2025 ISA指南：系统性淀粉样变性的支持治疗

指南血液内科· 其他血液疾病 · 2025

Authors

Keywords

transthyretin amyloidosis, ATTRv: variant (hereditary) transthyretin amyloidosis, ATTRwt: wild-type transthyretin amyloidosis, BIA: bioimpedance analysis, BMI: body mass index, BoNTA: botulinum toxin A, CA: cardiac amyloidosis, CAA: cerebral amyloid angiopathy, CBD: cannabidiol, CHA2DS2-VASc score: congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, previous stroke, vascular disease, age 65-74 years, sex category score, CKD: chronic kidney disease, CPAP: continuous positive air pressure, CTS: carpal tunnel syndrome, CVA: cerebrovascular event, DC: direct current, DOAC: direct oral anticoagulant, ECG: electrocardiogram, ER: extended release, ESKD: end-stage kidney disease, FFP: fresh frozen plasma, FLC: free light chain, FX: factor X, GDMT: guideline-directed medical therapy, GFR: glomerular filtration rate, GI: gastrointestinal, GLIM: global leader initiative on malnutrition, HFpEF: heart failure with preserved ejection fraction, HFrEF: heart failure with reduced ejection fraction, IASP: International Association for the Study of Pain, ICD: implantable cardioverter-defibrillator, IMiD: immunomodulatory drug, ISA: International Society of prothrombin time, RAS: rein-angiotensin system, rFVIIa: recombinant activated factor VII, RT: reptilase time, SAA: serum amyloid A, SGLT2i: sodium-glucose cotransporter inhibitor, SSRI: selective serotonin reuptake inhibitor, SWI: susceptibility-weighted imaging, TE: thromboembolism, TENS: transcutaneous Supportive care, palliation, symptoms, management, multidisciplinary care

Abstract

Systemic amyloidosis refers to a group of protein misfolding disorders resulting in organ deposition with amyloid, leading to organ dysfunction, ultimately resulting in organ failure and death if not successfully treated. Treatment is type-specific and aimed at the underlying source of the misfolded protein. In the past decades, treatments have become increasingly available across the various amyloidosis types with improved response rates and longer survival. Supportive care measures are an integral part of care for patients with systemic amyloidosis to improve symptom burden and quality of life, reduce healthcare costs, and potentially prolong survival while type-directed therapy takes effect. In these guidelines, we provide supportive care recommendations across eight areas of interest in systemic amyloidosis: cardiology, nephrology, peripheral neuropathy, central nervous system involvement, autonomic neuropathy, gastroenterology, coagulopathy and bleeding, nutrition and hematology. These guidelines were developed on behalf of the International Society of Amyloidosis (ISA) by experts in the above fields and provide the best available evidence and expertise for supportive care in these rare disorders.

The supportive care guidelines for systemic amyloidosis on behalf of the International Society of Amyloidosis (ISA) were conceived out of a growing need to provide professional, and clinically oriented recommendations by a broad expert panel from various clinical domains in amyloidosis. Amyloidosis patients now live longer owing to the increase in therapeutic interventions. Nonetheless, despite encouraging milestones of improving outcomes, patients may remain with a high symptom burden, requiring clinical attention and increased healthcare resource utilisation. Regardless of the specific treatment provided to the patient based on the amyloidosis type, supportive care measures to decrease symptom burden and support organ function are critical for the management of this disorder. The goals of supportive care are to preserve and improve organ function, maintain quality of life, and prolong survival. Multidisciplinary care at a centre of excellence is fundamental to navigating the unique challenges of this uncommon disease.

This expert panel was assembled at the direction of the ISA board with 1-2 experts for each of the eight clinical domains of interest (Figure 1 ). The recommendations were drafted based on the best available evidence and expertise. Given the dearth of data related to supportive care in amyloidosis, most recommendations are derived from recommendations in more common diseases and conditions (e.g. heart failure, nephrotic syndrome, peripheral neuropathy), with careful attention to the specific needs of amyloidosis patients. Given the limited data, we did not use the GRADE system to provide a ranking order based on the quality of the evidence. These guidelines were reviewed by all panel members and discrepancies were resolved by discussion. A summary of the main recommendations is provided in Table 1 .

# Cardiology supportive care guidelines

Cardiology supportive care guidelines

Management of heart failure in patients with cardiac amyloidosis (CA) present unique challenges, especially in those with advanced disease. Traditional recommendations have been to avoid heart failure guideline-directed medical therapy (GDMT) in CA, especially angiotensin receptor-neprilysin inhibitors (ARNIs), Angiotensin receptor blockers (ARBs) or ACE inhibitors (ACEIs), and beta-blockers due to the potential for hypotension and worsening hemodynamics in patients with advanced disease [1, 2] .

CA leads to diastolic dysfunction and reduced longitudinal function often manifesting as heart failure with preserved ejection fraction (HFpEF), but heart failure with reduced ejection fraction (HFrEF) may also occur. Patients with CA were not intentionally included in the major randomised clinical trials of heart failure therapy. However, several retrospective cohort studies have analysed the effect of standard heart failure treatment in CA. Overall, conventional heart failure medications are not well tolerated in CA, both light chain (AL) and transthyretin (ATTR) types, especially in patients with severe dysfunction (restrictive filling), reduced cardiac output, and baseline hypotension. ACEIs, ARBs, and ARNIs may cause symptomatic hypotension, especially in patients with autonomic dysfunction. Given fixed stroke volume due to restrictive filling in CA, the negative chronotropic effect of beta-blockers may reduce cardiac output, causing symptomatic hypotension, worsening heart failure, and organ hypoperfusion. A recent large retrospective study revealed a potential benefit of mineralocorticoid receptor antagonists and, interestingly, a lower risk of mortality for ATTR patients with ejection fraction below 40% treated with low-dose beta-blockers [3] . The role of sodium-glucose cotrasnporter-2 inhibitors (SGLT2i) in CA is expanding as studies demonstrated that SGLT2i are well tolerated in CA [4] and may be beneficial [5] . With earlier diagnosis and improved treatment of the underlying systemic amyloidosis, traditional avoidance of GDMT needs to be reconsidered. For example, patients with early wild-type ATTR (ATTRwt) with only mild diastolic dysfunction may tolerate GDMT and these patients may have hypertension, which rarely present with advanced amyloid heart disease. Conversely, patients with newly diagnosed cardiac AL and acute, decompensated heart failure will rarely tolerate GDMT. However, after adequate haematologic response and improved hemodynamics, these therapies could theoretically provide benefits for chronic heart failure due to AL. Comorbidities need to be considered as well, especially for elderly patients.

# multidisciplinary approach

multidisciplinary approach

Supportive care approach in amyloidosis Effective symptom management in systemic amyloidosis requires a multidisciplinary approach with proactive interventions to enhance quality of life. This approach should address both common and rare manifestations of the disease, treatment-related adverse effects and coexisting medical conditions.

Cardiology

Heart failure management The use of heart failure guideline-directed medical therapy in cardiac amyloidosis depends on individual patient characteristics and comorbidities. mineralocorticoid receptor antagonists and SGlT2 inhibitors usage mineralocorticoid receptor antagonists and sodium-glucose co-transporter-2 (SGlT2) inhibitors have potential benefits and should be administered if possible. Atrial fibrillation management Atrial fibrillation is common in cardiac amyloidosis with a high risk of thromboembolic events; anticoagulation is recommended regardless of the CHA2dS2-VASc score. Cardioverter-defibrillators (iCds)

The benefit of cardioverter-defibrillators (iCds) is not clear, but implantation should be considered in selected subgroups. Heart transplantation in advanced disease stages, heart transplantation should be considered for selected cohorts.

Nephrology management of nephrotic syndrome

The kidney is a frequently involved organ in both acquired and hereditary types of systemic amyloidosis, with the main presentation being nephrotic syndrome. Treatment is primarily based on dietary sodium restriction ( < 2 g/day) and oral loop diuretics. if unsuccessful, consider using the iV route and/or adding another diuretic class (thiazides, potassium-sparing diuretics). Renin-angiotensin system (RAS) blockers may be used to reduce albuminuria, particularly in patients with hypertension. However, they should be avoided in patients with cardiac or autonomic nervous system involvement due to the risk of severe hypotension.

