{"paper_id":"2e4364df-564d-4e97-8076-8b3ebba5b499","body_text":"Exploring AA Amyloidosis: Insights from A Case Series in an Under-Explored Indian Context | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Exploring AA Amyloidosis: Insights from A Case Series in an Under-Explored Indian Context Mohammad Saquib Alam, Mohd Aslam, Amir Husain, Sheikh Ashraf This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6611738/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction : AA amyloidosis is a systemic protein misfolding disorder characterized by the deposition of serum amyloid A protein, often leading to progressive renal dysfunction. While inflammatory etiologies have become more prominent globally, infection-related causes remain a major contributor in resource-limited settings. Data on the clinicopathological spectrum of renal AA amyloidosis in the Indian population are scarce. Methods: This retrospective cross-sectional study included 18 patients with biopsy-proven renal AA amyloidosis evaluated at a tertiary care center in India between March 2022 and May 2024. Clinical data, laboratory parameters, and renal biopsy findings were collected and analyzed. Results: The cohort was predominantly male (83.3%), with a mean age of 37.2 years (range 17–65). Chronic infections were the leading etiology (77.8%), with tuberculosis being most common (64.3%), followed by hepatitis B/C and HIV coinfections. Autoimmune conditions (Rheumatoid Arthritis, Ankylosing Spondylitis) accounted for 16.7% of cases. All patients presented with proteinuria (mean 3.2 ± 2.5 g/24h), and 38.9% showed hematuria with RBC casts. Severe hypoalbuminemia (<2.5 g/dL) was seen in 66.6% of patients and was significantly associated with higher proteinuria (p = 0.0123). Acute kidney injury was present in 33.3% of patients. Renal biopsy confirmed amyloid deposits with Congo red staining and strong SAA positivity on immunohistochemistry. Conclusions: In contrast to global trends, infectious diseases remain the predominant cause of AA amyloidosis in the Indian population. This study highlights the need for heightened clinical vigilance and timely renal biopsy in patients with chronic infections and unexplained proteinuria to improve early diagnosis and management. Figures Figure 1 Figure 2 Figure 3 Figure 4 1. INTRODUCTION AA amyloidosis, previously termed secondary amyloidosis, is a systemic disorder characterized by the extracellular deposition of serum amyloid A (SAA), an acute-phase reactant protein. [ 1 ]. This process arises from chronic inflammation or persistent infections. It leads to the misfolding and aggregation of SAA into insoluble β-pleated fibrils, which deposit in various organs, most commonly the kidneys.[ 2 , 3 ]. Renal involvement often dominates the clinical course, contributing substantially to morbidity and determining overall prognosis [ 1 ]. Globally, the epidemiology of AA amyloidosis has shifted. Improved infection control and widespread antibiotic use have reduced infection-related cases in many high-income countries, with autoimmune and autoinflammatory conditions, such as rheumatoid arthritis and familial Mediterranean fever, emerging as predominant causes [ 4 , 5 ]. However, in low- and middle-income countries, including India, infectious etiologies such as tuberculosis and chronic hepatitis infections continue to play a significant role. Also, other lesser-known causes of AA amyloidosis have come up, like Hidradenitis Suppurativa [ 6 ]. Despite this, there is a paucity of region-specific data characterizing the clinical spectrum, pathological features, and etiological patterns of AA amyloidosis in the Indian population. Most existing literature focuses on Western cohorts, limiting the generalizability of findings to South Asian settings. This study addresses this gap by analyzing the clinical, laboratory, and histopathological profiles of patients with biopsy-proven renal AA amyloidosis in a tertiary care center in India. Through this case series, we seek to elucidate AA amyloidosis's contemporary patterns and diagnostic characteristics within a high-burden infectious disease context. 2. MATERIALS AND METHODS Study Design and Setting This retrospective, cross-sectional study was conducted at the Nephrology Division, Department of Medicine, Jawaharlal Nehru Medical College Hospital (JNMCH), Aligarh, India. The study period spanned from March 2022 to May 2024. Patient Selection A total of 18 patients with biopsy-proven renal AA amyloidosis were included. Inclusion criteria were: Histological confirmation of AA amyloidosis on kidney biopsy, defined by: Pale eosinophilic deposits on Hematoxylin and Eosin (H&E) staining, Apple-green birefringence under polarized light with Congo red staining, Positive immunofluorescence (IF) staining for SAA protein on a separate biopsy core. Availability of complete clinical and laboratory records. Exclusion criteria included: Incomplete medical records, Absence of confirmatory kidney biopsy, Evidence suggesting other amyloid subtypes (e.g., AL amyloidosis). Biopsy Procedure and Histopathology Percutaneous kidney biopsies were performed under ultrasound guidance using a standardized protocol. Two cores were obtained per patient: The first core was fixed in formalin and stained using H&E, Periodic Acid-Schiff (PAS), and silver methenamine. The second core was reserved for immunofluorescence staining with monoclonal antibodies targeting SAA. A renal pathologist evaluated biopsies. Key parameters assessed included: Pattern of Amyloid Deposit : The specific distribution and morphology of amyloid deposits within the kidney tissue were documented. This included identifying if the deposits were primarily interstitial, fibrillar, or exhibited a particular localization pattern (e.g., glomerular, vascular). Sites of