Concurrence of renal amyloidosis and membranous nephropathy: a case series and literature review

Abstract

Background

Amyloidosis is a group of heterogeneous diseases characterized by the deposition of amyloid fibrils in various organs and tissues. Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults.

Case presentation

We report three cases of early-stage MN occurring concurrently with distinct types of renal amyloidosis: apolipoprotein A-I (AApoA-I) amyloidosis, leukocyte chemotactic factor 2 (ALECT2) amyloidosis, and monoclonal immunoglobulin light-chain (AL) amyloidosis. Each case represents a different pathogenic mechanism, therapeutic approach, and clinical prognosis.

Conclusions

These cases underscore the pivotal role of renal pathology in the accurate diagnosis of patients with coexisting amyloidosis and MN. Correct classification of renal amyloidosis is essential for guiding therapy and predicting outcomes. When amyloidosis coexists with MN or other potentially treatable renal diseases, therapeutic decisions should prioritize the condition with the greater potential for organ damage or the one most responsive to available treatment.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12882-026-04854-9.

Background

Amyloidosis is a heterogeneous group of diseases characterized by the extracellular deposition of amyloid fibrils in various organs and tissues. In each case, these fibrils are derived from a specific misfolded precursor protein. With advances in genetic testing, proteomics, and mass spectrometry, approximately 40 precursor proteins have been identified to date [1, 2]. The clinical and pathological features of amyloidosis vary depending on the biochemical composition of the amyloid deposits and the nature of the precursor proteins involved [3]. Amyloidosis can present as either a localized or systemic disorder; in the systemic form, multiple internal organs can be affected, with the kidney being the most commonly involved [4, 5].

Renal amyloidosis typically presents with proteinuria or nephrotic syndrome, and may also present as slowly progressive chronic kidney disease, sometimes without significant proteinuria. The most frequent precursor protein in renal amyloidosis is immunoglobulin light chain (AL), followed by serum amyloid A (AA), leukocyte chemotactic factor 2 (ALECT2), and fibrinogen A α-chain (AFib) amyloidosis [6]. The diagnosis and classification of renal amyloidosis rely on renal biopsy and histopathologic examination. For AL amyloidosis, without treatment, the disease often progresses to hypotension, restrictive cardiomyopathy, and ultimately death; however, treatment regimens including bortezomib have markedly improved patient outcomes. By contrast, although specific therapies exist for hereditary transthyretin (ATTR) amyloidosis and AA amyloidosis, effective disease-specific treatments are lacking for other forms of amyloidosis, and their prognoses remain uncertain due to their rarity [7, 8].

Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults and is pathologically characterized by thickening of the glomerular basement membrane (GBM) due to in situ formation of subepithelial immune complexes. MN may be primary or secondary to systemic conditions such as autoimmune diseases, neoplasms, chronic infections, or exposure to certain drugs [9]. Phospholipase A2 receptor (PLA2R), a podocyte-associated membrane glycoprotein, has been identified as the target antigen in approximately 70% of patients with primary membranous nephropathy (PMN) [10], a condition now referred to as PLA2R-associated MN [11]; in addition, at least 12 other antigens have also been reported in association with MN. Removal of circulating and tissue PLA2R antibodies is associated with clinical remission.

Renal amyloidosis and MN are distinct entities with different clinicopathologic features, pathogenic mechanisms, therapeutic strategies, and prognostic implications. Previous studies have reported MN coexisting with other glomerular diseases, including diabetic nephropathy [12], IgA nephropathy [13], and crescentic glomerulonephritis [14]; however, concurrent renal amyloidosis and MN are rarely described. Here, we present three cases of early-stage MN occurring concurrently with different types of renal amyloidosis, each associated with distinct therapeutic strategies and clinical outcomes. Two cases of MN were PLA2R-associated. The three types of amyloidosis identified were AApoA-I (apolipoprotein A-I), ALECT2, and AL amyloidosis, each exhibiting unique pathological features, treatments, and prognoses.

Case presentation

Case 1

A 52-year-old Chinese woman with no family history of kidney disease presented in October 2017 with a five-month history of facial and lower-limb edema and foamy urine. She was initially diagnosed with nephrotic syndrome and received oral prednisone (50 mg/day) for two months without improvement, after which she was referred to our hospital.

