The Unicorn of Nephrology: Leukocyte Chemotactic Factor 2 (ALECT2) Amyloidosis with Rare Associations - A Case Series

Introduction

Leukocyte-derived chemokine-2 (LECT2) is a 16 kDa chemokine that belongs to the interleukin-8 family. It mediates neutrophil migration. The LECT2 gene is located on chromosome 5q31.1-q32.¹ First described in 2008, leukocyte chemotactic factor 2 (ALECT2) is now considered one of the most common causes of renal amyloidosis in certain ethnic groups, particularly in individuals of Hispanic, Middle Eastern, and South Asian descent.^2,3 Unlike amyloid light chain (AL) or amyloid A (AA) amyloidosis, it has an indolent course, typically presenting with CKD, mild proteinuria, and the absence of systemic involvement.⁴

Histopathological analysis revealed amyloid deposits predominantly in the renal interstitium. Congo red staining demonstrated classic apple-green birefringence under polarized light, and immunohistochemistry (IHC) confirms LECT2 as the amyloidogenic protein.⁵ Mass spectrometry remains the gold standard for diagnosis.³

ALECT2 in renal allografts is emerging as an underrecognized cause of graft dysfunction, with some reports of donor-derived disease.² We present a six cases with rare and unique associations of this uncommon disease. These cases expand the phenotypic spectrum of ALECT2 amyloidosis and emphasize its clinical significance in renal pathology and transplantation.

Case Series

All cases with ALECT-2 amyloidosis diagnosed in the Nephrology Department of Sawai Man Singh Medical College and Hospital, Jaipur, India, in the past years were traced from hospital records. Informed consent was taken. The detailed description of the cases has been delineated in Table 1. Relevant histopathological images have been added in Figure 1.

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Figure 1:

(a) Light microscopy showing calcineurin inhibitor- associated thrombotic microangiopathy (Case1) (100X), (b) Immunohistochemistry showing leukocyte chemotactic factor 2 (ALECT2) Amyloidosis staining (Case 1) (100X), (c) Light Microscopy showing focal interstitial amyloid deposition (Case 2) (200X), (d) Immunohistochemistry showing ALECT2 staining (Case 2) (200X), (e) Light microscopy showing glomerular basement membrane thickening and glomerular amyloid deposits (Case 5) (400X), (f) Immunohistochemistry showing phospholipase A2 receptor positivity (Case 5) (400X), (g) Immunohistochemistry showing ALECT2 staining (Case 5) (200X), (h) congo red positivity under polarised light (Case 5) (200X).

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The mean age was 51.83±12.12 years, with three females. All patients presented with renal impairment. Two cases had AKI (Cases 3 and 6), two had nephrotic syndrome (Cases 4 and 5), and one each had RPGN and allograft injury (Case 1 and 2, respectively). Urinalysis revealed proteinuria in four patients, with active sediment in one case (Case 2). Bland sediment was noted in two (Cases 3 and 6), while two did not have significant urinary abnormalities beyond proteinuria (Cases 4 and 5).

Autoimmune screening revealed PR3-ANCA positivity in one case (Case 2) and PLA2R positivity in another case (Case 5). The remaining four had negative autoimmune panels, malignancy screening, including serum protein electrophoresis and immunofixation, was negative in all. One case was donor-derived (Case 1), diagnosed after renal allograft biopsy, and also revealed thrombotic microangiopathy.

Three cases showed progressive renal dysfunction despite treatment (Cases 1, 3, and 4), while three demonstrated improvement; one with rituximab for PLA2R-positive MN (Case 5), and the remaining two with steroids: one with PR3-ANCA positivity (Case 2) and another with possible drug-induced AIN (Case 6).

Discussion

We highlights the diverse and some previously unreported associations of ALECT2 amyloidosis in India, expanding its clinical spectrum beyond the traditionally described presentation. The serendipitous ALECT2 identification in conjunction with PLA2R-positive MN, ANCA positivity, donor-derived amyloidosis, and G6PD deficiency raises questions about potential pathogenic links, shared risk factors, or predispositions that warrant further investigation. The progressive decline in kidney function observed in some of our patients challenges the notion of ALECT2 as an indolent disease. And yet there were cases where prompt diagnosis and management of associated disease resulted in stabilization of renal function.

The case with possible donor-derived ALECT2 amyloid (Case 1) has previously been reported in isolated case reports, but there is still a lack of evidence regarding long-term effects on graft outcomes. In a case report by Singh et al.,² a renal transplant recipient developed graft dysfunction due to donor-derived ALECT2 amyloidosis.

The association of PLA2R and ALECT2 co-positivity, as seen in case 5, is also rarely described. In a case report by Xu et al.,⁶ a 60-year-old male was described with PLA2R-positive membranous nephropathy and concurrent ALECT2 amyloidosis. Despite initial treatment failure, the patient achieved complete remission with methylprednisolone and cyclosporine, highlighting the importance of recognizing coexisting renal pathologies.

Case 2 showed RPGN presentation with ANCA-PR3 and ALECT2 positivity, even without features of systemic vasculitis. The patient responded well to pulse steroids. In a case report by Khalighi et al.,⁷ an 84-year-old with ANCA-MPO-positivity and ALECT2 amyloidosis was treated with high-dose corticosteroids and cyclophosphamide for pulmonary-renal syndrome. Despite treatment, his renal function did not improve, and he progressed to ESKD. This case highlights the poor prognosis of ALECT2 amyloidosis, when coexisting with autoimmune conditions like ANCA vasculitis. The possible difference between treatment response in both cases could be because of more severe pulmonary and renal involvement in the case report by Khalighi et al.⁷

Future studies integrating genetic analysis, mass spectrometry, and mechanistic research are essential to better understand the pathophysiology and clinical implications of this rare amyloidosis subtype and to devise targeted therapies tailored to patient needs.

Our case series is limited by non-availability of EM findings, and absence of genetic analysis. Additionally, the lack of mass spectrometry, which remains the gold standard for amyloid subtyping, and the inability to perform liver biopsy in patients with concomitant liver involvement pose a diagnostic limitation.