearance from the plasma, SAP persists for very prolonged periods within amyloid deposits. The possibility that SAP may contribute to the pathogenesis and/or persistence of amyloid deposits in vivo has been confirmed in studies on SAP knockout mice.[3]

Amyloid deposits accumulate in the extracellular space, progressively disrupting the normal tissue architecture and consequently impairing organ function. Amyloid deposits can also produce space-occupying effects at both microscopic and macroscopic levels. Although amyloid is inert in the sense that it does not stimulate either a local or systemic inflammatory response, some evidence suggests that the deposits exert cytotoxic effects and possibly promote apoptosis.

Strong clinical impressions exist that suggest the rate of accumulation of amyloid has a major bearing on organ function, which can be preserved for very long periods in the presence of an extensive but stable amyloid load. This may reflect adaptation to gradual amyloid accumulation or may relate to toxic properties of newly formed amyloid material.

Prospective studies with serial SAP scintigraphy, a specific and semiquantitative nuclear medicine technique for imaging amyloid deposits, have confirmed that amyloid deposits are turned over constantly, albeit at a relatively low and variable rate. Therefore, the course of a particular patient's amyloid disease depends on the relative rates of amyloid deposition versus turnover. Amyloid deposits often regress when the supply of the respective fibril precursor protein is reduced, and, under favorable circumstances, this is accompanied by stabilization or recovery of organ function.

Many questions about amyloid deposition remain unanswered. Why only a small number of unrelated proteins form amyloid in vivo remains unclear, and, as yet, little is known about the genetic or environmental factors that determine individual susceptibility to amyloid or factors that govern its anatomical distribution and clinical effects. Hereditary amyloid deposition starts in the first or second decade in some patients, but possibly not until much later in life in other patients. In addition, the mechanism by which amyloid deposits are cleared and why the rate of this varies so substantially among patients are not understood.

Epidemiology

Frequency

No systematic data address the frequency of FRA, but the condition is not as rare as previously thought. The lack of awareness of the condition and the frequent absence of a family history (owing to its variable penetrance) have contributed to substantial underdiagnosis. The incidence of amyloidosis has been estimated at 5 to 13 cases per million population per year; prevalence data are scarce, but one United Kingdom study suggested a rate of about 20 per million inhabitants.[4]

Since the authors introduced routine DNA screening into their investigations of patients with systemic amyloidosis at their facility in the United Kingdom, approximately 5% of patients with presumed AL primary amyloidosis have been diagnosed with hereditary lysozyme, apolipoprotein AI, or fibrinogen A alpha-chain amyloid. The amyloidosis is associated with the fibrinogen A alpha-chain variant Glu526Val in more than 80% of these patients.[5]

Mortality/Morbidity

The natural history of familial renal amyloidosis is a relentless gradual progression, leading to renal and sometimes other organ failure and, eventually, death. Amyloid deposits can ultimately affect many organ systems, but they may be widespread and very extensive without causing symptoms.

The rate of progression and course of disease are extremely variable. Some patients with clinically overt involvement of multiple organs survive for many years or decades. Overall, the prognosis of patients with FRA is much better than that of those with acquired AA and AL amyloidosis.

Histological localization of amyloid deposits determines overall survival in patients with renal amyloidosis. In a study of 35 patients, the glomerulus was the most common and most severely affected renal compartment. Compared with patients without glomerular amyloid deposits, those with severe glomerular amyloidosis advanced more quickly towards end-stage renal disease and premature death.[6]

Race-, Sex-, and Age-related Demographics

Most patients are of northern European Caucasian ancestry, but fibrinogen A alpha-chain amyloidosis has been reported in Peruvian-Mexican, Korean, and African American families, and the authors are presently investigating a northern Indian family with uncharacterized FRA.

Gene carriage and the incidence of clinical disease are equal between men and women.

FRA may manifest any time from the first decade to old age but most typically in mid adult life. The age at presentation, like other clinical features, varies among mutations and even within individual kindreds.

 

Presentation

History

Patients with familial renal amyloidosis (FRA) typically present with proteinuria and/or hypertension followed by progressive renal failure. The latter may evolve extremely slowly, and patients with hereditary apolipoprotein AI and lysozyme amyloidosis may not develop end-stage renal failure for several decades. In contrast to AL amyloidosis, orthostatic hypotension is unusual, probably because autonomic involvement and amyloid cardiomyopathy are rare in FRA.[7, 8]

Many patients give a clear autosomal dominant family history of renal 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 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 renal impairment

  • 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 renal disease. Progression to end-stage renal failure occurs, and at least two patients have renal grafts that have functioned for more than a decade. There is one report of a patient with long-standing renal failure who subsequently developed evidence of amyloid cardiomyopathy.