On admission, physical examination revealed mild bilateral lower limb edema. Her blood pressure was 123/78 mmHg. Laboratory tests showed the following results: hemoglobin 116 g/L, albumin 35.4 g/L, blood urea nitrogen 8.60 mmol/L, serum creatinine 79.0 µmol/L, and triglycerides 2.70 mmol/L. The urine protein-to-creatinine ratio was 7.27 g/g Cr. Urinalysis showed 3 red blood cells per high-power field. Autoimmune tests including ANA, anti-dsDNA, and anti-Smith antibodies were negative; C3 and C4 levels were normal. Serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE) did not reveal a monoclonal immunoglobulin. The serum anti-PLA2R antibody was positive by ELISA (EUROIMMUN), with a cut-off ratio ≥ 1.00 considered positive. Bone marrow examination, including morphology and flow cytometry (FCM), showed no evidence of clonal plasma cell proliferation or light-chain restriction.

Renal biopsy was subsequently performed. Light microscopy with hematoxylin and eosin (H&E) and periodic acid–Schiff (PAS) staining demonstrated expansion of the mesangial matrix and irregular thickening of the glomerular basement membrane (GBM) (Fig. 1A, B). Silver staining showed non-argyrophilic mesangial expansion, GBM thickening, and spike formation (Fig. 1C). Masson’s trichrome staining revealed fuchsinophilic deposits in the subepithelial area (Fig. 1D). Congo red staining showed amyloid-positive deposits in the mesangial region (Fig. 1E). The tubulointerstitial compartment appeared normal (Fig. 1F). Immunofluorescence microscopy revealed granular IgG (++) deposition along the glomerular capillary walls (Fig. 1G) but not in the mesangium. Both κ and λ light chains were positive in the same distribution. AA amyloidosis staining was negative. Electron microscopy demonstrated subepithelial electron-dense deposits (Fig. 1H) and abundant amyloid fibril deposition in the mesangial regions (Fig. 1I, J). Laser microdissection of glomeruli followed by tandem mass spectrometry–based proteomic analysis identified AApoA-I as the predominant amyloid component, followed by γ-heavy chain fragments (Fig. 1K). Whole-exome sequencing (WES) using Illumina technology detected no ApoA1 gene mutations in the patient or her children. A diagnosis of nonhereditary AApoAI–related renal amyloidosis coexisting with PLA2R-associated membranous nephropathy (stage 2) was established. Tacrolimus (1 mg every 12 h) was initiated while prednisone was tapered to 10 mg/day. Proteinuria resolved within one month, and complete remission was maintained for two years, after which treatment was discontinued. At the latest follow-up, the patient remained asymptomatic, with serum creatinine of 106 µmol/L and mild proteinuria (protein/creatinine ratio 2.13 g/g Cr). No further immunosuppression was given, and she continues to be monitored.

Fig. 1.

Renal pathology figures of case 1. Microscopic images of HE staining (A) and PAS staining (B) show expansion of the glomerular mesangial matrix and irregular thickening of the glomerular basement membrane (GBM). Silver staining (C) reveals non-argyrophilic mesangial expansion, GBM thickening, and spike formation (arrows). Masson staining (D) highlights fuchsinophilic deposits in the subepithelial area (arrows). Congo red staining (E) indicates positivity in the mesangial region. (A, B, C, D, E; Bar = 200 μm). Silver staining also highlights the normal tubulointerstitium (F). Immunofluorescence examination (G) reveals granular deposition of IgG (++) along the glomerular capillary wall, with no involvement of the mesangial area. Electron microscopy (H, I, J) demonstrates electron-dense deposits in the subepithelial area (arrows) and numerous amyloid fibril deposits in the mesangial regions (H; Bar = 5 μm, I; Bar = 1 μm, J; Bar = 200 nm). Laser microdissection (LMD) of glomeruli and tandem mass spectrometry (MS)-based proteomics (K) show ApoA-1 as the most abundant protein, followed by heavy chain gamma

