Renal Section and Amyloid Treatment and Research Program, Boston University School of Medicine, Boston, Massachusetts
Address correspondence to: Dr. Laura M. Dember, Renal Section, Boston University School of Medicine, EBRC 504, 650 Albany Street, Boston, MA 02118. Phone: 617-638-7331; Fax: 617-859-7549; E-mail: ldember{at}bu.edu
The amyloidoses are a group of disorders in which soluble proteinsaggregate and deposit extracellularly in tissues as insolublefibrils, causing progressive organ dysfunction. The kidney isone of the most frequent sites of amyloid deposition in AL,AA, and several of the hereditary amyloidoses. Amyloid fibrilformation begins with the misfolding of an amyloidogenic precursorprotein. The misfolded variants self-aggregate in a highly orderedmanner, generating protofilaments that interact to form fibrils.The fibrils have a characteristic appearance by electron microscopyand generate birefringence under polarized light when stainedwith Congo red dye. Advances in elucidating the mechanisms ofamyloid fibril formation, tissue deposition, and tissue injuryhave led to new and more aggressive treatment approaches forthese disorders. This article reviews the pathogenesis, diagnosis,clinical manifestations, and treatment of the amyloidoses, focusingheavily on the renal aspects of each of these areas.
The amyloidoses constitute a group of diseases in which proteinsdeposit extracellularly in tissues as insoluble fibrils. Renaldisease is a frequent manifestation of the systemic amyloidosesand often is the major source of morbidity for individuals withthese disorders. Without treatment, amyloidosis-associated kidneydisease usually progresses to end-stage renal disease (ESRD).Substantial progress in understanding the process of amyloidfibril formation and the mechanisms underlying disease manifestationshave led to important advances in treatment, some of which haveapplicability not only to the amyloidoses but also to otherprotein-folding disorders and deposition diseases. Althoughthis review focuses on amyloidosis-associated kidney disease,it is important to appreciate the impact of extrarenal diseaseon outcomes and treatment approaches.
To date, 25 structurally unrelated proteins are known to causeamyloidosis (1). For each of these amyloidogenic "precursorproteins," the initial step in amyloid fibril formation is amisfolding event (Figure 1). The misfolding can result fromproteolytic cleavage (e.g., amyloid protein), an amino acidsubstitution (e.g., transthyretin [TTR]), or intrinsic propertiesthat become significant only at high serum concentration orin the presence of specific local factors (e.g., 2-microglobulin).Regardless of the protein or the trigger for misfolding, themisfolded variants are highly prone to self-aggregation. Theself-aggregation generates protofilaments that interact to formfibrils. Amyloid fibrils have a characteristic -pleated sheetconfiguration that produces birefringence under polarized lightwhen stained with Congo red dye (2).
Figure 1. Amyloid fibril formation. A thermodynamically unstable precursor protein undergoes folding events that generate folding intermediates. Self-aggregation of folding intermediates yields protofilaments with high -pleated sheet content. Amyloid fibrils consist of four to six protofilaments that are twisted around each other. Fibrillogenesis is promoted by glycosaminoglycans (GAGs), and amyloid deposits are stabilized and protected from proteolysis by GAGs and serum amyloid P (SAP), both universal components of amyloid deposits. The tissue amyloid burden is determined by the relative rates of amyloid formation and degradation. Adapted from reference 107.
Classification of the amyloidoses is based on the precursorprotein that forms the amyloid fibrils and the distributionof amyloid deposition as either systemic or localized. The majortypes of systemic amyloidosis are Ig light chain (AL), Ig heavychain (AH), amyloid A (AA), the familial or hereditary amyloidoses(TTR, fibrinogen A, lysozyme, apolipoprotein AI [apoAI], apoAII,gelsolin, and cystatin), senile systemic amyloidosis, and 2-microglobulin(2m) amyloidosis (Table 1). In AL amyloidosis, an immunoglobulin(Ig) light chain or light-chain fragment produced by clonalplasma cells deposits in tissue as amyloid. Any organ exceptthe central nervous system can be a site of AL amyloid deposition,and the kidney is affected in 50 to 80% of individuals (3–6).AA amyloidosis occurs in the setting of longstanding inflammation.The amyloidogenic protein is an N-terminal fragment of serumamyloid A (SAA), an apolipoprotein that is synthesized by theliver as an acute-phase reactant. Rheumatoid arthritis, familialMediterranean fever (FMF), inflammatory bowel disease, and chronicinfections are the diseases that most frequently underly AAamyloidosis. In the familial amyloidoses, an inherited genemutation renders a protein amyloidogenic. Despite the presenceof the abnormal protein from birth, disease manifestations donot become apparent until adulthood, suggesting a role for agingin the amyloidogenic potential of these proteins (7). 2m amyloidosis,also known as dialysis-related amyloidosis, occurs in ESRD butdoes not affect the kidney and therefore is not addressed inthis review. Similarly, senile systemic amyloidosis, in whichnormal TTR protein forms amyloid predominantly in the heart,and localized forms of amyloidosis, in which amyloid depositionis confined to the site of precursor protein production, typicallydo not involve the kidney and are not addressed here.
The diagnosis of amyloidosis requires histologic demonstrationof amyloid deposits. This usually is accomplished by stainingwith Congo red dye. Congo red–stained amyloid has an orange-redappearance under light microscopy and produces apple-green birefringenceunder polarized light. The birefringence results from the orderedintercalation of Congo red dye into the amyloid fibrils, andthis optical property must be present to consider the stainingCongo red positive. Congo red staining can be technically difficult,particularly if tissue sections are <5 µm in thickness.Overstaining the tissue is an additional potential problem andcan produce false-positive results. Thioflavin T, another moleculethat binds to amyloid fibrils, is used less frequently thanCongo red. Binding of thioflavin T to amyloid produces yellow-greenfluorescence.