Use of SGlT2 inhibitors

Adding SGlT2 inhibitors can be considered for renal patients with proteinuria and may be particularly suitable for patients with concomitant renal and cardiac amyloidosis. Prophylaxis in patients with severe hypoalbuminemia in patients with serum albumin levels below 20 g/l, prophylactic anticoagulation and statins to control dyslipidemia should be considered.

Progression to ESKd

Progression to end-stage kidney disease (ESKd) occurs in a variable proportion of patients, ranging from 15 to 31%. Both haemodialysis and peritoneal dialysis can be considered.

Kidney transplantation

Peripheral nerve and CNS

Prevention of trophic ulcers Patients with sensory loss are prone to trophic ulcers and should be instructed on skin self-examination and preventive care. management of ambulation difficulties Patients with difficulty ambulating should be referred to a physical therapy service to adjust appropriate walking aids and orthoses. management of painful neuropathy Consider pharmacotherapy for symptomatic relief in patients with painful neuropathy. First-line treatment options include gabapentin, pregabalin, and duloxetine. Second-and third-line options, as well as other interventions, are detailed in the guidelines. management of entrapment neuropathy Entrapment neuropathies caused by amyloidosis, such as carpal tunnel syndrome, are usually progressive and should be treated early to prevent irreversible nerve damage. Surgical release surgery is typically required. management of cerebral amyloid angiopathy Cerebral amyloid angiopathy can cause microbleeds, lobar haemorrhages, transient focal neurological episodes and cognitive impairment and requires evaluation with specialised imaging modalities.

Autonomic nerve

Non-pharmacological management of orthostatic hypotension

Patients with symptomatic orthostatic hypotension should be considered for conservative management measures, including reducing blood-pressure-lowering medications, relaxing fluid and salt restrictions, administering small fluid boluses, rising slowly from seated or recumbent positions, performing physical manoeuvres, elevating the head of the bed, using compression garments, and following graded exercise regimens. Although some patients with CA have pure low-output heart failure, most will have volume overload requiring diuretic therapy. With the increased use of SGLT2i, some patients may not need loop diuretics or require lower doses. The most used loop diuretics in CA include furosemide, torsemide, and bumetanide (Table 2 ), the latter two have better bioavailability and longer duration of action and are often used if the response to furosemide is sub-optimal. Most patients will be initiated on an aldosterone antagonist at the same time as loop diuretics to minimise hypokalaemia and due to the beneficial effects in heart failure in general. Close monitoring of electrolytes and renal function is essential. Caution is required with the use of diuretics in CA to avoid over-diuresis, hypotension, and worsening renal function. Close follow-up with a heart failure clinic team should be considered, especially for class III and IV heart failure. Modest fluid ( < 1.5-2 L/day) and sodium restriction ( < 2 g/day) are recommended. Compression stockings may assist in controlling edoema and mobilising fluid at a lower diuretic dose. Pulmonary hypertension is common in cardiac amyloidosis, especially with advanced disease. Pulmonary hypertension is usually secondary to elevated left heart filling pressures. Group I pulmonary arterial hypertension has been reported in rare cases and may warrant consideration of pulmonary vasodilator therapy after careful hemodynamic evaluation [6] .

Arrhythmias management including devices and anticoagulation

Atrial and ventricular arrhythmias and conduction system disease are common in CA resulting from structural and electrical changes of the myocardium caused by amyloid deposition. The most common rhythm disorder in CA is atrial fibrillation (AF) with a reported prevalence between 10 and 69%, most frequent in patients with ATTRwt, followed by ATTRv and AL patients [7, 8] .

Intracardiac thrombi and thromboembolic events are common in patients with CA, independent of the CHA 2 DS 2 -VASc score. AL patients have the highest risk, underlined by studies that found intracardiac thrombi in AL patients even without a history of AF [9, 10] . Therefore, anticoagulation should be recommended for all CA patients with AF, independent from the CHA 2 DS 2 -VASc score if a high bleeding risk is not expected. ECG monitoring may be considered to detect asymptomatic atrial fibrillation.

Rhythm control should be considered in CA patients with newly diagnosed AF, depending on their clinical status. However, compared to other heart diseases, both rhythm and rate control can be challenging in CA. Recurrence of AF after successful cardioversion is frequent in CA, especially in advanced disease stages. Therefore, long-term antiarrhythmic therapy is often necessary to maintain sinus rhythm. The class III agent amiodarone is the most multidisciplinary approach

Coagulation and bleeding laboratory investigation

Patients with Amyloidosis face risks of haemorrhagic and thrombotic complications. The use of patisiran, inotersen, eplontersen, and vutrisiran reduces vitamin A levels. Therefore, it is essential to regularly use vitamin A supplement at the daily recommended dose of 2500-5000 iU. frequently used. However, amiodarone can lead to clinically significant hypothyroidism in approximately half of AL patients [11] . Dofetilide is an alternative option, if available, but requires admission for monitoring and should be used cautiously in patients with renal dysfunction. Retrospective studies in selected patients have suggested that catheter ablation is feasible and beneficial [12] [13] [14] . However, AF recurrence was significantly more frequent compared to non-CA patients, and patients in advanced disease stages had the highest recurrence rates. If patients are not suitable for or rhythm control is unsuccessful, rate control is used to prevent the negative effect on diastolic filling due to high heart rates. Rate control is also often challenging in CA. Patients tend to have a narrow window of optimal heart rate to promote cardiac output. Both bradycardia and tachycardia are poorly tolerated in CA due to restrictive hemodynamics and low fixed stroke volume. Low-dose beta-blocker is often used as first-line therapy for rate control under close monitoring. Digoxin was considered contraindicated in CA for many years, based on in-vitro studies that demonstrated binding to amyloid fibrils and cases of sudden death after therapy initiation [15] . However, observational studies demonstrated the safe use of digoxin for rate control at low doses (trough level < 0.8 ng/mL) with close monitoring of electrolytes and renal function [16, 17] . Nondihydropyridine calcium channel blockers are usually avoided in CA due to negative inotropic effects and potential binding to amyloid fibrils [18, 19] . Some CA patients do not require rate control agents due to conduction disease.

An additional challenge in the management of atrial fibrillation in CA is the increased risk of left atrial appendage thrombus and increased risk of complications from DC cardioversion [20] . Atrial thrombi are often persistent in patients with CA despite therapeutic anticoagulation [9, 10] . Although guidelines have suggested that transesophageal echocardiography should be performed before elective cardioversion, independent of AF and anticoagulation duration, a recent publication has challenged this [21] . Clinicians should continue to be aware of the increased risk of intracardiac thrombosis in patients with CA, especially those with advanced disease, and even in the presence of sinus rhythm. The role of left atrial occlusion devices in CA is unclear. Due to the potential increased risk of device thrombus and unknown efficacy in CA, we recommend long-term anticoagulation rather than left atrial appendage closure in CA unless there is a significant risk of serious bleeding. Data on the role of an implantable cardioverterdefibrillator (ICD) for primary prevention is sparse and inconclusive. Several smaller studies demonstrated that ventricular arrhythmias (VA) are more common in AL than ATTR. However, syncope and sudden death in AL were often found to be due to bradycardia or pulseless electrical activity (PEA) [22, 23] . No clear mortality benefit of ICD in AL has been demonstrated, despite appropriate device therapy in some patients [24] . However, given improved response rates and survival, the role of ICD implantation deserves reconsideration in AL, and studies in the current era are warranted. AL patients with cardiac involvement and unexplained syncope, sustained ventricular tachycardia, or high suspicion of life-threatening arrhythmias may be considered for ICD implantation under conventional guidelines [25] . While non-sustained ventricular tachycardia is common in ATTR, sudden death is unusual. Conduction system disease requiring permanent pacemaker implantation is seen in both AL and ATTR types of CA and does not necessarily represent a progression of amyloid heart disease. Standard indications are followed for pacemaker implantation except for earlier consideration of intervention in ATTRv patients who have been reported to have an increased risk of sudden death due to conduction system disease [26] . Patients with CA and restrictive hemodynamics may require a higher baseline pacing rate to support cardiac output, although this needs to be individualised. CA patients requiring frequent right ventricular pacing may benefit from cardiac resynchronisation (biventricular pacing).