Case 2

A 55-year-old Han Chinese man presented in March 2022 with lower-limb edema lasting 11 months. Physical examination revealed facial and leg swelling, and elevated blood pressure (169/103 mmHg). Laboratory findings showed hemoglobin 103 g/L, albumin 19.8 g/L, blood urea nitrogen 23 mmol/L, serum creatinine 215.0 µmol/L, uric acid 356 µmol/L, triglyceride 5.08 mmol/L, and cholesterol 13.98 mmol/L. Complement levels (C3, C4) were normal. The serum and urine free light-chain ratio, SPE, and IFE were within normal limits, indicating no monoclonal immunoglobulin. N-Terminal Pro-Brain Natriuretic Peptide (NT-pro BNP), 2198 ng/L (normal range, < 227); Bone alkaline phosphatase (BALP), 7.97 ug/L (normal range 11.4–24.6 ug/L). Serum beta-2 microglobulin (β2-MG), 4.06 mg/L (normal range 0.70–1.80 mg/L). Serum PLA2Rab was 200.78 RU/mL. Urine sediments test showed RBC, 12 /HP. Urine protein/creatinine ratio was 11.14 g/g Cr. Ultrasonic cardiogram showed left ventricle hypertrophy, ejection fraction (EF) 64%, and renal ultrasound showed kidneys of normal size and echogenicity. Bone marrow biopsy revealed 3% plasma cells, and FCM showed no monoclonal proliferation. Urine tests in his brother, sister, and son were negative.

A renal biopsy was conducted. HE staining, PAS staining and silver staining revealed non-argyrophilic expanding mesangium and stiffness of GBM (Fig. 2A, B, C). Diffuse, granular depositions of IgG (3+), C3 (2+), kappa light chain (2+) and lambda light chain (2+) were observed along the capillary wall under IF microscopy. Congo red staining was positive in glomerular mesangium, interstitium and arteriole walls (Fig. 2D and E). Staining with antibodies against ALECT2 was positive in glomerular mesangium, interstitium, and arteriole walls, consistent with Congo red staining (Fig. 2H and I). Immunostaining for AA amyloidosis was negative. Electron microscopy revealed electron-dense deposits in the subepithelial area (Fig. 2F) and numerous amyloid fibril deposition in mesangial regions (Fig. 2G). These findings confirmed renal ALECT2 amyloidosis coexisting with PLA2R-associated membranous nephropathy (stage II).

Fig. 2.

Renal pathology figures of case 2. HE staining (A), PAS staining (B), and silver staining (C) reveal non-argyrophilic mesangial expansion and GBM stiffening (A, B, C; Bar = 200 μm). Congo red staining (D, E) shows positivity in the glomerular mesangium, interstitium, and arteriole walls (D, E; Bar = 200 μm). Electron microscopy demonstrates electron-dense deposits in the subepithelial area (arrows) (F; Bar = 1 μm) and numerous amyloid fibril deposits in the mesangial regions (G; Bar = 500 nm). Staining with antibodies against LECT2 is positive in the glomerular mesangium, interstitium, and arteriole walls, consistent with Congo red staining (H, I; Bar = 200 μm)

The patient had been treated with cyclosporine and prednisone. Cyclosporine was withdrawn because of decreased renal function. Rituximab (RTX) was administered intravenously at a dose of 1 g. Subsequent tests conducted during the last follow-up showed the Urinalysis was positive for + protein; and protein/creatinine ratio, 3.57 g/g Cr. Blood biochemistry analysis revealed albumin, 36.9 g/L; blood nitrogen urea, 12.0 mmol/L; serum creatinine, 169 µmol/L; cholesterol, 5.67 mmol/L and Serum PLA2Rab, < 2 RU/mL.

Case 3

A 65-year-old Chinese patient came to our hospital in August 2023 due to bilateral lower limb edema for one month. The patient also complained of fatigue, weight loss, dizziness, and chest discomfort. Physical examination revealed mild edema of the lower extremities. There were no signs of bilateral periorbital purpura or macroglossia. His blood pressure was 93/56mmHg, and the heart rate was 82 beats per minute. Notably, he had lost 4 kg in body weight within the month preceding hospitalization.

