Renal amyloidosis

INTRODUCTION — Amyloidosis is a group of diseases characterized by extracellular deposition of beta-sheet fibrils. In the systemic forms, the amyloid protein causes progressive organ dysfunction, which may lead to death of the patients. Over 35 proteins capable of amyloid formation have been identified.

Clinically evident kidney involvement most commonly occurs in AL (immunoglobulin light chain) or AA (previously referred to as secondary) amyloidosis but can also occur in other forms of amyloidosis. The deposition of beta-2 microglobulin occurs in patients on prolonged maintenance dialysis; deposition in the kidney has been reported in autopsies but has no clinical significance. (See "Dialysis-related amyloidosis".)

This topic will review the pathology, pathogenesis, clinical manifestations, diagnosis, management, and prognosis of renal amyloidosis. A broad overview of amyloidosis and the specific treatment of AL and AA amyloidosis are presented elsewhere.

●(See "Overview of amyloidosis".)

●(See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)

●(See "Treatment of AA (secondary) amyloidosis".)

EPIDEMIOLOGY — The prevalence of renal amyloidosis in native kidney biopsies is approximately 2 percent [1,2]. In a large biopsy series of 474 cases of renal amyloidosis, the most common type was immunoglobulin-associated (light chain [AL], heavy chain [AH], or both [AHL]) amyloidosis (86 percent), followed by AA amyloidosis (7 percent) and leukocyte cell-derived chemotaxin 2 (ALECT2) amyloidosis (3 percent) [1]. (See 'Types of renal amyloidosis' below.)

The prevalence of the various types of amyloid varies by geographic location and population studied [3-9]. As an example, in resource-limited countries, the prevalence of AA amyloidosis is higher than that of AL amyloidosis due to the high incidence of infectious diseases [3,4,6]. In the Southwest of the United States, where there is a large Mexican American population, ALECT2 amyloidosis is more frequent, accounting for over 50 percent of the cases of amyloidosis found in patients of Mexican descent [10]. By contrast, in Egypt, AA amyloidosis predominates, and ALECT2 amyloidosis is the second most common cause of amyloidosis [11,12]. Other countries (eg, Sweden) have a high prevalence of hereditary amyloidosis [13,14].

Kidney involvement is present in approximately 50 to 80 percent of patients with AL amyloidosis [15-17] and is the predominant clinical manifestation (97 percent of patients) among patients with AA amyloidosis [18].

TYPES OF RENAL AMYLOIDOSIS

AL amyloidosis — The amyloid fibrils in AL amyloidosis (previously referred to as primary amyloidosis) consist of monoclonal immunoglobulin light chains [19]. The composition of deposits is confirmed by immunofluorescence microscopy with either anti-lambda or anti-kappa light chain antibodies in most cases. Staining for only a single type of light chain should suggest a monoclonal gammopathy such as AL amyloidosis or myeloma. In cases where the immunofluorescence is equivocal, laser microdissection and tandem mass spectrometry, when available, should be used to establish the diagnosis [20]. Although AL amyloidosis is the result of clonal proliferation of plasma cells, most patients do not meet criteria for multiple myeloma. These patients are best categorized as having monoclonal gammopathy of renal significance [21]. Furthermore, most patients with myeloma and overproduction of light chains (light chain myeloma) do not develop systemic amyloidosis. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation" and "Diagnosis and treatment of monoclonal gammopathy of renal significance".)

Intrinsic factors of the pathogenic light chain are responsible for amyloid formation. Renal AL amyloidosis most frequently involves V lambda 6 light chains with several peculiarities, including somatic mutations in variable domains, hydrophobicity, posttranslational modifications (glycosylation), and aggregation features. Another property is the ability to be taken up by macrophages, where the intact light chains are metabolized to preamyloid fragments; these fragments must then have the biochemical properties that allow them to form amyloid fibrils [19]. The pathogenic nature of the light chain may determine the post-uptake trafficking and modification [22], resulting in either amyloid formation or light chain deposition disease. Amyloidogenic light chains induce phenotypic changes in the mesangial cells that make them resemble macrophages [23]. (See "Monoclonal immunoglobulin deposition disease", section on 'Pathogenesis'.)

In AL amyloidosis, lambda light chains are more amyloidogenic than kappa light chains. In one study of 145 patients with biopsy-proven AL amyloidosis, the ratio of patients with lambda versus kappa light chains was much higher among patients who had kidney involvement (12:1) compared with those who did not (4:1). Among 84 patients with known renal amyloidosis, those with lambda light chains had greater urinary protein loss compared with those with kappa light chains (7 versus 3 g/day, respectively) [24].