Heart transplantation/assist devices

Heart transplantation should be considered for younger patients with advanced heart failure, deep hematological response to treatment, and single-organ involvement (or predominant heart involvement) [27] . Several studies demonstrated a similar outcome after heart transplantation for CA patients compared to patients with non-amyloid cardiomyopathies, however, patient selection is crucial [28, 29] . Besides frailty and nutritional status, extracardiac manifestations must be evaluated carefully in ATTRv and AL patients to improve outcomes after transplant.

The role of left ventricular assist device (LVAD) for the treatment of end-stage heart failure in CA is still unclear due to limited data and a relative lack of experience. Small studies and several case reports indicate that LVAD implantation is feasible in a selected group of patients despite the challenges of small left ventricular cavity size and restrictive physiology with severe diastolic dysfunction [30] . The need for biventricular support should be considered when mechanical circulatory support is contemplated in CA, especially in ATTR where right heart dysfunction is common.

Nephrology supportive care guidelines

The kidney is a frequently involved organ in acquired (AL, AA, and ALect2) and hereditary types of systemic amyloidosis (such as AFib, AApoA1, AApoC2, and ALys) [31] [32] [33] [34] [35] . The pattern and severity of renal manifestations vary according to the amyloid precursor protein [35] .

In the most common renal amyloidosis types, AL and AA amyloidosis, amyloid fibrils are usually widely distributed in the renal parenchyma with predominant glomerular involvement. The main presentation is marked albuminuria, with nephrotic syndrome in up to 50% of patients, responsible for peripheral edoema and widespread fluid retention [35] . A glomerular filtration rate (GFR) value < 60 ml/min/1.73 m 2 is reported in 50-55 and 50-75% of patients with AL and AA amyloidosis, respectively. Up to 10% require dialysis at the time of diagnosis. Most patients with ALect2 and hereditary amyloidoses present with reduced GFR [32] [33] [34] . Uncommonly, AL amyloidosis may manifest with acute kidney injury (AKI) related to amyloid cast formation within tubule lumens [36] . Supportive measures to correct fluid retention and the other consequences of severe urine albumin loss should be rapidly introduced [32, 33, 37] . Edoema contributes to immobility, fatigue, discomfort, skin blistering, infections, and anxiety. Treatment is primarily based on dietary sodium restriction ( < 2 g/day) and loop diuretics. Water restriction is unnecessary and should be prescribed only in patients developing hyponatremia [38] . Loop diuretics can initially be used orally in the absence of severe fluid retention, preferentially with twice daily dosing. The dose should be adapted daily to clinical response (e.g. 24 h-diuresis and decrease in body weight, which should be ~1 kg/day). The IV route should be preferred in patients with diffuse edoema/anasarca or without response despite a high oral dose (e.g. furosemide ≥120 mg/ day). IV furosemide is usually administered continuously over 24 h after an initial IV bolus (40-125 mg) . The total dose should not exceed 600 mg/day (Table 2 ). In case of insufficient response, often observed in patients with severe hypoalbuminemia, replacement of furosemide with longacting loop diuretics with better bioavailability (i.e. bumetanide, torsemide) may be considered. If unsuccessful, adding another diuretic (acetazolamide, thiazide, potassium-sparing diuretic) may be helpful. Potassium-sparing diuretics offer the additional benefit of preventing hypokalemia. Combinations of diuretics are often effective, and serum electrolyte levels and the potential adverse effects should guide the choice. In patients with refractory edoema, intravenous albumin infusion (20-50 g) may be added to promote diuresis [39] .

Renin-angiotensin system (RAS) blockers, including ACEIs and ARBs, are frequently used in nephrotic syndrome patients to reduce albuminuria, albeit no evidence supporting their efficacy in amyloidosis exists. Importantly, these drugs should be avoided in patients with cardiac or autonomic nervous system involvement, particularly in the presence of hypotension due to poor tolerance in these patients' populations. Careful surveillance is required, due to the risk of AKI and hyperkalemia. Rarely, in patients who have reached end-stage kidney disease (ESKD) but still exhibit massive proteinuria with severe hypoalbuminemia and intractable anasarca, renal embolisation may be required to reduce urine protein loss and increase serum albumin [40] .

Large placebo-controlled clinical trials have shown that in patients with chronic kidney disease (CKD) or heart failure, SGLT2i delays renal function deterioration on top of RAS blockers and reduces cardiovascular events and mortality [41, 42] . International guidelines for heart failure (AHA) [43] and chronic kidney disease (KDIGO) [44] indicate that any subject with CKD or heart failure has a clear indication for the use of SGLT2i, regardless of the level of albuminuria. SGLT2i also decreases blood pressure, uric acid levels, fluid overload, and the risk of hyperkalemia [41, 42] . Within assessment of their well-established safety profile, SGLT2i may be particularly suitable for patients with concomitant renal and cardiac amyloidosis, used alone or in combination with loop diuretics or other diuretic classes [4] . Prospective studies are required to evaluate the efficacy and safety of SGLT2i in amyloidosis since current evidence is limited to clinical cases or small retrospective series [45] .

In AL amyloidosis, initial renal response (measured as a reduction of at least 30% in 24-h proteinuria) typically occurs 3-18 months following the achievement of a deep haematologic response [33, 46] . However, at least a 60% reduction in proteinuria is needed to improve renal and patient survival [47] . During this period of gradual achievement of renal response, the objective of supportive therapy is to preserve renal function. While serum creatinine is normal at diagnosis in many patients, it can easily worsen because of suboptimal or uncontrolled disease, excessive volume depletion, hypotension, infections, or the use of nephrotoxic agents including contrast media, all of which should be avoided. Progression to ESKD occurs in a variable proportion of patients ranging from 15 to 31% according to different series and amyloidosis types [46] . In AA amyloidosis, the median renal survival of patients with a baseline serum creatinine > 2 mg/dL is 11 months [48] . The probability of developing ESKD appears tightly related to the control of the underlying inflammatory condition, with an SAA level < 7 mg/L associated with a higher likelihood of renal survival [32] . In AL amyloidosis, 13% progress to ESKD within a median of 27 months, with higher CKD stage, lower serum albumin level, and inadequate FLC response being independent predictors of progression to ESKD [33] . A renal staging system in AL amyloidosis allows estimation of renal outcomes based on baseline proteinuria and eGFR value, using thresholds of 5 g/24 h and 50 ml/min/1.73 m 2 , respectively [46] . Recently, renal staging for AA amyloidosis using different cut-offs of proteinuria (3 g/24 h) and eGFR (35 ml/min/1.73 m 2 ) was reported [49] .

In patients with serum albumin levels below 20 g/L, prophylactic anticoagulation should be considered, particularly in the presence of other risk factors of thrombotic events (such as obesity, immobilisation, recent surgery, use of immunomodulatory drugs (IMiDs) and genetic factors). Further information on thromboembolic events in renal amyloidosis is covered in the section on coagulation and bleeding disorders below. Nephrotic syndrome is also accompanied by lipid abnormalities, including high plasma cholesterol levels, low-density lipoprotein, triglycerides, and lipoprotein(a). Treatment of dyslipidemia relies mainly on the use of statins [38] . Please refer to the nutrition segment in this paper for an assessment of malnutrition in patients with nephrotic syndrome and ESKD.