Any tissue can be evaluated for Congo red positivity, and theyield is greatest from sites with clinical evidence of involvement.However, if amyloidosis is suspected, the diagnosis often canbe confirmed with abdominal fat aspiration rather than an invasivebiopsy. The sensitivity of Congo red staining of abdominal fatis approximately 80 to 90% and 65 to 75% in AL and AA amyloidosis,respectively, but substantially lower in many of the familialamyloidoses (8). Therefore, the absence of Congo red positivityof abdominal fat does not eliminate the diagnosis. Salivarygland and rectal biopsies also are used as relatively noninvasivemethods for demonstrating amyloid in tissue.
Because Congo red staining is not a routine part of the histologicevaluation of most tissues, the diagnosis of amyloidosis frequentlyis missed unless the disease is suspected. The likelihood ofa missed diagnosis is lower with a kidney biopsy than with biopsiesof other tissues because amyloid fibrils are visible by electronmicroscopy, a standard component of the histologic examinationof kidney. The presence of characteristic fibrils by electronmicroscopy should trigger confirmatory staining of the tissuewith Congo red dye. However, even when electron microscopy isperformed, the diagnosis of amyloidosis can be missed if fibrilsare scant. Such cases sometimes are misdiagnosed as minimal-changedisease (9,10).
Different types of amyloid are indistinguishable by light orelectron microscopy. The most direct method for identifyingthe amyloidogenic protein is by mass spectrometry or amino acidsequencing of proteins that are extracted from amyloid deposits.These techniques are not available routinely and usually arenot necessary unless other approaches are unrevealing. The mostdefinitive method used in the clinical setting is immunofluorescenceor immunohistochemical staining of tissue using antibodies thatare directed against known amyloidogenic proteins. However,less direct methods often are required because of lack of sensitivityor availability of antibody reagents.
In the absence of immunoreactivity of tissue amyloid for or light chain, evidence for AL disease, the most common typeof amyloidosis, is provided by demonstration of a monoclonalIg protein in the blood or urine or clonal plasma cells in thebone marrow. Because the quantity of the circulating monoclonalprotein is lower in AL amyloidosis than in multiple myeloma,immunofixation electrophoresis rather than simple protein electrophoresisoften is required for detection of the monoclonal protein. Nephelometricquantification of free light chains in serum is useful in establishingthe presence of a monoclonal protein as well as in followingdisease progression or response to treatment (11,12). It isimportant to recognize that in the setting of renal impairment,it is the ratio of the serum concentrations of the two light-chainisotypes rather than the absolute serum concentrations thatis relevant, because free light chains are filtered by the kidney(13).
In addition to its use in assessing plasma cell clonality, abone marrow biopsy is important for determining the plasma cellburden. The percentage of plasma cells usually is normal oronly slightly increased in AL amyloidosis unless the diseaseoccurs in conjunction with multiple myeloma. Because of thefrequency of clinically unimportant monoclonal gammopathiesin elderly patients, the presence of a monoclonal gammopathyshould not lead to the conclusion that the amyloid is of thelight-chain variety unless there is immunohistochemical evidenceof light chains in the amyloid deposits or there has been athorough evaluation for other types of amyloidosis (14–16).
AA disease usually is suspected when amyloidosis occurs in thesetting of an inflammatory disease such as rheumatoid arthritis,inflammatory bowel disease, FMF or other periodic fever syndromes,bronchiectasis, or chronic osteomyelitis (17). The underlyingdisease usually is longstanding, and active inflammation typicallyis present when amyloidosis becomes evident. Some of the predisposingdiseases, such as rheumatoid arthritis, are very prevalent inthe adult population; therefore, immunohistochemical demonstrationof AA protein in tissue amyloid or a careful evaluation forother types of amyloidosis should be performed before concludingthat the type of amyloidosis is AA.
A hereditary form of amyloidosis may be suspected if there isa history of disease in other family members, but because thedisease is underdiagnosed and because there is variable penetrancefor some of the familial amyloidoses, a family history oftenis absent. The presence of a TTR variant can be identified byisoelectric focusing of the serum. Wild-type and variant formsof the protein will have distinctive migration patterns, andthe specific TTR gene mutation can be determined subsequentlyby DNA sequencing. For identification of other forms of hereditaryamyloidosis, DNA sequencing of exons of interest or mass spectrometryof known amyloidogenic proteins can be performed. Isolated glomerularinvolvement on kidney biopsy with no amyloid in the tubules,interstitium, or vessels has been found to be characteristicof fibrinogen A amyloidosis, and this histologic pattern shouldraise suspicion for fibrinogen A disease (14).
