Amyloidosis is a group of diseases resulting from the misfolding of a native or mutated protein. The misfolded proteins aggregate in the form of insoluble fibrils and deposit in the extracellular space of various tissues, eventually leading to end-organ damage.1 Although amyloidosis can be local, it is mostly a systemic disease which can involve almost every organ in the body, including the heart, kidneys, gastrointestinal (GI) tract, liver, peripheral, autonomic and central nervous system, joints, thyroid, skin and soft tissue.2-5 The misfolding of a precursor amyloidogenic protein can be driven by intrinsic properties of the particular protein and these properties can become more evident with aging, for example, in the case of wild-type transthyretin (wtTTR) protein that causes wtTTR amyloidosis (ATTRwt) leading to cardiomyopathy in older individuals.6 Some proteins seem to aggregate into amyloid fibrils when their serum concentrations are substantially elevated for a prolonged period of time (eg, β2-microglobulin in dialysis patients and serum amyloid A [SAA] in amyloid A [AA] amyloidosis).7,8 Fibril formation can also be triggered by a specific amino acid substitution in various mutant proteins in hereditary amyloidosis (previously referred to as familiar form).9 Considerable research has been done to elucidate the process of fibril formation and specific tissue tropism. In spite of substantial progress in this field, the exact mechanism of fibril formation remains unknown.
End-organ damage is primarily caused by aggregation and progressive deposition of the precursor proteins leading to disturbance in the local tissue structure; however, in certain types of amyloidosis the protein itself has also been shown to be cytotoxic.10-13 For example, in light-chain (AL) amyloidosis, it has been shown that the circulating light chains (LCs), in addition to causing structural damage in the form of amyloid deposits, are also directly cardiotoxic.10-12
The diagnosis of amyloidosis requires a tissue biopsy showing the presence of amyloid fibrils. On light micrograph, amyloid most commonly forms nodular amorphous deposits in the mesangium, which is pale when stained with H&E (Figure 1A) and weakly positive with periodic acid-Schiff (Figure 1B). As a result of the unique β-pleated sheet configuration, amyloid deposits show characteristic apple-green birefringence under polarized light when stained with Congo red (Figure 1C and D) or yellow-green fluorescence with Thioflavin T.1 The deposits contain randomly arrayed, nonbranching fibrils, sized 8–12 nanometer that can be visualized under electron microscopy (Figure 1G–I).
The histologic features of amyloid are the same regardless of its composition but the underlying pathogenesis and treatment strategy differ significantly depending on the precursor protein. For this reason, typing of the amyloidogenic protein should always be performed before treatment recommendations are made. Typing is most frequently done by immunofluorescence or immunohistochemistry staining with the use of antibodies directed against amyloidogenic protein components (Figure 1E and F). In challenging cases, immunogold electron microscopy on tissue sections or liquid chromatography–tandem mass spectrometry on laser dissected fibrils from amyloid deposits are also done, however, only a few centers offer such services worldwide.1 In cases where hereditary amyloidosis is suspected, protein sequencing and genetic analysis should also be added to the diagnostic workup.
AMYLOIDOSIS AND KIDNEY DISEASE
To date, 36 different precursor proteins have been described as the cause of amyloidosis.14 Some forms involving the kidneys include LCs (AL is by far the most common type of amyloidosis), heavy chains (AH), SAA, TTR, leukocyte chemotactic factor (ALECT)-2, fibrinogen A alpha (AFib), lysozyme (LYZ), gelsolin (AGel), and several apolipoproteins (Table 1).
TABLE 1. -
Summary of amyloid subtypes
|Type of amyloidosis
||Renal compartment involved
||Recommendation for kidney Tx
||Immunoglobulin LC λ/κ type in setting of plasma cell dyscrasia
||All organs except CNS.
||Mostly glomeruli, vessels and interstitium but possible in all compartments.1,15
||Proteinuria and CKD, ESRD within mo to y if not treated or if no response to treatment.15-18
||Improved outcomes since the introduction of new therapies, especially in patients with CR/VGPR.19
||Immunoglobulin heavy chain in setting of plasma cell dyscrasia
||All organs except CNS.
||Similar to AL but can have atypical features.20
||Similar to AL amyloidosis.20
||Approach to hematologic treatment is identical to AL amyloidosis and transplant recommendations are the same.
||Mutated transthyretin (TTRv)
||Nervous system, heart, kidney, and eyes.21
||Mostly glomerular but all renal compartments can be involved.21-23
||Pattern of renal injury (if present) depends on the specific mutation.21
||Most often combined liver-kidney transplantation.21,24-26
||Fibrinogen Aα chain
||Kidney. Rarely heart, vessels, and GI tract.27
||Striking glomerular involvement with little or no vascular or interstitial amyloid deposits.27-31
||Nephrotic syndrome with progressive renal dysfunction.30,31
||High rate of recurrence in the graft. Similar results with combined liver-kidney transplantation.27,30-33
||GI, liver, kidney, and salivary gland.
||Glomerular, vascular, and interstitial deposits.34,35
||Widespread phenotypic heterogeneity, variable rate of progression but mostly slow.