A decision regarding renal replacement therapy should consider several factors, such as age, the extent and severity of extrarenal organ involvement, and eligibility for kidney transplantation. Both haemodialysis and peritoneal dialysis can be considered [50] . Survival following dialysis initiation is shorter than in other renal diseases, mainly due to extrarenal involvement. In a series of 222 patients with AL amyloidosis, the median survival after initiation of dialysis was 39 months [33] . In patients with coexisting cardiac or autonomic involvement, haemodialysis sessions can be poorly tolerated because of hypotension. Although little data has been reported, peritoneal dialysis appears as a valuable option in the absence of contraindication (such as peritoneal scarring or hernias). By providing slow ultrafiltration, peritoneal dialysis may allow improved tolerance and control of fluid overload than haemodialysis in patients with CA [51] .

Kidney transplantation is a valid option in selected patients with systemic amyloidosis, with allograft and patient survival close to that of recipients with diabetes mellitus or patients aged over 65 years [52, 53] . In AApoA1 and ALys renal amyloidoses, which have a slowly progressive natural history, kidney transplantation alone is associated with favourable outcomes, even in the absence of directed therapy against the precursor protein. Although disease recurrence in the allograft is common in AApoA1 amyloidosis, degradation of the allograft function is slow, and median allograft survival is ~13 years. In AFib amyloidosis, recurrence of deposits is associated with more rapid deterioration in eGFR, leading to graft failure between 5 and 12 years after transplantation. Combined liver and kidney transplantation may be curative in AApoA1 and AFib amyloidoses, by removing the hepatic production of the amyloid precursor. However, the procedure is associated with increased morbidity and should be reserved for selected young patients, who showed a rapid disease course in their native kidneys [54] . In AA amyloidosis, the most recent series has highlighted favourable survival outcomes with an overall median survival of 13 years, and allograft survival rates around 90 and 80% at 5 and 10 years, respectively, with low amyloid recurrence rates (5.8%). Control of the underlying inflammatory condition at the time of transplantation appears as an independent predictive factor of patient and allograft outcomes [52, 55] .

More evidence has been accumulated on kidney transplantation in AL amyloidosis, which is more challenging given the propensity to multi-organ involvement in this amyloidosis type. In a multicentre cohort of 237 patients who underwent renal transplantation between 1987 and 2020, overall survival from renal transplantation was 8.6 years, with a median graft survival of 7.8 years [56] . Death-censored graft survival at 1-, 3-, and 5-years was 92, 79, and 69%, respectively. This study demonstrated the importance of deep haematologic response (very good partial response or better) at the time of transplantation. Overall and graft survival rates were higher in patients with deep hematological response, who also showed a significantly lower rate of amyloid recurrence, compared to those without deep response (16 vs. 37%). The presence of cardiac involvement with pretransplant diastolic interventricular septum thickness > 12 mm was independently associated with mortality [52] . Regular monitoring of serum free light chain levels is required to detect haematologic relapse which should prompt histological confirmation of recurrence in the allograft. Recurrence successfully treated rarely leads to graft loss. Transplantation from a living donor is a feasible option in patients aged < 70 years without cardiac stage IIIB disease or another severe extrarenal disease (autonomic neuropathy, extensive GI involvement), providing the procedure is performed after a sufficient delay from the end of clone-targeted therapy to reduce the risk of early post-transplant infections [57] . Kidney allograft recipients bear a significant risk of post-transplant neoplastic and infectious complications requiring preventive measures [58, 59] .

Peripheral neuropathy and central nervous system supportive care guidelines

Peripheral neuropathy management

Peripheral neuropathic manifestations include sensory and motor abnormalities. Positive symptoms include neuropathic pain, paresthaesia (abnormal sensation in the absence of specific stimuli), or dysesthesia (abnormal interpretation of a touch-based sensation). Negative sensory manifestations include hypoesthesia to anaesthesia to different sensory modalities [60] .

Most patients with neuropathic pain complain of ongoing or intermittent spontaneous pain. Neuropathic pain is often described as burning, shooting, pricking, pins and needles, squeezing, or freezing. Allodynia (pain after contact with a stimulus that is not normally noxious) and hyperalgesia (increased pain from a stimulus that normally provokes pain) can be found in addition to other sensory abnormalities [60] . In case of loss of thermal and pain sensation, and possible loss of vibratory sensation, trophic (pressure) ulcers may occur and need special care and attention to avoid progression to joint or bone infection, which may lead to amputation if not treated early [61, 62] . Self-exam is recommended for all patients with neuropathy who should be looking for the colour and temperature of the skin as well as signs of bleeding, blistering, edoema, and exudate. Self-recognition of skin lesions should prompt cleaning with saline solution, covering with gauze soaked in saline solution, and seeking medical attention. Preventive strategies carried out by patients are important. These may include washing the skin with glycerine soap, drying the skin after washing it, use of moisturising cream, avoiding walking without shoes, use of proper shoes, use of orthopaedic insoles, and visiting a specialised podiatry service [61, 62] .

Damage to large sensory and motor nerve fibres can significantly affect ambulation capacity and may lead to falls. Patients with difficult ambulation should be referred to a physical therapy service to receive guidance on the most suitable options of walking aid, such as a standard cane, multiple-legged cane, front-wheeled, 4-wheeled or standard walker, or a wheelchair. Walking aids help in strengthening weak muscles and may also reduce pain. The use of orthoses is an important consideration when a drop foot is noticed. Orthoses have different models and materials from which they are made, and it is important to adjust and evaluate the various options with expert guidance. Light material, such as carbon fibre is the ideal choice [63, 64] .

Treatment of neuropathic pain is primarily provided to treat the painful sensation associated with neuropathy. Patients with abnormal sensations (dysesthesias, paresthesias) will not substantially benefit from pharmacological intervention. Based on systematic reviews endorsed by the International Association for the Study of Pain (IASP) and other societal guidelines, a summary of recommendations for the management of neuropathic pain is provided below [65] [66] [67] [68] [69] .

First-line drug treatment of neuropathic pain includes gabapentin (300 mg at bedtime, increase every 4-7 days by 300 mg increments to a goal of 1.800 mg; maximum dose 3600 mg/day in 3-4 divided doses), or pregabalin (75 mg twice daily, increase after 4-7 days by 75 mg to a goal of 300 mg/day; maximum dose 600 mg/day in 2 divided doses). These two drugs received a strong recommendation based on high-quality evidence. When both drugs are available, pregabalin may be favoured over gabapentin due to its better tolerance and higher bioavailability compared to gabapentin, whose bioavailability decreases as dose increases making dose titration more challenging.

The major side effects of gabapentinoids are dizziness, sedation, confusion, and peripheral edoema (thus may be challenging in patients with heart failure or nephrotic syndrome). There is a need for dosage adjustment with kidney insufficiency and caution with a psychiatric history. Duloxetine (20-30 mg once daily, increase weekly by same dose to 60 mg once a day; maximum dose 120 mg/day in two divided doses), and venlafaxine (150-225 mg/day once a day) are also first-choice drugs for neuropathic pain treatment, with a strong recommendation based on high-quality evidence. The most common side effects of these serotoninnorepinephrine reuptake inhibitors are nausea, fatigue, and sedation. Precautions with their use include risk of serotonin syndrome, bleeding with concomitant use of anticoagulants, withdrawal syndrome, and hepatic failure. Most patients respond to the above first-line treatments for neuropathic pain. Those who are non-responders (provided they are at optimal dose for at least 2 weeks) would benefit from follow-up with a pain specialist who can consider opioids or other alternative treatments.

Second-line treatment options for neuropathic pain include tramadol/tramadol ER (200-400 mg/day bid) and tapentadol (50-600 mg/day) with a weak recommendation based on moderate-quality evidence. The most common side effects of these opioids are nausea, vomiting, and constipation. The tricyclic antidepressant amitriptyline (10-25 mg at bedtime, increase every 4-7 days to a goal of 100 mg/day; maximum dose 150 mg/day) has moderate-quality evidence for neuropathy management. Its major side effects are related to its anticholinergic effects (i.e., dry mouth, constipation, urinary retention, and orthostatic hypotension) and QT prolongation limiting its use in the amyloidosis patient population, especially patients with AL and ATTR who frequently have concomitant dysautonomia or hypotension. There is a risk of serotonin syndrome and sedation, and caution is needed in the presence of cardiac arrhythmia. Due to its potential side effects and the availability of alternative options, amitriptyline is not a good drug choice for neuropathic pain management in most patients with amyloidosis.