Because the kidney frequently is affected in AL, AA, and severalof the familial amyloidoses, a kidney biopsy often is the methodby which the disease is identified (Figure 2). Concern sometimesis raised about the risk for procedure-related bleeding as aresult of vascular fragility in individuals with amyloidosis;however, there is little evidence that rates of bleeding afterkidney biopsy actually are higher in these patients. Amyloidcan be found anywhere in the kidney, but glomerular depositiontypically predominates. By light microscopy, glomerular amyloidappears as amorphous material in the mesangium and capillaryloops. Substantial mesangial deposition can produce nodulesthat resemble lesions of diabetic nephropathy or light-chaindeposition disease (LCDD) (18). However, in amyloidosis, becausethe nodules are composed of amyloid protein rather than extracellularmatrix, periodic acid-Schiff (PAS) staining is weak. Amyloiddeposition in the tubulointerstitium produces tubular atrophyand interstitial fibrosis, and in a small proportion of patients,glomerular deposition is scant or absent and the amyloid isconfined to the tubulointerstitium or vasculature. Irrespectiveof the distribution of amyloid, Congo red staining producesthe disease-defining birefringence under polarized light.
Figure 2. Kidney biopsy from a patient with Ig light chain (AL) amyloidosis and a monoclonal IgG protein in the serum and urine. (A) The mesangium of the glomerulus is expanded by amorphous, weakly periodic acid-Schiff–positive material that produced an early nodular appearance. This material is also evident in the vessel wall. (B) Amyloid stained with Congo red dye appears orange-red under nonpolarized light. (C) Under polarized light, the Congo red–stained material produces the amyloid-defining apple-green birefringence (indicated by arrows), which is subtle in this image because of the relative positions of the polarizing filters and the tissue. (D) Immunofluorescence shows strong reactivity for light chains. (E) Reactivity for light chains is weak. (F) Randomly arrayed fibrils with a diameter of approximately 10 nm are evident by electron microscopy. Images courtesy of Helmut Rennke, MD.
Immunofluorescence or immunohistochemical studies are negativefor intact Ig, complement, and fibrin but, in AL disease, oftenwill reveal Ig light chain. Because the amyloidogenic lightchain is produced by clonal plasma cells, reactivity shouldbe restricted to a single light chain isotype, although thereoften is some degree of background staining for light chainsin general, as well as for albumin. In contrast to multiplemyeloma, the monoclonal protein in AL amyloidosis more oftenis of the than the isotype. It is important to be aware thatthe absence of reactivity for either or light chain does notrule out AL disease. Commercially available reagents do notalways detect amyloidogenic light chains because of conformationalchange or fragmentation that masks or eliminates the relevantepitopes (19). In contrast, AA amyloid usually is detected withavailable antibodies against AA protein. Loss of Congo red stainingafter treatment with potassium permanganate is a property ofAA amyloid that can distinguish it from other types (20), butthis technique is not as reliable as immunoreactivity with anti-AAantibodies that currently are available.
By electron microscopy, amyloid appears as nonbranching fibrilswith a diameter of 8 to 10 nm. The fibrils are randomly arrayedwithout a specific orientation in the mesangium, basement membranes,interstitium, and vessels. Immunoelectron microscopy can beused to determine the type of amyloid, but its availabilityis confined to research laboratories. The size of the fibrilsdifferentiates amyloidosis from other renal diseases with organizedIg deposits (21–23). The fibrils of fibrillary glomerulonephritisand the microtubules of immunotactoid glomerulopathy usuallyhave diameters of 15 to 20 and 30 to 60 nm, respectively. Thefibrils of fibrillary glomerulonephritis, like those of amyloid,are randomly arrayed, whereas the microtubules of immunotactoidglomerulopathy have an ordered, parallel orientation. The electronmicrographic appearance of amyloid fibrils is sufficiently characteristicthat, if present, the diagnosis of amyloidosis should continueto be considered even when Congo red staining is negative.
AL amyloidosis that involves the kidney differs histologicallyfrom other monoclonal Ig light-chain disorders (24). In LCDD,Congo red–negative deposits are distributed relativelyuniformly in a granular pattern along the glomerular and tubularbasement membranes. Immunoreactivity with anti- or anti- light-chainantibody usually is positive probably because the light-chainepitopes are maintained to a greater extent in LCDD than inAL amyloidosis. In LCDD, the light-chain isotype is more commonthan the isotype, and compared with AL amyloidosis, there usuallyis less background staining with antibodies that are directedagainst the nonpathologic light-chain isotypes or albumin. InLCDD, the deposition of light chains stimulates production ofcollagen and other extracellular matrix components; as a result,PAS staining is much more intense than in amyloidosis. In castnephropathy, also referred to as myeloma kidney, light chainsform intratubular casts. In contrast to hyaline casts, the light-chaincasts are PAS negative, they are highly refractile, and theyoften appear lamellated and fractured. Inflammatory cell infiltrationand, in some cases, granuloma formation often are present inthe interstitium that surrounds the affected tubules. WhereasAL amyloidosis and LCDD both occur either in conjunction withmultiple myeloma or in its absence, cast nephropathy rarelyoccurs in the absence of multiple myeloma. Most biopsies fromindividuals with monoclonal light-chain–associated renaldisease reveal a single manifestation of the light-chain disease;however, there are well-documented cases in which combinationsof amyloid, LCDD, and cast nephropathy are present together(25).
Proteinuria is present in the majority of individuals with renalamyloidosis and ranges from subnephrotic to massive with urinaryprotein excretion rates as high as 20 to 30 g/d. The urinaryprotein is composed mostly of albumin, and the proteinuria usuallyis accompanied by other components of the nephrotic syndrome.Hypoalbuminemia can be profound, and edema often is severe andrefractory to diuretics. The multisystem nature of systemicamyloidosis can contribute to the difficulty of managing fluidretention, particularly in AL amyloidosis, since cardiac andautonomic nervous system involvement can cause hemodynamic fragilitythat limits the effectiveness or tolerability of diuretics.When amyloid is confined to the tubulointerstitium or vasculature,proteinuria is minimal and reduced GFR is the principal clinicalmanifestation. Renal impairment tends to progress less rapidlywhen tubulointerstitial rather than glomerular deposition predominates.Vascular involvement often is accompanied by hypertension, anotherwise uncommon feature of amyloidosis.