Laboratory tests revealed hemoglobin, 141 g/L. Urine protein was 3.685 g/24 hour. Urine sediment test was normal. Blood biochemistry analysis revealed albumin, 16.2 g/L; blood nitrogen urea, 7.94 mmol/L; serum creatinine, 128.5 µmol/L; uric acid, 433 µmol/L; triglyceride, 4.02 mmol/L; cholesterol, 11.97 mmol/L; alkaline phosphatase (ALP), 614 U/L (normal range 49–125 U/L); γ-glutamyltranspeptidase (γ-GTs), 428 U/L (normal range 10–60 U/L); serum lactate dehydrogenase (LDH), 430 U/L (normal range 120–250 U/L). β2-MG, 7.29 mg/L (normal range 0.70–1.80 mg/L); Serum free light chain analysis showed markedly elevated free κ light chains (137.07 mg/L) with relatively preserved free λ light chains (21.49 mg/L), resulting in an abnormal κ/λ ratio of 6.37 (reference range 0.26–1.65); SPE and serum IFE did not reveal a detectable monoclonal immunoglobulin. Urine immunofixation electrophoresis was not performed; NT-pro BNP, 4514 ng/L, troponin-T (TnT) 56.2 ng/L (normal range 0–14). Cardiac MRI revealed ventricular septal thickening and patchy latent enhancement. Bone marrow biopsy revealed a clonal plasma cell population comprising approximately 3% of marrow cells. FCM analysis demonstrated a clonal plasma cell population accounting for approximately 3.27% of nucleated bone marrow cells, with κ light-chain restriction.

Renal pathologic exam revealed expanding mesangial area. Numerous amorphous, slightly eosinophilic, non-argyrophilic material was deposited in mesangium, arterioles and interstitium (Fig. 3A, B, C). These depositions were Congo red staining positive (Fig. 3D). Staining for IgG revealed fine granular positivity along the glomerular capillary loops (Fig. 3E). Staining for IgG subclass revealed positivity of IgG4 (1+, along the glomerular capillary loops; Fig. 3F) and IgG1 (+/-), whereas IgG2 and IgG3 were negative. Staining for light chains revealed positivity along the glomerular capillary walls, while the intensities were 3 + for kappa light chain and 2 + for lambda light chain. However, only kappa light chain was stained positive (+++) in the mesangial area and the arteriole wall (Fig. 3G, H). Staining for PLA2R and THSD7A were negative. Electron microscopy showed a few electron-dense deposits in the subepithelial area and within GBM (Fig. 3I, J). There were massive amyloid fibrils in the mesangial area (Fig. 3K). Systemic AL-kappa amyloidosis and MN were diagnosed. Treatment including bortezomib and dexamethasone was initiated. However, the patient succumbed to heart failure one month later.

Fig. 3.

Renal Pathology figures of case 3. HE staining (A), PAS staining (B), and silver staining (C) reveal numerous amorphous, slightly eosinophilic, non-argyrophilic material deposited in the mesangium, arterioles, and interstitium. Congo red staining (D) shows these deposits are positive (A, B, C, D; Bar = 200 μm). Immunofluorescence staining for IgG (E) reveals fine granular positivity along the glomerular capillary loops. Subclass staining for IgG (F) shows positivity for IgG4 (1+). Staining for light chains (G, H) reveals positivity along the glomerular capillary walls, with intensities of 3 + for kappa light chain and 2 + for lambda light chain. Only the kappa light chain showed strong positivity (+++) in the mesangial area and arteriole walls. Electron microscopy (I) shows a few electron-dense deposits in the subepithelial area and within the GBM, along with extensive amyloid fibrils in the mesangial area (J; Bar = 2 μm, K; Bar = 1 μm, L; Bar = 1 μm)

Discussion and conclusions

The cases with concurrence of MN and amyloidosis have been seldom reported. In 1978, the first case of perimembranous glomerulonephritis combined with glomerular amyloidosis was reported [15]. In 1991, Varshavskiĭ VA et al. reported 15 kidney biopsies from 13 patients with both MN and AA amyloidosis, demonstrating that MN preceded the development of AA amyloidosis. AA amyloidosis develops as a response to chronic inflammation or infection, which stimulates the liver to produce elevated levels of serum amyloid A (SAA) protein [16]. Recent literature has reported six cases of membranous nephropathy concurrent with renal amyloidosis, each exhibiting distinct clinicopathological characteristics [17]. In our study, we reported three cases whose clinicopathological features, treatments and outcomes are summarized in Table 1.

Table 1.

