📋 Key Information Summary
- Renal amyloidosis results from extracellular deposition of misfolded protein fibrils in the glomeruli and interstitium, most commonly AL (immunoglobulin light-chain) or AA (serum amyloid A) type.
- AL amyloidosis is the most frequent systemic amyloidosis in Australia; it arises from a clonal plasma-cell or B-cell disorder and deposits monoclonal κ or λ light chains.
- AA amyloidosis complicates chronic inflammatory conditions (rheumatoid arthritis, FMF, chronic infections) and deposits serum amyloid A fragments.
- Renal involvement presents predominantly with nephrotic-range proteinuria (≥3.5 g/day), progressing to chronic kidney disease and often end-stage kidney disease (ESKD).
- Diagnosis requires tissue biopsy with Congo red staining and apple-green birefringence under polarised light; renal biopsy has >95 % sensitivity for renal amyloid.
- Serum free light-chain (FLC) assay and immunofixation electrophoresis are essential to differentiate AL from AA type and to monitor treatment response.
- Technetium-99m-labelled SAP scintigraphy (where available) quantifies whole-body amyloid load but does not substitute for biopsy.
- AL amyloidosis treatment targets the underlying clone: bortezomib-based regimens (VCD) are first-line in Australia, with autologous stem-cell transplant in selected patients.
- AA amyloidosis management centres on suppressing the underlying inflammatory disease (biologic DMARDs, colchicine for FMF) to reduce SAA production to <4 mg/L.
- Eplagersen (an anti-siRNA targeting TTR) is PBS-listed for hereditary ATTR amyloidosis; AL amyloidosis therapies are funded via hospital authority and clinical trials.
- Aboriginal and Torres Strait Islander peoples have higher rates of chronic infections (rheumatic heart disease, bronchiectasis) predisposing to AA amyloidosis.
- Nephrology referral is mandatory for all suspected renal amyloidosis; haematology/oncology co-management is essential for AL amyloidosis.
- Supportive renal care includes RAAS blockade for proteinuria, loop diuretics for oedema, statin therapy, and VTE prophylaxis for severe nephrotic syndrome.
Introduction & Australian Epidemiology
The amyloidoses are a group of disorders characterised by extracellular deposition of insoluble fibrillar proteins derived from normally soluble precursors. These fibrils adopt a cross-β-sheet configuration, bind Congo red dye, and exhibit apple-green birefringence under polarised light microscopy. When fibrils accumulate in the kidney, they cause progressive glomerular and interstitial damage, manifesting as nephrotic-range proteinuria and chronic kidney disease (CKD).
Of the >30 known amyloidogenic proteins, two types account for the vast majority of renal amyloidosis encountered in Australian clinical practice:
- AL (primary) amyloidosis — derived from monoclonal immunoglobulin light chains produced by a clonal plasma-cell or B-cell neoplasm.
- AA (secondary) amyloidosis — derived from serum amyloid A (SAA), an acute-phase reactant produced during chronic inflammation.
Australian epidemiology: AL amyloidosis is the most common systemic amyloidosis diagnosed in Australia, with an estimated incidence of 8–12 per million per year. The median age at diagnosis is 63–65 years. Renal involvement occurs in approximately 50–70 % of AL cases. AA amyloidosis is rarer overall but remains clinically important in populations with chronic inflammatory diseases, particularly Aboriginal and Torres Strait Islander communities where rheumatic heart disease and suppurative lung disease persist at high prevalence. The Australian Amyloidosis Network (AAN) and the Australian and New Zealand Society of Nephrology (ANZSN) maintain disease registries that inform practice.
Diagnostic delay is common: Median time from symptom onset to AL amyloidosis diagnosis in Australia exceeds 12 months. Earlier recognition substantially improves outcomes.
AL vs AA Amyloidosis in the Kidney
Distinguishing AL from AA amyloidosis is critical because their treatments differ fundamentally. AL amyloidosis requires clone-directed therapy (chemotherapy), whereas AA amyloidosis requires suppression of the inflammatory driver.