An unusual but well-documented manifestation of renal amyloidosisis nephrogenic diabetes insipidus caused by amyloid depositionin the peri-collecting duct tissue (26,27). In fact, early evidencefor the role of the collecting ducts in the urinary concentratingmechanism of the kidneys was provided by postmortem dissectionof the kidneys from a patient with amyloidosis and vasopressin-unresponsivediabetes insipidus. The amyloid deposits in that patient wereconfined almost exclusively to the tissue surrounding the medullarycollecting ducts (26). Another extraglomerular manifestationof renal amyloidosis is Fanconi’s syndrome, reflectinginjury to proximal tubular cells by filtered light chains (28).Amyloid deposits that are isolated to the renal medulla is afeature in most patients with apoAI familial amyloidosis (29–31)and has been described in some individuals with AA amyloidosis(32). Medullary-limited disease can elude pathologic diagnosisif the biopsy specimen consists only of renal cortex.
Like other infiltrative diseases, amyloidosis can cause enlargementof the kidneys. However, in most patients, the kidneys seemto be of normal size by imaging studies, and the absence ofenlarged kidneys should not decrease suspicion for the diseaseduring diagnostic evaluation.
Clear relationships between the extent of amyloid depositionevident by kidney biopsy and severity of clinical manifestationshave not been demonstrated. Urinary protein excretion or rateof GFR decline cannot be predicted on the basis of biopsy findings.Whether this lack of clinicopathologic correlation reflectssampling bias or pathogenic mechanisms is not clear.
The factors that determine the organ distribution of amyloiddeposits are complex and not well understood. The kidney isa frequent site of amyloid deposition in AL, AA, fibrinogen,lysozyme, apoAII, and, to a lesser extent, apoAI disease. Incontrast, TTR amyloidosis typically does not involve the kidney.In AL amyloidosis, disease can be restricted to a single tissuetype in one individual and involve as many as five to six organsystems in another individual. This marked heterogeneity intissue distribution probably reflects the variety of light-chainsequences that are amyloidogenic. Small differences in aminoacid sequence of an amyloidogenic protein can alter its tissuetropism. For example, in familial TTR amyloidosis, individualswith an amino acid substitution of methionine for valine atposition 30 (Val30Met) have predominant neuropathic involvement,whereas cardiomyopathy is the major manifestation in individualswith the Val122Ile TTR variant (33). In apoAI amyloidosis, 12different mutations that cause amyloidosis have been identified.It is interesting that the position of the mutation in the apoAIprotein seems to be associated with the distribution of organinvolvement. Mutations in the amino terminal portion of theprotein are associated with kidney, liver, and occasionallyheart involvement, whereas mutations in the carboxy terminalportion of the protein seem to be associated with heart, skin,and often laryngeal involvement (34). How the position of themutation affects disease manifestations is not clear.
Efforts to identify light-chain features that are associatedwith kidney involvement in AL disease have led to the suggestionthat specific uptake by mesangial cells might underlie the predominantkidney tropism of certain light chains, particularly those thatare derived from the 6a VVI germline gene (35–37). Uptakeof the amyloidogenic protein by mesangial cells has been demonstratedfor light chains but does not seem to be a uniform requirementfor amyloid deposition in the kidney. Other factors that mightpromote or retard amyloid formation or deposition in the kidneyinclude the negative charge and high glycosaminoglycan contentof the glomerular basement membrane and the presence of certainproteases that could either render a protein amyloidogenic oraffect stability of amyloid deposits. A large body of work suggeststhat glycosaminoglycans promote fibrillogenesis by stabilizingor inducing conformational changes in amyloidogenic precursorsthat favor fibril formation and by providing protection fromproteolysis during fibril formation and after tissue deposition(38–42). Local pH can affect the relative stabilitiesof the abnormal and normal conformations of the precursor proteinand thereby favor or retard fibrillogenesis. In addition, thefunction of the amyloidogenic protein might affect tissue targeting.For example, it has been suggested that because the kidney isthe major site of HDL catabolism, apoAI, the major apolipoproteinof HDL, might be present in elevated concentrations in the kidney(31), increasing the likelihood of amyloid formation from amyloidogenicapoAI variants. The high urea content and acidic pH of the kidneymedulla are potential amyloid-promoting factors that might underliethe restriction of apoAI amyloid to the medulla (31).
The importance of local tissue characteristics is illustratedby a report that described eight patients with Ig depositiondisease that involved the heart (43). Four of the patients hadlight-chain amyloid deposits in one or more extracardiac tissuesin addition to the non-amyloid Ig deposits in the myocardium,indicating that the amyloidogenic potential of this Ig proteinwas determined, at least in part, by the local environment.