Most patients diagnosed with fibrinogen A alpha-chain Glu526Val amyloidosis present in late middle age with proteinuria or hypertension and progress to end-stage renal failure during the following 5-10 years. Amyloid deposition occurs predominantly in the kidneys and also variably in the spleen, liver, and adrenal glands.[9] 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 renal disease.

Physical

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.

Causes

Susceptibility to FRA is inherited in an autosomal dominant manner. In nearly all cases, the disease results from mutations in the genes encoding the following four plasma proteins:

  • Lysozyme
  • Apolipoprotein AI
  • Apolipoprotein AII
  • Fibrinogen A alpha-chain

In a small number of families, the cause has not yet been determined.

Lysozyme

Lysozyme is a ubiquitous bacteriolytic enzyme present in both external secretions and in leukocytes. Lysozyme mutations were identified as a cause of familial amyloidosis when, in 1993, amyloid fibrils in two British families were demonstrated to be derived from the lysozyme variants Asp67His and Ile56Thr, respectively. These represent the least common causes of FRA. The authors have identified a polymorphism encoding lysozyme Thr70Asn, which has an allele frequency of 5% in the British population and which has not been shown to be associated with amyloid deposition.

Apolipoprotein AI

Apolipoprotein AI is a major constituent of high-density lipoprotein (HDL) particles and participates in their central function of reverse cholesterol transport from the periphery to the liver. Approximately half of apolipoprotein AI is synthesized in the liver and half in the small intestine.

Variant forms of apolipoprotein AI are extremely rare in the general population and may be phenotypically silent or may affect lipid metabolism. In 1990, apolipoprotein AI Gly26Arg was identified as a cause of FRA. Since then, 12 other amyloidogenic apolipoprotein AI variants have been discovered. These are mostly other single amino acid substitutions but include deletions and deletion/insertions, not all of which are associated with clinical renal disease (see Pathophysiology). The amyloid fibril subunit protein has comprised the first 90 or so N-terminal residues of apolipoprotein AI in all cases that have been studied, even when the variant residue(s) has been more distal.

In contrast to lysozyme and fibrinogen A alpha-chain types, wild-type apolipoprotein AI is itself weakly amyloidogenic, and the various amyloidogenic variants are likely to render apolipoprotein AI less stable and/or more susceptible to enzymatic cleavage, promoting an abundance of a fibrillogenic N-terminal fragments.

Another potential mechanism could be reduced lipid binding, thereby increasing the amount of free (and therefore relatively less stable) apolipoprotein AI in the plasma.

Apolipoprotein AII

Apolipoprotein AII is the second major constituent of human HDL particles, accounting for approximately 20% of HDL protein. Like apolipoprotein AI, apolipoprotein AII is synthesized predominantly by the liver and the intestines.

In 2001, apolipoprotein AII stop78Gly was isolated from the amyloid fibrils of a patient who died of renal failure. Since then, an additional three mutations (encoding two protein variants) have been described in association with hereditary renal amyloidosis (see Pathophysiology).

Unlike serum amyloid A protein (another apolipoprotein and the amyloid precursor in AA amyloidosis) or apolipoprotein AI, in apolipoprotein AII amyloidosis, the protein fibrils are not derived from a cleavage fragment of the native precursor but instead consist of the whole protein plus a 21 amino acid extension.

Fibrinogen

Fibrinogen is a multimeric 340-kd circulating glycoprotein composed of six peptide chains (two each of alpha, beta, and gamma types), all of which are synthesized in the liver. The alpha chains are the largest and are involved in cross-linking fibrin strands. Numerous alpha-chain variants have been recognized that are either silent or are associated with abnormal hemostasis.

Variant fibrinogen A alpha-chain Arg554Leu was first identified as an amyloid fibril protein in 1993. Since then, five other amyloidogenic mutations have been discovered (see the Table). All of these mutations are clustered within the carboxyl terminus of the gene in a relatively small portion of exon 5.