|Recommended based on limited data of excellent graft function in several cases.34,35
||Nerves, eyes, skin, kidneys, blood vessel, heart, lung, liver, and muscles.36-38
||Mild, slow progressive CKD with variable proteinuria.36
||Recommended. Several successful kidney transplantations without clinically significant recurrence in the graft.38,39
||Kidney, heart, GI tract, nervous system, skin, larynx, liver, and testes.40,41
||Mostly glomerular but can have medullary and interstitial involvement.40
||Pattern of renal injury depends on the specific mutation. Mostly slow progression. Sometimes only tubulointerstitial/medullary involvement with urinary concentrating defect and minimal tubular proteinuria.40,41
||Recommended given excellent graft survival due to very slow disease recurrence. Combined liver-kidney transplant if widespread amyloid liver disease also present.41,42
||Mainly kidney. Rarely heart, liver, spleen, adrenal, and pancreas.43
||Mostly glomerular with some vascular involvement.43
||Proteinuria and slowly progressive renal disease. Timing of ESRD is variable.43,44
||Recommended given prolonged graft survival and no recurrence for long time.43,44
||Kidney and heart.45
||Slowly progressive CKD, usually no significant proteinuria.45
||Recommended although long-term outcome after renal transplantation is not known.
||Glomerular and medullary interstitium.46
||Proteinuria with CKD.46
||Renal transplantation has not been reported.
||Kidney, salivary gland, and hypotriglyceridemia.
||Prominent vascular involvement in all compartments. Variable glomerular and interstitial involvement.47
||Variable proteinuria. CKD advancing to ESRD over several y.47
||Renal transplantation has been reported with variable outcomes.47
||All organs except CNS.
||Mostly glomerular but all renal compartments can be involved.48,49
||Proteinuria and CKD. ESRD within y if no response to treatment. Good prognosis if source of inflammation is controlled achieving low SAA levels.48-50
||Recommended assuming control of underlying inflammatory process and achievement of low SAA level.33,50-54
||Leukocyte chemotactic factor
||Kidney, liver, and adrenal gland.55
||Glomerular, interstitial and vascular involvement, mostly in cortex and less in medulla.56,57
||Slow progressive course. Proteinuria can be absent or in variable degrees.55
||Limited information however outcomes after renal transplantation seem to be good. Donor kidneys with limited ALECT-2 did not develop allograft failure despite persistence of amyloid deposits.57,58
AA, amyloid A; AFib, fibrinogen A alpha; AGel, gelsolin; AH, heavy chain; AL, light chain; ALECT-2, leukocyte chemotactic factor-2; ApoAI, apolipoprotein AI; ApoAII, apolipoprotein AII; ApoAIV, apolipoprotein AIV; ApoCII, apolipoprotein CII; ApoCIII, apolipoprotein CIII; CKD, chronic kidney disease; CNS, central nervous system; CR, complete response; ESRD, end-stage renal disease; GI, gastrointestinal; LC, light chain; LYZ, lysozyme; SAA, serum amyloid A; TTR, transthyretin; TTRv, mutated TTR; Tx, transplantation; VGPR, very good partial response.
Factors that determine amyloid fibril formation and deposition in the kidneys are likely the result of the interaction between the amyloidogenic protein and local tissue factors. For example, the glomerular basement membrane has a high glycosaminoglycan content that might promote fibrillogenesis and protect fibrils from proteolysis by inducing conformational changes in precursor proteins.59-61 Local pH might also play a role in promoting amyloid formation as in the case of apolipoprotein AI (ApoAI) amyloidosis in the medulla.40 In addition, different amino acid sequences can alter tissue tropism of certain proteins and cause them to have a preference towards deposition in certain organs as in the case in the various TTR mutations.22,24-26,62,63 Proteolysis may also play a role in amyloid fibril formation. In the case of AL amyloidosis, it has been hypothesized that LCs are taken up by the mesangial cells, where they are disassembled by the lysosomal pathway and then form amyloid fibrils.13,64-66 AA amyloid proteins are proteolytic fragments from SSA and their lysosomal degradation might be involved in the pathophysiology of AA amyloidosis.67
Amyloid can deposit in all parts of the kidney; however, it most commonly involves the glomeruli15 followed by the vasculature, tubules, and interstitium. The localization of the amyloid deposits affects the clinical presentation. Renal involvement in amyloidosis usually manifests as proteinuria over 0.5 gram and/or deteriorating renal function due to glomerular deposition. However, there are exceptions to this rule: sometimes proteinuria is nonexistent or only minimal, as in cases where the deposits are found mainly in the vessels, in the interstitium or only in the medulla (sparing the cortex entirely), which can happen in AL, apolipoprotein AIV (ApoAIV) or ALECT-2 amyloidosis, etc.56,68 In rare cases, where only renal medullary deposits are present, the main symptom initially is urinary concentrating defect leading to polyuria and nocturia.40