Summary of the clinicopathological features, treatments and outcomes of the 3 patients included in this study

Cases	Case 1	Case 2	Case 3
Gender	Female	Male	Male
Age of onset	48	55	65
Chief Complain	edema of face and lower limbs and foamy urine for five months	edema of lower extremities for eleven months	bilateral lower limb edema for one month
Blood pressure	123/78 mmHg	169/103 mmHg	93/56 mmHg, postural hypotension
Serum creatinine	79.0 mmol/L	215.0 mmol/L	128.5 mmol/L
Serum nitrogen urea	8.60 mmol/L	23.00 mmol/L	7.94 mmol/L
Serum albumin	35.4 g/L	19.8 g/L	16.2 g/L
urine protein/creatinine ratio (UPCR)	7.27 g/g Cr	11.14 g/g Cr	9.34 g/g Cr
Serum Anti-PLA2R	Positive (ELISA, Cut-off ratio ≥ 1.00)	200.78 RU/mL (CLIA)	untested
Renal PLA2Ra (IHC)	untested	untested	Negative
SPE and sIFE	Monoclonal Immunoglobulin was not found	Monoclonal Immunoglobulin was not detected	Monoclonal Immunoglobulin was not detected
Serum or urine free light chain ratio (kappa/lambda)	negative	negative	Serum: 6.37 ratio (normal range 0.26–1.65)
Bone marrow aspiration and biopsy	Negative	a plasma cell population of 3.0%.	a clonal plasma cell population in the marrow, accounting for 3.0% of the cells
FCM analysis of bone marrow	did not reveal any evidence of restricted light chain expression.	no detection of monoclonal malignant plasma cells	clonal plasma cells comprised approximately 3.27% of the nuclear cells in the bone marrow
Method to classification diagnosis of Amloidosis	LMD/MS and WES	Immunohistochemistry	Immunofluorescence
Cardiac function	ultrasonic cardiogram: not notable changes, EF 64%	ultrasonic cardiogram: left ventricle hypertrophy (LVPW 12 mm), EF 64%	Cardiac MRI revealed ventricular septal thickening and patchy latent enhancement
Diagnosis	Nonhereditary ApoA-1-related renal Amyloidosis coexisting with PLA2R-associated MN (Stage 2)	Renal LECT2 Amyloidosis and PLA2R-associated MN (Stage 1)	Systemic AL Amyloidosis and MN (Stage 1)
Treatment	Prednisone and Tacrolimus	Prednisone and cyclosporine. Cyclosporine was replaced by Rituximab because of decreased renal function	Bortezomib and Dexamethasone Midodrine
Follow-up	8 years	3 years	sudden cardiac death happened after 4 weeks of being diagnosed

AApoA-I is a systemic amyloidosis, associated with mutations in the APOA1 gene and is inherited in an autosomal dominant. Over 20 pathogenic variants have now been identified. Only a few cases of nonhereditary AApoA-I amyloidosis have been reported, in patients born in China [18]. ApoA-I is the principal protein component of high-density lipoproteins and plays a central role in cholesterol transport. It is synthesized by the liver and small intestine and is mainly degraded in the kidney. AApoA-I amyloidosis is reported both as isolated cases and as clusters [7]. In AApoA-I amyloidosis, organ involvement and clinical phenotype are partly dependent on the specific disease-causing mutation. In the large series of UK AApoA-I [7] with 14 different APOA1 mutations, involvement of the kidneys, liver and heart by amyloid was detected in 81%, 67% and 28% of patients, respectively. Hereditary AAPOA-I mainly affects the kidney at the interstitium and inner medulla level. Patients typically present with chronic renal disease without proteinuria. However, many cases present the classic glomerular deposition pattern and nephrotic syndrome. Nonhereditary forms mainly involve the glomeruli. AApoA-I amyloidosis is an extremely rare form of systemic hereditary amyloidosis, reported only in isolated case studies; by contrast, hereditary ATTR amyloidosis represents the first described systemic hereditary form [7, 8]. Concurrence of nonhereditary AApoA-I amyloidosis and MN has been reported, with clinical remission achieved following glucocorticoid combined with cyclosporine therapy, as observed in Case 1 of our study. Whether a pathogenic relationship exists between these two diseases remains unknown.