Two of these mutations result in frame shifts that terminate the protein prematurely at codon 548; one is a single nucleotide deletion in the third base of codon 524 and the other is a deletion at codon 522. A single-base transversion, resulting in the substitution of leucine for arginine at codon 554, has been reported in three families of Peruvian-Mexican, African American, and French Caucasian ethnic backgrounds. Residue 554 may be a mutational hot spot because other (nonamyloidogenic) mutations have also been identified at this position.

By far, the most common amyloidogenic variant is fibrinogen A alpha-chain Glu526Val, which has been found in numerous families of Irish, English, German, and Polish origin with FRA.

Genetic information is depicted in the images below.

An extended kindred with hereditary amyloidosis as 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 f 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.
 

DDx

 

Workup

Laboratory Studies

No blood or urine test result is diagnostic of amyloidosis, but lab findings that exclude chronic inflammation or a monoclonal gammopathy in a patient with renal amyloid accumulation support the possibility of FRA. Lab tests also have a vital role in evaluating and monitoring amyloidotic organ function.

Protein-to-creatinine (Pr/Cr) ratio in random urine samples was strongly correlated with  24 hour urine protein excretion in a study of 44 patients with amyloidosis, and may be useful for screening for renal involvement. The optimal cut-off point of the Pr/Cr ratio for predicting renal involvement was 715 mg/g, with a sensitivity and specificity of 91.8% and 95.5%, respectively.[10]

Once the creatinine clearance has fallen to less than 20%, progression to end-stage renal failure is almost inevitable, although the rate of decline often does not accord with predictions and may be remarkably slow. On the other hand, step-wise deteriorations in renal function occur quite frequently, even in the absence of any identifiable intercurrent renal insult such as dehydration, infection, or venous thrombosis.

Liver function test results tend to remain normal until the liver has been extensively infiltrated by amyloid, and even marked hepatomegaly may be accompanied by only a modest elevation in serum alkaline phosphatase. Liver function in those with FRA is often well preserved for decades, and elevations of serum bilirubin and transaminase levels occur at a very late stage. A bilirubin value of just twice the upper limit of normal is associated with a very poor prognosis and incipient liver failure.

Hematological indices and coagulation tend to be unremarkable, although a hyposplenic picture can occur. Occult GI blood loss should be considered in patients with anemia that is not secondary to renal impairment.

Imaging Studies

Anatomical imaging modalities (eg, plain radiography, computed tomography [CT] scan, magnetic resonance imaging [MRI], ultrasonography) typically yield nonspecific findings in patients with systemic amyloidosis.[11] However, a study by Barreiros et al suggests that ultrasonography can reveal signs of amyloidosis in various organs.[12] In an examination of 30 patients with systemic amyloidosis, including 19 suffering from familial amyloid polyneuropathy, the investigators found the following ultrasonographic indications of amyloidosis:

  • Heart - Myocardial thickness, pericardial and pleural effusion, and typical echorich subendocardial depositions

  • Liver and spleen - Spontaneous subcapsular hemorrhages

  • Intestine - Inhomogeneous, patchy-like depositions

  • Kidney - Somewhat unspecific results in this organ

  • Amyloidotic organs may be enlarged in the late stage of the disease, but kidney size varies and may be normal or even small at presentation.

  • Amyloid deposits are rich in calcium, and areas of calcification may develop.

Scintigraphy

Radionuclide tracers used for bone scintigraphy occasionally localize in amyloidotic organs.

Serum amyloid P (SAP) component scintigraphy was introduced in 1987 and is a sensitive, specific, and noninvasive method of quantitatively imaging amyloid deposits in vivo.[13] All amyloid fibrils bind the normal plasma protein SAP by virtue of a specific calcium-dependent ligand-protein interaction. In patients with amyloidosis, iodine I123 –labeled SAP localizes rapidly and specifically to the amyloid deposits.[3] The technique has a high diagnostic sensitivity and is the only method available for serial monitoring of the progression or regression of amyloid throughout the body.

SAP scintigraphy is eminently suitable as a screening test in patients thought to be at risk for systemic amyloid deposition, including those with known amyloidogenic mutations. However, the technique is not yet available commercially.

Serial SAP scans have shown that accumulation of amyloid tends to be much slower in patients with FRA than in those with acquired AA and AL types, and progression may not be evident, even over the course of a decade. In all types of acquired and hereditary amyloidosis that have been studied, SAP scans have also shown that amyloid deposits are often cleared gradually when the supply of amyloid fibril precursor proteins can be reduced.[14]

Scintigraphic image findings are depicted below.