Involvement : The extent of amyloid involvement in different kidney structures was assessed, specifying if the deposits were localized primarily within the glomeruli, vasculature, or other compartments. Immunohistochemistry (IHC) Details : A direct IHC staining method was employed to detect SAA protein in the second core biopsy specimen. A specific monoclonal antibody against SAA was utilized. Intensity of IHC Staining : The intensity of SAA immunostaining was semi-quantitatively evaluated based on a pre-defined scoring system (weak, moderate, strong) using visual assessment by the pathologist. Data Collection Patient data were extracted from medical records and included: Demographics : Age, sex. Laboratory parameters : Renal function: Blood urea nitrogen (BUN), serum creatinine, and estimated glomerular filtration rate (eGFR). Urinalysis: Microscopy, red blood cells (RBCs), casts, and 24-hour urinary protein. Serum protein and albumin levels (categorized as: normal [3.5–4.5 g/dL], mild hypoalbuminemia [2.5–3.5 g/dL], and severe hypoalbuminemia [< 2.5 g/dL]). Hepatitis B, C, and HIV screening using rapid test kits. Lipid profile: HDL, LDL, triglycerides, and total cholesterol. Renal ultrasonography findings. Statistical Analysis Descriptive statistics were used for demographic and clinical variables. Continuous variables were expressed as means ± standard deviations or medians (interquartile range) as appropriate. The Mann-Whitney U test assessed the difference in urinary protein levels between groups with mild and severe hypoalbuminemia. A p-value < 0.05 was considered statistically significant. Statistical analysis was performed using GraphPad Prism 9.0. 3. RESULTS This retrospective study investigated the clinical characteristics, laboratory findings, and kidney biopsy features of 18 patients diagnosed with AA amyloidosis at a tertiary care center in India. Demographics and Disease Presentation The study cohort exhibited a male predominance (83.3%, n = 15) compared to females (16.7%, n = 3). The age of onset ranged from 17 to 65 years, with a mean of 37.2 years (SD ± 16.9 years). Chronic infectious diseases constituted the most frequent underlying cause of AA amyloidosis (77.8%, n = 14). Notably, pulmonary tuberculosis (old treated: 35.7%, n = 5; ongoing treatment: 28.6%, n = 4) was the most prevalent infectious etiology (Fig. 1 , Fig. 2 ). Other identified infectious causes included treated abdominal tuberculosis (14.3%, n = 2), chronic hepatitis C infection (7.1%, n = 1), and co-existing HIV and chronic hepatitis C infection (5.6%, n = 1). Additionally, 11.1% (n = 2) of patients had a history of rheumatoid arthritis, 5.6% (n = 1) had ankylosing spondylitis, and 5.6% (n = 1) presented with idiopathic AA amyloidosis (Fig. 2 ). Laboratory Findings All patients demonstrated proteinuria, with a mean of 3.2 ± 2.5 g/24h; range 0.8–8.4 g/24h. Nearly 39% (n = 7) exhibited nephrotic range proteinuria (> 3.5 g/24 hours), while the remaining 61.1% (n = 11) displayed sub-nephrotic range proteinuria (Fig. 3 ). Serum protein levels ranged from 2.5 to 6.4 g/dL (mean 4.1 g/dL ± 1.0 g/dL). Serum albumin levels varied significantly, ranging from 0.8 to 3.2 g/dL (mean 2.2 g/dL ± 0.6 g/dL), with 66.6% (n = 12) of patients categorized as having moderate to severe hypoalbuminemia (< 2.5 g/dL) and the remaining 33.3% (n = 6) classified as having mild hypoalbuminemia (2.5–3.5 g/dL). A statistically significant difference (p = 0.0123) in urinary protein levels was observed between patients with mild and severe hypoalbuminemia using the Mann-Whitney U test (Fig. 4 ) (Table 1). The median urinary protein level in the severe hypoalbuminemia group (3.800 g/24hr, n = 12) was significantly higher compared to the mild hypoalbuminemia group (1.265 g/24h4, n = 6). The 95.85% confidence interval for the difference in medians ranged from 0.4000 to 5.700 g/dL. Serum creatinine levels displayed substantial variability, ranging from 0.2 to 4.1 mg/dL (mean 1.1 mg/dL ± 0.9 mg/dL). Acute kidney injury (AKI) was observed in 33.3% (n = 6) of patients. Urinalysis and Kidney Biopsy Findings Urinalysis confirmed proteinuria in all cases, corroborating the clinical suspicion of AA amyloidosis. Additionally, 38.9% (n = 7) of patients exhibited red blood cells (RBCs) and RBC casts, suggesting glomerular involvement and potential complications. Kidney biopsy findings consistently demonstrated: Diffuse irregular mesangial matrix expansion Vascular deposition of SAA protein Strongly positive immunohistochemistry (IHC) staining for SAA Furthermore, chronic interstitial nephritis was identified in 44.4% (n = 8) of patients, and a non-necrotizing epithelial cell granuloma was observed in one case (6.7%), highlighting the potential for additional histological features within this patient cohort. Table No.1 Descriptive Statistics and Mann-Whitney U Test Results: Albumin Levels and Total Urinary Protein Levels Statistic Mild Hypoalbuminemia (2.5–3.5) Severe Hypoalbuminemia (< 2.5) P value (Mann-Whitney U) Number of values 6 12 0.0123 Mean 1.522 4.040 Std. Deviation 0.8159 2.606 4. DISCUSSIONS This case series highlights that, in contrast to evolving trends in high-income countries, chronic infectious diseases remain the dominant etiology of AA amyloidosis in India, with tuberculosis (TB) as the leading contributor. This finding is consistent with the high national TB burden reported by the WHO, which estimated India accounted for 27% of the global TB cases in 2022 [ 7 ]. In our cohort, TB (pulmonary and abdominal) accounted for 64.3% of all cases, substantially higher than proportions reported from Europe and North America, where rheumatologic and hereditary autoinflammatory conditions now predominate [ 4 , 8 ]. The male predominance (83.3%) and relatively young mean age (37.2 years) reflect