| Feature | AL Amyloidosis | AA Amyloidosis |
|---|---|---|
| Precursor protein | Monoclonal κ or λ immunoglobulin light chain | Serum amyloid A (SAA) protein |
| Underlying cause | Clonal plasma-cell or B-cell disorder (MGUS, myeloma) | Chronic inflammation — RA, FMF, IBD, bronchiectasis, chronic osteomyelitis |
| Typical age | 60–70 years | Variable; younger in FMF |
| Renal presentation | Nephrotic syndrome, rapid CKD progression | Nephrotic syndrome, slower CKD progression |
| Extrarenal organs | Heart (>70 %), liver, peripheral nerves, soft tissues, GI tract | Spleen, liver, GI tract; heart involvement uncommon |
| Serum FLC | Abnormal κ/λ ratio in >90 % | Normal FLC ratio |
| Immunohistochemistry | Positive for κ or λ light chain | Positive for SAA; negative for light chains |
| First-line treatment | Bortezomib-based chemotherapy (± ASCT) | Treat underlying inflammation (biologics, colchicine) |
| Median renal survival (untreated) | 12–18 months to ESKD | 3–7 years to ESKD |
Pathophysiology
In AL amyloidosis, monoclonal light chains—most commonly λ6—are secreted by a low-grade clonal plasma-cell population. These light chains misfold, resist proteolysis, and deposit as fibrils predominantly in the mesangium, glomerular basement membrane, and peritubular capillaries. Fibril deposition disrupts the glomerular filtration barrier, causing heavy proteinuria and podocyte dysfunction.
In AA amyloidosis, persistently elevated SAA (produced by hepatocytes under IL-6, IL-1, and TNF-α stimulation) is cleaved by macrophage enzymes into amyloid fibrils. Deposition is predominantly glomerular but extends to the medulla and vasculature. The degree of renal AA amyloidosis correlates with the magnitude and duration of SAA elevation.
Immunohistochemical typing is mandatory: Misclassifying AL as AA (or vice versa) leads to inappropriate therapy and worse outcomes. All renal amyloid biopsies must undergo immunohistochemistry and, ideally, mass spectrometry-based proteomics.
Clinical Features (Nephrotic Syndrome, CKD)
Renal amyloidosis may be asymptomatic at early stages, detected incidentally by proteinuria on urinalysis. As disease progresses, characteristic clinical syndromes emerge.
Nephrotic Syndrome
- Heavy proteinuria (≥3.5 g/day; frequently >5 g/day)
- Hypoalbuminaemia (serum albumin <25 g/L)
- Generalised oedema (peripheral, periorbital, ascites, pleural effusion)
- Hypercholesterolaemia and hypertriglyceridaemia
- Foamy or frothy urine
Chronic Kidney Disease
Progressive decline in eGFR is characteristic. In AL amyloidosis, CKD may progress rapidly to ESKD within 12–24 months if the underlying clone is untreated. In AA amyloidosis, the trajectory is more indolent but relentless if inflammation persists.
Extrarenal Features — AL Amyloidosis
Clues to systemic AL amyloidosis include:
- Cardiac: Restrictive cardiomyopathy, low-voltage ECG with pseudo-infarct pattern, raised NT-proBNP and troponin
- Hepatic: Hepatomegaly with elevated ALP, occasionally cholestatic jaundice
- Peripheral neuropathy: Symmetric sensory-predominant, autonomic (orthostatic hypotension, gastroparesis)
- Soft-tissue: Macroglossia, periorbital purpura (pathognomonic), carpal tunnel syndrome
- Gastrointestinal: Dysmotility, malabsorption, pseudo-obstruction, GI bleeding
Extrarenal Features — AA Amyloidosis
- Splenomegaly (common, may cause hyposplenism)
- Hepatomegaly
- Adrenal gland involvement (rare clinical insufficiency)
- GI tract involvement (usually subclinical)
Clinical pearl: Any patient with nephrotic syndrome plus unexplained peripheral neuropathy, cardiomyopathy, hepatomegaly, or periorbital purpura should be evaluated urgently for AL amyloidosis.
Investigations (Biopsy, SAP Scan, Serum FLC)
A systematic investigation pathway is essential to confirm amyloidosis, determine the amyloid type, and assess organ involvement.
Essential
Tissue biopsy with Congo red staining
Renal biopsy has >95 % sensitivity. Congo red with apple-green birefringence under polarised light is diagnostic. If renal biopsy is contraindicated, fat-pad aspirate (sensitivity ~60–80 %), labial salivary gland, or rectal biopsy may be performed.
Essential
Immunohistochemistry on biopsy tissue
Must include antibodies to κ, λ, SAA, transthyretin (TTR), and fibrinogen Aα. Mass spectrometry-based proteomics is the gold standard for typing and is available at specialised centres (Royal Prince Alfred, Royal Adelaide).