Progression of amyloid deposits in a patient with 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 fibrinog 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 apolipop 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.

Echocardiography

Amyloid causes diastolic dysfunction with well-preserved contractility until a very late stage. Significant cardiac amyloid deposition is relatively unusual in patients with FRA, especially in patients with lysozyme and fibrinogen types. When it is present, however, it confers a poor prognosis.

Cardiac amyloidosis is best evaluated by a combination of echocardiography, electrocardiography (ECG), and measurement of the N-terminal of the prohormone brain natriuretic peptide (NT-pro BNP).The classic findings with 2-dimensional Doppler echocardiography are as follows:

  • Concentric biventricular wall thickening
  • Increased myocardial echodensity
  • Thickened but pliable valves
  • A restrictive filling pattern

ECG findings may be normal in patients with substantial cardiac amyloidosis, but reduced voltages, pathological Q waves (ie, pseudoinfarct pattern) in the anterior chest leads, and conduction abnormalities usually signify advanced disease.

Other Tests

DNA analysis

DNA analysis is mandatory in all patients with systemic amyloidosis who cannot be confirmed absolutely to have the AA or AL type. Appreciating that the presence of a chronic inflammatory disease or a monoclonal gammopathy may be incidental is important.

Numerous mutations have been identified in most of the genes associated with hereditary amyloidosis, and new variants are being found regularly. Therefore, performing gene sequencing is better than using methods such as restriction fragment length polymorphism analysis, which is directed at particular known mutations.

The results of DNA analysis are not, by themselves, definitive proof of the presence of amyloid or the amyloid fibril type. These findings must be interpreted in light of other clinical and histologic findings.

Fibril protein sequencing

In cases in which identifying the amyloid fibril type by more conventional means is not possible, isolation of amyloid fibrils from a sample of fresh amyloidotic tissue enables amino acid sequencing of the fibril subunit peptide. This requires technical expertise and is time consuming but can be achieved using very small tissue samples. It is the most definitive method for typing amyloid deposits.

Procedures

The definitive diagnosis of amyloid accumulation requires histologic confirmation; however, biopsy procedures carry an increased risk of hemorrhage in patients with amyloidosis, and bleeding may be substantial and even life-threatening in 5% of patients who undergo biopsies. This is due to the increased fragility of amyloidotic blood vessels and the reduced elasticity of severely affected organs.

Less-invasive alternatives include fine-needle aspiration of subcutaneous fat and rectal or labial salivary gland biopsy. In experienced hands, these screening biopsies can yield positive results in as many as 80% of cases; however, in routine practice, sensitivity is only approximately 50%. Also, fat aspirates are usually not suitable for immunohistochemical typing.

Histologic Findings

Many cotton dyes, fluorescent stains such as thioflavine-T, and metachromatic stains have been used, but Congo red staining and its resultant green birefringence when viewed with high-intensity cross-polarized light has the best specificity and is the criterion standard histochemical test for amyloidosis. The stain is unstable and must be freshly prepared at least every 2 months. A section thickness of 5-10 µm and inclusion in every staining run of a positive-control tissue containing modest amounts of amyloid are critical to ensure specificity and quality control.[15]

Other problems in histologically based diagnoses include obtaining adequate tissue samples and an unavoidable element of sampling error. Biopsies cannot reveal the extent or distribution of amyloid accumulation, and failure to demonstrate amyloid in one or even several biopsies does not exclude the diagnosis.

Although many amyloid fibril proteins can be identified immunohistochemically, the demonstration of potentially amyloidogenic proteins in tissues does not, on its own, establish the presence of amyloid. Congo red staining and green birefringence are always required, and immunostaining may then enable the amyloid to be classified. Antibodies to serum amyloid A protein are commercially available and always stain AA deposits. However, in patients with AL amyloid, the deposits are stainable with standard antisera to kappa or lambda only in approximately half of all cases. This is probably because the light-chain fragment in the fibrils is usually the N-terminal variable domain, which is largely unique for each monoclonal protein.

Immunohistochemistry produces variable results in patients with FRA; the staining is typically weak in patients with fibrinogen A alpha-chain amyloid but is more reliable in patients with lysozyme and apolipoprotein AI types. Including positive tissue and absorption controls in each run is vital for optimal interpretation of the results.

The appearance of amyloid fibrils in tissues under the electron microscope is not always completely specific, and, sometimes, they cannot be identified convincingly. Although electron microscopy should be more sensitive than light microscopy, it is not sufficient by itself to confirm the diagnosis of amyloidosis.

