Introduction
Nephrotic syndrome in the elderly is a clinically significant and increasingly prevalent condition, reflecting the aging global population and improvements in diagnostic capabilities. It is characterized by the classical triad of heavy proteinuria (greater than 3 g/24 hours), hypoalbuminemia, and clinical edema, along with dyslipidemia and an increased risk of thromboembolic complications. Nephrotic syndrome was the most common indication for native kidney biopsy in a Brazilian study conducted between 1990 and 2006, involving 77 patients over 60 years of age [ 1 ]. Membranous nephropathy was identified as the most common primary etiology, followed by amyloidosis and focal segmental glomerulosclerosis (FSGS) [ 1 , 2 ]. The global prevalence of amyloid A (AA) amyloidosis is not precisely known but is estimated to range from 1 to 10 cases per million person-years [ 3 ]. AA amyloidosis is a recognized complication of chronic inflammatory diseases. In contrast, its association with malignant neoplasms is uncommon, likely because the rapid progression of many cancers often results in mortality before significant systemic amyloid deposition can occur [ 3 - 5 ]. According to extensive autopsy studies, renal cell carcinoma (RCC) is the predominant solid organ malignancy associated with AA amyloidosis, accounting for 25%-42% of documented cases [ 6 ]. The exact etiopathogenesis of AA amyloidosis secondary to RCC remains incompletely understood; current evidence suggests that chronic tumor-associated inflammation results in sustained production of pro-inflammatory cytokines, particularly interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α, which stimulate hepatocytes to produce serum amyloid A (SAA). Persistent elevation of circulating SAA promotes its extracellular deposition as AA amyloid fibrils in multiple organs, particularly the kidneys. Although local SAA expression by tumor cells has also been reported, hepatic synthesis remains the principal source of circulating SAA [ 7 ]. When RCC is complicated by secondary AA amyloidosis, patients typically present with proteinuric kidney disease, whereas hematuria may be absent, particularly when the renal manifestations are driven by amyloid deposition rather than the tumor itself [ 6 ]. Renal amyloidosis is diagnosed histologically by the presence of eosinophilic amorphous deposits that stain positively with Congo red and demonstrate the characteristic apple-green birefringence under polarized light [ 8 ]. This case describes the presentation of nephrotic syndrome in an elderly patient secondary to systemic AA amyloidosis associated with RCC, highlighting the importance of recognizing uncommon causes of nephrotic syndrome beyond membranous nephropathy in this population.
Case presentation
An 86-year-old male, with a medical history of hypertension and dyslipidemia, and a functional status of being bed-bound secondary to blindness, presented with a five-day history of acute upper respiratory symptoms and repeated episodes of vomiting. Initial examination revealed mild dehydration, basal crackles on the left side, bilateral lower limb edema, and stable vitals, including a blood pressure (BP) of 107/65 mmHg, heart rate (HR) of 95 beats/min, respiratory rate (RR) of 18 breaths/min, and oxygen saturation (SpO2) of 94% on room air, with no gross neurological deficits. Laboratory investigations showed a hemoglobin level of 10.9 g/dL, C-reactive protein of 89 mg/L, white blood cell count of 10.8 × 10⁹/L, neutrophil count of 9.9 × 10⁹/L, sodium level of 142 mmol/L, potassium level of 3.5 mmol/L, lactate level of 2.5 mmol/L, and non-oliguric acute kidney injury (AKI), with a serum creatinine of 185 µmol/L, estimated glomerular filtration rate (eGFR) of 30 mL/min/1.73 m², and urea of 10.5 mmol/L. Compared with his baseline renal function one year earlier, his serum creatinine had increased from 89 µmol/L, and his eGFR had declined from 70 mL/min/1.73 m². Urine dipstick testing was positive for proteinuria, with no hematuria. Due to deteriorating kidney function, further evaluation revealed severe nephrotic syndrome with a protein/creatinine ratio of 1520 and 1600 mg/mmol, respectively (normal < 15 mg/mmol), 24-hour urine protein of 4.8 g, and serum albumin at 13 g/L. Further investigations to identify secondary causes of nephrotic syndrome included a negative autoimmune workup, with negative anti-nuclear antibody (ANA) and anti-neutrophil cytoplasmic antibody (ANCA) results; a phospholipase A2 receptor (PLA2R) level of 1 IU/mL (normal reference: <20 IU/mL); a negative multiple myeloma workup, including a normal free light chain ratio and negative urine and serum electrophoresis; negative chronic hepatitis B and C screening and HIV serology; normal complement levels (C3 and C4); and negative tumor markers, including carcinoembryonic antigen (CEA), CA 19-9, and prostate-specific antigen (PSA), as illustrated in Tables 1 , 2 . A chest X-ray indicated a left-sided lung patch, suggesting community-acquired pneumonia (CAP) (Figure 1 ).
