Pathogenesis and kidney prognosis of renal amyloidosis.

Introduction

Systemic amyloidoses are a family of disorders characterized by organized deposition of aggregates of a conformationally unstable precursor protein in organs that are distant from the site of production. Amyloidoses are classified based on the identity of the precursor protein, such as an immunoglobulin light chain for AL amyloidosis. Kidneys can be involved and for AL amyloidosis, circa 60–70% of patients present with a degree of renal manifestations. Systemic amyloidoses lead to significant morbidity resulting in decreased quality of life for patients and healthcare burden for society [ 1 ]. In an analysis of Medicare beneficiaries, patients with AL amyloidosis had nearly 4 times higher mortality and 5 times higher healthcare costs compared to non-disease controls [ 2 ]. Over 40 proteins have been recognized as clinically amyloidogenic in humans, 15 of which have been reported to affect the kidneys and have been comprehensively overviewed [ 3 ]. Diagnosis is made by kidney biopsy, with direct immunofluorescence and immunohistochemical techniques aiding in diagnosing AL amyloidosis and non-AL amyloidses respectively [ 4 ]. Additionally, laser microdissection with mass spectrometry can be a valuable asset in identifying precursor proteins as a “one-stop” method [ 5 ].

In this article we will focus on the pathogenic mechanisms of renal involvement and risk factors of progression to end stage kidney disease (ESKD) of the more prevalent subtypes AL, AA, ATTR, ALECT2, and AFib.

AL amyloidosis

AL amyloidosis is caused by the deposition in target organs of amyloidogenic immunoglobulin kappa (κ) or lambda (λ) light chains organized in fibrils. Deposition of immunoglobulin heavy chain (AH) or both light and heavy chain (AHL) can also occur, but it is rarer. AL amyloidosis is typically driven by a plasma cell dyscrasia, rarely, a post germinal center B cell neoplasia [ 6 , 7 ]. Any organ can be involved by AL amyloid deposition, with the heart being the most common, followed closely by the kidney (circa 60–70% of patients). Altogether AL, AH and AHL contribute to the majority of renal amyloidosis presentation [ 8 , 9 ]. With a median diagnostic age of 63, the incidence of systemic AL amyloidosis ranges near 10.8 to 15.2 cases per million person-years with a slight predilection towards males [ 10 – 12 ]. AL amyloidosis is most typically a sporadic occurrence; however in 2015, Benson et al. reported a pedigree of patients with renal failure and renal amyloid deposition (some positive for κ light chains) inherited in an autosomal dominant pattern without an underlying monoclonal plasma cell dyscrasia [ 13 ]. The complete pathogenic mechanisms of light chain fibril formation, deposition, and injury to the kidneys are only partially understood.

AL amyloidosis: molecular mechanisms

Primary amino acid sequence, post translational modifications such as glycosylation and somatic hypermutation events contribute to tertiary structure changes, thermodynamic instability and propensity for amyloid fibril formation [ 14 – 17 ]. These intrinsic attributes of amyloidogenic light chain are relevant to explain why only 10–15% of patients with multiple myeloma develop systemic amyloidosis, although factors extrinsic to amyloidogenic protein are probably at play [ 18 ]. There is a significant bias toward λ versus κ light chain in AL amyloidosis and this may be due to over expression of two germline gene segments in the variable regions of amyloidogenic lambda chains, interestingly over expression of gene segment 6a preferentially form amyloid in the kidneys [ 19 ]. It is clinically evident that significant variability exists in clinical manifestations in the face of comparable concentrations of amyloidogenic light chains, suggesting a spectrum of direct cytotoxicity and aggregation propensities for distinct light chains.

AL amyloidosis: fibril formation

In the kidneys, amyloidogenic light chains result in glomerulopathy when they interact with mesangial cells through the sortilin-related receptor (SORLA also known as SORL1, encoded by the SORL1 gene) [ 20 – 22 ]. Subsequent transformation of mesangial cells into a macrophage phenotype with multiple lysosomes then ensues [ 23 ]. Mesangial cells endocytose amyloidogenic light chain through clathrin mediated mechanisms which are then intracellularly trafficked through the endolysosomal system with the assistance of Rab family proteins [ 21 , 24 – 27 ]. The amyloidogenic light chains undergo partial digestion preferentially in the mature lysosomal compartment where enzymatic activity (such as with cathepsin B) and the acidic environment stimulates fibrillogenesis prior to exocytosis into the extracellular space [ 21 , 24 , 26 – 28 ]. This is in contrast to tubulopathic light chains that affect proximal tubules after glomerular filtration through the apical megalin and cubulin complex. While the endo-lysosomal process of fibrillogenesis is unclear, Stevens et al. proposes amyloidogenic light chains start with noncovalent dimerization of the variable light (VL) domains before formation of higher order complexes and subsequent packing into fibrils [ 29 ]. Proposedly, the beta pleated sheet structures of AL amyloid fibrils seen on fiber diffraction methods are formed at some point during this process [ 30 ]. As an additional influence, there is also evidence that glycosylation of free light chain structures, which may itself be influenced by primary structure, play a role in its amylogenesis or provides tropism to specific organs [ 16 , 31 ]. Protein cleavage of free light chains adds another level of complexity in determining the patho-mechanisms of AL amyloidosis [ 31 , 32 ]. Kim et al. also revealed the importance of renal solutes, namely urea, enhancing light chain fibril formation by reducing thermodynamic stability and decreasing nucleation lag time which supports the possibility of non-intrinsic factors in the formation of AL amyloidosis [ 33 ].

