Familial Renal Amyloidosis

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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, as shown below. 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.


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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 un....

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. 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, 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 2 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).

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.

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


View Table

See Table

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 5 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.

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

International

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. 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.[1]

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.

Race

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.

Sex

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

Age

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.

History

Physical

Clinical features and their association with particular mutations are shown in the Table.

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 4 plasma proteins, lysozyme, apolipoprotein AI, apolipoprotein AII, and fibrinogen A alpha-chain. In a small number of families, the cause has not yet been determined.

Genetic information is depicted in the images below.


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An extended kindred with hereditary amyloidosis associated with fibrinogen A alpha-chain Glu526Val; disease penetrance is high in this particular fami....


View Image

Partial DNA sequence of the gene associated with fibrinogen A alpha-chain Glu526Val in a patient with familial renal amyloidosis, and a sequence from ....

Laboratory Studies

Imaging Studies

Other Tests

Procedures

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. 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.[6]

Medical Care

Surgical Care

Consultations

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.

Ramipril (Altace)

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

Class Summary

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

Furosemide (Lasix)

Clinical Context:  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.

Class Summary

Often help treat symptomatic peripheral edema resulting from nephrotic syndrome.

Omeprazole (Prilosec)

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

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.

Ranitidine (Zantac)

Clinical Context:  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)

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

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.

Metoclopramide (Reglan)

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

Class Summary

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

Further Outpatient Care

Deterrence/Prevention

Complications

Prognosis

Author

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

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 Editors

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

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

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

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

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.

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.

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