AA amyloidosis — AA amyloidosis (previously referred to as secondary amyloidosis), also called reactive amyloidosis or amyloidosis AA, occurs in patients with chronic inflammation due to chronic infections, autoimmune diseases, or genetic autoinflammatory diseases (table 1) [18]. In the United States and many resource-abundant countries, rheumatoid arthritis (adult or juvenile) currently accounts for up to 40 percent of cases [19,25]. A mutation in the promoter of the SAA1 gene has been associated with familial AA amyloidosis [26]. (See "Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases".)

AA amyloidosis is associated with increased hepatocyte production of the acute phase reactant serum amyloid A (SAA); this process may be stimulated by the release of cytokines (perhaps interleukin 1 [IL-1] and IL-6) from activated macrophages [19]. Cleavage in circulating monocytes/macrophages results in the generation of smaller fragments, called AA protein, which can then deposit in the tissues. (See "Pathogenesis of AA amyloidosis".)

AA amyloidosis often leads to end-stage kidney disease (ESKD), particularly in patients whose inflammatory etiology has not been altered and who have persistently high circulating levels of SAA.

ALECT2 amyloidosis — Leukocyte cell-derived chemotaxin 2 (ALECT2)-associated amyloidosis is a systemic form of amyloidosis with predominantly kidney and liver involvement [27-29]. Most reported cases in North America (88 to 92 percent) occur in older adults of Mexican descent, although Punjabis, First Nations people in British Columbia, and Native Americans also have a predisposition for this disorder [30-33]. In one study of renal amyloidosis among Egyptians, ALECT2 amyloidosis was the second most common form of renal amyloidosis behind AA and ahead of AL amyloidosis [11]. Cases have also been reported in Pakistani, Sudanese, and Chinese patients [34].

The pathogenesis of ALECT2 amyloidosis is not well understood. Patients typically present with chronic kidney disease (CKD) and variable proteinuria; nephrotic syndrome is uncommon [30,32]. A kidney biopsy, preferably with laser microdissection and mass spectrometry, is required to make the diagnosis. Patients with ALECT2 amyloidosis characteristically have diffuse Congo red-positive amyloid deposition in the cortical interstitium, with variable glomerular and vascular involvement [27,28,32]. In general, patients with ALECT2 amyloidosis have better overall survival than those with AL or AA amyloidosis, possibly due to the absence or rare occurrence of cardiac involvement. However, kidney survival is relatively poor, with up to 39 percent of patients progressing to ESKD [32]. There are no specific therapies for ALECT2 amyloidosis.

Apolipoprotein A-IV amyloidosis — Apolipoprotein A-IV (AApoAIV) amyloidosis is a rare form of renal amyloidosis that has been described in patients presenting with slowly progressive kidney function impairment and minimal or absent proteinuria [35-37]. The majority of the cases are secondary to wild-type ApoAIV. However, a hereditary form with autosomal dominant inheritance due to pathogenic APOA4 variants has been reported [35-37]. Similar to patients with AApoAI amyloidosis, patients with AApoAIV amyloidosis have Congo red–positive amyloid deposits that are restricted to the renal medulla (mostly peritubular and interstitial) and spare the cortex. This is even more evident in the mutant AApoAIV cases, in which the amyloid was only found in the medulla of the explanted kidneys.

Hereditary renal amyloidosis — Hereditary renal amyloidosis is an uncommon disorder in which amyloid deposition is most prominent in the kidneys. Although uncommon, one series reported that 10 percent of patients at an amyloidosis referral center who were thought to have AL amyloidosis actually had a hereditary form of the disease [38]. Mutations in a number of proteins can result in kidney deposition. These include the following:

●Fibrinogen A alpha chain [39-41]

●Lysozyme [42,43]

●Amyloid A [26]

●Apolipoprotein A-I [44,45]

●Apolipoprotein A-II

●Apolipoprotein A-IV [37]

●Apolipoprotein C-II

●Apolipoprotein C-III

●Gelsolin

●Transthyretin (ATTR) [46,47]

CLINICAL MANIFESTATIONS — The clinical manifestations of renal amyloidosis vary with the type of amyloid protein and the site and degree of amyloid deposition (table 2).