Topical agents, such as lidocaine (5%) and capsaicin (8%) patches are also recommended as second-choice drugs. Lidocaine patches have a weak recommendation based on low-quality evidence, whereas capsaicin patches have a weak recommendation based on high-quality evidence. The main side effects of these topical agents are erythema and itching.

The strong opioids, morphine (10-120 mg/day) and oxycodone (10-120 mg/day) are recommended as third-line pharmacotherapeutic options with a weak recommendation based on moderate-quality evidence. A bowel regimen to prevent constipation should be planned if these medications are used. The neurotoxin, BoNTA (subcutaneously, 50-200 IU BoNTA in 0.9% saline every three months), is a third-choice treatment option with a weak recommendation based on low-quality evidence.

Other therapeutic options for neuropathic pain management are limited. The role of cannabis-based medicines (herbal cannabis, plant-derived, or synthetic THC or THC/ CBD oro-mucosal spray) in treating neuropathic pain is controversial and has not yet been established. Physical therapies, such as heat and cold applications, fluidotherapy, massage, ultrasound, short-wave diathermy, low-frequency currents (e.g. TENS), high-voltage galvanic stimulation, and laser, may provide additional benefit. Exercise training combined with psychological therapy, is another possibility of add-on treatment with moderate effect.

Management of entrapment neuropathy

Tendon and ligament tissues are prone to amyloid deposition in systemic amyloidosis. Entrapment neuropathy, particularly carpal tunnel syndrome (CTS), is common in ATTRv and ATTRwt, AL, and β2-microglobulin (Aβ2m) amyloidoses [70] . Bilateral CTS often precedes cardiac involvement in ATTRwt amyloidosis and is an important symptom for early diagnosis [71] . On the other hand, due to the high incidence of peripheral neuropathy in patients with ATTRv and AL amyloidosis, careful evaluation is needed to distinguish the presence of CTS. CTS often presents with numbness, tingling, and/or paresthaesia in the thumb, index, middle, and radial halves of the ring finger that worsen at night, especially at dawn, or after an exercise involving the hand [72] . As the disease progresses, weakness and atrophy of the median nerve-innervated muscles of the hand, such as the thenar muscles, make pinching with the thumb and index finger difficult. On examination, worsening paresthaesia in the median nerve distribution after percussion of the median nerve at the wrist (Tinel's sign) and passive flexion of the wrist for 30-60 s (Phalen's sign) may indicate CTS. Nerve conduction studies and electromyography are useful tests for the objective assessment of CTS and may be performed to confirm the diagnosis. Additionally, ultrasonography and magnetic resonance imaging (MRI) are also useful for detecting median nerve compression in the carpal tunnel. In general, initial treatments for CTS include avoidance of symptom-provoking activities and using a wrist splint, oral steroids, nonsteroidal anti-inflammatory drugs, and intracarpal steroid injections; however, there is no evidence that any of these conservative treatments are effective in amyloidosis. CTS caused by amyloidosis is usually progressive and often requires surgical treatment to prevent irreversible nerve damage [73] . A release surgery involves an open or endoscopic technique to release the median nerve entrapment by incising the transverse carpal ligament. In Aβ2m amyloidosis, minimally invasive endoscopic surgery is non-inferior to open surgery [74] . Although effective therapies have become available for ATTR and AL amyloidosis, post-treatment follow-up of neurological and electrophysiological findings is important because CTS often relapses if the amyloid precursor protein is uncontrolled. Similar attention should be paid to other entrapment neuropathies, such as cubital tunnel syndrome and tarsal tunnel syndrome.

Management of CNS symptoms

In ATTRv amyloidosis, several specific variants, such as D18G, A25T, G53E, and Y114C cause leptomeningeal and ocular amyloidosis in the early stages of the disease [75] . As the prognosis improves with liver transplantation and disease-modifying drugs, leptomeningeal amyloidosis has recently become a concern, even in common variants, such as V30M [76] . Amyloid deposition around the leptomeninges and cortical vessels can cause microbleeds, lobar haemorrhages, transient focal neurological episodes (TFNEs), and cognitive impairment. TFNEs are recurrent, stereotyped, and brief (usually < 30 min) episodes of somatosensory, motor, visual, or speech dysfunction that often mimic transient ischaemic attacks (TIAs). Cerebral amyloid angiopathy (CAA) is classified according to the amyloid precursor protein, including amyloid β (Aβ), ATTR, cystatin C, and gelsolin. Its manifestations may include focal neurological findings [77] . Differentiating between TFNE and TIA is important in this setting to avoid unnecessary use of antithrombotic agents, which increase the risk of cerebral haemorrhage in CAA [78] . For CAA evaluation, T2*-weighted imaging (T2*WI), susceptibility-weighted imaging (SWI), and gadolinium enhancement on MRI are useful for detecting microbleeds, hemosiderin deposition on the brain surface, and disruption of the blood-brain barrier. In addition, amyloid PET, which is used in Alzheimer's disease, is also useful in ATTR-type CAA. Although there are no systematic studies on the treatment of ATTR-type CAA, management of vascular risk factors, including blood pressure control, is considered important, as in the case of Aβ-type CAA [79] . Because the use of antiplatelet and anticoagulant agents to manage comorbidities increases the risk of intracerebral haemorrhage and mortality, the risks and benefits must be carefully weighed.

In systemic amyloidosis, the risk of cerebrovascular accidents (CVA) is multifactorial and requires careful monitoring and risk management. Atrial fibrillation and heart failure due to cardiac amyloidosis are major risk factors for cardioembolic stroke. Coagulation abnormalities and blood pressure fluctuations due to autonomic neuropathy and renal dysfunction are also risk factors for CVA.

Supportive care guidelines for autonomic neuropathy

Orthostatic hypotension

Orthostatic hypotension is defined as a drop in blood pressure of either 20 mmHg systolic or 10 mmHg diastolic within the first 3 min of a change to upright posture or a 60-degree head-up tilt [80] . This can occur due to neurogenic autonomic dysfunction, cardiac and renal dysfunction (due to intravascular volume depletion), or secondary to medications. When symptomatic, patients frequently describe light-headedness, dizziness, or syncope. However, symptoms may be more subtle including imbalance and falls, blurred vision, poor concentration or 'brain fog' , leg or generalised weakness, fatigue, chest pain, shortness of breath, backache, or posterior scapular and cervical pain ('coat-hanger pain'). When treating orthostatic hypotension, the goal is to reduce the patient's symptom burden and improve quality of life and day-to-day function. Treatment of postural hypotension is required when the patient is symptomatic, often commencing with conservative, non-pharmacological measures, and progressing to pharmacological treatments if persistent or severe.

Various medications can cause de-novo postural hypotension or can exacerbate existing postural hypotension from neurogenic or cardiogenic causes. Offending medications include diuretics, traditional heart failure treatments (e.g. ACEIs, ARBs, beta-blockers), vasodilators (e.g. phosphodiesterase-5 inhibitors, nitrates), alpha-blockers (e.g. for prostatism or pre-existing hypertension) or analgesics (e.g. tricyclic antidepressants, SSRIs, opioids). These medications should be de-prescribed where possible, and alternative medications less likely to cause postural hypotension instituted. A multidisciplinary approach to de-prescribing is necessary, particularly for diuretics or other cardiac medications, to avoid precipitating heart failure exacerbation. Similarly, if volume is depleted, relaxation of fluid restrictions and increasing salt intake could be undertaken with multidisciplinary discussion. In the acute setting, a small fluid bolus, e.g. 250 ml, can be helpful to improve symptoms, without typically exacerbating heart failure management.