Table 1
Laboratory results upon presentation (quantitative results).
| Category | Parameter | Result | Reference range |
| Hematology & inflammatory markers | Hemoglobin | 10.9 g/dL | 12-16 g/dL |
| White cell count (WCC) | 10.8 ×10⁹/L | 4-11 ×10⁹/L | |
| Neutrophils | 9.9 ×10⁹/L | 2-7 ×10⁹/L | |
| C-reactive protein (CRP) | 89 mg/L | <5 mg/L | |
| Renal function (Admission) | Sodium (Na) | 142 mmol/L | 135-145 mmol/L |
| Potassium (K) | 3.5 mmol/L | 3.5-5.0 mmol/L | |
| Creatinine | 185 µmol/L | 45-90 µmol/L | |
| Baseline creatinine (1 year prior) | 89 µmol/L | 45-90 µmol/L | |
| Estimated glomerular filtration rate (eGFR) | 30 mL/min | > 90 ml/min/1.75 m2 | |
| Baseline eGFR (1 year prior) | 70 mL/min | > 90 ml/min/1.75 m2 | |
| Urea | 10.5 mmol/L | 2.5-7.8 mmol/L | |
| Lactate | 2.5 mmol/L | 0.5-2.0 mmol/L | |
| Bone profile | Albumin | 13g/L | 35-50 g/L |
| Alkaline phosphatase (ALP) | 129 IU/L | 44-147 IU/L | |
| Calcium (Albumin adjusted) | 2.39 mmol/L | 2.2-2.6 mmol/L | |
| Calcium (Total) | 1.84 mmol/L | 2.1-2.6 mmol/L | |
| Phosphate | 1.29 mmol/L | 0.81-1.45 mmol/L | |
| Liver function test (LFT) | Alanine aminotransferase (ALT) | 20 U/L | 7-55 U/L |
| Albumin | 13 g/L | 35-50 g/L | |
| Alkaline phosphatase (ALP) | 129 IU/L | 44-147 IU/L | |
| Aspartate aminotransferase (AST) | 33 U/L | 8-48 U/L | |
| Bilirubin, Total | 3 micmol/L | 1.7-20.5 micmol/L | |
| Nephrotic syndrome assessment | Protein/creatinine ratio (Reading 1) | 1520 mg/mmol | <15 mg/mmol |
| Protein/creatinine ratio (Reading 2) | 1600 mg/mmol | <15 mg/mmol | |
| 24-hour urine protein | 4.8 g/day | <0.15 g/day | |
| Serum albumin | 13 g/L | 35-50 g/L | |
| Lipid profile | Cholesterol, Total | 6.3 mmol/L | <5.0-5.2 mmol/L |
| Cholesterol, high-density lipoprotein (HDL) | 1.33 mmol/L | >1.0-1.2 mmol/L | |
| Cholesterol, low-density lipoprotein (LDL) | 4.4 mmol/L | <2.6-3.0 mmol/L | |
| Triglycerides | 1.2 mmol/L | <1.7 mmol/L | |
| Autoimmune workup | Phospholipase A2 receptor (PLA2R) antibody | 1 IU/mL | 0.00-19.00 IU/mL |
| Anti-myeloperoxidase (MPO) | 1 U/ml | 0.00-20.00 U/mL | |
| Anti-proteinase 3 (PR3) | 1 U/ml | 0.00-20.00 U/mL | |
| Complement levels | C3 | 0.96 g/L | 0.8-1.78 g/L |
| C4 | 0.41 g/L | 0.10-0.40 g/L | |
| Myeloma screening | Free κ/λ ratio | 1.69 | 0.26-1.65 |
| Tumor markers | Carcinoembryonic antigen (CEA) | 6.1 ng/mL | 0-3 ng/mL |
| CA 19-9 | <2 U/mL | 0-37 U/mL | |
| Prostate-specific antigen (PSA) | 0.31 micg/L | 0.00-4.00 micg/L |
Table 2
Laboratory results upon presentation (qualitative results).
