|Year : 2020 | Volume
| Issue : 2 | Page : 508-514
|A case of renal and splenic LECT 2 amyloidosis: A recently recognized cause of renal and systemic amyloidosis
Michael Shye1, Anthony Sisk2, Carl Schulze1, Marina Barsoum1, Mira Mikhail1, Farid Arman1, Anjay Rastogi1, Ramy M Hanna3
1 Department of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
2 Department of Pathology, Division of Renal Pathology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
3 Department of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Los Angeles; Department of Medicine, Division of Nephrology, University of California, Irvine School of Medicine, Irvine, CA, USA
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|Date of Submission||11-Feb-2019|
|Date of Decision||17-May-2019|
|Date of Acceptance||20-May-2019|
|Date of Web Publication||09-May-2020|
| Abstract|| |
Amyloidosis has traditionally been of a few defined varieties, most commonly including light-chain amyloidosis (AL amyloidosis) and secondary amyloidosis due to chronic inflammation (AA amyloidosis). Apolipoprotein A-I/A-II cystatin C, gelsolin, lysozyme, fibrinogen alpha chain, beta 2 microglobulin, and transthyretin familial amyloidosis represent rarer but reported varieties. Ten years ago, the first reports linked leukocyte chemotactic factor 2 (LECT2) amyloidosis as a pathological agent identified as a novel class of amyloid-generating protein. Epidemiology suggested that this was a new cause of amyloidosis that is especially common in Hispanic patients and somewhat common among patients from the Middle East-North Africa (MENA) region. We report a case of splenic and renal LECT 2 amyloidosis in a 62-year- old Hispanic male with diabetes mellitus. After an unremarkable serological workup, LECT 2 amyloidosis was diagnosed on renal biopsy. The case presentation is reviewed as a typical presentation, and the literature is reviewed regarding this newly reported entity, resulting in infiltrative renal amyloidosis and chronic renal disease.
|How to cite this article:|
Shye M, Sisk A, Schulze C, Barsoum M, Mikhail M, Arman F, Rastogi A, Hanna RM. A case of renal and splenic LECT 2 amyloidosis: A recently recognized cause of renal and systemic amyloidosis. Saudi J Kidney Dis Transpl 2020;31:508-14
|How to cite this URL:|
Shye M, Sisk A, Schulze C, Barsoum M, Mikhail M, Arman F, Rastogi A, Hanna RM. A case of renal and splenic LECT 2 amyloidosis: A recently recognized cause of renal and systemic amyloidosis. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Jul 13];31:508-14. Available from: http://www.sjkdt.org/text.asp?2020/31/2/508/284027
| Introduction|| |
Amyloidosis is a well-known cause of renal failure that historically has been caused by a few known proteins. The pathological mechanism common to amyloidosis is that these pro- eins tend to form fibrils generally in the beta-pleated sheet configuration that infiltrate renal, cardiovascular, neurological, and other organ systems, resulting in pathology. The more common types of amyloid protein are due to the light-chain amyloidosis related to myeloma (AL amyloidosis) and secondary amyloidosis due to chronic inflammatory disorders such as rheumatoid arthritis (AA amyloidosis).
More atypical presentations can occur due to apolipoprotein A-I/A-II cystatin C, gelsolin, lysozyme, fibrinogen alpha chain, beta 2 microglobulin, and hereditary transthyretin, amyloidosis (hereditary ATTR). Within the last 10 years, multiple reports have emerged describing a hitherto unknown protein as a cause of an insidious form of amyloidosis.,,, The presentation of LECT 2 amyloidosis (also notated as ALECT2 amyloidosis) has generally been more indolent and in some cases, the diagnosis was not made for many years prior to identification of this novel entity. Some presentations were more unusual with features of a pulmonary renal syndrome as reported by Khaligi et al in 2014.
The exact function of LECT2 is under investigation, but it is described as a multifunctional cytokine capable of chemotaxis and enhancement of opsonization. The phenotype of LECT2 amyloidosis has been primarily observed in Hispanics, Native Americans,, and patients of middle eastern descent, particularly Egyptians. This disease has also been reported in different ethnicities, and its incidence in different populations will likely be elucidated as it becomes more readily identified. We present a case of splenic and renal LECT2 amyloidosis, first identified incidentally after splenectomy, following trauma from a motor vehicle accident. The cause of the amyloidosis was then identified definitively after a renal biopsy for proteinuric chronic kidney disease (CKD). We review the literature of the recent reports of renal, nonrenal, and multisystemic cases of LECT2 amyloidosis.
| Case Report|| |
Informed consent was obtained from the patient before publishing the case.