Before the development of more precise methods of diagnosing the specific forms of amyloidosis and the introduction of new, effective therapies for the treatable forms of amyloidosis, transplant outcomes in amyloidosis patients were discouraging.69,70 Amyloidosis patients who were transplanted between 1973 and 1981 had worse 3year survival than patients with end-stage renal disease (ESRD) due to glomerulonephritis (51% versus 79%).70 Mortality was concentrated in the early posttransplantation period and a high rate of amyloid recurrence in the graft was observed. A more recent report based on the United Network for Organ Sharing registry data of 576 patients with ESRD due to systemic amyloidosis of all forms (AL, AA, and hereditary combined) transplanted between 1987 and 2015, indicated that patient and graft survivals were somewhat diminished compared to kidney transplant recipients overall.71 However, they were comparable to other high-risk subgroups including diabetes-associated ESRD and elderly patients (>65 y of age at the time of transplant).71
AL amyloidosis is the most common type of amyloidosis.72,73 It results from overproduction of aberrant LCs by a malignant plasma cell clone. The kidneys are involved in 70%–80% of cases16,74,75 and 19%–42% of patients require renal replacement therapy during the course of their disease.16,76 The life expectancy and quality of life of AL amyloidosis patients on dialysis from the early 1990s had been reported as worse than those with ESRD from other causes.77-79 However, in recent reports, the median overall survival (OS) of AL amyloidosis patients from dialysis initiation was 39 months, similar to the general ESRD population, suggesting that mortality is mainly driven by ESRD after dialysis initiation not by amyloidosis. This improvement in survival on dialysis is likely attributable to the fact that AL amyloidosis has become a more treatable disease with much improved mortality rate.16,17
Treatment of AL amyloidosis is aimed at the abnormal plasma cell clone to halt the production of LCs (Table 2). Until the mid-1990s, treatment of AL amyloidosis was limited to melphalan and prednisone. Hematologic response to this therapy was insignificant and delayed, resulting in a median OS of only 12–18 months from the time of diagnosis.89,90 Survival has improved considerably in the past 2 decades due to the rapidly expanding arsenal of newer and more effective therapies. These include high-dose melphalan with autologous stem cell transplantation (HDM/SCT), protease inhibitors (PIs; bortezomib, ixazomib, and carfilzomib), immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide), and monoclonal antibodies (daratumumab, elotuzumab, and isatuximab).80-82
TABLE 2. -
Current treatment options for various amyloid subtypes to prevent end-stage renal disease
|Type of amyloidosis
||Current treatment options
||Chemotherapy directed at the underlying plasma cell dyscrasia: melphalan with autologous stem cell transplantation (HDM/SCT), proteasome inhibitors (bortezomib, ixazomib, and carfilzomib), immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide), monoclonal antibodies (daratumumab, elotuzumab, and isatuximab).80-82
||Good renal outcomes with potential reversal of renal damage especially in patients with CR/VGPR.17-19,83,84
||Renal involvement only with a few mutations. New therapies with TTR stabilizers (diflunisal and tafamidis) and gene silencing (patisiran and inotersen)22,85-88 were introduced for polyneuropathy and cardiac involvement.
||The effect of these drugs on renal outcomes is not yet known.
|AFib, LYZ, AGel, ApoAI, ApoAII, ApoAIV, ApoCII, ApoCIII, ALECT-2
||Conservative management, no disease-specific therapy is currently available.
||Variable, depending on mutation.
||Treatment of the underlying infectious or inflammatory process.33,50-54
||Potential reversal of renal damage with successful treatment.
AA, amyloid A; AFib, fibrinogen A alpha; AGel, gelsolin; AH, heavy chain; AL, light chain; ALECT-2, leukocyte chemotactic factor-2; ApoAI, apolipoprotein AI; ApoAII, apolipoprotein AII; ApoAIV, apolipoprotein AIV; ApoCII, apolipoprotein CII; ApoCIII, apolipoprotein CIII; CR, complete response; HDM/SCT, high-dose melphalan with autologous stem cell transplantation; LYZ, lysozyme; TTR, transthyretin; VGPR, very good partial response.
These breakthroughs in treatment resulted in more frequent and durable hematologic response.72,91-93 According to the response criteria described by Palladini et al,18 complete hematologic response (CR) is defined as negative serum and urine protein electrophoresis and immunofixation, as well as normal serum free LC (FLC) ratio; very good partial response (VGPR) is defined as the difference between involved and uninvolved LCs (dFLC) <40 mg/L.94 Partial hematologic response (PR) is achieved when dFLC is decreased by >50% in patients with baseline dFLC > 50 mg/L and in some cases it has also led to improved outcomes.72,95 A rapid decrease of the circulating amyloid precursor protein concentration can reverse renal dysfunction with time (median time from hematologic response to renal response is about 10 mo17,18,83) but not all patients can achieve a good renal outcome. Concurrent with the overall improvement in patient survival, there now is the increasing incidence of chronic kidney disease (CKD) leading to ESRD.