Disruption of tissue architecture by amyloid deposits had longbeen accepted as the underlying mechanism of organ dysfunctionin the amyloidoses. A deleterious impact of amyloid on surroundingtissue is appreciated easily from histologic examination ofkidneys that have extensive amyloid deposits. However, severalobservations suggest that amyloidogenic precursor proteins,folding intermediates, and protofilaments have toxicities thatare independent of the amyloid deposits and that these toxicitiescontribute to the disease manifestations as well (Figure 3).Findings that support the latter mechanism include the lackof correlation between quantity of amyloid in tissue and organdysfunction (44,45), in vitro demonstrations of direct toxicityof amyloidogenic precursor proteins on cultured cells or tissues(37,46–49), detection of amyloidogenic precursor proteinsin tissue in the absence of amyloid (50), and rapid improvementin markers of organ dysfunction after treatment-induced reductionsin precursor protein production (12,51). A recent study of agroup of patients with AL amyloidosis–associated cardiacdisease found that the serum concentrations of N-terminal natriureticpeptide type B (proBNP), a marker of cardiac dysfunction, decreasedsubstantially after only three monthly cycles of anti-plasmacell therapy. The decreases in proBNP levels were concurrentwith treatment-induced reductions in the concentrations of thecirculating monoclonal light chains and, in most cases, werenot accompanied by a reduction in cardiac wall thickness. Therapid improvement in proBNP, occurring too early to be attributableto regression of existing amyloid deposits, suggests that theamyloidogenic light chains are responsible, at least in part,for AL amyloidosis–associated cardiac dysfunction (12).
Figure 3. Two mechanisms of organ dysfunction in amyloidosis. The right side depicts the traditional view that amyloid fibrils accumulate in the extracellular space, causing physical disruption and malfunction of surrounding tissue. The left side depicts an alternative mechanism of direct cellular toxicity by amyloidogenic precursor proteins, folding intermediates, aggregates, or fibrils. This toxicity may be mediated through interactions with cell surface receptors or via entry into cells.
In amyloidosis-associated renal disease, indirect support fora role of the amyloidogenic precursors in disease manifestationscomes from several observations. Proteinuria decreases rapidlyafter treatment that eliminates or markedly reduces productionof the amyloidogenic precursor protein. In AL disease, thisobservation has been made after high-dose chemotherapy thateliminates the clonal plasma cells that produce the monoclonalamyloidogenic light chain (51,52) and in AA disease, when theunderlying inflammatory disease becomes quiescent (53–55).Similar to the proBNP response in cardiac amyloidosis, the reductionin proteinuria occurs in many patients before substantial degradationof existing amyloid deposits would be expected to occur (2).Indeed, in small series of patients with AL amyloidosis whounderwent serial kidney biopsies, the extent of amyloid depositionseemed to be similar in biopsies that were performed beforetreatment and after treatment-induced resolution of proteinuria(56,57). A lack of biopsy improvement after proteinuria resolutionin AA amyloidosis also has been reported (58). Also consistentwith a functional effect of amyloidogenic precursor proteinsare in vitro demonstrations of specific phenotypic changes incultured mesangial cells that are exposed to amyloidogenic lightchains, changes that are not seen when the cells are exposedto non-amyloidogenic light chains (37).
Ongoing amyloid deposition in the kidney is associated withprogressive deterioration in renal function. In a group of patientswho had AL amyloidosis and kidney involvement followed in the1980s, progression to ESRD occurred at a median of only 14 moafter diagnosis (3). Overall, renal deterioration probably ismost rapid in AL amyloidosis; however, the rate of progressionvaries considerably within all types of amyloidosis and probablyreflects, at least to some extent, the rapidity of productionof the amyloidogenic precursor protein. Hemodynamic alterationsthat result from severe nephrotic syndrome, autonomic dysfunction,or heart failure often underlie abrupt changes in kidney functionand contribute to the fragility in renal function that frequentlyis present in this disease. The sections that follow reviewthe treatment approaches for several types of amyloidosis withan emphasis on the impact of treatment on the kidney. Most ofthe detailed information about renal response to treatment comesfrom experience with AL amyloidosis.
AL Amyloidosis
The goal of current treatment approaches for AL amyloidosisis to eradicate the clonal plasma cells that produce the amyloidogeniclight chain. The prognosis of AL amyloidosis has improved substantiallyduring the past decade with the increasing use of aggressiveanti-plasma cell treatment. Several chemotherapeutic regimenshave been evaluated, and high-dose intravenous melphalan followedby autologous stem cell transplantation to support bone marrowrecovery (HDM/SCT) has emerged as the most likely to eliminatethe clonal plasma cells (5,59,60). Experience from several treatmentcenters has suggested that 25 to 50% of patients who undergosuch treatment have complete hematologic responses, meaningthat there is no evidence of ongoing production of the monoclonallight chain (5,61,62). In contrast, complete hematologic responsesare exceedingly rare with oral melphalan and prednisone administeredin repeated cycles, an approach that was standard treatmentuntil relatively recently (63,64).
As depicted in Figure 4, attainment of a complete hematologicresponse after HDM/SCT is associated with improved survival.In addition to prolonging survival, elimination of the amyloidogeniclight chain is associated with improvements in the functionof affected organs. The impact of HDM/SCT on AL amyloidosis–associatedkidney disease illustrates the association between hematologicresponse and organ function response (Figure 5). In a studyof 65 patients with AL amyloidosis and kidney involvement, arenal response, defined as a 50% reduction in urinary proteinexcretion in the absence of 25% or greater decrease in creatinineclearance, had occurred by 12 mo after HDM/SCT in 36% of survivingpatients. Among the patients who had a complete hematologicresponse, urinary protein excretion decreased from 9.6 to 1.6g/d at 12 mo, and 71% had a renal response. In contrast, amongthose with ongoing production of the monoclonal light chain,median urinary protein excretion was not different after treatment,and only 11% had a renal response (51). Creatinine clearancewas maintained at 75% of the pretreatment value at last follow-up(12 to 48 mo) in 90% of those with a hematologic response butonly in 48% of those with persistent hematologic disease, mostof whom had a partial hematologic response. Similar resultswere found several years later from the same institution after114 patients with renal involvement had undergone HDM/SCT (5).Among patients with a hematologic remission, proteinuria reductioncontinues beyond 12 mo, and in a substantial proportion, itultimately normalizes. The rate of hematologic relapse afterHDM/SCT seems to be <10%; however, an increase in proteinuriaseems to be one of the early signs that monoclonal protein productionhas recurred (51). In an analysis of 58 patients who had kidneyinvolvement and underwent HDM/SCT, Leung et al. (52) found anassociation between renal response and patient survival thatwas not fully attributable to the greater likelihood of hematologicremission among those with a renal response.