A recent advance in diagnostic techniques is the use of laser microdissection and mass spectrometry to directly identify the components of the amyloid deposits. A large, single center study has demonstrated that proteomics can be successfully used to type amyloid deposits with more accuracy than conventional immunohistochemistry.[16]

 

Treatment

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. To reduce the risk of acute organ failure, scrupulous attention must be paid to the following:

  • Blood pressure control
  • Salt and water balance
  • Maintenance of circulating volume
  • Prompt treatment of sepsis

Elective surgery and general anesthesia are best avoided in patients with systemic amyloidosis, unless compelling indications are present.

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.

Surgical Care

Solid organ transplantation has been used in patients with FRA. Most have been kidney transplants, although liver and heart transplants have also been performed.[9]

Kidney transplantation

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.[17]

Kidney transplantation 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

Liver transplantation has occasionally been performed for liver failure or acute liver rupture in patients with extensive hepatic amyloidosis.[4] However, clinically significant hepatic amyloidosis is always associated with substantial amyloid deposition in other systems, so transplantation for liver failure 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) because the variant amyloidogenic protein is produced mainly in the liver.[18]

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.[19, 20]

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 35 years old 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.

Consultations

See the list below:

  • 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.

 

Medication

Medication Summary

The aims of current medical therapy are to support compromised organ function and to ameliorate symptoms.

Patients are at increased risk of hemorrhage because of increased vascular fragility and/or substantial GI amyloid deposits. Unless overwhelming indications for anticoagulation therapy are present, it is best avoided.

No existing treatment specifically results in mobilization and regression of amyloid deposits, but novel drug compounds that inhibit the formation, persistence, and/or effects of amyloid deposits are presently in development.

Antihypertensive agents

Class Summary

Hypertension is common and can accelerate the decline in renal function. Maintain blood pressure within the lower end of normal range.

Ramipril (Altace)

Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Diuretics

Class Summary

Often help treat symptomatic peripheral edema resulting from nephrotic syndrome.

Furosemide (Lasix)

Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. Dose must be individualized to patient. Depending on response, administer at increments of 20-40 mg, no sooner than 6-8 h after previous dose, until desired diuresis occurs.

Proton pump inhibitors

Class Summary

Acute GI bleeding or perforation is the cause of death in a large proportion of patients with lysozyme amyloidosis, and long-term prophylactic treatment with a proton pump inhibitor is advisable.

Omeprazole (Prilosec)

Decreases gastric acid secretion by inhibiting the parietal cell H+/K+ -ATP pump.

Histamine2-receptor antagonists

Class Summary

Reversible competitive blockers of histamine at the H2 receptors, particularly those in the gastric parietal cells, where they inhibit acid secretion. The H2 antagonists are highly selective, do not affect the H1 receptors, and are not anticholinergic agents.

Ranitidine (Zantac)

Inhibits histamine stimulation of the H2 receptor in gastric parietal cells, which, in turn, reduces gastric acid secretion, gastric volume, and hydrogen concentrations.

Cimetidine (Tagamet)

Inhibits histamine at H2 receptors of gastric parietal cells, which results in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.

Prokinetic agents

Class Summary

Gastric emptying may be delayed, and some patients respond quite well to prokinetic agents or antiemetics.

Metoclopramide (Reglan)

A dopamine antagonist that stimulates gastric emptying and small intestinal transit.

 

Follow-up

Further Outpatient Care

Ensure regular follow-up care with scrupulous attention to control of blood pressure.

Deterrence/Prevention

Genetic screening is possible for family members. Adequate counseling is a necessity because the age of onset and penetrance are highly variable and no specific treatment is available.

Prenatal diagnosis is technically possible but is of uncertain value because many individuals with these particular gene mutations have a normal life expectancy.

Complications

Acute kidney injury and chronic kidney disease can occur in the following forms of familial renal amyloidosis (FRA):

  • FRA due to variant lysozyme

  • FRA due to variant apolipoprotein AI

  • FRA due to variant apolipoprotein AII

  • FRA due to variant fibrinogen A alpha-chain

Acute and chronic liver failure can occur in the following forms of FRA:

  • FRA due to variant apolipoprotein AI
  • Potentially FRA due to variant lysozyme and fibrinogen A alpha-chain (very rarely)

The following complications can occur in these forms of FRA:

  • Restrictive cardiomyopathy - Some apolipoprotein AI and AII variants

  • GI hemorrhage/perforation - Lysozyme FRA

  • Progressive neuropathy - Some patients with apolipoprotein AI Gly26Arg and Leu178His

Prognosis

Many patients with FRA survive until the seventh decade or older, and most patients survive for at least 10 years after diagnosis. Life expectancy has increased substantially since kidney and liver transplantations have been introduced as treatments for these diseases. Liver transplantation is potentially curative in patients with fibrinogen A alpha-chain FRA and, possibly, in some patients with apolipoprotein AI amyloidosis.