AL amyloidosis: renal toxicity

Soluble amyloidogenic light chains were previously proposed to exert direct cytotoxicity. Spatial transcriptomics has supported the presence of tissue metalloproteinase activity as well as the presence of heat shock proteins which may play a role in mesangial destruction and mesangial cell apoptosis [ 27 ]. Recently, Charalampous and colleagues discovered 7 different proteomic signatures in AL amyloidosis suggesting at least 7 different patterns of renal toxicity [ 34 , 35 ]. These proteomic findings also suggest a distinct spectrum of contribution of fibrosis and inflammation to the pathophysiology of AL amyloid renal injury [ 36 , 37 ]. These latest advancements in the study of the -omics of AL amyloidosis bring much excitement to the field in targetable areas for novel therapies.

The histopathological findings of AL amyloidosis reveal amorphous, acellular, silver-negative, pale-pink congophillic mesangial expansion at times additionally extending to the glomerular basement membrane, arterioles, arteries, and/or interstitium on light microscopy [ 38 ]. On immunofluorescence, mesangial deposits stain for a single light chain (κ or λ), consistent with a clonal process, and electron microscopy reveals extracellular mesangial deposits of randomly arranged fibrils of 9–11 nm in diameter [ 38 ]. Clinical presentations of renal AL amyloidosis can vary. Most patients present with proteinuria ranging from mild to nephrotic (in two thirds of patients). However bland urine sediment owing to the lack of glomerular inflammation; acute or chronic renal injury; and rarely Fanconi’s syndrome, crescentic glomerulonephritis, or intratubular amyloidosis “cast” nephropathy can occur and reflect distinct distribution of amyloid deposits in across renal structures [ 39 – 42 ].

AL amyloidosis: outcomes and progression to end stage renal disease (ESKD)

In prior decades, median overall survival with plasma cell-directed therapy was about 18–38 months from time of diagnosis; however, use of targeted therapies, immunotherapies and autologous stem cell transplant (ASCT) has extended median survival estimates to 47–70 months from time of diagnosis [ 43 – 48 ]. Extent of cardiac involvement is the single most relevant factor contributing to early mortality and loss of quantity and quality of life [ 44 , 49 ]. Historically, 13–39% of patients were expected to develop end stage renal disease with a median time from diagnosis to ESKD of 26.8–29.5 months although it remains yet to be seen if time to ESKD has improved with current standard of care [ 43 – 47 ]. Pallidini and colleagues validated a renal staging system to prognosticate likelihood of ESKD progression based on eGFR (estimated glomerular filtration rate) and proteinuria at time of diagnosis. EGFR less than 50 mL/min/1.73 m² and proteinuria exceeding 5 g in the 24 h both provide one risk factor. For example, patients presenting with both risk factors (Palladini stage III) had a 60–85% risk of progression to ESKD within 3 years as compared to 7–30% risk for patients with only one risk factor (Palladini stage II) [ 46 ]. It is unclear as to what factors trigger accelerated amyloid formation, deposition, and subsequent nephrotic syndrome portending a worse renal survival. Median overall survival for AL amyloidosis patients on renal replacement therapy has improved from 10.4 to 39 months to 24–39 months with improved supportive care and anti-plasma cell directed therapy [ 43 – 46 , 48 ]. Proteomic analysis suggested that lower levels of matrix fibrosis in amyloid plaques may confer an improved renal survival in specific proteomic clusters of AL amyloid; however, the clinical applicability of these findings is yet to be validated [ 34 ]. Additionally after achieving hematological complete response (CR), minimal residual disease (MRD), detected using next generation flow cytometry, appears to portend a better renal response [ 50 ].

Renal replacement therapy (RRT) in patients with AL amyloidosis is often limited by disease-specific manifestations such as hypotension, gastrointestinal bleeding, and chronic diarrhea [ 51 ]. While hemodialysis (HD) was the chosen RRT modality in the majority of patients in published studies, peritoneal dialysis (PD) remains an option for those with barriers in vascular access and hemodynamic stability. Consideration for use of PD, short daily or long nocturnal hemodialysis for patients with AL amyloidosis with cardiovascular manifestations that limit standard HD have been advocated by the American College of Cardiology (ACC) [ 52 ]. Unfortunately, the impact on outcome of distinct RRT modalities have been poorly studied in AL amyloidosis and there is no objective consensus on best practice at this time consistent with the notion that there are no survival advantages between HD and PD in AL amyloidosis [ 53 ].

For those who underwent renal transplantation with standard selection criteria in the setting of very good partial response (VGPR) or better hematologic response, the overall survival was approximately 9 years from solid organ transplantation [ 54 , 55 ]. Disease recurrence in this subgroup was less than 20% [ 54 ]. For patients with partial response, no response or treatment naïve, overall survival was estimated at 6.8 years from time of solid organ transplantation [ 54 ].