Figure 4. Survival after high-dose melphalan and autologous stem cell transplantation for AL amyloidosis. Median survival among 312 patients who initiated treatment was 4.6 yr. Among those who were able to be evaluated 1 yr after treatment, survival was better in the group that had a complete hematologic response than in those with persistent hematologic disease (P < 0.001). Reprinted from reference (5), with permission.
Figure 5. Reduction in proteinuria after treatment with high-dose melphalan and autologous stem cell transplant for AL amyloidosis. (Left) Patients who had a complete hematologic response. (Right) Patients with persistent hematologic disease. Reprinted from reference (51), with permission.
Substantial progress has been made in the treatment of AL amyloidosis,but treatment-associated toxicity remains a challenge. The treatment-associatedmortality with HDM/SCT is 12 to 14% and may be higher in patientswith heart involvement (5,65,66). This is substantially higherthan the treatment-associated mortality that occurs when similartreatment is used for multiple myeloma, illustrating the impactthat organ dysfunction has on the rate and the severity of treatmentcomplications. The tolerability of the treatment is particularlydifficult when there is severe cardiac involvement. Treatmentcomplications occur not only after administration of the melphalanbut also during the stem cell mobilization phase of treatment.Stem cell mobilization requires administration of high dosagesof growth factors, typically granulocyte colony-stimulatingfactor, and this can be complicated by fluid retention thatcan be severe and difficult to treat, particularly in patientswith nephrotic syndrome, heart failure, or autonomic nervoussystem dysfunction. Splenic rupture after granulocyte colony-stimulatingfactor administration is a rare, life-threatening complicationthat occurs predominantly in patients with substantial splenicamyloid (67). The risk for bleeding during periods of thrombocytopeniais increased when there is extensive amyloid deposition in thegastrointestinal tract or amyloidosis-associated factor X deficiency(68–70). Infections during periods of neutropenia probablyoccur at similar frequency in patients with amyloidosis as inother patients who undergo myeloablative therapy but they areless well tolerated in the former as a result of organ dysfunction.
Studies from two different centers found that acute renal failure(ARF) occurred as a complication of HDM/SCT in approximately20% of patients with AL amyloidosis (71,72). In the first ofthese studies, dialysis was required in one fourth of the casesof ARF, which was 5% of the entire cohort of 173 treated patients.Among those who required dialysis, renal recovery occurred in44%, a rate similar to that of the entire group of patientswith ARF (46%). The development of ARF was associated with decreased90-d survival, but long-term survival did not differ betweenpatients who had ARF and those who did not (71). ARF was morelikely to develop in patients with impaired renal function,heavy proteinuria, or cardiac involvement before treatment;among those who received the highest dosage of melphalan (200mg/m2); and among those with bacteremia during the peritransplantationperiod. ARF occurred during all phases of treatment (duringstem cell mobilization, after melphalan administration, andafter neutrophil engraftment). The causes were varied, but hemodynamiccompromise was the most frequent identified cause or contributingfactor. In the study by Leung et al. (72), dialysis was requiredin a greater proportion of patients (13.8% of 80 treated patients),and only one of those who required dialysis had renal recovery.Eight of the 11 dialysis-dependent patients died, and most ofthe deaths were within the first few weeks after dialysis wasinitiated (72). On the basis of the findings of these studies,as well as ongoing experience with larger numbers of patients,it is appropriate to anticipate a need for dialysis during theperitransplantation period when the serum creatinine concentrationis 3 mg/dl or greater before treatment with HDM/SCT.
Eligibility criteria for HDM/SCT vary among centers and areevolving as experience accumulates. Cardiac function, autonomicnervous system function, and performance status are importantfactors for determining both eligibility for HDM/SCT and thedosage of melphalan administered (5,65). Specific eligibilitycriteria at one center include left ventricular ejection fraction>40%, room air oxygenation saturation >95%, supine systolicBP >90 mmHg, and Southwestern Oncology Group PerformanceStatus 2 (5).
Regimens that are less intensive than HDM/SCT are being usedwhen the toxicity risk with HDM/SCT is prohibitive. Impressiveresults have been reported in such patients with the combinationof oral melphalan and high-dose dexamethasone. In a study of46 patients who were ineligible for HDM/SCT, 31 (67%) had apartial hematologic response and 15 (33%) had a complete hematologicresponse (73). Other approaches that are being used in high-riskpatients include thalidomide or lenalidomide, related drugswith immunomodulatory and antiangiogenic effects and activityagainst plasma cells. These agents, often administered in conjunctionwith steroids, are being investigated not only as primary therapybut also as salvage therapy when the response to high-dose melphalanis inadequate (74–76).