Patients should be advised to rise slowly from lying and seated positions, to minimise venous pooling and improve venous return. Micturition syncope can arise, and male patients should be advised to consider passing urine seated and rising slowly thereafter. Furthermore, physical manoeuvres can be employed to increase venous return, particularly if becoming symptomatic while standing, including toe-raising, leg crossing, forward bends, belt-tightening before rising, and sitting on folding chairs [81, 82] . Elevating the head of the bed when lying by 10-20°, is recommended to improve baseline lower limb vascular tone and maintain activation of the RAS system [81, 83] . Whole-body head-up tilts (reverse Trendelenburg positioning), can be achieved by foam bolsters, bed chocks, or specific hospital beds or aids. Compression garments, worn only when in the upright position, can provide a significant boost to blood pressure by increasing venous return. These include thigh-or abdominal-high compression stockings or abdominal binders. However, these can be difficult to put on and poorly tolerated, particularly if there is significant fluid overload or neuropathic pain.

Hypotension occurring within 2 h of eating, so-called 'postprandial hypotension' may occur due to the diversion of blood flow to the splanchnic vasculature and is more commonly seen with warm than cold foods. When occurring, individuals are encouraged to limit large-volume and carbohydrate-rich meals, and alcohol-and sugar-dense beverages, to limit splanchnic vasodilation. Instead, multiple-, low-carbohydrate, small-volume meals are recommended [84] [85] [86] . Caffeine, which blocks vasodilatory adenosine receptors can also be consumed with meals, to increase splanchnic vasoconstriction. However, tolerance may develop [87] .

Exercise is critical for patients with orthostatic hypotension. Individuals often become inactive due to their symptoms, which leads to deconditioning, and loss of the lower limb muscle pump, which provides venous return. Increased urine output due to pressure diuresis often exacerbates volume depletion and lowers daytime blood pressures, further aggravating symptoms. This vicious cycle often feels counterintuitive for patients, so education and encouragement to continue with exercise are essential. A graded exercise program can be helpful to guide patients, and recumbent exercise may be initially required [80] . Hydrotherapy can be advised, where the hydrostatic pressure of water improves venous return, thereby allowing upright exercise without significant hypotension. Furthermore, educating patients about safety, including the fall risk is necessary, and assistive home modifications (including bathroom rails, shower chairs, and over-the toilet assistance), mobility aids, and personal alarms should be performed.

Further considerations include reducing gastrointestinal loss, from vomiting or diarrhoea, optimising serum albumin levels to maximise intravascular volume, and avoiding triggers, such as heat exposure, overexertion, and straining when urinating or defaecating [80] . Anaemia, not uncommon in amyloidosis (due to GI blood losses, reduced intake of haematinics, or low erythropoietin levels) may further exacerbate hypotension. A normocytic anaemia with low erythropoietin levels is identified in 25% of patients with ATTRv and is typically improved by erythropoiesis-stimulating agents (25-50 units/kg, subcutaneously, 3 times a week) [88, 89] .

Pharmacological management of orthostatic hypotension is frequently required. Several medications (Table 3 ) can be utilised. In general, medications should only be given if the patient intends to be upright, and no doses should be prescribed within 4 h of bedtime, to prevent supine hypertension. Medications can be titrated to the maximum dose tolerated. If there is no benefit, switching to an alternate treatment or adding a second medication titrated from the lowest starting dose may be required [80] . Preferably medications with differing mechanisms of action should be prescribed. Typically, midodrine or less commonly droxidopa are prescribed as first-line therapies, however, the choice of which medication depends on availability, comorbidities, cost, and potential side effects. For example, fludrocortisone which increases volume expansion is effective but is not recommended as first-line therapy when there is concomitant CA or nephrotic syndrome. Pyridostigmine can exacerbate gastrointestinal symptoms and has an attenuated effect on blood pressure when compared to other available medications. However, it has utility as an add-on therapy in severe autonomic dysfunction [90] .

Supine hypertension is commonly observed in neurogenic orthostatic hypotension and is frequently exacerbated by its pharmacological management [91] . Supine hypertension is defined as systolic and diastolic blood pressures > 140 and 90 mmHg, respectively [91] . However, in the setting of orthostatic hypotension, it is recommended that intervention should occur if supine systolic blood pressures are persistently above 160-180 mmHg [80] . Nocturnal hypertension can result in worsening cardiac and renal dysfunction, impaired cerebral autoregulation, and haemorrhagic strokes [91, 92] . Furthermore, elevated nocturnal blood pressure results in pressure diuresis, resulting in nocturia and risk of falls, fluid depletion, and worsening orthostatic hypotension [93, 94] . It is recommended that patients with orthostatic hypotension on pharmacological treatments should have supine blood pressures recorded, typically in the early morning after lying recumbent overnight. If supine hypertension is identified, optimisation of the timing and dose of medications to improve orthostatic hypotension should initially be performed as well as increasing the head-up tilt angle, if tolerated. In addition, a change to an alternative blood pressure boosting medication may be warranted, with Pyridostigmine tending to cause less supine hypertension, or intermittent dose withholding can be employed [90, 95] . Ingestion of carbohydrates before bed to increase splanchnic vasodilation, thereby improving systemic hypertension, can be utilised [96] . If these measures are unsuccessful, short-acting antihypertensives (e.g. low doses of losartan, captopril, nifedipine, hydralazine clonidine), can be carefully administered [80] .

Management of genitourinary autonomic dysfunction

Autonomic urinary symptoms include urinary frequency, urgency, overflow incontinence, recurrent urinary tract infections, incomplete bladder emptying, or urinary retention. Timed voiding strategies can be employed alongside caffeine and fluid intake restriction, especially in the evening. Nocturia can be improved by minimising supine hypertension or nocturnal administration of desmopressin (orally or intranasal), which acts as an antidiuretic hormone analog [97, 98] . Urinary urgency due to detrusor hyperactivity can be improved with the use of anti-muscarinic agents (e.g. oxybutynin, solifenacin, tolterodine, trospium). However, side effects, including cognitive impairment may arise [97, 99, 100] . Alternatively, a β3-adrenergic agonist, Mirabegron, can be utilised with minimal side effects [101] . Alpha-blockers, typically used for urethral and prostatic relaxation, should be avoided, as these frequently exacerbate orthostatic hypotension. Intermittent self-catheterization may be required for urinary retention, with, or without an additional detrusor relaxant, to limit recurrent urinary tract infections, sepsis, and progressive renal impairment [97] . Erectile dysfunction is a common and early manifestation of genitourinary autonomic dysfunction, with retrograde ejaculation and lack of vaginal lubrication also occurring. It is important to discuss and normalise sexual dysfunction. Treatment includes a review of contributory medications (e.g. antidepressants, neuroleptics, sedatives, beta-blockers, and diuretics) and if suitable, from a hypotension and cardiac perspective, a trial of a phosphodiesterase-5 inhibitor (e.g. Sildenafil, Tadalafil) [97, 102] . Patients should be advised to avoid upright positioning for hours after using these medications. If unsuccessful, a referral to a sexual health clinic to consider alternative strategies, such as vacuum devices, intracavernous injections, intraurethral prostaglandin E1 analogs, or implanted prostheses [97] . Topical oestradiols and vaginal lubricants can assist with vaginal dryness.

Supportive care guidelines for gastrointestinal involvement

The GI system is the largest organ system in the human body and, not surprisingly, is significantly involved in most systemic disorders. Amyloidosis is no exception, and most affected patients report prominent GI concerns. However, GI involvement with amyloidosis is heterogeneous as amyloid deposition is not uniform and can vary significantly in affected patients. Specifically, deposition can occur at the level of the luminal GI mucosa, the muscular layers of the gut, the GI vascular supply, and/or the enteric nervous system. Involvement of each region can lead to different complications, including malabsorption, altered GI motility, bleeding, ischaemia, small intestinal bacterial overgrowth, and/or obstructive symptoms. Even in the absence of direct luminal mucosal or muscular deposition, amyloid can result in significant GI dysfunction mediated by polyneuropathy involving the enteric nervous system with resultant dysautonomia. The most common GI symptoms reported include early satiety, weight loss, abdominal pain, nausea, constipation, and diarrhoea-and the specific symptom pattern for each patient may differ based on their individual pattern of disease involvement [69, [103] [104] [105] .