Available
Serum free light-chain (FLC) assay
MBS item 66847. Measures κ and λ FLC concentrations and ratio. Abnormal ratio (outside 0.26–1.65) supports AL amyloidosis. Serial measurements monitor clonal response. Highly sensitive but not specific for AL.
Available
Serum and urine protein electrophoresis with immunofixation
MBS item 66841 (serum) / 66842 (urine). Detects monoclonal protein. Required in all patients to exclude AL amyloidosis even if FLC ratio is normal.
Available
Serum amyloid A (SAA) level
Elevated SAA (>4 mg/L sustained) supports AA amyloidosis. Serial SAA monitoring guides anti-inflammatory treatment adequacy. Available at major pathology laboratories.
Specialist centre
Technetium-99m-labelled SAP scintigraphy
Quantifies whole-body amyloid burden. Limited availability in Australia (primarily research settings and Royal Adelaide Hospital). Not a substitute for tissue diagnosis. Useful for monitoring treatment response in AL amyloidosis.
Available
Echocardiography (including strain imaging)
Essential for AL amyloidosis staging. Apical sparing pattern on global longitudinal strain is characteristic of cardiac amyloid. Assesses wall thickness, diastolic function, pericardial effusion.
Available
NT-proBNP and troponin T/I
Biomarkers for cardiac AL amyloidosis staging (Mayo 2012 staging system). NT-proBNP >1800 ng/L and troponin T >0.025 µg/L define advanced disease.
Available
Urine protein quantification (24-hour or ACR)
Quantify proteinuria for nephrotic syndrome confirmation and monitoring. ACR ≥220 mg/mmol roughly equates to ≥3 g/day proteinuria.
Investigation Algorithm
1
Screen for monoclonal protein
Serum FLC, serum and urine immunofixation electrophoresis. If monoclonal protein detected → suspect AL amyloidosis.
2
Confirm amyloid deposition
Tissue biopsy (renal preferred if renal involvement suspected) with Congo red staining. If negative and suspicion remains, consider alternative site biopsy.
3
Type the amyloid
Immunohistochemistry (κ, λ, SAA, TTR). Mass spectrometry if available. Determines AL vs AA vs hereditary.
4
Assess organ involvement
Echocardiography with strain, NT-proBNP, troponin, liver function tests, nerve conduction studies, SAP scan (if available).
Management (Treat Underlying Disease)
The overarching principle of amyloidosis management is to reduce production of the amyloidogenic precursor protein. In AL amyloidosis this means eliminating the clonal plasma-cell population; in AA amyloidosis it means suppressing the underlying chronic inflammation. Supportive renal care is provided in parallel.
AL Amyloidosis — Clone-Directed Therapy
Treatment should be initiated promptly after diagnosis in conjunction with a haematologist experienced in amyloidosis (via state amyloidosis centres of excellence).
Bortezomib
Velcade® · Proteasome inhibitor
Adult dose
1.3 mg/m² SC weekly (or twice-weekly in induction), Days 1, 8, 15, 22 of 28-day cycle
Paediatric dose
Not applicable — AL amyloidosis is an adult disease
Renal adjustment
No dose adjustment required
Hepatic adjustment
Reduce to 0.7 mg/m² if bilirubin >1.5× ULN
Key toxicity
Peripheral neuropathy, orthostatic hypotension, cardiac arrhythmias — use with caution in cardiac AL
PBS status
⚠ Authority Required — Hospital
Cyclophosphamide
Cytoxan® · Alkylating agent
Adult dose
300 mg/m² PO/IV weekly in VCD regimen
Renal adjustment
Reduce by 25 % if eGFR <25 mL/min
PBS status
✔ PBS General Benefit
Dexamethasone
Dexamethasone · Corticosteroid
Adult dose
20–40 mg PO on Days 1–4, 9–12, 17–20 of 28-day cycle (reduced to 20 mg if age >70 or cardiac involvement)
Renal adjustment
No adjustment
PBS status
✔ PBS General Benefit
Daratumumab
Darzalex® · Anti-CD38 monoclonal antibody
Adult dose
16 mg/kg IV weekly × 8 weeks, then fortnightly × 16 weeks, then monthly (ANDROMEDA regimen with VCD)
Renal adjustment
No adjustment required
PBS status
⚠ Authority Required — Hospital
Melphalan
Alkeran® · Alkylating agent (ASCT conditioning)
Adult dose (ASCT)
200 mg/m² IV (reduced to 140 mg/m² if age >65, eGFR <30, or cardiac involvement)
Key note
ASCT considered in patients with ≤2 organs involved, age ≤70, eGFR ≥30, NYHA I–II, no significant pleural effusion
PBS status
✔ PBS General Benefit
VCD (Bortezomib–Cyclophosphamide–Dexamethasone) ± Daratumumab is the current standard-of-care first-line regimen for AL amyloidosis in Australia, as per the ANDROMEDA trial evidence. Daratumumab addition significantly improves haematologic complete response rates (~53 % vs ~18 %).