●Proteinuria and nephrotic syndrome – Proteinuria is the most common manifestation and is generally associated with glomerular deposition of amyloid. As an example, approximately 75 percent of patients with AL amyloidosis (most of whom have predominant glomerular deposition) present with proteinuria, often accompanied by edema [48,49]. The degree of proteinuria can range from mild to massive (>20 g/day), depending upon the extent of glomerular involvement. Patients with AL amyloidosis frequently present with heavy proteinuria (mean of 6.2 g/day in one study [1]), and approximately two-thirds present with the nephrotic syndrome [1]. The urine sediment is typically bland (reflecting the lack of glomerular inflammation), and the plasma creatinine concentration may be normal or only moderately elevated. End-stage kidney disease (ESKD) develops in approximately 20 percent of those with the nephrotic syndrome [48,49].

●Slowly progressive CKD with little or no proteinuria – Slowly progressive chronic kidney disease (CKD) with little or no proteinuria is the usual presentation of patients with AA amyloidosis who have amyloid deposits primarily limited to the vessels and tubulointerstitial areas (picture 1) [50,51]. Why this occurs is unclear, but the site of deposition may be determined at least in part by the physicochemical property of the peptide [51]. Prognosis in such patients appears to be more favorable [50,52]. Similar findings have also been reported in 5 percent of patients with AL amyloidosis [53].

Kidney function impairment without significant proteinuria is also the primary manifestation of patients with predominantly tubulointerstitial amyloid deposition, such as those with ALECT2 [29], apolipoprotein A-I (AApoAI) amyloidosis associated with the Leu75Pro mutation [45], or AApoAIV [36] amyloidosis. In ALECT2, the cortical interstitium is typically involved, and in some patients with AA, AApoAI, AApoAIV, or transthyretin (ATTR)-associated amyloidosis, amyloid deposits are limited to the medullary interstitium [46,47,54].

●Tubular dysfunction – Tubular dysfunction such as type 1 (distal) renal tubular acidosis or polyuria due to arginine vasopressin resistance (previously called nephrogenic diabetes insipidus) can be the presenting features in patients with heavy tubular deposition (picture 2) [55]. Acquired Fanconi syndrome has been reported in rare cases of AL amyloidosis [56].

●Crescentic glomerulonephritis – Crescentic glomerulonephritis is a rare presentation in patients with renal AA amyloidosis [57,58]; in one series, 13 percent of the cases of AA amyloidosis had glomerular crescents [59]. Almost all reported patients have had AA amyloidosis due to rheumatoid arthritis or its variants. A possible mechanism is amyloid fibril-induced ruptures in the capillary loops, leading to fibrin entry into Bowman space. Crescentic glomerulonephritis has also been reported in patients with AL and AHL amyloidosis, with a prevalence of 1.1 percent [1].

●Acute kidney injury – In rare cases, patients with AL amyloidosis can present with acute kidney injury due to intratubular amyloid cast nephropathy [60-62]. In such patients, the immunoglobulin light chain can precipitate to form intratubular casts resembling those in myeloma light chain cast nephropathy. However, these casts are congophilic and display fibrillar structures under electron microscopy. The majority of patients with intratubular amyloid cast nephropathy have concomitant multiple myeloma [62].

PATHOLOGY — Characteristic histologic findings of renal amyloidosis on kidney biopsy include the following:

●Light microscopy – Light microscopy in renal amyloidosis typically reveals diffuse glomerular deposition of amorphous hyaline Congo red-positive material, initially in the mesangium and then along the capillary loops (picture 3A-D). These nodules stain weakly with periodic acid-Schiff and methenamine silver stain because they are composed mostly of amyloid fibrils and not extracellular matrix as in diabetes mellitus [63]. Scanty deposits of amyloid may go undetected by light microscopy. In some patients, amyloid is deposited primarily in the interstitium and along the tubular basement membranes or in the small arteries and arterioles (table 2).

There are multiple other causes of nodular glomerulosclerosis observed by light microscopy, most of which are identified by characteristic findings observed by immunofluorescence or electron microscopy. (See "Diabetic kidney disease: Manifestations, evaluation, and diagnosis", section on 'Pathology'.)

