| Abstract|| |
Amyloidosis is a complex multi-system disorder characterized by deposition of an aberrant protein in tissues with kidney being the main target organ. The age of presentation of amyloid A (AA) amyloidosis is highest among adults aged 60–80 years followed by 45–55 years. However, presentation in younger age group is rare. We aimed to study the clinicopathological spectrum of patients with biopsy-proven renal AA amyloidosis aged <35 years in the last five years. This retrospective study was done on patients admitted from January 2015 to December 2019. Nine cases of AA amyloidosis diagnosed on kidney biopsy in ≤35 years of age were included in the study. Clinical, laboratory, and demographic data of all patients were obtained. Histopathological and direct immunofluorescence findings were further evaluated. The mean age (±standard deviation) was 22.5 ± 6.7 years with a range of 14–32 years. The most common underlying disorder of AA renal amyloidosis was Tuberculosis (TB) (88.88%, 8/9) with cyclosporine induced in one of the cases (11.11%). In all nine cases, glomeruli were mostly enlarged with moderate to marked mesangial expansion with thickened arteries and arterioles due to deposition of pink hyaline acellular material. Renal amyloidosis is rare in young age and is mostly secondary in nature. The association of TB with renal amyloidosis is common in adults (3.6%–50%), but only infrequently reported in children. It is important, especially in developing countries to be aware, as successful treatment of TB can result in remission of nephrotic syndrome due to secondary renal amyloidosis.
|How to cite this article:|
Garg N, Jain S, Chauhan S, Dixit S, Sharma S. Clinicopathological Spectrum of Renal Amyloidosis in Young. Saudi J Kidney Dis Transpl 2020;31:1085-90
|How to cite this URL:|
Garg N, Jain S, Chauhan S, Dixit S, Sharma S. Clinicopathological Spectrum of Renal Amyloidosis in Young. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2022 Oct 3];31:1085-90. Available from: https://www.sjkdt.org/text.asp?2020/31/5/1085/301175
| Introduction|| |
The term “amyloidosis” was coined by Virchow in 1854 and it is characterized by deposition of hyaline extracellular material into various tissues throughout the body. Amyloidosis is a complex multisystem disorder characterized by extracellular deposition of an aberrant protein in various tissues such as kidney, heart, and disrupting the normal organ function. The classification of the amyloidosis is based on the type of the precursor amyloid protein and the distribution of amyloid fibril deposition as either localized or systemic. The most common types of systemic amyloidosis are AL (primary or light chain) and amyloid A (AA) (secondary or reactive).
Systemic AA amyloidosis is a complication of chronic inflammatory disorders. Autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, chronic juvenile arthritis, inflammatory bowel disease, hereditary inflammatory diseases like familial Mediterranean fever (FMF) are the most common underlying conditions in western countries while chronic infectious diseases such as tuberculosis (TB), osteomyelitis, and bronchiectasis are the main causes of AA amyloidosis in developing countries.,,, The kidney is the main target organ of AA amyloid deposition with asymptomatic proteinuria, nephrotic syndrome and/ or progressive impairment of renal function, leading to end stage kidney disease (ESKD) in majority of the patients. The age of presentation of AA amyloidosis is highest among adults aged 60–80 years followed by 45–55 years. AA amyloidosis affecting younger age group is rare. Although a few authors have studied the spectrum of renal amyloidosis in young in the West, however, there is no such study from India., In this study, we studied the clinicopathological spectrum of patients with biopsy-proven renal AA amyloidosis aged <35 years in the last five years.
| Materials and Methods|| |
This is a retrospective study done on patients admitted from January 2009 to December 2019 in the department of pathology of a tertiary care hospital. Nine cases of AA amyloidosis diagnosed on kidney biopsy in ≤35 years of age were included in the study. Clinical, laboratory, and demographic data of all patients were obtained from the patient files at the time of kidney biopsy. Demographical and clinical characteristics recorded are age at presentation, sex, presenting complaint, and etiology of amyloidosis. Among laboratory results serum urea, serum creatinine, 24-h urine protein amount were taken into consideration. The diagnosis of chronic kidney disease (CKD) was made on the basis of KDOQI guidelines of the National Kidney Foundation, USA. Glomerular filtration rate (GFR) was calculated using abbreviated modification of diet in renal diseases study equation:
estimated GFR (mL/min/1.73 m2) = 1.86 × (Plasma creatinine)−1.154 × (age) −0.203 (multiply by 0.742 for women and 1.212 if African American).