Over the past decade, renal staging and renal response criteria have been developed to predict the risk of ESRD in AL amyloidosis patients.16,17,83 The risk for progression to dialysis was found to correlate with stages of renal involvement (stage I: eGFR ≥ 50 mL/min/1.73 m2 and <5 g/24 h proteinuria; stage II: either eGFR <50 mL/min/1.73 m2 or ≥ 5 g/24 h proteinuria; and stage III: eGFR <50 mL/min/1.73 m2 and ≥ 5 g/24 h proteinuria). The cutoff for predicting favorable renal outcome was a ~30% decrease in proteinuria at 6-month posttreatment (or a drop of proteinuria below 0.5 g/24 h) without worsening of eGFR, while a ~25% decrease in eGFR correlated with worse renal outcome.18,83
Regardless of hematologic response to treatment, amyloid fibrils are very stable structures that can take years to disintegrate.4,96,97 Advanced CKD due to amyloid deposition in the kidneys can continue to progress to ESRD even without additional amyloidogenic LC deposition. The exact mechanism has not yet been elucidated, but it seems that there is a certain point of no return, and in some cases, the chronic damage is too advanced and therefore irreversible. An alternative explanation is that in some cases there are still amyloidogenic LCs albeit below the detection level leading to additional fibril deposition.98
Kidney Transplantation in AL Amyloidosis
Referral for kidney transplantation in AL amyloidosis has been limited given the initial experience of early graft loss and shorter OS due to recurrence of disease in the renal graft or extrarenal organs.70,99
Following the introduction of HDM/SCT in the late 1990s, a study published in 2003 from Boston University demonstrated encouraging results in 3 patients with AL amyloidosis who underwent kidney transplantation after successful treatment with HDM/SCT. All 3 patients were alive with functioning grafts for a minimum of 64 months.100
Two years later (2005), a group from the Mayo Clinic101 reported the results of a novel treatment approach in 8 patients who underwent living donor kidney transplantation followed by HDM/SCT. Two patients died from surgical complications 10- and 3-month postkidney transplantation. Two cases of subclinical acute cellular rejection and 1 case of clinical acute cellular rejection occurred, all treated successfully. Five of the 6 patients who remained alive underwent HDM/SCT with a favorable hematologic response and no evidence of AL amyloid-producing clone. Renal function remained stable following treatment in 4 and was reduced in 1 patient due to infectious and bleeding complications. Not surprisingly, the sixth patient, who elected not to undergo HDM/SCT after he received his kidney transplantation, developed proteinuria and histologic evidence of recurrent renal amyloidosis. The study concluded that living donor kidney transplantation followed by HDM/SCT is a viable option for carefully selected patients with ESRD due to AL amyloidosis. Since then, 2 other studies reported no difference in outcomes of highly selected patients undergoing kidney transplantation either before HDM/SCT or after19,102 but in most of the recent studies patients had successful hematologic treatment first followed by kidney transplantation.
A study published in 2010 by a group from the UK103 reported the outcomes of 22 patients with systemic AL amyloidosis followed between 1984 and 2009 who underwent kidney transplantation following first-line hematologic treatment (either chemotherapy, HDM/SCT or both). One- and 5-year survival was 95% and 67%, respectively. Median estimated OS from diagnosis and from renal transplantation according to Kaplan-Meier analysis was 9.1 and 6.5 years, respectively. No graft failed due to amyloid deposition over a median follow-up of 4.8 years (range, 0.2–13.3), although recurrence was evident in 5 patients after a median time of 5.6 years (range, 4.4–7.8) from renal transplantation. One patient developed proteinuria from amyloid deposition in the graft 6.2-year postrenal transplantation, which resolved after successful chemotherapy with preservation of graft function. Amyloid recurrence in this study was demonstrated by serum amyloid P scintigraphy. Serum amyloid P is a glycoprotein which is present in all amyloid deposits and likely protects them from degradation.104,105 This imaging technique, however, is available only at the NHS National Amyloidosis Centre and it has not been developed commercially.106
Another study published in 2011 from the Mayo Clinic reported 19 patients with AL amyloidosis who underwent renal transplantation between the years 1999–2008.102 Outcomes were compared between 3 groups: kidney transplant post HDM/SCT (n = 6), kidney transplant followed by SCT/HDM (n = 8), and kidney transplantation following CR achieved using standard chemotherapy (nonmyeloablative; n = 5). Graft survival was not different between the 3 groups and median time to death/graft loss was not reached. Two patients were diagnosed with recurrent amyloidosis in the graft; however, at the median follow-up time of 41.4 months, grafts were still functioning.
We recently published a study reporting the largest series of patients with AL amyloidosis who underwent kidney transplantation over a period of 3 decades (1987–2017).19 Outcomes of our cohort were better than previously reported in this patient population with a median OS from diagnosis and kidney transplantation of 15.4 and 10.5 years, respectively, and comparable to other high-risk populations including patients with diabetes and over the age of 65.107,108 Patients who achieved CR/VGPR had significantly better survival compared to those with PR or no response to treatment. One- and 5-year graft survival were 94% and 81%, respectively. There was a trend towards better graft survival in patients with favorable hematologic response—median time to graft loss was 10.4 years in the CR/VGPR group versus 5.5 years in PR/no response group. Patients with better hematologic response also had lower rates of disease recurrence in the graft. Additionally, and in concordance with more effective antiplasma cell treatments (including HDM/SCT and PIs), OS and graft survival of transplantations performed during the most recent decade were significantly better compared to transplants performed in the first 2 decades of the study period. In light of these outcomes, in their commentary Nuvolone and Merlini109 recommended consideration for kidney transplantation of those patients who achieved at least a VGPR to hematologic treatment.
Importantly, second- and third-line treatments have been successfully used in renal transplant recipients who had a hematologic relapse substantially prolonging OS and graft survival.19 Notably, there were no reports of higher rates of graft rejection or infectious complications with the use of HDM/SCT or PIs in renal transplant recipients; however, immunomodulatory drugs have been reported to increase immune responses by causing activation of T cells, natural killer cells, and cytokine excretion as well as inhibition of the PD-L1/PD-1 axis which might increase the risk of allograft rejection.110-113
There are several important questions that remain open. First, what is the best timing for kidney transplantation in this patient population? There is usually a time-lag between successful hematologic treatment and renal transplantation that is attributed not only to the evaluation process for kidney transplantation and recovery from treatment-related toxicities but also to the time needed to ascertain the type and durability of hematologic response. We usually recommend waiting 6–12-month posttreatment before consideration for transplantation. While in the various studies the majority of the patients underwent kidney transplantation following successful hematologic treatment, some patients had them in reverse order: kidney transplantation first, followed by hematologic treatment. Even though the numbers are small in this second group, this approach seems to be also applicable in selected patients who are close to or at ESRD at diagnosis, without major extrarenal involvement and who meet other standard criteria for renal transplantation. If these patients have a living donor, kidney transplantation would be feasible within a short period of time followed by HDM/SCT.19,102
Another important question would be whether dialysis-dependent patients without extrarenal amyloidosis but still with detectable disease should receive hematologic treatment while on dialysis for the sole purpose of achieving a clonal response to allow listing for renal transplantation. Alternatively, such patients could undergo renal transplantation first followed by hematologic treatment to prevent ongoing amyloid deposition and disease recurrence in the graft.