●Immunofluorescence – Immunofluorescence microscopy is negative for immunoglobulins and complement in non-AL amyloidosis but is positive for lambda or kappa light chain in AL amyloidosis. The finding of only one light chain type, lambda or kappa, is required to confirm the diagnosis of AL amyloid. False negatives with immunofluorescence can occur in 25 to 35 percent of cases, especially if the antisera against kappa and lambda light chains used for immunofluorescence are obtained from only a single vendor. To increase sensitivity in this setting, the antisera from multiple vendors may be used, and immunoperoxidase can also be helpful. False-positive immunofluorescence has also been reported in some cases of AA amyloidosis thought to be the result of nonspecific immunoglobulin trapping. In cases where immunofluorescence is equivocal, addition immunohistochemistry should be performed to look for other types of amyloid. The gold standard for amyloid typing is laser microdissection with mass spectrometry-based proteomic analysis [64,65]. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Determining the type of amyloid'.)

Laser dissection of the tissue followed by tandem mass spectrometry-based proteomic analysis is the gold standard but is not needed in most patients for a diagnosis and is only available in specialized laboratories [20,66].

●Electron microscopy – Electron microscopy demonstrates straight, solid, nonbranching fibrils that are randomly arranged and measure 8 to 12 nm in diameter, typically in the mesangium and along the glomerular capillary walls. The size of the fibrils distinguishes renal amyloidosis from other kidney diseases with organized immunoglobulin deposits, such as fibrillary glomerulonephritis. Immunoelectron microscopy has a high diagnostic accuracy for typing amyloidosis, but this technique is not widely available. (See "Glomerular diseases due to nonamyloid fibrillar deposits", section on 'Pathology and pathogenesis'.)

DIAGNOSIS — Renal amyloidosis should be suspected in any patient presenting with proteinuria with or without the nephrotic syndrome. Suspicion is even higher if other systemic symptoms (such as heart failure, orthostatic hypotension, gastrointestinal symptoms, or neuropathy) are also present. The evaluation of patients presenting with proteinuria with or without the nephrotic syndrome is discussed in detail elsewhere. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

A kidney biopsy is generally required to make a definitive diagnosis of renal amyloidosis. However, a kidney biopsy may be deferred if amyloidosis is suspected in a patient with a monoclonal gammopathy, in which case an abdominal fat pad aspirate may secure the diagnosis of systemic AL amyloidosis. If the fat pad aspirate is negative and the diagnosis of renal AL amyloidosis is still suspected, then a kidney biopsy should be performed. Of note, AL amyloidosis may be present in the bone marrow biopsy of patients with a monoclonal gammopathy; however, this is considered localized amyloidosis unless amyloid is discovered elsewhere in the body. (See "Overview of amyloidosis", section on 'Selection of biopsy site' and "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Choosing a biopsy site'.)

Once amyloidosis is confirmed by biopsy, the underlying etiology should be determined by typing the amyloid. This point cannot be overemphasized. Even when amyloid deposits are identified, the presence of a monoclonal gammopathy does not ensure the diagnosis of AL amyloidosis. One study showed that approximately 10 percent of patients at an amyloid referral center initially thought to have AL amyloidosis had hereditary amyloidosis [38]. Misdiagnosis not only results in exposure to unnecessary cytotoxic agents but also prevents the patient from receiving the appropriate therapy. It is also important to note that two different types of amyloid have sometimes been identified in a single organ. Biopsy of the affected organ is important to make sure the correct type of amyloid is being targeted by therapy [67]. A discussion of the methods used to determine the type of amyloid is presented elsewhere. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Determining the type of amyloid'.)

MANAGEMENT — In the absence of treatment, ongoing deposition of amyloid protein in the kidney results in a progressive decline in kidney function and ultimately end-stage kidney disease (ESKD) in most patients. Treatment of renal amyloidosis involves therapies targeting the production of amyloid protein as well as supportive measures. The goal of therapy is to achieve the best possible reduction in the amyloid protein precursor in order to limit further kidney injury and to preserve or improve kidney function.

Treatment of specific amyloid types — Specific therapy of renal amyloidosis is guided by the type of amyloid. However, there are no specific therapies for ALECT2, apolipoprotein A-IV (AApoAIV), or many of the hereditary renal amyloidoses. A novel approach using gene editing technology has been shown to reduce the production of transthyretin (ATTR) in patients with the mutant form of ATTR amyloidosis [68], suggesting that a similar approach might be applied to other forms of hereditary amyloidosis.