AL Amyloidosis — Response Criteria
| Response Level | Haematologic Criteria | Organ Response |
|---|---|---|
| Complete response (CR) | Negative serum and urine immunofixation; normal FLC ratio | ≥30 % reduction in 24-hr proteinuria if nephrotic |
| Very good partial response (VGPR) | dFLC <40 mg/L | eGFR improvement or stabilisation |
| Partial response (PR) | ≥50 % reduction in dFLC | May take 6–12 months to manifest |
| No response / progression | <50 % reduction or rising dFLC | Worsening proteinuria, rising creatinine |
AA Amyloidosis — Suppress the Inflammatory Driver
The primary therapeutic target is to maintain serum SAA <4 mg/L. This requires aggressive management of the underlying inflammatory or infectious disease.
Colchicine
Colgout® · Anti-inflammatory (FMF-specific)
Adult dose
1–2 mg/day PO (preventive in FMF); 0.5 mg BD–TDS for acute flares
Paediatric dose
0.5–1 mg/day (age ≥5 years)
Renal adjustment
Use cautiously if eGFR <30; reduce dose and monitor for toxicity
PBS status
✔ PBS General Benefit
Anakinra
Kineret® · IL-1 receptor antagonist
Adult dose
100 mg SC daily (can increase to 1–2 mg/kg/day in refractory FMF)
Renal adjustment
Use with caution if eGFR <30; consider dose reduction
PBS status
⚠ Authority Required
Tocilizumab
Actemra® · IL-6 receptor monoclonal antibody
Adult dose
8 mg/kg IV 4-weekly or 162 mg SC weekly
Indication
AA amyloidosis refractory to conventional DMARDs and IL-1 inhibition; effective in RA-associated AA amyloidosis
Renal adjustment
No dose adjustment
PBS status
⚠ Authority Required — Restricted Benefit
Methotrexate / Leflunomide / SSZ
Conventional DMARDs
Indication
RA-associated AA amyloidosis — tight disease control to suppress SAA
Target
SAA <4 mg/L; escalate to biologic if target not met
PBS status
✔ PBS General Benefit
Supportive Renal Care (AL and AA)
While disease-modifying therapy targets the precursor protein, supportive measures reduce symptoms and slow CKD progression.
ACE inhibitor or ARB
Ramipril / Perindopril / Losartan · RAAS blockade
Adult dose
Ramipril 2.5–10 mg PO daily; titrate to maximum tolerated dose
Renal adjustment
Start low if eGFR <30; monitor potassium and creatinine within 1 week
PBS status
✔ PBS General Benefit
Furosemide
Urex® / Lasix® · Loop diuretic
Adult dose
20–80 mg PO/IV daily (up to 250 mg/day in severe nephrotic oedema)
Key note
Albumin infusion (20 % IV) may be considered in severe hypoalbuminaemia to enhance diuresis
PBS status
✔ PBS General Benefit
Atorvastatin / Rosuvastatin
Lipitor® / Crestor® · HMG-CoA reductase inhibitor
Adult dose
Atorvastatin 20–80 mg PO daily or Rosuvastatin 10–40 mg PO daily
Indication
Dyslipidaemia associated with nephrotic syndrome; CV risk reduction
PBS status
✔ PBS General Benefit
Enoxaparin (prophylactic)
Clexane® · LMWH
Adult dose
40 mg SC daily for VTE prophylaxis when serum albumin <20 g/L
Renal adjustment
Reduce to 20 mg SC daily if eGFR <30 mL/min
PBS status
✔ PBS General Benefit
VTE prophylaxis: Patients with nephrotic syndrome (serum albumin <20 g/L) have a high risk of venous thromboembolism. Consider prophylactic anticoagulation with LMWH or warfarin (target INR 2.0–2.5). Direct oral anticoagulants are generally avoided in severe CKD.