GI symptom burden may also vary based on the amyloid subtype. In patients with AL amyloidosis, GI symptoms (not synonymous with GI involvement) are reported in ~60% of patients [106] . GI symptom burden with ATTR amyloidosis is often anecdotally suggested to be more significant; however, data distinguishing the two remains limited. In an analysis of the Transthyretin Amyloidosis Outcomes Survey (THAOS), 63% of patients with hereditary ATTR amyloidosis reported GI symptoms at enrolment, with unintentional weight loss and early satiety most frequent, followed by alternating diarrhoea and constipation [105] . Of note, GI symptoms were more common in certain mutations with increased polyneuropathy, such as V30M, and were also more prominent in patients with younger age of onset (age < 50). Conversely, patients with hereditary amyloidosis with predominantly cardiac manifestations and ATTRwt amyloidosis appeared to have a lower degree of GI symptom burden, with only 15% of patients reporting significant GI symptoms at the time of enrolment. The authors went so far as to conclude that for these two subgroups specifically 'the prevalence of gastrointestinal manifestations was not evidently higher than that expected in the general population' [105] .

The specific symptoms reported can also reflect the location in the GI tract where deposition is most prominent. Oesophageal involvement can lead to dysphagia, reflux, and occasionally food impaction. Stomach involvement may result in abdominal pain, early satiety, nausea, vomiting, and distension. Small bowel involvement can lead to malabsorption and diarrhoea, but also to dysmotility, pseudo-obstruction, and small intestinal bacterial overgrowth. Colonic involvement can result in diarrhoea, constipation, and faecal incontinence. Weight loss may result from involvement anywhere along the GI tract but is non-specific and not necessarily reflective of GI involvement alone [69] .

Diagnostic evaluation

Diagnostic evaluation can be considered (a) to evaluate for amyloidosis, (b) to exclude other conditions that may cause similar symptoms, and (c) to guide therapy. Endoscopy/ colonoscopy is usually the first step in the evaluation as it can be utilised to obtain mucosal biopsies to assess directly for amyloid deposition, treat bleeding or other complications, and exclude other GI inflammatory conditions. However, endoscopic biopsies only allow detection of potential mucosal involvement-which is not universal in amyloidosis, particularly with neuropathic variants. Three large retrospective studies of primarily AL patients from Massachusetts, California, and Korea reported biopsy-proven GI amyloid deposition in only a small minority of affected patients (3, 6 , and 15%, respectively) [106] [107] [108] . In contrast, a recent study from the United Kingdom National Amyloid Centre reported positive GI biopsies in 75% of highly selected AL Amyloidosis patients [109] . Data regarding biopsy detection rates in ATTR amyloidosis are far more limited but suggest a lower sensitivity for endoscopic biopsy in amyloid detection [109] . While endoscopic biopsies are specific for amyloid deposition, they are relatively insensitive as a lack of amyloid on mucosal biopsies may fail to demonstrate amyloid involvement in other layers of the GI tract.

While endoscopy and colonoscopy are often first-line for diagnostic testing, other diagnostic studies can be considered on a case-by-case basis. Cross-sectional imaging studies, such as CT and MRI can be utilised to assess GI wall thickness, gut diameter, potential obstruction, extra-luminal GI manifestations, stool burden, and anatomical abnormalities. Barium fluoroscopy can be utilised to evaluate GI motility, gut diameter, and potential obstruction. Dedicated motility studies, such as oesophageal manometry, wireless pH testing, and pH impedance can assess oesophageal motility and reflux. Similarly, gastric and small bowel motility can be assessed through scintigraphy, electrogastrography, antroduodenal manometry, and wireless motility testing. Potential small intestinal bacterial overgrowth can be evaluated via lactulose/glucose breath testing or endoscopic small bowel aspiration for quantitative cultures. Finally, colonic motility can be assessed through radio-opaque marker studies, scintigraphy, colonic manometry, and anorectal manometry. These tests are not necessary for each patient, but selective choice of diagnostic testing can help elucidate the specifics of gut function and lead to tailored treatment.

When evaluating GI symptoms in amyloidosis, it is important to remember that most GI symptoms are non-specific and may also be seen in the general population. For example, gastroesophageal reflux is reported in 20% of American adults, dyspepsia may be reported in up to 30% of adults, irritable bowel syndrome is described in 13% of adults and constipation is reported in ~15% of adults [110, 111] . Moreover, just because an individual may have amyloidosis, they are not excluded from having other unrelated GI conditions that can be seen in the general population including inflammatory bowel disease, coeliac disease, eosinophilic esophagitis, and cancer. Finally, GI symptoms are among the most common adverse effects listed for most medications and need to be considered given the substantial number of medications that patients may be taking.

Management of GI symptoms

The management of GI amyloidosis consists of supportive therapy to alleviate GI symptoms and improve quality of life. As none of the GI treatments detailed below affect amyloid deposition, it is reasonable to treat empirically to improve the GI symptom burden. Diagnostic testing can be considered if initial treatments are unsuccessful or if the clinical presentation is unusual. Dietary and lifestyle modifications are always the first step, and it can be helpful to liaison with a trained dietician. Pharmacologic treatment can be tailored to the predominant symptoms and suspected regions of amyloid involvement.

Prominent oesophageal symptoms include reflux and swallowing dysfunction. Options to consider for reflux include antacids, histamine-receptor blockers, proton pump inhibitors, and alginates. Recently, the first potassium-competitive acid blocker was released in the United States and represents a more potent acid-suppressive option for those few patients with ongoing acid reflux despite the use of the aforementioned categories [112] . In truly refractory cases, mechanical anti-reflux procedures can be considered but we find this necessary only in rare cases. Swallowing dysfunction can be treated with smooth muscle relaxants, endoscopic dilation, or occasionally endoscopic botulinum toxin injection.

Symptoms suggestive of gastric dysfunction include early satiety, postprandial fullness, nausea, vomiting, and abdominal pain. Frequent small-volume, small particle-sized meals, particularly meals low in fat and insoluble fibre, are recommended [113, 114] . Pharmacological treatment options include prokinetics (such as metoclopramide, domperidone, or prucalopride), gastric accommodation enhancers (buspirone and peppermint/caraway), and anti-emetics (such as ondansetron and promethazine). If these are unsuccessful and comorbidities allow, prokinetic macrolides (erythromycin 50 mg pre-meals], clarithromycin, and azithromycin) can be prescribed [115] . Patients should be monitored for potential side effects including QT prolongation and cardiac arrhythmia [115] .

Potential small bowel symptoms include bloating/distention, pseudo-obstruction, diarrhoea, and small intestinal bacterial overgrowth/dysbiosis. Prokinetics can again be considered and prucalopride/pyridostigmine may be helpful in this region. Octreotide can improve small bowel contractility. Antibiotics can be extremely helpful in the context of potential small intestinal bacterial overgrowth. Several regimens have been suggested, with rifaximin often considered first-line given the excellent safety profile.

Finally, colonic involvement may lead to constipation and diarrhoea. Constipation is very treatable with multiple over-the-counter options, such as magnesium, polyethylene glycol and non-osmotic aperients (e.g. docusate, senna, lactulose) can be prescribed [116] . Patients should be encouraged to optimise fluid intake and increase exercise and dietary fibre intake. However, there are now several FDA-approved medications for constipation widely available including linaclotide and prucalopride. Diarrhoea can sometimes be a struggle to treat as it may be a result of multiple potential mechanisms. However, if agents detailed above, such as antibiotics, prokinetics, and occasionally octreotide, are unhelpful, then we have a low threshold to use anti-diarrheal agents, including loperamide and occasionally deodorised tincture of Opium. A diet lower in fat, and higher in soluble fibre can also be considered, with the addition of bulking agents, such as Psyllium husks [113, [117] [118] [119] [120] .