Heavy chain (AH) and Heavy/Light chain (AHL) amyloidosis

AH and AHL amyloidoses are significantly rarer than AL amyloidosis but are similarly driven by a plasma cell disorder or less often a B cell lymphoproliferative disorder [ 56 ]. Due to the paucity of reports, little is known about specific mechanisms of renal injury and outcome of AH and AHL amyloidosis. Epidemiologically, AH and AHL amyloidosis affect males to females in an approximate 2 to 1 ratio with a median age of diagnosis around 63–70 years [ 34 , 57 ]. Renal clinical findings appear similar to AL amyloidosis with similar rates of nephrotic syndrome although with greater rates of hematuria, less cardiac involvement and better response to therapy [ 57 ]. While the mechanisms of renal injury are unclear, recent proteomic study discovered some proteomic overlap between leukocyte chemotactic factor 2 (ALECT2) and AH amyloidosis. AL and AH amyloidosis proteomic signatures were similar, except for the unique presence of AHNAK, immunoglobulin heavy constant mu, and secreted phosphoprotein 2 and absence of apolipoprotein A-I, myosin heavy chain 11, H1.0 linker histone, immunoglobulin lambda constant 3, and tissue inhibitor of metallopeptidase inhibitor 3 in AH amyloidosis. The significance of these differences is yet to be determined.

AA amyloidosis

AA amyloidosis is a complication of chronic inflammatory syndromes which result in the production of the acute phase reactant serum amyloid A family proteins. Serum amyloid A (SAA) encompasses a family of proteins SAA1, SAA2, and SAA4 that are synthesized mostly by the liver and also in minutiae by macrophages, endothelial cells, and smooth muscle cells [ 58 – 60 ]. Levels of SAA may rise up to 1000 fold in inflammatory conditions [ 59 ]. Underlying disorders driving AA amyloidosis include but are not limited to chronic infections, inflammatory bowel disease, hereditary inflammatory syndromes, autoimmune disorders, and various neoplastic processes [ 61 ]. The incidence of systemic AA amyloidosis is about 1–2 cases per million person years with a median age at diagnosis of 50–70 years of age and a slight predilection towards male sex. Incidence appears higher in certain European and developing countries, likely reflecting epidemiology of underlying driver disorders whether primarily infectious or inflammatory [ 4 , 62 , 63 ]. For example, AA amyloidosis can occur secondary to chronic inflammation stemming from familial mediterranean fever, an inherited disorder with high incidence in individuals of the Mediterranean basin and middle eastern countries of origin [ 64 ].

While most cases of AA amyloidosis have an underlying chronic inflammatory driver disease, Sikora and colleagues recently reported mutations in the SAA1 promoter (which encodes serum amyloid A1), leading to the development of AA amyloidosis in the absence of chronic inflammation [ 65 , 66 ].

Clinically 97% of patients exhibited proteinuria greater than 500 milligrams per day, with median proteinuria at 3.9 g per day, and serum creatinine greater than 1.5 milligrams per deciliter [ 67 ]. In Lachmann et. al.’s cohort of AA amyloidosis about half exhibited hypoalbuminemia with a median C-reactive protein of 20 milligrams per liter.

AA amyloidosis: molecular mechanisms

In humans, SAA1 protein comprises the majority of AA amyloid plaques and is presumed to be the major amyloidogenic species [ 68 ]. Production of SAA protein is stimulated by various cytokines in inflammatory syndromes such as Interleukin (IL)−1 and IL-6 [ 69 ]. It is believed that sustained increase in circulating SAA alongside its aberrant proteolysis is required to generate fibril aggregation [ 70 , 71 ]. Consequently, treatment of AA amyloidosis focuses on controlling inflammation and thus SAA levels, consistent with a state of dynamic transition between soluble protein and insoluble aggregates [ 72 ].

AA amyloidosis: fibril formation

AA amyloidosis has a distinct pattern of organ involvement with the kidneys often being the solely involved organ [ 67 ]. As mentioned, combination of both quantitative (concentration) and qualitative (proteolysis) factors contribute to aggregation of SAA. Once a critical concentration threshold is reached, SAA is presumed to interact with renal cell-specific receptors, leading to its endocytosis and partial proteolysis by matrix metalloproteinases within the lysosomal pathway [ 73 , 74 ]. SAA fragments of various lengths, ranging between 50 and 94 amino acid with a predominant 76 amino acid fragment, are then deposited in the renal glomeruli where they interact with glycosaminoglycans, apolipoproteins and serum amyloid P component (SAP) to form amyloid [ 75 ]. How distinct SAA fragments are generated and their relative pathogenicity is unclear at this time [ 76 ].

AA amyloidosis: renal toxicity

The exact mechanisms of AA amyloid plaque-related renal injury is unknown. There is suspicion that SAA soluble protofibrils may induce glomerular toxicity and that local inflammatory factors may contribute to injury [ 77 , 78 ]. In support of this latter hypothesis, complement proteins, fibrinogen, and midkine were increasingly detected in AA amyloid plaques, consistent with an inflammatory microenvironment [ 34 ].

Histologically, AA amyloidosis manifests as congophillic, weakly periodic acid Schiff (PAS) positive deposits in the mesangial areas with a majority of biopsies also showing involvement in the juxtaglomerular arterioles [ 4 , 79 ]. There are two known histological forms of renal AA amyloidosis, a glomerular form (circa 80% of patients) with predominant glomerular involvement with a spectrum of vascular deposition and a vascular form (around 20% of patients) with predominant vascular involvement and minimal glomerular involvement, usually at the vascular pole [ 79 ]. Inflammatory tissue reaction with infiltrates of multinucleated giant cells, macrophages or neutrophils and presence of fibrinoid necrosis or crescents have also been reported [ 79 ].