findings from other South Asian studies, including a recent Pakistani cohort reporting a similar male skew and infectious dominance [ 9 ]. This demographic pattern may reflect gender-based disparities in healthcare access and exposure risks, particularly regarding pulmonary TB. Renal involvement, as expected, was universal, with proteinuria present in all patients and nephrotic-range levels observed in nearly 40%. The statistically significant association between severe hypoalbuminemia and higher proteinuria (p = 0.0123) aligns with the glomerular distribution of amyloid deposits observed histologically. These findings echo those from European biopsy registries, where glomerular SAA deposition is a hallmark of renal AA amyloidosis [ 4 ]. Interestingly, chronic interstitial nephritis (CIN) was found in 44.4% of cases—a higher-than-expected rate. This may reflect prolonged disease evolution or chronic inflammation. The presence of RBCs and RBC casts in nearly 39% further supports glomerular injury as a key clinical marker in these patients. From a public health and nephrology standpoint, our findings emphasize the need for earlier diagnostic consideration of AA amyloidosis in patients with chronic infections and unexplained proteinuria. While Congo red and SAA-specific immunostaining availability varies across centers, renal biopsy remains an essential diagnostic tool. The significant proportion of patients presenting with acute kidney injury (33.3%) further underscores the disease’s impact on renal function. 5. Conclusion AA amyloidosis in India remains predominantly infection-related, particularly linked to tuberculosis. This contrasts with global trends and underscores the need for enhanced surveillance, early renal biopsy, and infection control strategies. Further multicentric studies are warranted to validate and expand these findings. Declarations Ethics approval and consent to participate: This study was approved by the Institutional Ethics Committee of Jawaharlal Nehru Medical College and Hospital, Aligarh Muslim University, Aligarh, India (Ref No. IECJNMC/1610). The study adhered to the ethical principles outlined in the Declaration of Helsinki. As this was a retrospective study using anonymized patient data, the need for informed consent was waived by the Ethics Committee. Consent for publication: Not Applicable Competing interests: The authors declare that they have no competing interests Funding No Funding was received Acknowledgements Not applicable Author Contribution Mohammad Saquib Alam: Conceptualization, Methodology, Formal analysis, Writing – Original Draft, Visualization.Mohd Aslam: Data curation, Investigation, Writing – Review & Editing.Amir Husain: Resources, Supervision, Writing – Review & Editing.Sheikh Ashraf: Histopathological analysis, Validation, Writing – Review & Editing.All authors read and approved the final manuscript. Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. References Papa R, Lachmann HJ, Secondary AA, Amyloidosis. Rheum Dis Clin N Am. 2018;44:585–603. https://doi.org/10.1016/j.rdc.2018.06.004 . Mirioglu S, Uludag O, Hurdogan O, Kumru G, Berke I, Doumas SA, et al. AA Amyloidosis: A Contemporary View. Curr Rheumatol Rep. 2024. https://doi.org/10.1007/s11926-024-01147-8 . Lachmann HJ, Gallimore JR, Sabin CA, Hawkins PN. Natural History and Outcome in Systemic AA Amyloidosis. N Engl J Med 2007. Khellaf G, Benziane A, Kaci L, Benabadji M. AA renal amyloidosis: Clinical observations over 20 years. Clin Nephrol. 2022;97:167–72. https://doi.org/10.5414/CN110577 . Hemminki K, Li X, Försti A, Sundquist J, Sundquist K. Incidence and survival in non-hereditary amyloidosis in Sweden. BMC Public Health. 2012;12:974. https://doi.org/10.1186/1471-2458-12-974 . Helvacı Ö, Güz G, Adışen E, Cevher S, Güz G. Hidradenitis Suppurativa: a lesser-known cause of AA amyloidosis. Hippokratia. 2020;24:33–7. Global Tuberculosis Report. 2023 n.d. https://www.who.int/teams/global-programme-on-tuberculosis-and-lung-health/tb-reports/global-tuberculosis-report-2023 (accessed May 6, 2025). Lane T, Pinney JH, Gilbertson JA, Hutt DF, Rowczenio DM, Mahmood S, et al. Changing epidemiology of AA amyloidosis: clinical observations over 25 years at a single national referral centre. Amyloid. 2017;24:162–6. https://doi.org/10.1080/13506129.2017.1342235 . Ahmed S, Nasir H, Moatasim A, Khalil F. Renal Amyloidosis: A Clinicopathological Study From a Tertiary Care Hospital in Pakistan. Cureus. 2022;14:e21122. https://doi.org/10.7759/cureus.21122 . Biederman LE, Dasgupta AD, Dreyfus DE, Nadasdy T, Satoskar AA, Brodsky SV. Kidney Biopsy Corner: Amyloidosis Glomerular Dis. 2023;3:165–77. https://doi.org/10.1159/000533195 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-6611738\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":459589456,\"identity\":\"db994f77-cda9-4ea1-a399-e75155c56759\",\"order_by\":0,\"name\":\"Mohammad Saquib Alam\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYHACxgMMDBI8/OwNCKEDhPQAFVjISfYcQBEhqKXC2OBGApGu0u0//ODAzxyJxA03X6dJ/Mw5zMDffoDxcAEeLWY30gwO9m6TSJx5O3ebZO+2wwwSZxIYDs/Aq4XB4AAvUEsfUIsEL1ALww0GhsM8+LScP/7h4F+gloabZ7dJ/gVqkSeo5UCOwWGgLcYCN3i3SYNsMSCo5UZOwWHZbRLAQM7dbC27LZ3H8ExiAyGHbXz4dlsdMCrPbrz5dpu1nNzxw4c/49OCDFgkgARQMWMDkRoYGJg/EK10FIyCUTAKRhQAAMOpV281zNyDAAAAAElFTkSuQmCC\",\"orcid\":\"\",\"institution\":\"Jawaharlal Nehru Medical College\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Mohammad\",\"middleName\":\"Saquib\",\"lastName\":\"Alam\",\"suffix\":\"\"},{\"id\":459589457,\"identity\":\"c590df1b-59f6-4c67-a832-27fe35e0f110\",\"order_by\":1,\"name\":\"Mohd Aslam\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Jawaharlal Nehru Medical College\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Mohd\",\"middleName\":\"\",\"lastName\":\"Aslam\",\"suffix\":\"\"},{\"id\":459589458,\"identity\":\"e6899211-8872-4a7e-956e-07761bf0e5a6\",\"order_by\":2,\"name\":\"Amir