●AL amyloidosis – The approach to the treatment of AL amyloidosis is discussed in detail elsewhere. (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)

Factors that influence kidney response to therapy include the degree of baseline proteinuria and the serum creatinine [24,69]. This was shown in a study of 122 patients with AL amyloidosis [69]. At a median follow-up of 45 months posttherapy, multivariate analysis found that low baseline proteinuria (and cardiac troponin T) levels predicted a kidney response, which was defined as greater than 50 percent reduction in proteinuria with less than 25 percent decline in kidney function. A hematologic response (72 percent of patients) also correlated significantly with kidney response (43 percent of patients). Ninety-six percent of kidney responders also had a hematologic response versus only 54 percent of kidney nonresponders.

Elimination of the monoclonal protein and the plasma cell clone may lead to reversal of organ damage [17,69]. However, the small size of the monoclonal protein and low clonal plasma cells load often makes determination of hematologic response difficult. This process has been made easier with the serum-free light chain assay, which has a sensitivity more than 1000 times that of serum protein electrophoresis and 300 times that of immunofixation. In separate studies, significant (>90 percent) reduction or normalization of serum-free light chain levels after autologous stem cell transplantation was associated with better organ response and improved overall survival [70,71]. However, a 50 percent reduction in proteinuria can take up to 12 months to occur. In one study, a 30 percent reduction in proteinuria with less than 25 percent decline in estimated glomerular filtration rate (eGFR) was shown to predict response and avoidance of ESKD in two separate cohorts [72]. (See "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis", section on 'Prognosis'.)

A hematologic response to therapy is strongly associated with improved outcomes, even in patients with advanced amyloid-related kidney disease at the time of diagnosis. This was shown in a study of 84 patients with AL amyloidosis and an eGFR of <20 mL/min/1.73 m² at the time of diagnosis [73]. Forty-five patients had renal-limited amyloidosis, and 39 had both kidney and cardiac involvement. At baseline, median eGFR and 24-hour urine protein excretion were 10 mL/min/1.73 m² and 6.2 grams, respectively. Among the 78 patients who received chemotherapy, 55 percent received a bortezomib-based regimen as first-line therapy. Patients who achieved ≥90 percent reduction in the amyloidogenic free light chain (defined as the difference between the involved and uninvolved free light chain [dFLC]) within three months of baseline had better median overall survival and a prolonged time to dialysis (23 months versus 6.1 months) compared with those who achieved a lesser degree of clonal response. However, achieving the same reduction in dFLC after three months from baseline was not associated with a benefit in kidney survival. Thus, patients with AL amyloidosis and advanced chronic kidney disease (CKD) at presentation may benefit from treatment, but the magnitude and speed of hematologic response appear to be critical factors in determining outcome.

●AA amyloidosis – Treatment of AA amyloidosis is targeted at the underlying chronic inflammatory disease responsible for the production of serum amyloid A (SAA). The treatment of AA amyloidosis is discussed in detail elsewhere. (See "Treatment of AA (secondary) amyloidosis".)

Supportive measures in all patients — General supportive measures in all patients with renal amyloidosis include dietary sodium and protein restriction, blood pressure control, treatment of dyslipidemia, and, in selected patients, anticoagulation. Other aspects of therapy include diuretics to control edema and maintenance of adequate nutrition. Importantly, patients with amyloidosis may experience hypotension and intolerance to diuretics related to cardiac involvement and autonomic dysregulation; thus, angiotensin inhibitors and diuretics should be used with caution. This approach is consistent with the 2021 Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for the Management of Glomerular Diseases [74]. These issues are discussed in greater detail elsewhere:

●Dietary sodium and protein restriction (see "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Salt intake' and "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Protein intake')

●Antihypertensive therapy (see "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults")

●Renin-angiotensin system inhibition (see "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Renin-angiotensin system inhibitors')

●Lipid lowering (see "Lipid abnormalities in nephrotic syndrome", section on 'Management')

●Anticoagulation (see "Hypercoagulability in nephrotic syndrome", section on 'Patients with other causes of nephrotic syndrome')

●Treatment of edema (see "Overview of the management of chronic kidney disease in adults", section on 'Volume overload')

DIALYSIS AND KIDNEY TRANSPLANTATION — Patients with renal amyloidosis who progress to end-stage kidney disease (ESKD) can be treated with either dialysis or kidney transplantation.

Outcomes in AL amyloidosis

●Dialysis – In general, outcomes among patients with AL amyloidosis who require dialysis are not as good as those for patients with other kidney diseases who require dialysis [16,75-77]. In earlier studies, median survival ranged from 8 to 26 months [16,75,76]. Subsequent studies have shown a modest improvement in outcomes. As an example, a United Kingdom study of 222 patients with AL amyloidosis on dialysis reported a mean survival of 39 months [78].