Up until now, all AL amyloidosis patients received standard antirejection medications according to protocols of local transplant centers and no modified immunosuppressive strategies have been evaluated in this disease.
In terms of detecting disease activity, much progress has been made over the past decade. Newer, more sensitive detection methods have become available that utilize next-generation sequencing, next-generation flow cytometry or mass spectrometry to find aberrant plasma cell clones in the bone marrow or circulating amyloidogenic LCs in the blood which are below the detection level for standard methods.114 To date, these methods have been used primarily in multiple myeloma (MM) to ascertain hematologic response and led to the identification of minimal residual disease (MRD).115 The presence of MRD in patients with MM who achieve CR has been shown to be associated with inferior disease-free survival compared to MM patients achieving CR that had no evidence of MRD.114,116 MRD was also evaluated in AL amyloidosis showing that 45%–60% of those thought to be in sustained CR are actually MRD positive.98,117 These new methods could help further define the quality of hematologic response and rule out ongoing clonal LC production in patients thought to be in CR. Nevertheless, one must bear in mind that the clinical significance of MRD is yet to be proven in AL amyloidosis.
In conclusion, treatment for AL amyloidosis patients has advanced dramatically in the past 2 decades, resulting in prolonged patient survival and increasing number of AL amyloidosis patients on chronic dialysis. Recent studies demonstrated good renal transplant outcomes, especially in patients with a favorable response to hematologic treatment. Additionally, second- and third-line treatments have been successfully deployed in renal transplant recipients and they substantially prolonged OS and graft survival after hematologic relapse. We therefore recommend consideration of renal transplantation for those patients with AL amyloidosis who develop ESRD and achieve hematologic CR/VGPR to plasma cell clone directed treatment. Determining eligibility criteria, as well as peritransplant and posttransplant management, requires a multidisciplinary approach involving nephrologists, transplant surgeons, and hematologists with experience in the treatment of this disease.
AH AND AH/AL AMYLOIDOSIS
AH and heavy/light-chain amyloidosis are rare entities in which the amyloid deposits are derived from fragments of the AH only or from both AH and AL.20 Light microscopic features are similar to AL amyloidosis but sometimes there are atypical features, including periodic acid-Schiff positivity, mesangial hypercellularity, or more prominent glomerular basement membrane than mesangial involvement. These patients seem to have less frequent concurrent cardiac involvement, higher likelihood of having circulating complete monoclonal immunoglobulin, lower sensitivity of fat pad and bone marrow biopsy for detecting amyloid deposits and better patient survival. Approach to hematologic treatment is identical to AL amyloidosis and therefore our recommendation regarding renal transplantation is the same as for AL amyloidosis patients.
Hereditary renal amyloidosis is associated with mutated proteins encoded by 8 genes: TTR, AFib chain, LYZ, AGel, ApoAI, apolipoprotein AII (ApoAII), apolipoprotein CII (ApoCII), and apolipoprotein CIII (ApoCIII).28 They tend to be inherited in an autosomal dominant pattern with highly variable penetrance among those affected. The diagnosis of hereditary amyloidosis can be challenging since 3%–5% of older individuals have a monoclonal protein hence some patients with hereditary amyloidosis and a monoclonal gammopathy of undetermined significance can be misdiagnosed as having AL amyloidosis. To avoid exposure to unnecessary harmful treatments, in every case the amyloid protein has to be typed from tissue deposits by one or more of the following techniques: immunohistochemistry, immunogold electron microscopy and tandem mass spectrometry-based proteomic analysis. Protein sequencing and genetic analysis should also be performed, where hereditary amyloidosis is suspected. Given the lack of effective treatment for most of the hereditary forms of amyloidosis,14 there is high incidence of progressive CKD and ESRD in these patients. Emerging therapies that seek to inhibit the synthesis of the mutant protein, prevent the formation or promote the clearance of amyloid fibrils may alter the therapeutic approach to these diseases in the future.