Husain\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Jawaharlal Nehru Medical College\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Amir\",\"middleName\":\"\",\"lastName\":\"Husain\",\"suffix\":\"\"},{\"id\":459589459,\"identity\":\"0ed8394d-f28d-4fb7-bbb3-777b16244ad7\",\"order_by\":3,\"name\":\"Sheikh Ashraf\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Jawaharlal Nehru Medical College\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Sheikh\",\"middleName\":\"\",\"lastName\":\"Ashraf\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2025-05-07 11:53:10\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-6611738/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-6611738/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":83436219,\"identity\":\"35c57303-bfd3-4892-94e9-856bb7019826\",\"added_by\":\"auto\",\"created_at\":\"2025-05-26 08:33:27\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":22291,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eDistribution of etiologies in AA amyloidosis cohort (n=18)\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6611738/v1/096ae0e0f59f385e517848d2.png\"},{\"id\":83436235,\"identity\":\"aa563526-854a-4f8f-99ee-24d067b584ec\",\"added_by\":\"auto\",\"created_at\":\"2025-05-26 08:33:27\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":27344,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eDifferent Chronic Infectious diseases presenting as AA Amyloidosis\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6611738/v1/c2804ad1bf6235af83a8d3c7.png\"},{\"id\":83436221,\"identity\":\"aa13f733-5689-4fa7-9689-1a70a9cc22aa\",\"added_by\":\"auto\",\"created_at\":\"2025-05-26 08:33:27\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":18068,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eDegree of Proteinuria\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6611738/v1/0bf7187371bd608d92e1a043.png\"},{\"id\":83437267,\"identity\":\"6d30d642-13fa-455d-9ea4-1742e682d49e\",\"added_by\":\"auto\",\"created_at\":\"2025-05-26 08:41:27\",\"extension\":\"png\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":21052,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eBox plot of urinary protein levels compared to serum albumin levels. Higher urinary protein levels are associated with lower serum albumin levels.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"4.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6611738/v1/92871587f12f9e9f2606f9e4.png\"},{\"id\":98441086,\"identity\":\"27824b89-492f-4d9a-b73a-76c646c55340\",\"added_by\":\"auto\",\"created_at\":\"2025-12-17 17:04:51\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":644838,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6611738/v1/314cddcd-eb8c-475d-b264-6876aa0ba0d0.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"\\u003cp\\u003eExploring AA Amyloidosis: Insights from A Case Series in an Under-Explored Indian Context\\u003c/p\\u003e\",\"fulltext\":[{\"header\":\"1. INTRODUCTION\",\"content\":\"\\u003cp\\u003eAA amyloidosis, previously termed secondary amyloidosis, is a systemic disorder characterized by the extracellular deposition of serum amyloid A (SAA), an acute-phase reactant protein. [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]. This process arises from chronic inflammation or persistent infections. It leads to the misfolding and aggregation of SAA into insoluble β-pleated fibrils, which deposit in various organs, most commonly the kidneys.[\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]. Renal involvement often dominates the clinical course, contributing substantially to morbidity and determining overall prognosis [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eGlobally, the epidemiology of AA amyloidosis has shifted. Improved infection control and widespread antibiotic use have reduced infection-related cases in many high-income countries, with autoimmune and autoinflammatory conditions, such as rheumatoid arthritis and familial Mediterranean fever, emerging as predominant causes [\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]. However, in low- and middle-income countries, including India, infectious etiologies such as tuberculosis and chronic hepatitis infections continue to play a significant role. Also, other lesser-known causes of AA amyloidosis have come up, like Hidradenitis Suppurativa [\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eDespite this, there is a paucity of region-specific data characterizing the clinical spectrum, pathological features, and etiological patterns of AA amyloidosis in the Indian population. Most existing literature focuses on Western cohorts, limiting the generalizability of findings to South Asian settings.\\u003c/p\\u003e \\u003cp\\u003eThis study addresses this gap by analyzing the clinical, laboratory, and histopathological profiles of patients with biopsy-proven renal AA amyloidosis in a tertiary care center in India. Through this case series, we seek to elucidate AA amyloidosis's contemporary patterns and diagnostic characteristics within a high-burden infectious disease context.\\u003c/p\\u003e\"},{\"header\":\"2. MATERIALS AND METHODS\",\"content\":\"\\u003cp\\u003e \\u003cb\\u003eStudy Design and Setting\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003eThis retrospective, cross-sectional study was conducted at the Nephrology Division, Department of Medicine, Jawaharlal Nehru Medical College Hospital (JNMCH), Aligarh, India. The study period spanned from March 2022 to May 2024.