Light microscopic evaluation was done with the help of hematoxylin and eosin (H&E), periodic acid–Schiff (PAS), methenamine silver (SM), Masson's trichrome (MT), and Congo red with polarization. In all the cases, amyloid was visualized as amorphous eosinophilic extracellular material on H&E which was congophilic and showed apple green birefringence under polarizer.
Direct immunofluorescence (DIF) was performed on fresh frozen renal biopsy using fluorescein isothiocyanate (FITC) conjugated antibodies against kappa and lambda light chains along with IgG, IgA, IgM, C3, C1q, and fibrinogen followed by incubation for 30–40 min. The slides were examined under fluorescent microscope with FITC filter.
Interstitial fibrosis and tubular atrophy (IFTA) were graded as T0 (mild): <25%, T1 (moderate): 25%–50%, and T2 (severe): >50%.
Statistical analysis was performed using Microsoft Excel and IBM SPSS statistics for Windows software version 20.0 (IBM Corp., Armonk, NY, USA).
| Results|| |
A total of nine patients with biopsy-proven renal AA amyloidosis were evaluated in this study. At the time of kidney biopsy, mean age (±standard deviation) was 22.5 ± 6.7 years with a range of 14–32 years. The M:F ratio was 2:1 with 66.66% (6/9) males and 33.33% (3/9) females. The most common underlying disorder of AA amyloidosis was TB (88.88%, 8/9) with cyclosporine induced in one of the case (11.11%). Out of the eight patients with history of TB, four were on antitubercular treatment (ATT) for pulmonary TB at the time of presentation and four had past history of pulmonary TB. Out of these four, two were defaulters and two received complete ATT. The duration of TB at the time of presentation ranged from four months to 10 years. All the patients presented with anasarca with nephrotic syndrome under evaluation at the time of presentation. None of the patients had significant hematuria, hyperlipidemia or evidence of any other glomerular diseases.
The mean blood urea was 61.66 ± 72.6 mg/dL and the mean serum creatinine was 1.57 ± 1.60 mg/dL. The mean 24-h urinary protein was 4.8 ± 3.6 g/day. The mean eGFR was 93.7 ± 58.9 mL/min/1.73 m2. There were 5/9 patients in stage 1 CKD (eGFR >90), 2/9 patients in stage 2 CKD (eGFR 60–89), and two in stage 4 CKD (eGFR 15–30) at the time of kidney biopsy.
Direct immunofluorescence findings
Renal biopsy for DIF was inadequate in 1/9 of the cases. Out of eight cases, IgG was positive in 6/8 cases ranging from focal 1+ to 2+. IgM was positive in 7/8 cases ranging from 1–2+ focal mesangial and capillary wall. C3 was positive in 6/8 cases ranging from focal 1–3+. C1q was positive in 2/8 cases focal 1+. IgA and fibrinogen were negative in all the cases. Immunostaining for lambda and kappa showed no restriction.
All the biopsies were adequate for opinion.
In all nine cases, glomeruli were mostly enlarged with moderate to marked mesangial expansion with deposition of pink hyaline acellular material and partial obliteration of glomerular capillaries in most of them [Figure 1]a and [Figure 1]b.
|Figure 1a and b: Deposition of pink hyaline acellular material within the glomeruli (H&E 400×).|
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Amyloid stained violet with crystal violet and was congophilic and showed apple-green birefringence under polarizer [Figure 2]a and [Figure 2]b.
|Figure 2: (a) Crystal violet: Showing violet-colored deposition within the glomeruli and focally in surrounding tubules, (b) Congo red: Deposits showing apple-green birefringence under polarizer.|
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Five out of 9 cases were graded as T0, 3/9 as T1 and 1/9 as T3.