Hereditary TTR Amyloidosis
TTR, which functions as a binding protein for thyroxine and vitamin A, is one of the most abundant proteins in the body. It is manufactured primarily in the liver (90%); however, it is also produced in the retina and choroid plexus in smaller amounts.118 Wild-type TTR (ATTRwt) protein circulates in the form of a tetramer, and to form amyloid fibrils the TTR configuration needs to first dissociate into monomers, undergo conformational change and then reassemble to form the fibrils.23 Deposition of the nonmutated, ATTRwt can form deposits mainly in the heart and causes ATTRwt amyloidosis leading to cardiomyopathy mostly in men over 70 years of age and is not hereditary.63 This disorder is separate from hereditary TTR amyloidosis, which is an autosomal dominant disorder, as a result of misfolding and self-aggregation of the mutated TTR (TTRv) protein. Hereditary TTR amyloidosis is the most common form in the hereditary group and over 100 single or double point mutations of the TTR gene have been described. The most common presentations are amyloid cardiomyopathy and severe, progressive peripheral neuropathy with dysautonomia.21 Each genetic variant has a characteristic organ involvement pattern, although clinical differences attributed to environmental and genetic factors exist even within the same family. Several mutations (Val30Met, Val30Ala, Phe33Cys, and Gly47Glu) result in TTR amyloid deposition in the kidney leading to variable degrees of proteinuria and CKD.21 On kidney biopsy, TTRv deposits have been described in all renal compartments.23,25,26
Given the fact that TTR is produced mainly in the liver, kidney transplantation in hereditary TTR amyloidosis has only been reported in small series and mainly as part of combined liver-kidney transplantation. In a small series of 6 patients who underwent combined liver-kidney transplantation, none of the patients had evidence of recurrence of kidney disease 7-year posttransplantation.24 Preemptive liver transplant has also been utilized in a small number of patients but orthotopic liver transplantation (OLT) outcomes are not always favorable, and even successful treatments are controversial in terms of nephropathy progression.26,119-122 Interestingly, explanted livers from these patients have been utilized for domino transplantation despite their production of aberrant TTR, as they are otherwise functionally and anatomically normal. As hereditary TTR amyloidosis takes many years to manifest clinically, the assumption is that the recipient of the new liver will likely not live long enough to develop significant disease.123 Recent studies though reported an accelerated time course in some TTR liver recipients with de novo amyloid manifestations after 8–10 years making domino liver transplants less desirable.124
New therapies for TTR amyloidosis have been developed in the past few years (Table 2). The 2 major types of therapies are TTR stabilizers (diflunisal and tafamidis) and gene silencing therapies (patisiran and inotersen).22,85 Tafamidis is approved for TTR neuropathy (both TTRv and TTRwt), has shown benefit in reduced mortality and cardiovascular-related hospitalizations compared to placebo and is under review for the treatment of TTRv cardiac amyloidosis.86-88 The effect of these drugs on renal outcomes is not yet known.
Fibrinogen is a plasma glycoprotein synthesized by the liver and essential for coagulation.29 AFib amyloidosis is an autosomal dominant disease resulting from a single amino acid substitution or frameshift mutation and causes nephrotic syndrome with progressive renal dysfunction. On renal biopsy, glomerular involvement is striking with little or no vascular or interstitial amyloid deposits.28,32 Renal progression is somewhat faster than with the other hereditary forms: median time from diagnosis to ESRD is 4.6 years.30 Clinically significant extrarenal organ involvement is rare but deposits can be found in the heart, vessels, abdominal fat, GI tract, and atheromatous plaques.32
Gillmore et al30 followed 71 patients with biopsy-proven renal AFib amyloidosis with 44 patients reaching ESRD. Twelve of these patients underwent kidney transplantation with a median graft survival of 6 years (range, 0–12.2). Seven grafts had failed after a median follow-up of 5.8 years, including 3 from recurrent amyloid after 5.8, 6.0, and 7.4 years; 3 due to surgical complications immediately after transplantation and one that failed from transplant glomerulopathy after 5.8 years without histological evidence of recurrent amyloid. Given that the aberrant protein is produced by the liver, preemptive liver transplantation or combined liver-kidney transplantation to replace the source of the circulating amyloidogenic fibrinogen with the wild-type protein can be considered, but this remains controversial due to the higher posttransplant mortality rate with OLT versus solitary kidney transplantation.27,31,125 For example, Stangou et al27,32 reported a series of 9 patients who underwent preemptive combined liver-kidney transplantation. In this study, there was a high death rate observed with 2 deaths from postoperative complications immediately after liver transplantation. One out of the 7 surviving patients had to go back on dialysis due to chronic allograft nephropathy by the end of the median follow-up period of 67 months. In another study of 19 patients, the median graft survival among patients with isolated kidney transplant was 7.3 years compared to 6.4 years in those who received combined liver-kidney transplants (P = nonsignificant).33 Five- and 10-year graft survival were 85% and 30% in patients with isolated renal transplantation, and 63% and 31%, respectively, in those with combined liver-kidney transplantation. After a median time of 4.9 years, recurrent amyloid was documented in 7 of the 12 patients who underwent isolated kidney transplantation leading to 3 graft losses. No patient with a combined liver-kidney transplant developed amyloid in the new renal allograft.33 In a series of 6 patients from Portugal, 2 patients lost their grafts due to nonamyloid-related complications soon after transplantation but the patients without these complications did reasonably well; 1 patient died after 16 years with a functioning graft and 3 more patients were stable with functioning grafts at last follow-up.126 Some patients benefited from liver transplantation alone even with advanced CKD and removal of the mutant protein production from the liver seems to have arrested or in a few cases reversed kidney disease progression.127,128
LYZ is a bacteriolytic enzyme that is synthesized by hepatocytes as well as macrophages and GI cells. This autosomal dominant subtype has been associated with a variety of GI symptoms including abdominal pain, nausea, vomiting, diarrhea, hepatic infiltration, GI bleed, malabsorption, and weight loss, as well as sicca syndrome due to salivary gland involvement, lymphadenopathy, and heart disease.33 Renal function decline is usually slow (median time from diagnosis to ESRD of 10.6 y) with some degree of proteinuria (mostly subnephrotic) but there is widespread phenotypic heterogeneity between subjects and some patients progress to ESRD rapidly.34,35
In a series of 3 patients who received kidney transplants, all had excellent graft function at 0.9, 2.9, and 6.2 years posttransplant without evidence of amyloid recurrence in the allografts.33,34 At this time there are no documented cases of graft failure from LYZ amyloidosis in the literature but there is 1 case report, where the patient who underwent renal transplantation had documented amyloid recurrence in the graft 17-year posttransplantation albeit with only mild renal failure and proteinuria and no sign of amyloid extrarenal progression.35 The role of preemptive liver transplantation or combined liver-kidney transplantation in this disease has not been defined but isolated renal transplantation outcomes seem to be very good even without replacement of the liver producing the mutant protein, likely due to the slowly progressive nature of this disease. In addition, LYZ is also synthetized in the GI tract and therefore liver transplantation would not be able to completely eliminate the production of the mutant protein making the potential benefit from OLT less significant.