AA amyloidosis: outcomes and ESKD

It should not be understated the striking association between high SAA levels and the increased risk of mortality [ 67 , 72 ]. Thus, treatment of the underlying inflammatory pathology remains quintessential with the goal of ultimately reducing circulating SAA protein production. Anti-cytokine therapy such as IL-1 and IL-6 inhibitors, if not already indicated in the treatment of primary etiology, have emerged as promising candidates with small studies and case series supporting its ability to improve renal outcomes [ 75 ]. These agents have also demonstrated their capabilities to lower SAA levels, although one should note, SAA assays have not yet been standardized for use in routine clinical practice for following disease trajectory in AA amyloidosis [ 80 , 81 ]. Such targeted pathway thearapies may also be useful in cases of AA amyloidosis of unknown etiology where small studies have implicated its ability to stabilize and regress amyloid load [ 82 ].

Between 11 and 39% patients newly diagnosed with AA amyloidosis require RRT at the time of diagnosis, with a median time to ESKD between 33 and 256 months [ 67 , 83 – 85 ]. Factors predictive of progression to ESKD include Crohn’s disease, chronic sepsis, pre-existent chronic kidney disease, hepatic amyloid deposits, cardiac involvement, and proteinuria [ 44 , 67 ]. Median survival of AA amyloidosis patients on RRT has been reported between 17 and 20.1 months, as compared to 50.3 to 133 months for all AA amyloidosis patients with age, tubular involvement, RRT requirement, serum creatinine and serum albumin associating with worse survival [ 44 , 83 – 85 ].

There are no prospective comparative studies and retrospective evidence is sparse on RRT modalities for AA amyloidosis. Patients with AA amyloidosis might be less suited for peritoneal dialysis due to concerns of hypoalbuminemia, reduced dialysis adequacy, and increased peritonitis; however, the evidence remains inconclusive [ 86 , 87 ]. Peritoneal dialysis patients may experience lower serum albumin (attributed to protein loss, especially in high average transporters) and higher frequency of infections (namely peritonitis) when compared to hemodialysis [ 88 ]. Hemodialysis patients may experience complications stemming from vascular access issues, chronic diarrhea, and gastrointestinal hemorrhage in patients with AA amyloidosis [ 89 ].

Recent data demonstrates favorable outcomes for renal transplantation in AA amyloidosis [ 90 ]. Median survival is estimated to be greater than 9 years from time of transplantation and amyloid recurrence occurred in 5.8% attributed to improvements in controlling underlying inflammation with more active therapies [ 90 ].

ATTR amyloidosis

ATTR amyloidosis is caused by the misfolding and abnormal aggregation of transthyretin (TTR), a tetrameric transport protein that is synthesized mainly by the liver with minor contribution from the choroid plexus and retinal and ciliary pigment epithelia [ 91 – 93 ]. ATTR amyloidosis comprises a genetic form (variant ATTR or vATTR) and a wild type form (wtATTR). Variant ATTR amyloidosis is caused by autosomal dominant mutations in the TTR gene on chromosome 18. In the United States, the most common mutations are the Val122Ile, Thr60Ala, and the Val30Met mutation [ 94 , 90 ]. While Val30Met, Val122Ile, and Glu89Gln are the most common mutations worldwide [ 95 ]. Over 120 distinct mutations in the TTR gene have been identified thus far [ 96 ]. The incidence of vATTR amyloidosis has been estimated at 3.96–18.96 cases per million person-years [ 91 , 97 , 98 ]. The majority of manifestations of vATTR are related to cardiac and peripheral nervous system involvement while renal manifestations occur in about 15–20% vATTR cases overall and up to 30% in patients with Val50Met mutation [ 99 – 103 ]. Age of onset and penetrance of the cardiac and peripheral nervous system phenotypes are highly variable across distinct mutations, geographical groups and racial backgrounds [ 95 ]. Renal manifestations are reported to typically occur in the 6th to 7th decade of life [ 99 , 104 ]. Amyloid fibril length and size vary across distinct genetic variants and depending on age of onset, suggesting that there different pathogenic mechanisms may drive disease presentation and the specific pathogenetic mechanisms are still a subject of dispute [ 91 , 105 ].

vATTR amyloidosis: molecular mechanisms and fibril formation

Genetic mutations, coupled with sporadic and environmental factors, decrease the tertiary and quaternary structural stability of the tetrameric form of TTR, facilitating the formation of dimers and eventually monomers which are the conformationally unstable protein species necessary for amyloid formation [ 106 – 110 ]. These monomeric intermediates can spontaneously assemble into protofibrils functioning as a seed and initiating a cascade for amyloid fibril formation [ 105 , 111 , 112 ]. Data suggests that surface interactions with serum extracellular vescicles and proteolytic cleavage occuring in the monomeric form of TTR contributes to its aggregability [ 112 – 116 ]. Variable fibril isoforms have also been demonstrated per mutation, such as in the case of Val30Met, including a long and thick fibril versus a short and thin fibril which implicate different disease manifestations [ 117 ].

vATTR amyloidosis: renal toxicity

Little is known about the mechanisms promoting renal deposition of mutant TTR. It has been suggested that external factors such as extracellular vesicles may play a role in enhancing Val50Met mutated TTR aggregation in the kidney [ 113 , 118 ]. Mendez Sousa et al. has also reported low level uptake of TTR by megalin receptors at the level of the proximal tubule, however clinical significance is unclear [ 119 ]. Both the fibrillar form and nonfibrillar oligomers of vATTR have been suggested in direct cytotoxicity through formation of membrane pores or direct tissue traction causing ultrastructural distortion in the former and biochemical stresses in the latter although neither has been specifically proven in renal epithelia [ 120 – 122 ].

