Key Information
AL amyloidosis is caused by the excessive production of nonfunctional immunoglobulins, leading to the formation of amyloid fibrils that damage vital organs, especially the heart and kidneys. AL amyloidosis presents with non-specific symptoms such as fatigue, weight loss, numbness, pain, and nephrotic syndrome. Consequently, diagnosis is often delayed, and patients typically present with advanced disease at diagnosis. The Pavia renal staging model stratifies patients based on their likelihood of progressing to dialysis. Treatment with daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (i.e., Dara-CyBorD) was effective in inducing renal response in the landmark phase III ANDROMEDA trial and reducing early mortality. However, determining the most appropriate treatment regimen for relapsed or refractory cases remains a challenge due to various patient- and disease-related factors. Encouragingly, t(11:14) may be a positive indicator of therapy responses to the anti-BCL2 therapy venetoclax. Moreover, it is increasingly possible—for the first time—to clear AL amyloid fibrils from peripheral organs by leveraging novel anti-fibril immunotherapeutic approaches, although these medications are still under investigation in clinical trials. Given these advancements, this review provides a comprehensive overview of the current strategies for diagnosing, staging, treating, and monitoring AL amyloidosis, emphasizing renal involvement.
1. Introduction
Immunoglobulin light chain (AL) amyloidosis arises from a plasma cell dyscrasia that results in the overproduction of nonfunctional immunoglobulins [1external link, opens in a new tab]. These misfolded proteins aggregate into insoluble β-pleated amyloid fibrils, commonly known as AL amyloids, which deposit within various organs. Cardiac and renal damage are most prevalent among patients with AL amyloidosis [2external link, opens in a new tab,3external link, opens in a new tab]. Renal involvement, leading to nephrotic syndrome, occurs in about two-thirds of AL amyloidosis cases, with 25% of these patients progressing to end-stage renal disease (ESRD) and requiring renal replacement therapy, including dialysis and kidney transplantation [4external link, opens in a new tab,5external link, opens in a new tab].
Currently, the goal of treatment is to reduce amyloid production by targeting the aberrant plasma cell clone in the bone marrow [3external link, opens in a new tab,6external link, opens in a new tab]. However, the prospect of clearing peripheral amyloid deposits with the novel anti-fibril antibodies looks promising, through approval of these medications is still subject to ongoing clinical trials [7external link, opens in a new tab]. Ongoing Phase III studies testing the efficacy of these anti-fibril medications focus on advanced cardiac amyloidosis. Novel imaging techniques applied to the early diagnosis of AL amyloidosis are also primarily concentrated on cardiac involvement, given its importance to patient prognosis. In contrast, renal patients, who also often present with advanced disease at diagnosis reflecting delayed or incorrect diagnoses, are relatively underrepresented in such studies. Furthermore, biomarkers of renal involvement are limited to conventional renal functional tests such as estimated glomerular filtration rate (eGFR) and measures of proteinuria. This paper provides an overview of the diagnosis, staging, and management of renal AL amyloidosis while highlighting prevailing challenges that future studies must address.
2. Diagnostic Approach
Patients with AL amyloidosis exhibit a non-specific symptom profile, which may include fatigue, unintentional weight loss, arrhythmia, numbness, paresthesia, pain, enlarged tongue (macroglossia), and nephrotic syndrome. Consequently, the diagnosis of AL amyloidosis is often delayed, with the median time from symptom onset to diagnosis potentially extending between 2 and 4 years [8external link, opens in a new tab]. Indeed, approximately 37% of patients are diagnosed over 12 months post symptom onset, with 32% consulting at least five doctors before receiving a diagnosis [9external link, opens in a new tab]. This delay leads to irreversible organ failure at presentation, including progressive heart failure, ESRD, and death.
The consequences of renal involvement range from mild proteinuria to nephrotic-range proteinuria, its associated manifestations (hyperlipidemia, peripheral edema, hypercoagulability, and increased susceptibility to infections), and progressive renal dysfunction [10external link, opens in a new tab]. Timely recognition and the prompt initiation of treatment facilitate the preservation of organ function, mitigating dysfunction and improving overall survival [11external link, opens in a new tab].
For a diagnosis of AL amyloidosis, there must be evidence of an amyloid-related syndrome, positive Congo Red staining on biopsy (or detection of AL amyloid on mass spectrometry), and the presence of a plasma cell dyscrasia. The initial step in diagnosing AL amyloidosis involves detecting circulating monoclonal light chains (Table 1external link, opens in a new tab). Serum protein electrophoresis with immunofixation, 24 h urine protein collection for electrophoresis with immunofixation, and serum-free light chain (FLC) assay can detect amyloidogenic monoclonal components effectively. The absence of a monoclonal component renders the diagnosis of AL amyloidosis unlikely [12external link, opens in a new tab]. Amyloid typing is a critical step, and methods include immunofluorescence (IF), immunohistochemistry (IHC), electron microscopy (EM), immunoelectron-microscopy (IEM), and laser microdissection with tandem mass spectroscopy (LMD-MS)-based proteomic analysis [13external link, opens in a new tab,14external link, opens in a new tab,15external link, opens in a new tab,16external link, opens in a new tab]. Commonly sampled surrogate biopsy sites include the abdominal fat pad, bone marrow, and minor salivary glands. At referral centers, the diagnostic sensitivity of abdominal fat pad biopsy is 70–80%, that of bone marrow biopsy is 70%, and that of the minor salivary gland is 80% [17external link, opens in a new tab]. Simultaneously sampling the abdominal fat and bone marrow can increase sensitivity to 89% [18external link, opens in a new tab].