●Transplantation – By contrast, outcomes with kidney transplantation appear to be more favorable, especially in selected patients without other severe organ failure and who have a complete or very good partial hematologic response prior to transplantation [78-82]:

•The largest study included 237 patients with AL amyloidosis who underwent kidney transplantation and were followed for a median of 8.5 years [82]. Median overall survival from kidney transplantation was 8.6 years and was longer in patients with complete or very good partial hematologic responses compared with those who had less than very good partial response at the time of transplant (9 versus 6.8 years, respectively). Median graft survival was 7.8 years and greater in patients with complete or very good partial response (8.3 versus 5.7 years, respectively).

•Similar findings were reported in a study of 60 patients with AL amyloidosis who underwent kidney transplantation and were followed for a median of 61 months [80]. Prior to transplantation, 37 had achieved a complete hematologic response, 6 had a very good partial response, 5 had a partial response, 3 had no response, and 9 were treatment-naïve (never treated). Median overall survival for the group was 123 months. Median overall survival was not reached in the complete response group and was 8, 47, 81, and 117 months for the no response, partial response, very good partial response, and treatment-naïve groups, respectively. Death-censored graft survival at one and five years was 98 and 96 percent, respectively. Three patients (5 percent) developed graft failure, 19 (32 percent) died with a functioning graft, and 13 (22 percent) had amyloid recurrence.

•In another study of 49 patients who underwent kidney transplantation, median patient survival was 15.4 years from the time of diagnosis and 10.5 years from the time of transplant [79]. One-, three-, and five-year graft survival were 94, 89, and 81 percent, respectively. Patient survival was better among patients with hematologic complete response or very good partial response prior to transplant compared with those who had partial or no response.

Recurrence is a problem in AL amyloidosis. Two separate strategies have been used to address this issue, both of which have been shown to produce similar outcomes [83]. One restores kidney function first with a living donor kidney transplant prior to an autologous stem cell transplantation to treat the plasma cell dyscrasia [84]. This approach was evaluated in a report from the Mayo Clinic, which described their experience with the first eight patients with ESKD treated with this regimen [84]. Of eight patients who received a living donor kidney transplant, five subsequently underwent successful autologous stem cell transplantation, two died (one prior to stem cell transplantation and one after stem cell transplantation), and one patient elected not to undergo stem cell transplantation. At follow-up 0.4 to 2.3 years post-stem cell transplantation, kidney function was adequate in the five survivors who underwent both procedures (serum creatinine concentration ranging from 0.9 to 1.9 mg/dL [80 to 168 micromol/L]).

Alternatively, autologous stem cell transplantation can be performed first in patients with AL amyloidosis and ESKD, and kidney transplantation can be considered once hematologic complete response is achieved. Boston University reported their experience of this approach with 15 patients [85]. While toxicity, especially mucositis, and transfusion requirement were greater in those with ESKD, overall survival and response were similar to those in patients without ESKD. One advantage of this approach is avoidance of immunosuppression during autologous stem cell transplantation, which can be challenging.

Outcomes in AA amyloidosis

●Dialysis – Outcomes among patients with AA amyloidosis who require dialysis are generally unfavorable although much of the data are from older studies [75,76,86]. As examples:

•In a retrospective study of 73 patients with AA amyloidosis, of whom 45 developed ESKD and required dialysis (41 with hemodialysis, 4 with peritoneal dialysis), median survival on dialysis was 20 months [86]. Among patients receiving dialysis, one- and two-year patient survival were 64 and 56 percent, respectively, compared with 84 and 74 percent, respectively, among patients who did not require dialysis. Survival on dialysis did not differ significantly with regards to the underlying etiology of AA amyloidosis (mostly Familial Mediterranean fever and tuberculosis).

•In another retrospective study that included 20 patients with AA amyloidosis requiring dialysis, three patients (15 percent) died over a mean of 32 months [76].

●Transplantation – The experience with kidney transplantation may be more favorable than that of dialysis [81,87-90]:

•In a study of 43 patients with AA amyloidosis who underwent kidney transplantation, 5- and 10-year graft survival rates were 86 and 59 percent, respectively [91]. Sixteen patients (37 percent) died over a median of 5 years, mostly from infectious causes. Recurrence of amyloidosis in the allograft occurred in nine patients (21 percent), two of whom experienced graft failure as a result. Similar graft survival rates have been reported in other studies [89].