Histologically the pattern of deposition of vATTR amyloid fibrils varies depending on specific mutations. For example, Ser72Pro vATTR predominantly deposits in the vasculature and tubular basement membrane [ 99 ]. The corticomedullary region is mostly involved and relative sparing of glomeruli is typical [ 123 ]. Other variants can involve medulla, distal tubule basement membrane, loops of henle, interstitial, glomeruli, arteriole, and medium vessels [ 99 , 124 ]. Immunohistochemistry (IHC)/fluorescence analysis of tissue with TTR antibodies often leads to equivocal results and mass spectrometry is critical for definitive diagnosis [ 3 , 99 , 124 ]. Clinical findings of vATTR renal amyloidosis are largely dependent on the pattern of deposition and often follow onset of cardiovascular and neurologic symptoms [ 104 ]. Variable degrees of proteinuria and decreased renal function have been reported and dysuria, incontinence, and urinary retention can occur as sequalae of neurological involvement [ 104 , 125 – 127 ].

vATTR amyloidosis: outcomes and ESKD

As mentioned, only a fraction of patients with vATTR amyloidosis (and a fraction of mutations) develop renal disease. Outcome statistics are further complicated by the paucity of data. For the portion of of patients who develop renal disease, a smaller portion develop ESKD. For example, in a prospective Portugese study of 22 Val30Met patients, about half developed renal disease with about 20% progressing to renal failure in 1–5 years past microalbuminuria [ 99 , 128 ]. The overall prevalence of chronic kidney disease (CKD) in vATTR amyloidosis patients has been reported to be between 10 and 50% with confounding factor of contribution of cardiomyopathy [ 104 ]. Risks factors for CKD development include older age at onset of symptoms, hypertension, proteinuria, cardiac involvement, severe neuropathy, and certain mutations such as the Val142Ile mutation [ 104 ]. In the Val50Met mutation, renal failure has been reported to occur in about one third of patients with overt nephropathy (mean age 51.5 years) [ 128 , 129 ]. With the limitation of scant data, mean survival for Val50Met vATTR amyloidosis patients with ESKD in the setting of amyloid nephropathy is reported around 21 months. Presence of decubitus ulcers, advanced neurological involvement, and absence of arteriovenous fistula or graft are predictive factors for worse survival [ 129 ]. Nonexclusive of ESKD, survival estimates vary broadly depending on the methodology and an author’s selected studied factors which may include presence of liver transplantation, use of TTR stabilizing agents, cardiac involvement, age, sex, renal function, genotype, body mass index, and duration of clinical overt disease prior to liver transplantion [ 110 , 129 – 132 ].

RRT is often complicated by the systemic symptoms of vATTR amyloidosis. Intra-hemodialytic hypotension, diarrhea, and orthostatic hypotension occurs in a majority of patients, making volume removal challenging [ 129 , 133 ]. Decreased heart rate variability, a purported indicator of the heart’s ability to respond to external stimuli, has been shown to be more severe in uremia with amyloidosis compared to uremia alone and raises caution in the face of the autonomic symptoms of ATTR [ 99 , 134 , 135 ]. Literature is sparse regarding peritoneal dialysis in vATTR amyloidosis but this modality should be considered particularly in patients where HD may not be tolerated and with an expected good long term outcome [ 99 ].

Although no systematic data are available to comment on outcome, simultaneous liver-kidney transplantation may be used as definitive therapy in patients with vATTR amyloidosis and advanced renal disease related to amyloid nephropathy [ 136 ].

Wild type ATTR amyloidosis

Wild type ATTR (wtATTR) amyloidosis is a disorder of aging related to aggregation of otherwise normal (non mutant) TTR [ 137 ]. The overall prevalence of wtATTR is rising due to increased aging of the population, improved diagnostics and increased awareness and it is currently estimated around 90 cases per million persons [ 138 ]. Involvement of the kidneys by wtATTR is rare but can occur [ 124 ]. Zhao et al. previously suspected the mechanistic cause of instability in wtTTR to be related to age-related oxidative modifications [ 139 ]. Whether a proteolytic cleavage is necessary for TTR amyloid formation is unclear as previous work has shown fibril formation stemming from non proteolyzed TTR monomers in mice [ 140 ]. Whether or not wtTTR exert direct cytotoxic effect and how to the kidneys is currently unclear.