AA Amyloidosis
The current treatment approach for AA amyloidosis is to treatthe underlying inflammatory disease and thereby reduce productionof SAA. In FMF, a disease that is associated with a high rateof AA amyloidosis, life-long treatment with colchicine to inhibitFMF-associated inflammation prevents the development of amyloidosisin many patients (77). Once amyloidosis occurs, whether secondaryto FMF or to other inflammatory diseases, suppression of inflammationcan result in reduction in the clinical manifestations of amyloidosisand improved survival (78). Marked reductions in proteinuriahave been reported in individuals with AA amyloidosis–associatedkidney disease from a variety of underlying inflammatory conditionsafter treatment with cytotoxic agents or TNF antagonists (53–55,79).These functional improvements are presumed to be due to suppressionof SAA production and resultant reduction in AA amyloid formation.However, as the authors of some of these reports suggested,it is possible that these agents also have additional anti-amyloideffects through suppression of cytokine production or by alteringthe expression of specific mediators of amyloid fibril–inducedcellular toxicity. For example, it has been proposed that anti-TNFtherapies, by inhibiting the expression of receptors for advancedglycation end products (RAGE), might reduce interactions betweenAA fibrils and RAGE (46) and thereby prevent, at least in part,AA-mediated cell toxicity (79).
In many individuals with AA amyloidosis, adequate suppressionof SAA production is not possible. Fibrillogenesis inhibitionusing small molecules that have structural similarity to glycosaminoglycan(GAG) moieties is an alternative treatment approach that isunder investigation in AA amyloidosis as well as in Alzheimer’sdisease (80–82). By interfering with interactions betweenGAGs and amyloid proteins, such agents would be expected toreduce new amyloid formation and decrease the stability of existingamyloid deposits. A phase II/III multicenter trial of eprodisate,a negatively charged sulfonated molecule with in vivo activityagainst experimentally induced AA amyloidosis, was completedrecently. The full study results should be published in thenear future. Because of the universal presence of GAGs in amyloiddeposits, this approach should have applicability to other typesof amyloidosis.
Hereditary Amyloidoses
Orthotopic liver transplantation has been performed in >660individuals with TTR amyloidosis and is considered the definitivetreatment for the disease (83). The abnormal amyloidogenic TTRvariant disappears from the circulation after the liver, thesite of TTR synthesis, is removed and replaced with a liverthat expresses only wild-type TTR. Unfortunately, amyloid depositionsometimes persists because wild-type TTR can deposit as amyloidat sites of preexisting amyloid deposits (84). Nonetheless,disease progression usually is slowed, and in many patients,clinical manifestations improve after liver transplantation(85–87). There is substantially less experience usingliver transplantation for fibrinogen A amyloidosis, a diseasethat is more likely than TTR amyloidosis to involve the kidney.Case reports describe individuals who had fibrinogen A diseaseand underwent combined liver and kidney transplantation (88–90).Outcomes were considered satisfactory without evidence of amyloidin the transplanted organs 2 to 6 yr later. Liver transplantationis not appropriate for lysozyme amyloidosis because lysozymeis synthesized by polymorphonuclear cells and macrophages. BecauseapoAI is synthesized by the intestine in addition to the liver,amyloid formation would be anticipated to continue after livertransplantation although perhaps at a slower rate (91).
The renal response to orthotopic liver transplant was evaluatedin a small series of patients with TTR amyloidosis and kidneyinvolvement (45). Proteinuria did not change significantly inthese patients, but serum creatinine levels remained relativelystable over several years. Although these patients had histologicallyevident renal amyloid, the clinical manifestations were mildbefore liver transplantation, limiting generalization of thefindings to patients with more pronounced kidney manifestations.
A study that described the outcomes of a large cohort of patientswith amyloidosis-associated dialysis dependence found that themedian survival after initiation of dialysis was 8.5 mo (3).Most of the patients died as a result of progression of extrarenaldisease, in particular, cardiac amyloidosis, or as a resultof malnutrition. This study was published in the early 1990sand reported on patients who were followed during the decadebefore that. With the advances in the treatment of amyloidosisthat have occurred during the past 10 to 15 yr, it is likelythat the prognosis for patients with amyloidosis-associatedESRD is better now than it was at the time that study was published.
Dialysis dependence, in and of itself, should not preclude aggressivetreatment that aims to reduce ongoing amyloid production. Concernhas been expressed about the appropriateness of offering HDM/SCTto dialysis-dependent patients with AL amyloidosis because oftreatment-associated toxicities (92). However, experience withtreating selected patients with HDM/SCT suggests that both thehematologic response rate and treatment-associated mortalityare similar in dialysis-dependent patients compared with theoverall population of patients who undergo this treatment (93).Other treatment toxicities also seem to be similar for dialysis-dependentpatients with the exception that mucositis is more severe andblood product requirements are greater during the period beforestem cell engraftment. The attainment of a complete hematologicresponse has enabled subsequent kidney transplantation in someof these patients (93).
Performing kidney transplantation before treatment with HDM/SCThas been proposed as an alternative to treating dialysis-dependentpatients (94). The rationale for this approach is that adequatekidney function might reduce treatment-associated toxicitiesand increase the likelihood of a complete hematologic responseby allowing higher dosages of melphalan to be administered.However, given that the hematologic response rates seem to besimilar among dialysis-dependent patients and those with preservedkidney function (93), it may not be justified to expose a renalallograft to the risk for treatment-associated injury and possiblyto a risk for acute rejection during immunologic reconstitutionif HDM/SCT can be performed at a center with experience withtreating dialysis-dependent patients.