In all 9 cases, arteries and arterioles appear thickened with focal similar acellular material deposition.
| Discussion|| |
Amyloidosis occurs rarely in young and is mostly secondary in nature. Primary amyloidosis characterized by deposition of monoclonal light chain of immunoglobulin (AL type) is the commonest form in adults, but extremely rare in young. Secondary amyloidosis occurs due to deposition of serum amyloid A (SAA) is the most common type occurring in younger age group. SAA is produced by inflammatory signals, interleukin- 1β, tumor necrosis factor-α, and interleukin-6. Polymerization of SAA into amyloid fibrils requires removal of the C-terminal of the AA protein. The persistent augmentation of an inflammatory pathway through the innate immune system might be crucial in the deposition of the amyloid protein leading to the clinical picture of renal amyloidosis.
The most frequent cause of secondary amyloidosis in young in developed nations are auto-inflammatory diseases.,,, Among this group of diseases, the most frequent one is FMF. Most cases of FMF have been reported in Turkish children.,,, Other reported etiologies in young include TB,,, inflammatory bowel disease, neutropenia due to reticular dysgenesis, hypergammaglobulinemia D syndrome (hereditary periodic fevers) and Hodgkin's disease. In contrast to the western literature, the most common etiology of renal amyloidosis in young in the present study is TB. TB continues to be an overwhelming public health problem in India even in the 21st century. The prevalence of TB in India was 3.8 million cases in 2000 with over 1.96 million new cases diagnosed annually. Sharma et al reported TB to be the most common cause of secondary amyloidosis in Indian patients irrespective of the age group.
The duration of TB required to cause secondary amyloidosis ranged from four months to 10 years, implying that patients can develop amyloidosis even shortly after disease manifestation. However, the actual trigger for its development might have occurred a long time ago in the form of mycobacterial infection. Tubercular infection is prevalent in India. The long latent period between mycobacterial infection and TB disease and the rapid increase and relatively higher levels of SAA production triggered by mycobacterial infection may have initiated the process a long time ago. This hypothesis is in accordance with known fact that a time interval of decades is required prior to the development of amyloidosis.,, Furthermore, we observed that 2/8 (25%) of TB patients despite taking complete ATT and declared cured developed secondary amyloidosis. This can be attributed to presence of dormant mycobacterium bacilli which continue to be the focus of inflammatory stimuli without producing clinical disease. Furthermore, it is hypothesized that amyloidosis formation is a nucleation-initiation process. In some cases of destroyed lung due to TB, the constant production of large quantity of SAA act as a constant source of inflammation and may accelerate deposition of amyloid fibrils on a preexisting nidus and may perpetuate amyloidosis, even after apparent cure.
In secondary amyloidosis, kidney is the most affected organ, other organs are rarely involved. The amount of proteinuria and renal function impairment vary in each case, which is related to the amount and site of amyloid deposition. Uda et al demonstrated that glomerular amyloid deposition is more common and have a poorer prognosis than patients having vascular and tubular amyloid deposition in rheumatoid arthritis-related AA amyloidosis. In the present series, despite predominant glomerular involvement by amyloid with only mild deposition in blood vessels or tubules, 5/9 (55.5%) of patients had normal eGFR with only 2/9 (22.2%) with eGFR of <30. And all the patients presented with nephrotic range proteinuria.
Renal amyloidosis has a poor prognosis if untreated. The prognosis is greatly influenced by the type of amyloid protein involved and the extent of organ damage. Hence, the diagnosis of amyloidosis and typing are crucial. Specific treatment of the underlying disorder, for example, ATT for TB, aiming to suppress the inflammatory activity is the first and the major strategy. This can lead to improvement in renal function, reduction in protein excretion and partial resolution of amyloid deposits. In patients with TB, remission of nephrotic syndrome can also be achieved following timely treatment of TB but this is rare. However, most of the patient's progress to ESKD despite the start of ATT., Follow-up of the patients was not available which the major limitation of this study is.
To conclude, TB continues to be a major infectious disease in developing countries like India and is the most cause of secondary amyloidosis in young in this part of the world in contrast to the western literature. Due to variable preclinical stage, the true interval between the preceding disease and the onset of amyloidosis is not known exactly, so it is reasonable to suspect renal amyloidosis in any young patient with pulmonary TB (past or present infection), presenting with anasarca and nephrotic syndrome. Early diagnosis can benefit the patient with timely institution of appropriate treatment, as though rare, remission can be achieved in renal amyloidosis post-ATT.
Conflict of interest: None declared.
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Department of Pathology, University College of Medical Sciences and Guru Teg Bahadur Hospital, New Delhi
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]