Risk Stratification / Severity Scoring
AL amyloidosis staging determines prognosis and guides treatment intensity. The Revised Mayo 2012 staging system is most widely used:
Stage I
Low Risk
NT-proBNP ≤1800 ng/L, troponin T ≤0.025 µg/L, dFLC <180 mg/L — 0 high-risk factors
Median survival: 94 months. Eligible for ASCT.
Stage II
Intermediate Risk
1 high-risk factor (NT-proBNP or troponin T or dFLC threshold exceeded)
Median survival: 40 months. Consider VCD + daratumumab.
Stage III
High Risk
2 high-risk factors. Stage IIIb: NT-proBNP >8500 ng/L (congestive heart failure pattern)
Median survival: 6–14 months (IIIb). Urgent therapy; avoid ASCT.
Renal Risk Stratification (AL Amyloidosis)
Renal staging (Palladini criteria):
- Renal stage I: Proteinuria <5 g/day AND eGFR ≥50 mL/min
- Renal stage II: Either proteinuria ≥5 g/day OR eGFR <50 mL/min
- Renal stage III: Proteinuria ≥5 g/day AND eGFR <50 mL/min
Median time to ESKD: Stage I >10 years; Stage II ~4 years; Stage III ~1.5 years.
Monitoring
Regular monitoring assesses treatment response, disease progression, and organ function.
Every cycle (monthly)
Serum FLC and dFLC; FBC, LFTs, UEC; troponin and NT-proBNP if cardiac involvement; 24-hr urine protein
Every 3 months
Formal haematologic response assessment (serum/urine IFE, FLC). SAA level for AA amyloidosis. eGFR trend. Oedema and weight. Echocardiography (if cardiac AL)
Every 6–12 months
Full organ reassessment — echo with strain, cardiac MRI (if available), liver imaging if hepatic involvement. SAP scan if available.
Post-ASCT
Day +100 response assessment: FLC, IFE, NT-proBNP. Then 3-monthly for 2 years, then 6-monthly.
Organ response lag: Haematologic response typically precedes organ response by 6–12 months. Proteinuria may transiently worsen after haematologic CR due to fibril resorption. Do not assume treatment failure if organ metrics do not improve immediately.
Special Populations
Pregnancy
AL amyloidosis in pregnancy
Exceptionally rare. Most chemotherapy agents (bortezomib, cyclophosphamide, melphalan) are teratogenic (Category D). MDT discussion with obstetrics, nephrology, and haematology is essential. Supportive care only in first trimester.
AA amyloidosis in pregnancy
Colchicine can be continued in FMF (Category B3 in Australia) — cessation risks flare and accelerated amyloid. Avoid anakinra in pregnancy unless life-threatening disease.
Paediatrics
AA amyloidosis
The predominant type in children — FMF, autoinflammatory syndromes, chronic infections. Early colchicine prophylaxis prevents amyloid in FMF. Renal transplant outcomes are reasonable if inflammation controlled.
AL amyloidosis
Extremely rare in children. Consult with paediatric haematology-oncology at a tertiary centre.
Elderly
AL amyloidosis
Median age at diagnosis >65 years. Dose-reduce bortezomib to weekly SC schedule; consider reduced dexamethasone (20 mg). ASCT generally limited to age ≤70 with preserved organ function. Palliative care input for symptom management.
Diuretic sensitivity
Increased risk of over-diuresis and AKI. Target euvolaemia, not weight loss targets.
Renal Impairment
Bortezomib
No dose adjustment required — advantage over other agents in CKD. Monitor for peripheral neuropathy.
Dialysis patients
AL amyloidosis patients on dialysis can still receive VCD. Renal transplant may be considered for AA amyloidosis if underlying disease controlled (SAA <4 mg/L for ≥2 years).
ESKD management
Refer for dialysis access planning early. Avoid peritoneal dialysis if possible (protein losses, peritonitis risk in immunosuppressed).
Hepatic Impairment
AL hepatic amyloidosis
Hepatomegaly with ALP elevation. Dose-reduce bortezomib if bilirubin >1.5× ULN. Avoid hepatotoxic agents. Monitor for cholestatic jaundice.
Immunocompromised
Chemotherapy-related
VCD causes immunosuppression — neutropenic precautions, antiviral prophylaxis (aciclovir), PJP prophylaxis (trimethoprim-sulfamethoxazole) if prolonged corticosteroid use.
Daratumumab
Hypogammaglobulinaemia — monitor immunoglobulins, consider IVIG replacement if recurrent infections.
Aboriginal and Torres Strait Islander Health Considerations
Aboriginal and Torres Strait Islander Health
📚 References
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