\\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003ePatient Selection\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003eA total of 18 patients with biopsy-proven renal AA amyloidosis were included. Inclusion criteria were:\\u003c/p\\u003e \\u003cp\\u003e \\u003cul\\u003e \\u003cli\\u003e \\u003cp\\u003eHistological confirmation of AA amyloidosis on kidney biopsy, defined by:\\u003c/p\\u003e \\u003cp\\u003e \\u003cul\\u003e \\u003cli\\u003e \\u003cp\\u003ePale eosinophilic deposits on Hematoxylin and Eosin (H\\u0026amp;E) staining,\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eApple-green birefringence under polarized light with Congo red staining,\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003ePositive immunofluorescence (IF) staining for SAA protein on a separate biopsy core.\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/ul\\u003e \\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eAvailability of complete clinical and laboratory records.\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/ul\\u003e \\u003c/p\\u003e \\u003cp\\u003eExclusion criteria included:\\u003c/p\\u003e \\u003cp\\u003e \\u003cul\\u003e \\u003cli\\u003e \\u003cp\\u003eIncomplete medical records,\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eAbsence of confirmatory kidney biopsy,\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eEvidence suggesting other amyloid subtypes (e.g., AL amyloidosis).\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/ul\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eBiopsy Procedure and Histopathology\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003ePercutaneous kidney biopsies were performed under ultrasound guidance using a standardized protocol. Two cores were obtained per patient:\\u003c/p\\u003e \\u003cp\\u003e \\u003cul\\u003e \\u003cli\\u003e \\u003cp\\u003eThe first core was fixed in formalin and stained using H\\u0026amp;E, Periodic Acid-Schiff (PAS), and silver methenamine.\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eThe second core was reserved for immunofluorescence staining with monoclonal antibodies targeting SAA.\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/ul\\u003e \\u003c/p\\u003e \\u003cp\\u003eA renal pathologist evaluated biopsies. Key parameters assessed included:\\u003c/p\\u003e \\u003cp\\u003e \\u003cul\\u003e \\u003cli\\u003e \\u003cp\\u003e \\u003cb\\u003ePattern of Amyloid Deposit\\u003c/b\\u003e: The specific distribution and morphology of amyloid deposits within the kidney tissue were documented. This included identifying if the deposits were primarily interstitial, fibrillar, or exhibited a particular localization pattern (e.g., glomerular, vascular).\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003e \\u003cb\\u003eSites of Involvement\\u003c/b\\u003e: The extent of amyloid involvement in different kidney structures was assessed, specifying if the deposits were localized primarily within the glomeruli, vasculature, or other compartments.\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003e \\u003cb\\u003eImmunohistochemistry (IHC) Details\\u003c/b\\u003e: A direct IHC staining method was employed to detect SAA protein in the second core biopsy specimen. A specific monoclonal antibody against SAA was utilized.\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003e \\u003cb\\u003eIntensity of IHC Staining\\u003c/b\\u003e: The intensity of SAA immunostaining was semi-quantitatively evaluated based on a pre-defined scoring system (weak, moderate, strong) using visual assessment by the pathologist.\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/ul\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eData Collection\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003ePatient data were extracted from medical records and included:\\u003c/p\\u003e \\u003cp\\u003e \\u003cul\\u003e \\u003cli\\u003e \\u003cp\\u003e \\u003cb\\u003eDemographics\\u003c/b\\u003e: Age, sex.\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003e \\u003cb\\u003eLaboratory parameters\\u003c/b\\u003e:\\u003c/p\\u003e \\u003cp\\u003e \\u003cul\\u003e \\u003cli\\u003e \\u003cp\\u003eRenal function: Blood urea nitrogen (BUN), serum creatinine, and estimated glomerular filtration rate (eGFR).\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eUrinalysis: Microscopy, red blood cells (RBCs), casts, and 24-hour urinary protein.\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eSerum protein and albumin levels (categorized as: normal [3.5\\u0026ndash;4.5 g/dL], mild hypoalbuminemia [2.5\\u0026ndash;3.5 g/dL], and severe hypoalbuminemia [\\u0026lt;\\u0026thinsp;2.5 g/dL]).\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eHepatitis B, C, and HIV screening using rapid test kits.\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eLipid profile: HDL, LDL, triglycerides, and total cholesterol.\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eRenal ultrasonography findings.\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/ul\\u003e \\u003c/p\\u003e \\u003c/li\\u003e \\u003c/ul\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eStatistical Analysis\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003eDescriptive statistics were used for demographic and clinical variables. Continuous variables were expressed as means\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;standard deviations or medians (interquartile range) as appropriate. The Mann-Whitney U test assessed the difference in urinary protein levels between groups with mild and severe hypoalbuminemia. A p-value\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05 was considered statistically significant. Statistical analysis was performed using GraphPad Prism 9.0.\\u003c/p\\u003e\"},{\"header\":\"3. RESULTS\",\"content\":\"\\u003cp\\u003eThis retrospective study investigated the clinical characteristics, laboratory findings, and kidney biopsy features of 18 patients diagnosed with AA amyloidosis at a tertiary care center in India.