ALECT2 amyloidosis

The leukocyte cell derived chemotaxin 2 (LECT2) protein was first purified in 1996 and has since been show to participate in a wide variety of physiologic and pathophysiologic processes including but not limited to chemotaxis, inflammation, and cell signaling [ 141 , 142 ]. ALECT2 amyloidosis was first described in 2008 by Benson et al. in a patient presenting with nephrotic syndrome and renal cell carcinoma and is now considered the third most common type of renal amyloidosis [ 143 , 144 ]. ALECT2 amyloidosis typically involves the kidney and the liver with discrete sparing of the heart. ALECT2 amyloidosis affects certain ethnic populations disproportionately. For example, 88–92% of patients with ALECT2 amyloidosis are Hispanic (2.1% of cases out of 524 autopsy cases in New Mexico) [ 145 , 146 ]. Individuals from Punjab, Sudan, China, Israel and Egypt, Native Americans and First Nations people of British Columbia are also disproportionately affected [ 145 , 147 ]. The global prevalence of ALECT2 amyloidosis has not yet been accurately reported. Median age of diagnosis is around 59–71 years of age [ 145 – 147 ]. Despite the obvious ethnic variant, a hereditary cause for ALECT2 amyloidosis has not been identified and presumably this is a sporadic disorder. No gene mutations have been detected in the LECT2 gene in patients with ALECT2 amyloidois; however, a common polymorphism for a homozygous G allele at single nucleotide polymorphism (SNP) rs31517 has been detected whose mechanistic significance is currently unknown [ 144 , 148 ].

ALECT2 amyloidosis: molecular mechanisms and fibril formation

The molecular mechanisms at the basis of ALECT2 deposition in the kidneys are unknown. In particular, LECT2 concentration were not increased in patients, ruling out the possibility that sustained overexpression is a pathogenic mechanism [ 148 ]. Charalampous et al. describes in their recent publication 2 different ALECT2-related amyloid proteome subtypes which perhaps suggest that there may be multiple pathogenic mechanisms [ 34 ]. One ALECT2 subtype had increased complement proteins and collagen remodeling proteins with less albumin, hemoglobin, haptoglobin, transferrin, serum amyloid A4, protein s100-A8 perhaps representing a loss of these proteins in the renal interstitial space [ 34 ]. Complement and collagen proteins are also increased in expression in ALECT2 when compared to AL amyloidosis [ 34 ].

Ha et al. recently demonstrated that shear stress can induce LECT2 aggregation and fibril formation in a microfluidic device mimicking renal blood flow [ 149 ]. This is particularly interesting given the histological findings of relative medullar interstitial sparing as mentioned below. Some authors have hypothesized that a common LECT2 single nucleotide polymorphism may itself increase protein instability and amyloidogenic potential versus interaction with yet unknown local factors, resulting in aggregation [ 147 ]. Other hypotheses to explain LECT2 aggregation include alterations in LECT2 binding partners, resulting in increased free circulating LECT2 to participate in amyloidogenesis, as well as presence of locally produced LECT2 in the kidney [ 145 ].

ALECT2 amyloidosis: renal toxicity

Histologically, ALECT2 amyloidosis deposition typically occurs in the glomerular interstitium and mesangium with relative sparing of the medullary interstitium [ 144 , 145 ]. Arteries and arterioles typically present with moderate involvement while glomerular basement membrane can present with variable to no involvement [ 150 ]. Concurrent glomerular pathology may be present including nodular diabetic glomerulosclerosis, membranous glomerulopathy, ANCA associated crescentic glomerulonephritis, and focal segmental glomerulosclerosis [ 144 ]. IHC with anti- LECT2 antibody can provide suspected diagnosis which should be confirmed via liquid chromatography mass spectrometry whenever possible [ 3 , 151 ].

Clinical findings of renal ALECT2 amyloidosis are highly variable ranging from chronic kidney disease with minimal proteinuria to nephrotic syndrome and reflect the broad spectrum of vascular and glomerular deposition [ 143 , 152 ]. A minority of patients present with microhematuria; however, in some patients, a concurrent diagnosis of transitional cell carcinoma of the urinary tract was observed, confounding the specificity of this finding [ 153 ]. Larsen and colleagues reported that CKD was the indication to pursue a renal biopsy in more than 50% of patients later diagnosed with ALECT2 amyloidosis [ 144 ]. Serum creatinine correlates best with the extent of interstitial fibrosis, tubular atrophy, global glomerulosclerosis, and arteriosclerosis rather than renal amyloid burden [ 153 ].

ALECT2 amyloidosis: outcomes and ESKD

The median renal survival for patients with ALECT2 amyloidosis has been estimated at 62–98.4.4 months although the reported range was broad (0–73 months) [ 153 , 154 ]. Factors that were associated with increased risk for ESKD include presence of diabetes and extent of renal impairment and global glomerularsclerosis at diagnosis [ 153 ]. Overall survival is thought to be excellent with a median of 181.3 months, which largely reflect the absence of cardiac involvement in patients with ALECT2 amyloidosis [ 154 ]. At this time there is no objective guidance in the literature for renal replacement therapy. More studies need to be performed to evaluate the outcomes and options in renal replacement.

Renal transplantation has been successfully performed in patients with ALECT2 amyloidosis without reports of renal disease recurrence [ 3 ]. Donor ALECT-2 has been reported in kidney allografts, in one case the donor was Hispanic and the recipient was non Hispanic [ 155 , 156 ]. Outcomes data in ALECT2 renal transplantation is very limited potentially due to the indolent nature of the disease.