Patient Education

Patient education should include the following:

  • Patients should be advised to avoid any potential systemic insults such as dehydration, nephrotoxic drugs, and avoidable general anesthetics or surgery.

  • Patients should not only be aware that first-degree relatives each have a 50% chance of carrying the gene but also that disease penetrance is highly variable.

  • For further information, see Mayo Clinic - Kidney Transplant Information.

 

Questions & Answers

Overview

What is familial renal amyloidosis (FRA)?

What is the pathophysiology of familial renal amyloidosis (FRA)?

What is the prevalence of familial renal amyloidosis (FRA)?

What is the mortality and morbidity associated with familial renal amyloidosis (FRA)?

What are the racial predilections of familial renal amyloidosis (FRA)?

What are the sexual predilections of familial renal amyloidosis (FRA)?

At what age does familial renal amyloidosis (FRA) typically first present?

Presentation

Which clinical history findings are characteristic of familial renal amyloidosis (FRA)?

Which physical findings are characteristic of familial renal amyloidosis (FRA)?

What is the role of fibrinogen in the etiology of familial renal amyloidosis (FRA)?

What causes familial renal amyloidosis (FRA)?

What is the role of lysozyme in the etiology of familial renal amyloidosis (FRA)?

What is the role of apolipoprotein AI in the etiology of familial renal amyloidosis (FRA)?

What is the role of apolipoprotein AII in the etiology of familial renal amyloidosis (FRA)?

DDX

What are the differential diagnoses for Familial Renal Amyloidosis?

Workup

What is the role of lab tests in the workup of familial renal amyloidosis (FRA)?

What is the role of protein-to-creatinine (Pr/Cr) ratio in the workup of familial renal amyloidosis (FRA)?

What is the role of liver function tests in the workup of familial renal amyloidosis (FRA)?

What is the role of hematological indices and coagulation tests in the workup of familial renal amyloidosis (FRA)?

What is the role of imaging in the workup of familial renal amyloidosis (FRA)?

What is the role of scintigraphy in the workup of familial renal amyloidosis (FRA)?

What is the role of echocardiography in the workup of familial renal amyloidosis (FRA)?

What is the role of DNA analysis in the workup of familial renal amyloidosis (FRA)?

What is the role of fibril protein sequencing in the workup of familial renal amyloidosis (FRA)?

What is the role of biopsy in the workup of familial renal amyloidosis (FRA)?

Which histologic findings are characteristic of familial renal amyloidosis (FRA)?

Treatment

How is familial renal amyloidosis (FRA) treated?

What is the role of surgery in the treatment of familial renal amyloidosis (FRA)?

What is the role of kidney transplantation in the treatment of familial renal amyloidosis (FRA)?

What is the role of liver transplantation in the treatment of familial renal amyloidosis (FRA)?

What is the role of heart transplantation in the treatment of familial renal amyloidosis (FRA)?

Which specialist consultations are beneficial to patients with familial renal amyloidosis (FRA)?

Medications

What is the role of medications in the treatment of familial renal amyloidosis (FRA)?

Which medications in the drug class Prokinetic agents are used in the treatment of Familial Renal Amyloidosis?

Which medications in the drug class Histamine2-receptor antagonists are used in the treatment of Familial Renal Amyloidosis?

Which medications in the drug class Proton pump inhibitors are used in the treatment of Familial Renal Amyloidosis?

Which medications in the drug class Diuretics are used in the treatment of Familial Renal Amyloidosis?

Which medications in the drug class Antihypertensive agents are used in the treatment of Familial Renal Amyloidosis?

Follow-up

What is included in the long-term monitoring of familial renal amyloidosis?

What is the role of genetic screening in familial renal amyloidosis?

What are the possible complications of familial renal amyloidosis?

What is the prognosis of familial renal amyloidosis?

What is included in patient education about familial renal amyloidosis?