•In another study that compared long-term transplant outcomes between 24 patients with ESKD secondary to amyloidosis (22 with AA amyloidosis, 2 with AL amyloidosis) and 24 control patients with ESKD from other causes, rates of biopsy-proven acute rejection and graft failure were similar between the groups [90]. However, patient survival rates were lower among patients with AA amyloidosis compared with those with ESKD due to other causes (68 versus 86 percent, respectively, at 10 years and 37 versus 60 percent, respectively, at 20 years).

Outcomes in other types of amyloidosis — Data on dialysis or transplant outcomes in patients with other forms of amyloidosis are more limited.

Recurrence appears to be common in patients with fibrinogen A alpha-chain amyloidosis who received kidney transplantation alone. In the largest series to date, recurrence was noted in four of eight successful kidney allografts [92]. Three of the grafts were lost as a direct result of recurrence (median of six years), with one remaining functional after 12 years. By comparison, seven patients have undergone combined liver-kidney transplantation and no recurrence has been found in the six surviving patients.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults" and "Society guideline links: Immunoglobulin light chain (AL) amyloidosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: AL amyloidosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview – Amyloidosis is a group of diseases characterized by extracellular deposition of beta-sheet fibrils. Kidney involvement occurs in AL amyloidosis, characterized by the deposition of immunoglobulin light chains, or AA amyloidosis, characterized by the deposition of amyloid A. Kidney involvement is also the dominant presentation in some hereditary forms of amyloidosis. (See 'Introduction' above and 'Epidemiology' above.)

●Types of renal amyloidosis – The etiology of renal amyloidosis depends upon the type (table 2). An abnormal clonal proliferation of plasma cells causes AL amyloidosis. Chronic inflammatory diseases (such as rheumatoid arthritis) cause AA amyloidosis. Other major conditions associated with AA amyloidosis include ankylosing spondylitis, psoriatic arthritis, chronic pyogenic infections, inflammatory bowel disease, cystic fibrosis, some neoplasms, Familial Mediterranean fever, and other genetic autoinflammatory diseases (table 1). Less commonly, genetic disorders associated with chronic inflammation may cause AA amyloidosis. (See 'Types of renal amyloidosis' above.)

●Clinical manifestations – Clinical manifestations of renal amyloidosis vary with the site and degree of involvement (table 2). The most common presentation of AL and AA amyloidosis is heavy proteinuria which is associated with glomerular deposits. Patients with tubulointerstitial or vascular deposits present with slowly progressive chronic kidney disease (CKD) with little or no proteinuria. Less commonly, patients with pure tubular deposits present with tubular dysfunction such as type 1 (distal) renal tubular acidosis or polyuria due to arginine vasopressin resistance (previously called nephrogenic diabetes insipidus), and, in rare cases, Fanconi syndrome. Crescentic glomerulonephritis is extremely rare. (See 'Clinical manifestations' above.)

●Diagnosis – Renal amyloidosis should be suspected in any patient presenting with proteinuria with or without the nephrotic syndrome. A kidney biopsy is generally required to make a definitive diagnosis. However, a kidney biopsy may be deferred if amyloidosis is suspected in a patient with a monoclonal gammopathy, in which case an abdominal fat pad aspirate may secure the diagnosis of systemic AL amyloidosis. Once amyloidosis is confirmed by biopsy, the underlying etiology should be determined by typing the amyloid. (See 'Diagnosis' above.)

●Management – In the absence of treatment, ongoing deposition of amyloid protein in the kidney results in a progressive decline in kidney function and ultimately end-stage kidney disease (ESKD) in most patients. Treatment of renal amyloidosis involves therapies targeting the production of amyloid protein as well as supportive measures. The goal of therapy is to decrease the burden of amyloid protein in order to limit further kidney injury and to preserve or improve kidney function. (See 'Management' above.)

●End-stage kidney disease (ESKD) – Patients with renal amyloidosis who progress to ESKD can be treated with either dialysis or kidney transplantation. In general, outcomes among patients with amyloidosis who require dialysis are not as good as those for patients with other kidney diseases who require dialysis. Outcomes with kidney transplantation in selected patients appear to be more favorable. (See 'Dialysis and kidney transplantation' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert A Kyle, MD, who contributed to earlier versions of this topic review.