A 62-year-old Hispanic man had a remote history of splenic amyloidosis, incidentally found after a motor vehicle accident in 2005, complicated by splenic laceration requiring splenectomy. He also had noninsulin requiring diabetes mellitus type 2, systemic hypertension, hyperlipidemia, and morbid obesity.
He was initially referred to nephrology for the management of CKD in 2017. He was using nonsteroidal-anti-inflammatory drugs for chronic back pain and was taking ibuprofen 200 mg four to five tablets per week for three years, resulting in the development of a gastric ulcer. During the initial investigation, he denied any urinary symptoms. His past medical history also included anxiety, obstructive sleep apnea, and gout. Surgical history included splenectomy, partial omentectomy, and back surgery.
Medications included allopurinol 300 mg daily, amlodipine 5 mg daily, benazepril 40 mg daily, escitalopram 10 mg daily, feno- fibrate 160 mg daily, gabapentin 100 mg TID, pantoprazole 40 mg daily, and hydrocodone- acetaminophen 10-325 mg as needed. Vital signs revealed blood pressure of 139/71 mm Hg, heart rate of 69 beats/min, temperature of 37°C, 18 breaths/min, and body mass index of 45.2 kg/m2. Physical examination showed no positive signs.
Comprehensive metabolic panel and complete blood count with differential was only significant for serum creatinine of 1.71 mg/dL, which was stable for six months. Urinalysis showed 2+ protein without leukocyte esterase, nitrite, blood, red blood cells, or white blood cells. Urine total protein/creatinine ratio was 1.4. Serologic workup was also unremarkable. [Figure 1] demonstrates patterns of serum crea- tinine (mg/dL) and urine protein/creatinine ratio (g protein/g creatinine) in our reported case, which indicates the natural history of kidney disease in this patient.
|Figure 1: Serum creatinine (mg/dL) and urine protein-to-creatinine ratio gram protein/gram creatinine versus date in the LECT2 amyloidosis patient.|
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Ultrasound of the abdomen revealed normal kidneys and hepatomegaly with coarse echo- genic hepatic parenchyma suggestive of hepatic steatosis. The postoperative pathology report of the spleen was obtained and showed leukocytes present in the sinusoids that were predominantly granulocytes and small lymphocytes. There was no plasma cell proliferation, and Congo red stain was positive. Amyloidosis was diagnosed and classified as unknown type.
Bone marrow biopsy showed normocellular bone marrow with multi-lineage hematopoie- sis and was negative for B-lymphoprolife- ration, plasma cell dyscrasia, and amyloid. Fat pad biopsy showed no evidence of amyloid. Bone survey for myeloma only showed osteo- penia. Echocardiogram was significant for moderate basal septal left ventricular hypertrophy (most probably in the setting of longstanding systemic hypertension) with an ejection fraction of 55%-60%. No speckled pattern was noted that would have been suggestive of cardiac amyloidosis.
Given the patient’s remote history of splenic amyloidosis without active disease noted in other organs, proteinuria, and CKD, a renal biopsy was pursued and revealed marked expansion of the mesangium that stained pale on PAS and negative on the Jones silver stain. The same finding was also seen throughout the interstitium and tubular basement membranes as well as vessel walls. They stained positive with Congo red stain. There was diffuse interstitial fibrosis and tubular atrophy involving about half of the cortex. Arteries also showed mild intimal fibrosis. The amyloid-containing samples showed weak staining for IgG (trace). There was no other significant staining for the remaining antibodies [immunoglobulin (Ig) IgA, IgM, or associated binding proteins C3, C1q].
Electron microscopic examination revealed thin, nonbranching fibrils measuring 9-12 nm in the mesangium and interstituim, consistent with amyloidosis. Basement membranes were generally of normal thickness, other than mild, occasional increased thickness and patchy effacement of foot processes. Renal tissue was sent for amyloid typing, which was consistent for LECT-2 (leukocyte chemotactic factor-2). Congo red stain was used to confirm the presence of amyloid. Further subtyping was performed using liquid chromatography tandem mass spectrometry/mass spectrometry by micro-dissecting the amyloid from the paraffin block in Congo red-positive areas. A peptide profile was detected that was consistent with ALECT2.