| Category | Parameter | Result |
| Urinalysis | Urine dipstick protein | Positive |
| Hematuria | Absent | |
| Autoimmune workup | Antinuclear antibody (ANA) | Negative |
| Anti-neutrophil cytoplasmic antibody (ANCA) | Weak positive | |
| Myeloma screening | Serum electrophoresis | Negative |
| Urine electrophoresis | Negative | |
| Infectious screening | Hepatitis B | Negative |
| Hepatitis C | Negative | |
| HIV serology | Negative |
An ultrasound showed bilateral normal-sized kidneys with increased renal echogenicity, degraded corticomedullary differentiation, a right hypochondrial soft tissue mass with calcification, and mild ascites, as illustrated in Figure 2A . Abdominal MRI indicated a complex lesion at the upper pole of the right kidney, likely renal and possibly malignant (Figure 2B ). In view of the severe nephrotic syndrome, the decision was made to perform ultrasound-guided biopsies of the right kidney and the mass. A Tru-Cut biopsy of the renal mass revealed a malignant renal tumor with features most consistent with the International Society of Urological Pathology (ISUP) grade 3 clear cell RCC. Moreover, histopathological evaluation (Figure 3 ) revealed positive Congo red stain and positive apple green birefringence, which highlight the presence of scanty amyloid material in the tumor stroma (Figures 3C , 3D ). Furthermore, the needle biopsy of the native kidney confirmed the diagnosis of AA amyloidosis by positive Congo red staining and positive immunohistochemical staining (IHC) for amyloid A, which is consistent with secondary amyloidosis, as shown in Figures 3G , 3H . The explanation of nephrotic syndrome and progressive deterioration of the kidney function in this case is due to systemic AA amyloidosis secondary to RCC. Following multidisciplinary discussion, the patient was evaluated for definitive management. Radiofrequency ablation was considered but deemed unsuitable because of the anatomical location of the tumor. Consequently, radical nephrectomy was identified as the potential curative treatment option. However, given the patient's advanced age, poor functional status, and multiple comorbidities, he was considered a high-risk candidate for major surgery. Following discussion of the diagnosis, prognosis, and available management options, the decision was made to pursue conservative management with palliative intent. As this management approach was not expected to change with further oncological staging, additional staging investigations, including CT of the thorax and formal TNM (tumor, node, and metastasis) classification, were not undertaken. Four months later, the patient re-presented to the emergency department in an unresponsive state, and despite the resuscitative measures, his death was declared.
Written consent was obtained from the next of kin of the patient for publication of this case report.
Discussion
Among 1,192 renal biopsies performed in elderly patients, nephrotic syndrome was the most common indication for biopsy, followed by rapidly progressive glomerulonephritis [ 2 ]. The causes of nephrotic syndrome in this population include membranous nephropathy, renal amyloidosis, non-collapsing FSGS, collapsing FSGS, minimal change disease, diabetic nephropathy, lupus nephritis, fibrillary glomerulonephritis, membranoproliferative glomerulonephritis, and IgA nephropathy [ 2 ]. The association between systemic AA amyloidosis and solid malignancies has been recognized for more than a century, with RCC representing the most frequently reported solid tumor. Autopsy studies have demonstrated systemic AA amyloidosis in approximately 2.1% of patients with RCC [ 5 , 6 ]. Renal involvement in systemic AA amyloidosis typically presents with severe nephrotic syndrome, postural hypotension, and AKI, often in the absence of hematuria. In severe cases, AKI may require renal replacement therapy. In our patient, AKI was non-oliguric and was managed conservatively. Consequently, renal biopsy was performed following imaging that identified a suspicious right renal mass. Histopathological examination confirmed clear cell RCC, with Congo red-positive amyloid deposits within the tumor stroma. These deposits demonstrated the characteristic salmon-pink appearance on light microscopy and apple-green birefringence under polarized light (Figures 3A - 3D ). The diagnosis of secondary AA amyloidosis was confirmed by positive immunohistochemical staining for amyloid A in the native kidney biopsy (Figure 3H ). Congo red staining followed by polarized microscopy has an overall sensitivity of 