AFib amyloidosis

One of the most common forms of autosomal dominant renal amyloidosis in Europe is alpha fibrinogen amyloidosis (AFib) which results from the mutation of fibrinogen α-chain gene ( FGA ). Outside of Europe, this form has also been reported around the world such as in those of Chinese, Korean, Russian, North African, Japanese and Peruvian descent [ 157 – 160 ]. AFib is believed to be quite heterogenous in its presentation and can present as early as childhood to elderly, although median age is presumed to be late 50 s [ 161 – 163 ]. Patients usually present with proteinuria, have family history, and progression to dialysis can happen within five years [ 161 ]. Cardiac involvement can occur in the form of atheromatous plaque disease which is composed of mutant fibrinogen Aα-chain material; this, may even pre-date the proteinuria and renal dysfunction [ 163 ].

AFib amyloidosis: pathogenesis

Like most forms of amyloid, the pathogenesis of this disorder leaves much to be desired. Fibrinogen is a protein synthesized in the liver and plays an integral role in the coagulation cascade [ 164 ]. It is composed of 3 polypeptide chains, which is encoded by a 3 gene cluster on human chromosome 4, FGA , FGB , FGG [ 164 ]. Mutations within the FGA gene portion are the inciting event for AFib hereditary amyloidosis with over 15 mutations currently reported [ 165 , 166 ]. The most common type of mutation is a valine substitution by glutamic acid (E526V) [ 160 , 163 ]. Once synthesized in the liver, the mutated fibrinogen chain is presumed to follow similar pathogenic progression as other amyloidosis forming beta pleated sheets in antiparallel fashion, and protofilaments through hydrogen bond interactions [ 167 ]. It is suspected that the Aα- chain carboxy terminus’ sensitivity to proteases facilitates amyloid deposition [ 167 ]. Of note, mutated Aα chains have not been detected in plasma presumptively due to the metabolism of the mutated protein being faster in comparison to its wild type [ 167 ].

AFib amyloidosis: outcomes and management

One of the more comprehensive evaluation of outcomes in AFib amyloidosis was done by Gillmore et al. In which they prospectively studied 71 patients from the United Kingdom with 4 novel fibrinogen mutations, P552H, E540V, T538K, and T525fs [ 161 ]. They reported the median age of presentation was 58 years old and all had primary renal involvement. Their cohort had a median time to ESRD of 4.6 years and estimated survival of 15.2 years, renal progression appears to be slower when compared to AL amyloidosis. In this cohort, there were no typical cardiac features found using noninvasive cardiac testing. Two patients did undergo endomyocardial biopsy and only 1 had some amyloid deposition. Two patients were found to have hepatic involvement in their cohort, potentially suggesting a more renally limited phenotype. Ten patients underwent kidney transplant and median graft survival was 8.9 years, one graft had recurrence of amyloid deposition as detected by scintigraphy after increasing proteinuria but was still functional 12.2 years after transplantation. This cohort also included the first patient that received a combined liver and kidney transplant for AFib amyloid and had functioning allografts without amyloid 11.5 years after transplantation. Of note, 7 patients in this cohort were found to have incidental plasma cell clones. From a survival standpoint ESRD patients had a lower survival rate of 9.3 years but still substantially more than patients with AL Amyloid (treated and untreated), and age matched nondiabetic kidney disease [ 161 , 163 ].

Diagnosis of AFib amyloid is universally done through kidney biopsy. One consistent feature on the various cohorts reported is the fact there is complete histological involvement of glomeruli by the AFib amyloid often obliterating its architecture with sparing of vessels [ 158 ]. In the Gillmore cohort, immunohistochemical staining for AFib was positive in 93% of their patients, making it one of the few hereditary renal amyloidoses that have robust immunohistochemical staining [ 161 ]. Additionally, DNA amplification and sequencing can be used as a method for detection of novel variants [ 158 ]. Radiolabeled scintigraphy can be used but is not specific for type of amyloid protein [ 168 ]. Laser microdissection–mass spectrometry achieves accurate diagnoses in most cases of AFib amyloidosis; however, in specific situations, complementary techniques such as IHC and DNA sequencing may be required [ 160 , 167 ].

Management of AFib amyloid is unclear. Because fibrinogen is mainly produced in the liver and 10-year graft survival for kidney only transplants with AFib is a mere 5.5%, there may be an emerging role for combined liver and kidney transplant albeit with consideration to added risk [ 163 ]. Stangou et al. reported 22 AFib patients (primarily E526V and R554L mutations) at a median age of 55, with stage 3–5 chronic kidney disease that were under consideration for combined liver and kidney transplantation. Ultimately, within the nine patients who received a combined liver and kidney transplant, 5 out of the 6 who remained alive had both normal liver and kidney function at a median follow up of 67 months [ 163 ].