The final diagnosis of LECT2 amyloidosis was made. [Figure 2] shows details of the renal biopsy demonstrating LECT 2 amyloidosis in our reported patient. The most recent assessment for the patient demonstrated a stable kidney function with creatinine of 1.69 mg/dL and urine protein-to-creatinine ratio of 1.4 mg/g.
|Figure 2: Pathology slides demonstrating diagnosis of LECT2 amyloidosis. (a) Low-power view of renal cortex showing mild scar. Glomeruli appear dense. (PAS, ×20). (b) Glomerulus with pink material within the mesangium. PAS demonstrating weak staining of this material compared to the darker staining basement membranes, (×200). (c) Apple-green birefringence is seen under polarization, (×100). (d) Jones Silver stain, note negative staining within the expanded mesangium, (×400). (e) Higher power demonstrating the eosinophilic material within the mesangium. (PAS, ×400). (f) Higher power of Congo red stain highlighting the same areas, (×100).|
(g) Amyloid within the mesangium (×13,800): The mesangium is expanded by variably dense fibrillary
H) Amyloid within the mesangium (×35,000): Higher power showing haphazardly arranged, thin nonbranching fibrils, consistent with amyloid
I) High-power (×138,300) magnification of amyloid demonstrating randomly arranged fibrils with th typical diameter ranging from 11.4 to 13.4 nm.
J) Amyloid fibrils extending into the basement membrane and into subendothelial locations. Note the endothelial cell is lifted off of the basement membrane (×17,500).
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| Discussion|| |
Amyloidosis is a systemic disorder that can be either primary or secondary to chronic inflammation. Numerous proteins have been discovered that can lead to a positive Congo red stain and diagnosis of amyloidosis. The first case reports became apparent in 2010 where LECT2 was added to apolipoprotein and gelsolin as new proteins whose misfolded state result in systemic disease., Reports on LECT 2 amyloidosis have described involvement of the liver,,,,,,, the spleen, and the adrenal glands, but typically not the brain or heart. It can co-exist with other systemic diseases, and some rare presentations have mimicked pulmonary renal syndromes. Renal sediment is not always clearly positive, and proteinuria is lower grade than other types of amyloidosis that typically present with nephrotic albuminuria. Currently, there are about 196 reports on this subject, in multiple case series and reports, that have been published in the literature.
Its prevalence among Hispanic and Middle Eastern patients requires a higher index of suspicion in patients with these genetic backgrounds presenting with unexplained CKD., [Table 1] reviews all the published clinical reports on LECT2 amyloidosis,,,,,,,,,,,,,,,,,,,,,,,,, highlighting data regarding the gender, age, race, and end-organs effected of published reports regarding LECT2 amyloidosis.
|Table 1: Published case reports and case series of LECT2/ALECT2 amyloidosis|
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Future directions include molecular investigation of the exact physiological function and signaling of LECT2 and a detailed analysis of epidemiology of this disease across the spectrum of multiple ethnicities. Further genetic studies may also be enlightening, to understand the development of LECT 2 amyloidosis.,, The association of LECT2 amyloidosis with diabetes, rheumatoid arthritis, biliary processes, and obesity remains to be investigated more thoroughly.,
When it comes to the treatment of LECT2 amyloidosis, current knowledge is very limited. There are no clear guidelines on how to approach treatment in these patients. However, it is important to differentiate LECT2 from AL and AA amyloidosis. The latter are treated with chemotherapeutic agents (including but not limited to bortezomib, rituximab, immuno- modulatory agents, and standard-dose alky- lating agent, thalidomide, and lenalidomide), with guidelines similar to multiple myeloma. However, these treatment options have not shown to be of any significant benefit in the treatment of LECT2. Proper diagnosis of amyloidosis type can determine the need for supportive care versus more aggressive interventions, where appropriate.
New clinical information is providing further information that may overturn previous patterns regarding LECT 2 amyloidosis. New decedent studies show that LECT 2 deposits in the heart, gastrointestinal tract, and lungs, which was not widely seen in prior series. More work needs to be done to catalog the full clinical and epidemiological spectrum of LECT2 amyloidosis in patient groups of varied ethnicities.
Conflict of interest: None declared.
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Ramy M Hanna
Department of Medicine, Division of Nephrology, UCLA David Geffen School of Medicine, Los Angeles, CA
[Figure 1], [Figure 2]
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