LECT2 is a 16-kDa protein mainly produced by hepatocytes. It is a pleiotropic protein with multifunctional roles, including involvement in liver regeneration, neuronal development, hematopoietic stem cell homeostasis, liver injury, liver fibrosis, and metabolic disorders, among others [19]. ALECT2 amyloidosis was first reported in 2008 [20] and has since become the third most common type of renal amyloidosis (1–10% of renal amyloidosis) [21]. This type of amyloidosis predominantly affects patients of Mexican ancestry and other non-Caucasian populations, with a mean age at diagnosis of 62–67 years. Many patients present with chronic kidney disease and mild to moderate proteinuria, while some may have little or no proteinuria. In Case 2, the markedly elevated NT-pro BNP likely reflected volume overload and impaired renal function rather than direct cardiac amyloid infiltration [22, 23]. No mutations in the ALECT2 gene were detected. Renal biopsy showed that amyloid fibrils can deposit in all compartments of the kidney. Approximately 25%–30% of ALECT2 amyloidosis patients have other concurrent kidney diseases, including membranous nephropathy, IgA nephropathy, diabetic nephropathy, and AA amyloidosis. The reasons for the high concurrence of ALECT2 amyloidosis with other kidney diseases remain unclear. Some studies suggest that some type of amyloidosis, such as ALECT2 may be associated with inflammatory processes in humans [24], perhaps the inflammatory milieu present in ALECT2 amyloidosis triggers the onset of disease in susceptible individuals with MN risk alleles [25]. Effective treatment of LECT2 amyloidosis is lacking.

AL amyloidosis is the most common form of systemic amyloidosis. Only several cases of concurrence of AL amyloidosis and MN have been reported, and these studies did not clarify whether the associated antibodies were polyclonal or monoclonal [26–28]. Identification of the antigen and its subtype is therefore important. Indeed, monotypic PLA2R antibodies have been reported [29], raising the possibility that a monoclonal antibody may contribute both to amyloid deposition and to the formation of subepithelial immune-complex deposits in MN. In addition, proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) must be considered in the differential diagnosis. PGNMID is a recently described entity among the spectrum of monoclonal gammopathy of renal significance (MGRS). It is renal-limited and manifests with chronic glomerular disease, altered renal function and albuminuria. PGNMID may occasionally manifest a predominantly membranous pattern with regularly spaced subepithelial, electron-dense deposits and deposition of monotypic immunoglobulin, mainly IgG3-kappa type [30–32]. AL amyloidosis is also a form of MGRS and also presents restricted immunoglobulin; however, to date, concurrence of PGNMID and AL amyloidosis has not been reported. In Case 3, immunofluorescence revealed IgG4 positivity without light-chain restriction, a pattern that is not consistent with PGNMID and also does not support a diagnosis of monoclonal membranous nephropathy [33]. For patients with concurrent AL amyloidosis and primary MN, treatment targeting an identified or suspected clonal B-cell or plasma cell population is preferred, as such therapy can potentially eliminate both amyloidogenic clones and MN-associated antibodies.

For Case 1, at the time of diagnosis in 2017, kidney biopsy was routinely performed, as the noninvasive diagnostic role of serum anti-PLA2R antibody testing had not yet been incorporated into clinical guidelines. In Case 2, kidney biopsy was undertaken because the patient presented with atypical clinical features, including impaired renal function at presentation (serum creatinine 215.0 µmol/L) and a clinical suspicion of concomitant renal pathology. In Case 3, serum anti-PLA2R antibody testing was not performed because the patient was transferred to the Hematology department before the biopsy results became available, and the assay required external testing at the patient’s own expense. The biopsy ultimately demonstrated coexisting renal amyloidosis and MN, thereby confirming the clinical necessity of kidney biopsy. Several histopathologic features can help distinguish amyloidosis from MN. First, subepithelial deposits of amyloid may show widely spaced subepithelial spikes (so-called amyloid spicules) [34], whereas in MN, subepithelial spikes tend to be more diffuse, relatively uniform in size, and generally smaller. Electron microscopy further differentiates these entities: amyloidosis exhibits characteristic amyloid fibrils, while MN shows electron-dense deposits on the epithelial side without a defined fibrillar structure. Immunofluorescence (IF) can also aid differentiation, with MN typically showing deposits of IgG and C3. Second, the anatomical distribution of deposits differs. MN is characterized by immune complex accumulation along the subepithelial (outer) aspect of the glomerular capillary wall. In contrast, amyloid deposition often involves the mesangium, with additional involvement of the interstitium, arteriole walls, and sometimes the GBM. Careful assessment of deposit location and the presence of precursor amyloid fibrils is essential for accurate histopathologic identification.