\\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eDemographics and Disease Presentation\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003eThe study cohort exhibited a male predominance (83.3%, n\\u0026thinsp;=\\u0026thinsp;15) compared to females (16.7%, n\\u0026thinsp;=\\u0026thinsp;3). The age of onset ranged from 17 to 65 years, with a mean of 37.2 years (SD\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;16.9 years). Chronic infectious diseases constituted the most frequent underlying cause of AA amyloidosis (77.8%, n\\u0026thinsp;=\\u0026thinsp;14). Notably, pulmonary tuberculosis (old treated: 35.7%, n\\u0026thinsp;=\\u0026thinsp;5; ongoing treatment: 28.6%, n\\u0026thinsp;=\\u0026thinsp;4) was the most prevalent infectious etiology (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e, Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). Other identified infectious causes included treated abdominal tuberculosis (14.3%, n\\u0026thinsp;=\\u0026thinsp;2), chronic hepatitis C infection (7.1%, n\\u0026thinsp;=\\u0026thinsp;1), and co-existing HIV and chronic hepatitis C infection (5.6%, n\\u0026thinsp;=\\u0026thinsp;1). Additionally, 11.1% (n\\u0026thinsp;=\\u0026thinsp;2) of patients had a history of rheumatoid arthritis, 5.6% (n\\u0026thinsp;=\\u0026thinsp;1) had ankylosing spondylitis, and 5.6% (n\\u0026thinsp;=\\u0026thinsp;1) presented with idiopathic AA amyloidosis (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e).\\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eLaboratory Findings\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003eAll patients demonstrated proteinuria, with a mean of 3.2\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;2.5 g/24h; range 0.8\\u0026ndash;8.4 g/24h. Nearly 39% (n\\u0026thinsp;=\\u0026thinsp;7) exhibited nephrotic range proteinuria (\\u0026gt;\\u0026thinsp;3.5 g/24 hours), while the remaining 61.1% (n\\u0026thinsp;=\\u0026thinsp;11) displayed sub-nephrotic range proteinuria (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e). Serum protein levels ranged from 2.5 to 6.4 g/dL (mean 4.1 g/dL\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;1.0 g/dL). Serum albumin levels varied significantly, ranging from 0.8 to 3.2 g/dL (mean 2.2 g/dL\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.6 g/dL), with 66.6% (n\\u0026thinsp;=\\u0026thinsp;12) of patients categorized as having moderate to severe hypoalbuminemia (\\u0026lt;\\u0026thinsp;2.5 g/dL) and the remaining 33.3% (n\\u0026thinsp;=\\u0026thinsp;6) classified as having mild hypoalbuminemia (2.5\\u0026ndash;3.5 g/dL).\\u003c/p\\u003e \\u003cp\\u003eA statistically significant difference (p\\u0026thinsp;=\\u0026thinsp;0.0123) in urinary protein levels was observed between patients with mild and severe hypoalbuminemia using the Mann-Whitney U test (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e) (Table\\u0026nbsp;1). The median urinary protein level in the severe hypoalbuminemia group (3.800 g/24hr, n\\u0026thinsp;=\\u0026thinsp;12) was significantly higher compared to the mild hypoalbuminemia group (1.265 g/24h4, n\\u0026thinsp;=\\u0026thinsp;6). The 95.85% confidence interval for the difference in medians ranged from 0.4000 to 5.700 g/dL. Serum creatinine levels displayed substantial variability, ranging from 0.2 to 4.1 mg/dL (mean 1.1 mg/dL\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;0.9 mg/dL). Acute kidney injury (AKI) was observed in 33.3% (n\\u0026thinsp;=\\u0026thinsp;6) of patients.\\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eUrinalysis and Kidney Biopsy Findings\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003eUrinalysis confirmed proteinuria in all cases, corroborating the clinical suspicion of AA amyloidosis. Additionally, 38.9% (n\\u0026thinsp;=\\u0026thinsp;7) of patients exhibited red blood cells (RBCs) and RBC casts, suggesting glomerular involvement and potential complications.\\u003c/p\\u003e \\u003cp\\u003eKidney biopsy findings consistently demonstrated:\\u003c/p\\u003e \\u003cp\\u003e \\u003cul\\u003e \\u003cli\\u003e \\u003cp\\u003eDiffuse irregular mesangial matrix expansion\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eVascular deposition of SAA protein\\u003c/p\\u003e \\u003c/li\\u003e \\u003cli\\u003e \\u003cp\\u003eStrongly positive immunohistochemistry (IHC) staining for SAA\\u003c/p\\u003e \\u003c/li\\u003e \\u003c/ul\\u003e \\u003c/p\\u003e \\u003cp\\u003eFurthermore, chronic interstitial nephritis was identified in 44.4% (n\\u0026thinsp;=\\u0026thinsp;8) of patients, and a non-necrotizing epithelial cell granuloma was observed in one case (6.7%), highlighting the potential for additional histological features within this patient cohort.\\u003c/p\\u003e \\u003cp\\u003eTable No.1 Descriptive Statistics and Mann-Whitney U Test Results: Albumin Levels and Total Urinary Protein Levels\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"No\\\" id=\\\"Taba\\\" border=\\\"1\\\"\\u003e \\u003ccolgroup cols=\\\"4\\\"\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eStatistic\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMild Hypoalbuminemia (2.5\\u0026ndash;3.5)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eSevere Hypoalbuminemia (\\u0026lt;\\u0026thinsp;2.5)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eP value (Mann-Whitney U)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eNumber of values\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e12\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\" morerows=\\\"2\\\" rowspan=\\\"3\\\"\\u003e \\u003cp\\u003e0.0123\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eMean\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1.522\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e4.040\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eStd. Deviation\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e0.8159\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2.606\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e\"},{\"header\":\"4. DISCUSSIONS\",\"content\":\"\\u003cp\\u003eThis