57%-85% and specificity of 92%-100% for detecting AA amyloidosis [ 8 ]. The etiopathogenesis of AA amyloidosis secondary to RCC has been previously described but remains incompletely understood. Current evidence suggests that chronic tumor-associated inflammation results in sustained production of pro-inflammatory cytokines, particularly IL-1, IL-6, and TNF-α, which stimulate hepatic synthesis of SAA. Persistent elevation of circulating SAA promotes its misfolding and extracellular deposition as AA amyloid fibrils in multiple organs, particularly the kidneys. Although local SAA expression by tumor cells has also been reported, hepatic synthesis remains the principal source of circulating SAA [ 7 , 9 ]. Unfortunately, in our hospital, the SAA level was not available for measurement. Treatment of secondary AA amyloidosis is primarily directed at controlling the underlying inflammatory process. In chronic inflammatory diseases, this may include corticosteroids, colchicine, disease-modifying anti-rheumatic drugs, cytotoxic agents, or biologic therapies targeting TNF-α, IL-1, or IL-6, depending on the underlying disease [ 9 ]. In patients with solid malignancies such as RCC, definitive treatment of the underlying tumor remains the cornerstone of management. Surgical resection, when feasible, has been associated with reductions in SAA levels, improvement in proteinuria, and stabilization of renal function [ 6 , 9 ]. Although paraneoplastic AA amyloidosis has been reported more frequently in patients with advanced RCC, there is currently no established correlation between tumor stage or grade and the development of AA amyloidosis. Rather, persistent tumor-associated inflammation is thought to be the principal driver of sustained SAA production [ 6 , 9 ]. In our patient, the multidisciplinary discussion concluded that radiofrequency ablation was not feasible because of the anatomical location of the tumor. Although radical nephrectomy represented the suitable curative treatment option, the patient was considered a high-risk candidate for major surgery because of his advanced age, poor functional status, and multiple comorbidities. Therefore, conservative management with palliative intent was pursued.
A limitation of this case report is that SAA levels were not measured, and formal oncological staging, including TNM classification, was not performed because it was not expected to alter the management plan.
Conclusions
This case highlights the importance of considering secondary AA amyloidosis as a rare but clinically significant cause of nephrotic syndrome in elderly patients, particularly when common causes have been excluded. Although RCC is the solid malignancy most frequently associated with AA amyloidosis, this paraneoplastic manifestation remains uncommon and may delay diagnosis. Early recognition, comprehensive evaluation, and histopathological confirmation are essential to facilitate timely multidisciplinary management. Published reports suggest that successful treatment of the underlying malignancy, particularly nephrectomy when feasible, may stabilize or improve AA amyloidosis. However, the prognostic impact of AA amyloidosis in patients with RCC has not been fully established because of the rarity of this association. Further studies are warranted to better define its clinical course and determine the extent to which treatment of the underlying malignancy influences renal and overall clinical outcomes.
Dr. Basit Salam, Radiology Department, Sultan Qaboos University Hospital, University Medical City (UMC).
Disclosures
Human subjects: Informed consent for treatment and open access publication was obtained or waived by all participants in this study.
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:
Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.
Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.
Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
Author Contributions
Concept and design: Aya AalHamad, Saja Mahmood, Khalfan Al Zeedy, Dawood Al Riyami, Marwa Al Riyami
Acquisition, analysis, or interpretation of data: Aya AalHamad, Saja Mahmood, Khalfan Al Zeedy, Dawood Al Riyami, Marwa Al Riyami
Drafting of the manuscript: Aya AalHamad, Saja Mahmood, Khalfan Al Zeedy, Dawood Al Riyami, Marwa Al Riyami
Critical review of the manuscript for important intellectual content: Aya AalHamad, Saja Mahmood, Khalfan Al Zeedy, Dawood Al Riyami, Marwa Al Riyami
Supervision: Aya AalHamad, Saja Mahmood, Khalfan Al Zeedy, Dawood Al Riyami, Marwa Al Riyami
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