Most of the published experience with kidney transplantationin amyloidosis-associated ESRD is in patients with AA amyloidosis.The patient and allograft survivals vary substantially in theseseries, with outcomes that were worse (95) as well as outcomesthat were similar (96,97) compared with the general renal transplantpopulation. Recurrence of AA amyloidosis in the allograft occurredin 71% in one series (98). Because of the efficacy of colchicinein preventing AA amyloidosis in FMF, recurrence in the allograftshould be avoidable in this subset of patients. In addition,because of the low rate of hematologic relapse in AL amyloidosis,kidney transplantation is a good option for patients who attaina complete hematologic response and do not have significantextrarenal disease. The appropriateness of kidney transplantationis more difficult to determine when there is ongoing productionof the amyloidogenic precursor protein. Proceeding with kidneytransplantation might be reasonable if disease is limited tothe kidney and if the progression to ESRD had occurred overmany years rather than rapidly.
There is general consensus that amyloid deposits can regressover time via endogenous degradation. The rapidity of such degradationand the relationship between amyloid regression and functionalimprovements that occur after new amyloid production is haltedare less clear. Scinitigraphy with radiolabeled serum amyloidP (SAP), a protein that binds to all types of amyloid, is availablein a limited number of centers as a noninvasive tool for monitoringdisease status (99). Dramatic reductions in SAP uptake aftertreatments that eradicate amyloidogenic precursor proteins havebeen attributed to rapid regression of amyloid deposits (100).However, firm confirmation that either SAP scan improvementsor rapid functional improvements reflect amyloid regressionis lacking. An alternative possibility is that new amyloid bindsSAP more avidly than does amyloid that has been incorporatedinto tissue for long periods. Similarly, new amyloid depositsmight have a greater impact on organ function than do incorporateddeposits. Therefore, improvements that occur rapidly after treatmentmay be due to elimination of new amyloid deposition and precursorproteins rather than to regression of existing amyloid deposits.
Tremendous advances have been made during the past several yearsin elucidating the structure and the chemistry of amyloid proteins,the mechanisms of fibril formation and tissue deposition, andthe processes involved in tissue injury. This increased understandinghas been accompanied by progress in developing novel treatmentapproaches that are directed not only at the source of the precursorprotein but also at each of the steps in the pathway from precursorprotein production to amyloid degradation. Small molecules thatstabilize precursor proteins in their native conformation andthereby prevent generation of the misfolded variants have beenidentified (101,102). One such agent, the nonsteroidal anti-inflammatorydrug diflunisal, maintains TTR as a homotetramer, a conformationthat is thermodynamically more stable and thus less amyloidogenicthan its monomeric counterpart (103). This strategy is beingevaluated in a clinical trial for hereditary TTR amyloidosis.The use of small, sulfonated molecules that are designed tointerfere with interactions between amyloid proteins and GAGstargets both amyloid fibril formation and tissue deposition(80). Fibrillogenesis also is being targeted with syntheticpeptides that inhibit aggregation and with antibodies that aredirected against amyloid fibrils (104,105). Enhancing amyloidmobilization from tissue by targeting components of amyloiddeposits that protect fibrils from proteolysis is yet anotherstrategy under development (106). Ultimately, one can envisionmultipronged approaches composed of treatments that are directedat several different targets.
Acknowledgments
Support for this work was provided by the Boston UniversityAmyloid Research Fund. L.M.D. gratefully acknowledges the long-standingcollaboration with the faculty, staff, and patients of the BostonUniversity Amyloid Treatment and Research Program and is thankfulto Dr. Helmut Rennke for providing the pathology images forthis article. L.M.D. reports having received research fundingand consultation fees from Neurochem, Inc., Laval, Canada.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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protein), an amino acid substitution (e.g., transthyretin [TTR]), or intrinsic properties that become significant only at high serum concentration or in the presence of specific local factors (e.g., 
, lysozyme, apolipoprotein AI [apoAI], apoAII, gelsolin, and cystatin), senile systemic amyloidosis, and 
or 
light chain, evidence for AL disease, the most common type of amyloidosis, is provided by demonstration of a monoclonal Ig protein in the blood or urine or clonal plasma cells in the bone marrow. Because the quantity of the circulating monoclonal protein is lower in AL amyloidosis than in multiple myeloma, immunofixation electrophoresis rather than simple protein electrophoresis often is required for detection of the monoclonal protein. Nephelometric quantification of free light chains in serum is useful in establishing the presence of a monoclonal protein as well as in following disease progression or response to treatment (11,12). It is important to recognize that in the setting of renal impairment, it is the ratio of the serum concentrations of the two light-chain isotypes rather than the absolute serum concentrations that is relevant, because free light chains are filtered by the kidney (13). 
75% of the pretreatment value at last follow-up (12 to 48 mo) in 90% of those with a hematologic response but only in 48% of those with persistent hematologic disease, most of whom had a partial hematologic response. Similar results were found several years later from the same institution after 114 patients with renal involvement had undergone HDM/SCT (5). Among patients with a hematologic remission, proteinuria reduction continues beyond 12 mo, and in a substantial proportion, it ultimately normalizes. The rate of hematologic relapse after HDM/SCT seems to be <10%; however, an increase in proteinuria seems to be one of the early signs that monoclonal protein production has recurred (51). In an analysis of 58 patients who had kidney involvement and underwent HDM/SCT, Leung et al. (52) found an association between renal response and patient survival that was not fully attributable to the greater likelihood of hematologic remission among those with a renal response. 
2 (5). 
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Abstract
Introduction