case series highlights that, in contrast to evolving trends in high-income countries, chronic infectious diseases remain the dominant etiology of AA amyloidosis in India, with tuberculosis (TB) as the leading contributor. This finding is consistent with the high national TB burden reported by the WHO, which estimated India accounted for 27% of the global TB cases in 2022 [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]. In our cohort, TB (pulmonary and abdominal) accounted for 64.3% of all cases, substantially higher than proportions reported from Europe and North America, where rheumatologic and hereditary autoinflammatory conditions now predominate [\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eThe male predominance (83.3%) and relatively young mean age (37.2 years) reflect findings from other South Asian studies, including a recent Pakistani cohort reporting a similar male skew and infectious dominance [\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]. This demographic pattern may reflect gender-based disparities in healthcare access and exposure risks, particularly regarding pulmonary TB.\\u003c/p\\u003e \\u003cp\\u003eRenal involvement, as expected, was universal, with proteinuria present in all patients and nephrotic-range levels observed in nearly 40%. The statistically significant association between severe hypoalbuminemia and higher proteinuria (p\\u0026thinsp;=\\u0026thinsp;0.0123) aligns with the glomerular distribution of amyloid deposits observed histologically. These findings echo those from European biopsy registries, where glomerular SAA deposition is a hallmark of renal AA amyloidosis [\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eInterestingly, chronic interstitial nephritis (CIN) was found in 44.4% of cases\\u0026mdash;a higher-than-expected rate. This may reflect prolonged disease evolution or chronic inflammation. The presence of RBCs and RBC casts in nearly 39% further supports glomerular injury as a key clinical marker in these patients.\\u003c/p\\u003e \\u003cp\\u003eFrom a public health and nephrology standpoint, our findings emphasize the need for earlier diagnostic consideration of AA amyloidosis in patients with chronic infections and unexplained proteinuria. While Congo red and SAA-specific immunostaining availability varies across centers, renal biopsy remains an essential diagnostic tool. The significant proportion of patients presenting with acute kidney injury (33.3%) further underscores the disease\\u0026rsquo;s impact on renal function.\\u003c/p\\u003e\"},{\"header\":\"5. Conclusion\",\"content\":\"\\u003cp\\u003eAA amyloidosis in India remains predominantly infection-related, particularly linked to tuberculosis. This contrasts with global trends and underscores the need for enhanced surveillance, early renal biopsy, and infection control strategies. Further multicentric studies are warranted to validate and expand these findings.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e \\u003ch2\\u003eEthics approval and consent to participate:\\u003c/h2\\u003e \\u003cp\\u003e This study was approved by the Institutional Ethics Committee of Jawaharlal Nehru Medical College and Hospital, Aligarh Muslim University, Aligarh, India (Ref No. IECJNMC/1610). The study adhered to the ethical principles outlined in the Declaration of Helsinki. As this was a retrospective study using anonymized patient data, the need for informed consent was waived by the Ethics Committee.\\u003c/p\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cstrong\\u003eConsent for publication:\\u003c/strong\\u003e \\u003cp\\u003eNot Applicable\\u003c/p\\u003e \\u003c/p\\u003e\\u003cp\\u003e \\u003ch2\\u003eCompeting interests:\\u003c/h2\\u003e \\u003cp\\u003eThe authors declare that they have no competing interests\\u003c/p\\u003e \\u003c/p\\u003e \\u003cp\\u003e \\u003cstrong\\u003eFunding\\u003c/strong\\u003e \\u003cp\\u003eNo Funding was received\\u003c/p\\u003e \\u003c/p\\u003e\\u003cp\\u003e \\u003ch2\\u003eAcknowledgements\\u003c/h2\\u003e \\u003cp\\u003eNot applicable\\u003c/p\\u003e \\u003ch2\\u003eAuthor Contribution\\u003c/h2\\u003e\\u003cp\\u003eMohammad Saquib Alam: Conceptualization, Methodology, Formal analysis, Writing \\u0026ndash; Original Draft, Visualization.Mohd Aslam: Data curation, Investigation, Writing \\u0026ndash; Review \\u0026amp; Editing.Amir Husain: Resources, Supervision, Writing \\u0026ndash; Review \\u0026amp; Editing.Sheikh Ashraf: Histopathological analysis, Validation, Writing \\u0026ndash; Review \\u0026amp; Editing.All authors read and approved the final manuscript.\\u003c/p\\u003e\\u003ch2\\u003eAvailability of data and materials:\\u003c/h2\\u003e \\u003cp\\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003ePapa R, Lachmann HJ, Secondary AA, Amyloidosis. Rheum Dis Clin N Am. 2018;44:585\\u0026ndash;603. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1016/j.rdc.2018.06.004\\u003c/span\\u003e\\u003cspan address=\\\"10.1016/j.rdc.2018.06.004\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMirioglu S, Uludag O, Hurdogan O, Kumru G, Berke I, Doumas SA, et al. AA Amyloidosis: A Contemporary View. Curr Rheumatol Rep. 2024. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1007/s11926-024-01147-8\\u003c/span\\u003e\\u003cspan address=\\\"10.1007/s11926-024-01147-8\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLachmann HJ, Gallimore JR, Sabin CA, Hawkins PN. Natural History and Outcome in Systemic AA Amyloidosis. N Engl J Med 2007.