Conclusions

In our review, we summarize the pathophysiologic mechanisms and histopathologic patterns of five forms of renal amyloidosis and we provide a brief overview of outcomes including progression to ESKD. In this perspective, AL amyloidosis is the most aggressive type of systemic amyloidosis described with frequent multi-organ/system involvement and increased risk for renal and overall survival. We additionally report how distinct amyloidogenic proteins have different mechanisms of pathogenesis and impact variably renal and overall survival. It should be duly noted that a majority of prior patho-biological studies leaned heavily towards AL amyloidosis, yet the formation of amyloid, mechanisms of injury, and the organ specific receptors may be vastly different between each type of amyloidosis. And, despite significant therapeutic advancements in AL and ATTR amyloidosis, there remains still significant knowledge gaps in organ involvement and outcome. Thus, the further independent study, including gene expression and more detailed proteomic studies, of amyloids is greatly needed to reveal the full spectrum of injury in this complex disease. Only through an accurate understanding of the molecular basis of amyloidosis pathogenesis, can more active treatments be developed. We look with great interest at basic science efforts in the field of systemic amyloidoses. (Table 1 ). Table 1 Epidemiologic characteristics, treatment and outcome of different systemic amyloidosis targeting the kidneys. The table outlines main epidemiologic characteristic, treatment approach and outcome of AL, AA, ATTRv, ALECT2 and AFIB renal amyloidosis AL AA variant ATTR ALECT2 AFIB Average Age at Diagnosis 63 [ 11 ] 50–70[ 4 , 5 ] 68 [ 10 , 97 ] 62 [ 13 , 153 ] 46 [ 15 , 165 ] Geographical Prevalence Presumed worldwide: Ranging from Japan at 14.3 per million persons, United States at 9.91 per million persons, Brazil 6.72 per million persons in studied countries. [ 1 , 11 ] Incompletely studied: 5–78% of patients with Rheumatoid Arthritis (favors United States and Northern Europe [ 6 , 172 ]), 10–13% of patients with Familial Mediteranian Fever (favors Mediterranian basin and middle eastern origin [ 7 , 8 , 63 , 64 ] Incompletely studied and incompletely segregated between variant ATTR and wild type ATTR: highest reported prevalence is currently portugal at 229.3 persons per million. Favoring Hispanics (88–92%). Additional groups include Punjabis, First Nations people in British Columbia, Arabs, Israelis, and Native Americans. [ 4 , 144 ] Incompletely studied: Literature predominantes in western countries (white population) and Asians [ 15 , 17 , 159 , 165 ] Classic Etiology Plasma cell dyscrasias or B cell neoplasms (less commonly) Chronic Inflammation Genetic Mutations Unknown Genetic Mutations Precursor Protein Immunoglobulin light chain Serum Amyloid A (SAA) Variant transthyretin (TTR) Leukocyte Cell–Derived Chemotaxin 2 Fibrinogen Aα-chain Pathophysiology Unstable light chains are partially digested resulting in noncovalent dimerization and packing into higher order fibrils. Cytokine stimulation of Serum Amyloid A production followed by aberrant proteolysis in the renal lysosomal pathway. Genetic mutations in transthyretin decrease the stability of tetrameric TTR facilitating formation of monomers, the precurors of amyloid fibrils. Unknown. Possible contribution of shear stress induced aggregation and fibril formation. Unknown. Protease sensitivity potentially facilitates deposition Worldwide Incidence 5.1–12.8 cases per million person years [ 2 , 169 ] 1–2 cases per million person years [ 4 , 5 ] 3.9–18 cases per million person years [ 10 , 97 ] Unknown Unknown Organs Involved Heart (70%), kidney (60%), liver (20%), nerve(15%), gastrointestinal(10%), lung (Unknown), soft tissue (Unknown) [ 3 , 170 ] Kidney, spleen, adrenal glands, liver, gut [ 9 , 67 ] Peripheral and central nerves, heart, eyes, kidneys, gastrointestinal tract [ 11 , 102 ] Kidney (majority), liver (minority), additionally reported spleen, prostate, gallbladder, pancreas, small bowel, parathyroid [ 14 , 144 ] Kidney, heart (13%), liver (13%), spleen (9%), lung (2%), vessel (2%), fat (2%), gingiva (2%) [ 15 , 165 ] Average Time to ESRD 26.8–29.5 months 33–356 months 60–120 months 62 −98.4 months About 55 months [ 16 , 160 ] First Line Therapy Anti plasma cell therapy (Dara-CyBorD) [ 4 , 171 ] Treatment of underlying inflammatory process Disease modifying therapies (TTR gene silences, antisense oligonucleotides, TTR stabilizers) with symptomatic therapy [ 12 , 173 ] No specific therapy, consider renal transplantation Unknown, consider liver and/or kidney transplantation.

Publisher’s note

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Author contributions

All authors contributed to the study conception and design. Alvin Hu performed the literature search, data analysis, and first draft on the sections regarding AL, AA, ATTR, and ALECT2. Raad B. Chowdhury performed the literature search, data analysis, and first draft on the section regarding AFib. All authors critically revised, commented, and edited on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

G.B. was funded by NIH/NCI grant K08CA245100. The authors thank the Demarest Lloyd Jr Foundation, the Darling Fund, and the Appleby Cardiac Amyloidosis Fund for their support of the Amyloidosis Program. A.H and R.B.C did not receive funds, grants or other support during the preperation of this manuscript.

Data availability

N/A.

Declarations

Consent to participate

N/A.

Consent to publish

N/A.

Ethics approval

N/A.

Competing interests

A.H and R.B.C declare they have no financial and non-financial interests that are directly or indirectly related to the work submitted for publication. G.B has received honoraria for consulting engagements from Prothena and Pfizer.

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