In this context, we also emphasize the critical importance of accurately classifying renal amyloidosis, as precise typing is essential for selecting appropriate treatment strategies and assessing prognosis. Renal biopsy remains indispensable, since in some cases, histopathologic evaluation provides more comprehensive information than serum antibody testing. Amyloidosis typing can be initially performed using IHC, IF on frozen sections remaining a primary method. However, mass spectrometry (MS) is considered the gold standard for definitive typing [35]. In hereditary amyloidosis, precise classification can be further achieved through genetic testing, such as whole-exome sequencing (WES). In this report, to identify the amyloidogenic precursor protein, we employed laser microdissection coupled with MS (LMD/MS), IHC for ALECT2, IF for light chains, and WES.

For patients with concurrence of amyloidosis and MN, it is essential to assess the relative contribution of each disease to the clinical presentation. In Cases 1 and 2, amyloid deposition was mainly confined to the mesangial areas, whereas serum anti-PLA2R antibodies were elevated, supporting PLA2R-associated MN as the primary cause of nephrotic syndrome. Consistently, MN-directed immunosuppressive therapy resulted in complete or partial remission of nephrotic syndrome, further confirming that MN, rather than amyloidosis, was the major driver of proteinuria in these patients, in line with previous reports [36]. Currently, no specific therapies are available for AApoA-1–related amyloidosis or ALECT2 amyloidosis [29, 36, 37]. Moreover, these two forms of amyloidosis typically present with mild or absent proteinuria and are therefore unlikely to account for nephrotic syndrome when amyloid deposits are predominantly mesangial. As for Case 3 with AL amyloidosis and MN, the anti-clonal treatment not only improved AL amyloidosis but also eliminated MN-causing antibodies [38]. However, Case 3 was an AL amyloidosis with severe restrictive cardiomyopathy and hypotension, who died a few weeks after diagnosis, although treatment for AL amyloidosis was prescribed. These findings highlight that when amyloidosis coexists with MN or other treatable kidney diseases, priority should be given to treating the condition that poses a greater anticipated harm or is amenable to treatment.

The prognosis of amyloidosis largely depends on the specific amyloid type and the patient’s response to therapy. In AApoA-I–related amyloidosis, prognosis can vary according to factors such as the specific mutation, the extent and distribution of amyloid deposition, and individual patient characteristics [18]. ALECT2 amyloidosis is generally considered a relatively mild form of renal amyloidosis, typically associated with a slow decline in glomerular filtration rate (GFR) [21]. Patients with ALECT2 amyloidosis typically have an excellent survival rate, likely due to the absence of concurrent cardiac involvement [12]. In contrast, patients with AL amyloidosis may have multi-organ involvement, with 20% to 52% exhibiting involvement of more than two organs simultaneously. Kidney involvement often presents as the initial manifestation, while the heart is the most frequently affected organ [39, 40]. Cardiac involvement markedly increases morbidity and mortality in these patients [41]. In the present series, the patient with systemic AL amyloidosis and MN experienced a poor outcome, whereas the other two patients achieved clinical remission.

This study has several limitations, chiefly due to the small number of cases and the limited availability of tissue samples. Consequently, we cannot definitively determine whether amyloid formation is directly associated with PLA2R antibodies. The concurrence of MN and amyloidosis in these cases may be coincidental, as no mechanistic link has been established. Thus, the interplay between renal amyloidosis and membranous nephropathy warrants further investigation.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

MN

Membranous nephropathy

ApoA-1

Apolipoprotein A-1

AL

Light chain

SAA

Serum amyloid A protein

Lect2

Leucocyte chemotactic factor 2

GBM

Glomerular basement membrane

PLA2R

Phospholipase A2 receptor

SPE

Serum protein electrophoresis

IFE

Serum immunofixation electrophoresis

FCM

The flow cytometry

HE

Hematoxylin and eosin

PAS

Periodic acid-schiff

IF

Immunofluorescence

LMD

Laser microdissection

WES

Whole-exome sequencing

NT-pro BNP

N-terminal pro-brain natriuretic peptide

BALP

Bone alkaline phosphatase

β2-MG

Beta-2 microglobulin

EF

Ejection fraction

RTX

Rituximab

ALP

Alkaline phosphatase

LDH

Lactate dehydrogenase

TnT

Troponin-T

PGNMID

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits

MGRS

Monoclonal gammopathy of renal significance

MS

Mass spectrometry

Author contributions

LL: Writing – original draft, Writing – review & editing. YW: Writing – review & editing. ZXH: Writing – review & editing.

Funding

Not applicable.

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

The patient has given written informed consent for publication of this case report and any accompanying images.

Competing interests

The authors declare no competing interests.