AGel amyloidosis (also is known as familial amyloidosis of Finnish type) is an autosomal dominant form where the mutated AGel deposits in a variety of tissues including nerves, eyes, skin, kidneys, blood vessel, heart, lung, liver, and muscles.36,37,129 It is an actin filament severing protein and this disease has a 100% penetrance. The severity of the symptoms varies remarkably between patients though. Symptoms usually emerge after the 3rd decade of life and typically include lattice corneal dystrophy, progressive neuropathies including involvement of the cranial nerves (eg, bilateral facial paresis), and development of cutis laxa requiring plastic surgery. Renal involvement is not universal and when it presents, it is usually mild, slowly progressive with nephrotic or subnephrotic range proteinuria. Nevertheless, a small percentage of the patients do progress to ESRD.36,38 Several patients underwent successful kidney transplantation without clinically significant recurrence in the graft with the follow-up period of >6 years and therefore we recommend renal transplantation in this patient population.38,39
ApoAI is a major constituent of high-density lipoprotein (HDL) and is secreted by the liver and intestine.32,41 The clinical presentation of ApoAI amyloidosis is widely variable depending on the affected organs and can involve the kidney, heart, GI tract, nerves, skin, larynx, liver, and testes.40,41 The pattern of renal injury is inconsistent and depends on the specific mutation. The timing of ESRD can be vastly different even within families. Nonetheless, progression of renal impairment is often very slow. In addition to nephrotic syndrome and progressive renal dysfunction, a small number of cases have been shown to mainly involve the tubulointerstitium or medulla leading to only minimal tubular proteinuria or urinary concentrating defects with polyuria.40 Heart, liver, and kidney transplantation, isolated or combined, have been reported in patients with ApoAI.41
In one series of 10 patients who underwent kidney transplantation for ApoAI amyloidosis, 7 out of 10 patients had functioning grafts with a median follow-up of 9 years (range, 0.2–27) posttransplant.41 Two patients died, one of disseminated cytomegalovirus infection 2 months after renal transplantation and the other of severe trauma >13 years after renal transplantation. Five patients had histologic evidence of recurrent amyloidosis in the graft but disease progression was very slow and only 1 graft failed due to recurrence of amyloidosis after 25 years. In this series, 2 patients had combined liver-kidney transplantation, where the indication for liver transplantation was advanced liver involvement. In both of these cases, regression of existing extrahepatic amyloid deposits was documented. In spite of this favorable outcome with liver transplantation, the case for combined liver-kidney transplant remains weak without evidence of widespread liver disease, given the good outcomes of isolated kidney transplantation and the fact that only approximately 50% of plasma ApoAI is derived from liver synthesis.41,42
In another report of 16 patients, 14 had kidney only transplantation, 1 had kidney-liver and 1 had kidney and heart. Five- and 10-year graft survival was 100% and 77%, respectively. Three patients were found to have recurrent amyloid in their grafts after a median of 3.5 years.33 Similar outcomes were reported in another series of 5 patients, where only 1 graft was lost after 5 years due to recurrent disease.130 Organ transplantation should be offered in hereditary ApoAI amyloidosis since graft survival is excellent with substantial survival benefit due to very slow disease recurrence.
Similar to ApoAI, ApoAII is also a large component of the HDL protein that is synthesized in the liver and intestine. Organ involvement is usually limited to kidneys but extrarenal amyloid deposits were found either accidentally or at postmortem evaluation in the heart, liver, spleen, adrenal gland, and pancreas.43 The pattern of kidney injury typically results in proteinuria and slowly progressive renal disease but the onset of symptoms and the timing of renal failure is variable.43,44 In 1 case report, the patient developed ESRD at age 45 and underwent successful deceased kidney transplantation with stable graft function over the 9-year follow-up period.44 At our center, we currently follow 3 patients who underwent renal transplantation without amyloid recurrence in the graft 16, 4, and 2-year posttransplantation suggesting that renal transplantation is a good option for these patients.
ApoCII amyloidosis predominantly involves the glomeruli and medullary interstitium resulting in renal failure and proteinuria. To date, 2 mutations have been described for ApoCII.46 No renal transplantations have been reported in this form.