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKhellaf G, Benziane A, Kaci L, Benabadji M. AA renal amyloidosis: Clinical observations over 20 years. Clin Nephrol. 2022;97:167\\u0026ndash;72. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.5414/CN110577\\u003c/span\\u003e\\u003cspan address=\\\"10.5414/CN110577\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHemminki K, Li X, F\\u0026ouml;rsti A, Sundquist J, Sundquist K. Incidence and survival in non-hereditary amyloidosis in Sweden. BMC Public Health. 2012;12:974. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1186/1471-2458-12-974\\u003c/span\\u003e\\u003cspan address=\\\"10.1186/1471-2458-12-974\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHelvacı \\u0026Ouml;, G\\u0026uuml;z G, Adışen E, Cevher S, G\\u0026uuml;z G. Hidradenitis Suppurativa: a lesser-known cause of AA amyloidosis. Hippokratia. 2020;24:33\\u0026ndash;7.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eGlobal Tuberculosis Report. 2023 n.d. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://www.who.int/teams/global-programme-on-tuberculosis-and-lung-health/tb-reports/global-tuberculosis-report-2023\\u003c/span\\u003e\\u003cspan address=\\\"https://www.who.int/teams/global-programme-on-tuberculosis-and-lung-health/tb-reports/global-tuberculosis-report-2023\\\" targettype=\\\"URL\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e (accessed May 6, 2025).\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLane T, Pinney JH, Gilbertson JA, Hutt DF, Rowczenio DM, Mahmood S, et al. Changing epidemiology of AA amyloidosis: clinical observations over 25 years at a single national referral centre. Amyloid. 2017;24:162\\u0026ndash;6. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1080/13506129.2017.1342235\\u003c/span\\u003e\\u003cspan address=\\\"10.1080/13506129.2017.1342235\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAhmed S, Nasir H, Moatasim A, Khalil F. Renal Amyloidosis: A Clinicopathological Study From a Tertiary Care Hospital in Pakistan. Cureus. 2022;14:e21122. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.7759/cureus.21122\\u003c/span\\u003e\\u003cspan address=\\\"10.7759/cureus.21122\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBiederman LE, Dasgupta AD, Dreyfus DE, Nadasdy T, Satoskar AA, Brodsky SV. Kidney Biopsy Corner: Amyloidosis Glomerular Dis. 2023;3:165\\u0026ndash;77. \\u003cspan class=\\\"ExternalRef\\\"\\u003e\\u003cspan class=\\\"RefSource\\\"\\u003ehttps://doi.org/10.1159/000533195\\u003c/span\\u003e\\u003cspan address=\\\"10.1159/000533195\\\" targettype=\\\"DOI\\\" class=\\\"RefTarget\\\"\\u003e\\u003c/span\\u003e\\u003c/span\\u003e.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":true,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-6611738/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-6611738/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cem\\u003eIntroduction\\u003c/em\\u003e\\u003cem\\u003e\\u003cstrong\\u003e:\\u003c/strong\\u003e\\u003c/em\\u003e\\u003cstrong\\u003e \\u003c/strong\\u003eAA amyloidosis is a systemic protein misfolding disorder characterized by the deposition of serum amyloid A protein, often leading to progressive renal dysfunction. While inflammatory etiologies have become more prominent globally, infection-related causes remain a major contributor in resource-limited settings. Data on the clinicopathological spectrum of renal AA amyloidosis in the Indian population are scarce.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eMethods:\\u003c/em\\u003e\\u003cstrong\\u003e \\u003c/strong\\u003eThis retrospective cross-sectional study included 18 patients with biopsy-proven renal AA amyloidosis evaluated at a tertiary care center in India between March 2022 and May 2024. Clinical data, laboratory parameters, and renal biopsy findings were collected and analyzed.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eResults:\\u003c/em\\u003e\\u003cstrong\\u003e \\u003c/strong\\u003eThe cohort was predominantly male (83.3%), with a mean age of 37.2 years (range 17–65). Chronic infections were the leading etiology (77.8%), with tuberculosis being most common (64.3%), followed by hepatitis B/C and HIV coinfections. Autoimmune conditions (Rheumatoid Arthritis, Ankylosing Spondylitis) accounted for 16.7% of cases. All patients presented with proteinuria (mean 3.2 ± 2.5 g/24h), and 38.9% showed hematuria with RBC casts. Severe hypoalbuminemia (\\u0026lt;2.5 g/dL) was seen in 66.6% of patients and was significantly associated with higher proteinuria (p = 0.0123). Acute kidney injury was present in 33.3% of patients. Renal biopsy confirmed amyloid deposits with Congo red staining and strong SAA positivity on immunohistochemistry.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eConclusions:\\u003c/em\\u003e\\u003cstrong\\u003e \\u003c/strong\\u003eIn contrast to global trends, infectious diseases remain the predominant cause of AA amyloidosis in the Indian population. This study highlights the need for heightened clinical vigilance and timely renal biopsy in patients with chronic infections and unexplained proteinuria to improve early diagnosis and management.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Exploring AA Amyloidosis: Insights from A Case Series in an Under-Explored Indian Context\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-05-26 08:33:22\",\"doi\":\"10.21203/rs.3.rs-6611738/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"f427556f-00f6-447e-9431-24e946e76c06\",\"owner\":[],\"postedDate\":\"May 26th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-12-17T08:10:00+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-05-26 08:33:22\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-6611738\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-6611738\",\"identity\":\"rs-6611738\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}