ApoCIII is a small exchangeable apolipoprotein carried in the circulation by very low-density lipoprotein (VLDL) and HDL and a mutant variant was reported to be associated with progressive renal amyloidosis, hypotriglyceridemia, and sicca syndrome secondary to diffuse salivary gland deposits.47 There is prominent vascular involvement in all compartments of the kidney with ischemic glomerular lesions that would explain the low-grade proteinuria and severe hypertension but can also have glomerular and interstitial involvement. Renal transplantations have been reported in a few cases but long-term outcomes are not known.47
NON-AL, NONHEREDITARY FORMS OF AMYLOIDOSIS
Systemic AA amyloidosis is the result of a longstanding chronic inflammatory state that leads to the deposition of the acute phase protein SAA in the form of amyloid fibrils in various organs. SAA is synthesized as a precursor protein by the liver in response to transcriptional stimuli from various proinflammatory cytokines. Similar to AL amyloidosis, this form can also affect almost every organ but renal involvement usually dominates the clinical picture. Autoimmune diseases (rheumatoid arthritis, inflammatory bowel disease, and ankylosing spondylitis), chronic infections (osteomyelitis, chronic skin ulcers, and tuberculosis), and certain neoplasms (renal cell carcinoma, Hodgkin lymphoma, and Castleman disease) have all been well described in the pathogenesis of this disease.48,49,51 A number of genetic disorders can also cause AA amyloidosis including familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome. In 1 series, the median duration of symptomatic inflammatory disease before the diagnosis of amyloidosis was 17 years.48 Renal disease is particularly common in patients with persistently elevated circulating SAA levels and presents with nephrotic syndrome and progressive renal failure.33,48,49,51 The time to ESRD after diagnosis is variable, depending on the underlying pathology and response to treatment.
Depending on the population studied, AA amyloidosis is the second or third most common form of systemic amyloidosis; however, it is becoming less prevalent as a result of advances in the recognition and treatment of the commonest pathologies underlying AA amyloidosis. There is an increasing subset of patients though, that have no identifiable cause even after extensive workup. In more recent cohorts, this number was up to 27% from 6%–10%.48,49 Interestingly, an increasing proportion of patients reach ESRD likely due to the fact that patients survive longer.49
Before undergoing kidney transplantation, it is vital to determine and control the underlying inflammatory process to prevent recurrent amyloid deposition in the allograft or new fibril formation in other vital organs (Table 2). In cases where no underlying etiology is found, we recommend empiric treatment with colchicine or biologics with activities against proinflammatory cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-1, and IL-6) with close monitoring of inflammatory markers and SAA levels. If there is an adequate response to these treatments, then we recommend renal transplantation even for these patients.
Renal transplant outcomes have been excellent in FMF patients since the introduction of colchicine therapy.52,53 In a cohort of 16 FMF patients, both patient and graft survival were comparable to nonamyloid renal transplants patients and colchicine therapy prevented the recurrence of both FMF symptoms and AA amyloidosis.54 In some cohorts of FMF patients, transplant outcomes were reported to be somewhat less favorable than propensity score-matched controls though.131 In 1 multicenter retrospective study of 59 AA amyloidosis patients who underwent kidney transplantation, the recurrence rate of renal amyloid was estimated at 14%. It was also noted that the 5- and 10-year patient survival was somewhat lower for the AA amyloidosis patients than for the control group (82.5% versus 94.2% at 5 y and 61.7% versus 83.4% at 10 years) but there was no statistically significant difference in 5- and 10-y graft survival.51 In another study that sought to determine an association between SAA levels and transplant outcomes, graft survival (noncensored for death) was 14.5 years in patients with a median SAA value of <10 mg/L, and 7.8 years in those with a median SAA of >10 mg/L (P = ns).33 Consequently, SAA level, along with other inflammatory markers, should be closely monitored after renal transplantation.
Leukocyte Cell-derived Chemotaxin-2–associated (ALECT-2) Amyloidosis
ALECT-2 systemic amyloidosis mainly affects the kidney and the liver; it is currently without effective treatment for the disease. Proteinuria is variable and can also be completely absent. Renal failure is usually slowly progressive but there is no typical course. Initially, ALECT-2 amyloidosis was described in older Hispanics from Mexican origin; however, it has increasingly been found in other ethnicities as well.55,57 The pathogenesis has not yet been elucidated but does not seem to be inherited. Clinically meaningful extrarenal involvement is rare, which results in excellent OS. Outcomes after renal transplantation seem to be good: in a series of 5 patients, no graft loss was reported at a median follow-up of 20 months and only 1 patient had amyloid recurrence on a kidney biopsy, albeit without significant renal impairment.57 Interestingly, patients who accidentally received kidneys with donor-derived limited ALECT-2 amyloidosis did not develop allograft failure even though amyloid deposits persisted for up to 8 years on protocol biopsies or in evaluation of suspected rejection.57,58
ApoAIV is a common, constitutive, but usually noncausative component of amyloid deposits, except when it is found in extensive medullary deposits with a large spectra number by mass spectrometry and without other amyloidogenic proteins. This form of amyloidosis causes slowly progressive renal failure almost always without significant proteinuria and can also involve the heart.45,132 Of note, this variant may be underdiagnosed because the renal medulla is often not sampled during renal biopsy. The pathophysiology of the disease is not known and genetic analysis has not identified definitive pathological mutations. Given the rarity of this disease, the long-term outcome after renal transplantation is not known but considering what is known about this form we do recommend renal transplantation for ApoAIV patients.
In recent years, an increasing number of patients with systemic amyloidosis are referred for renal transplant evaluation. Due to the complex nature of the pathophysiology and treatment of these diseases, determining eligibility, as well as peritransplant and posttransplant management, requires a multidisciplinary approach with close monitoring and follow-up (Figure 2).
We acknowledge the participation of colleagues in the Amyloidosis Center at Boston University School of Medicine and Boston Medical Center, as well as other clinical colleagues involved in the evaluation and management of the patients with amyloidosis.
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