At present, the treatment of GI symptoms related to amyloidosis is largely geared towards symptom reduction and improvement in quality of life-and, to some extent, is palliative. However, that paradigm may be shifting with the arrival of multiple disease-modifying therapies for ATTR amyloidosis. While data are limited, long-term analysis of patients treated with patisiran in the APOLLO study showed continued benefits with regard to polyneuropathy-likely a key component of GI symptoms-and quality of life [121, 122] . Subsequent analyses of these data also reported improvement in diarrhoea specifically over time [123] and also stabilisation in weight and potential improvement in GI symptoms [124] . As further data appear with long-term disease-modifying therapy and combination therapies, there is optimism that sustained control of amyloid production and enhanced clearance will improve GI symptoms.

Coagulation and bleeding disorders supportive care guidelines

Management of haemorrhagic episodes

Patients with systemic AL amyloidosis experience both haemorrhagic and thrombotic complications. Bleeding manifestations occur in ~15% of patients. The pathophysiology of bleeding disorders includes organ amyloid deposition, vascular fragility secondary to amyloid deposition [125] , dysfibrinogenemia, hyperfibrinolysis [126] , development of inhibitors to coagulation factors [127] , and acquired coagulation factor deficiencies, of which factor X (FX) deficiency is common [128] [129] [130] . The mechanism of FX deficiency is the binding of FX to amyloid fibrils. However, alternative, co-existing mechanisms are likely possible [131, 132] . The presence of a monoclonal protein may result in the development of an acquired von Willebrand syndrome (aVWS), dysfibrinogenemia, and nutritional deficiency of vitamin K-dependent proteins (II, VII, IX, and X) [133] . Laboratory testing for bleeding manifestations should include a panel of screening tests [prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), and reptilase time (RT)] with reflexive mixing studies and specific coagulation factor assays as indicated (Table 4 ) [134] . It should be noted that screening tests (PT/aPTT) have limited sensitivities to coagulation factor deficiencies as screening tests remain normal until clotting factor activities reach 30-40% activity. Additional specific assays may include von Willebrand factor assays. For symptomatic patients in whom initial test results are normal, more specialised testing, e.g. platelet function testing and assays for fibrinolytic proteins (plasminogen activator inhibitor-1 and alpha-2 plasmin inhibitor) should be considered. Coagulation abnormalities found in asymptomatic patients do not need to be treated, however, ongoing monitoring is important. Attention should be paid to nutritional status to avoid or correct potential vitamin K deficiency. For those with symptoms, or those requiring an invasive procedure, haemostatic management needs to be considered. While amyloid-directed therapy typically ameliorates the severity of underlying coagulopathy, this effect may take time, and options for management of hemostasis for acute bleeding or in the periprocedural setting should be considered while coagulation abnormalities persist. In one report of 27 patients undergoing stem cell transplantation, all patients experienced a median increase in FX activity of 32% and normalisation of FX in 46% of patients [129] . Haemostatic options can be tiered according to the level of risk for thrombosis with the lowest risk being options that simply replace the missing clotting factors vs. options, such as activated coagulation factor concentrates which potentially increase the risk of thrombosis.

Fresh frozen plasma (FFP) contains all the clotting factors at varying concentrations. The typical recommended dosage is 15-20 ml per kilogram (kg) body weight, which raises the baseline clotting factor by ~20% or higher. This approach poses challenges including the risk of volume overload and transfusion-related reactions, e.g. allergic reactions, febrile reactions, and transfusion-associated lung injury (TRALI). To circumvent volume overload, and in situations where no specific factor concentrate is available, one strategy that has been adapted is plasma exchange (PLEX). This approach temporarily clears the monoclonal protein (if present) and avoids volume overload associated with FFP infusion. Alternatively, infusion of non-activated prothrombin complex concentrates (PCC), which contains vitamin K-dependent proteins [135] results in a lower volume of infusion compared to FFP. The dosage of PCC is 20-40 international units/kg. Finally, off-label use of plasma-derived FX concentrate at 25 international units/kg can be considered for isolated FX deficiency. To reduce the risk of thromboembolic (TE) complications, the FX target should not be > 50%. Other potentially more thrombogenic agents include recombinant activated FVII (rFVIIa) used at a dose of 15-30 μg/kg and activated prothrombin complex concentrates (APCC) [136] . However, given the elevated risk of TE associated with amyloidosis, APCCs should be avoided. For minor bleeding symptoms or adjuncts to haemostatic agents, antifibrinolytic agents, such as tranexamic acid at 1300 mg orally every 8 h, or epsilon amino caproic acid at 1 g orally every 6 h can be considered.

Hyperfibrinolysis associated with amyloidosis is rare but can be easily diagnosed by demonstrating reduced plasminogen, plasminogen activator inhibitor-1, and alpha 2 antiplasmin levels [137] . The management of haemorrhage in this setting depends on the clinical presentation. Gastrointestinal haemorrhage appears to be the most common complication [138] , and provided the patient is hemodynamically stable, endoscopy and treatment of the bleeding source would be a conservative approach. This avoids the empiric administration of potentially thrombogenic haemostatic agents. With more severe manifestations, e.g. intracranial bleeding, administration of haemostatic agents should be strongly considered.

Management and prevention of thromboembolic events

TEs, both venous and arterial, are common in patients with amyloidosis. TE may occur prior to, at the time of, or subsequent to the diagnosis of amyloidosis, and overall suggests a poor prognosis [139] . The frequency of arterial events ranges from 6 to 33% [138, 140] . Arterial events include ischaemic stroke, transient ischaemic attacks (TIA), and peripheral arterial thrombosis (PAT). In one large study, the incidence rate was 2.2 per one hundred patient-years [141] . Venous TEs include deep vein thrombosis and pulmonary embolism. In one study of 40 AL patients with documented thromboembolism, 29 (73%) experienced VTE which was associated with a poor prognosis [142] . It is well recognised that TE is a multifactorial disorder, thus contributing factors include atrial fibrillation, heart failure, and enlarged left atrium [10] ; in one study, CHADS 2 -Vasc score of ≥3 resulted in a hazard ratio of 2.84 for TE [141] . Additional contributing factors include nephrotic syndrome (due to loss of natural anticoagulants like antithrombin), immobility, chemotherapy, and the presence of vascular access devices. Of particular importance, the use of IMiDs puts AL patients at a significantly elevated risk of TE.

There are no specific guidelines on laboratory testing for risk stratification of TE. Testing is focused on amyloid-associated comorbidities, with very limited role for inherited thrombophilia testing. There are reports of increased prevalence of acquired activated protein C resistance in the absence of factor V Leiden mutation and reduced levels of the naturally occurring anticoagulants, e.g. antithrombin, protein S, in patients with TE compared to those without [143] . However, there is limited data on whether such testing adds to the information obtained during amyloidosis evaluation and whether TE is attributable to these coagulation abnormalities. The approach to clinical management of TE includes consideration of prophylactic anticoagulation in high-risk patients and therapeutic anticoagulation in those with established thrombosis. The choice of anti-thrombotic agent will vary with comorbidities, such as renal failure, therapy with agents that affect CYP3A4 (which metabolises the oral direct-acting anticoagulants), and involvement of the gastrointestinal tract (which may affect the absorption of drugs and nutrients, e.g., warfarin and vitamin K). The decision to initiate anticoagulant therapy needs to be weighed against the risk of haemorrhage and the degree of protection from initial and recurrent TE with anticoagulant therapy. The lack of randomised trials addressing this issue precludes accurate assessment of the net benefit of anticoagulation.

Anticoagulant options currently available include low molecular weight heparins (LMWH), vitamin K antagonists (VKA) (warfarin), oral direct thrombin inhibitor (dabigatran), and oral direct factor Xa inhibitors (apixaban, rivaroxaban, and edoxaban). Each agent has a different pharmacology that impacts safety and efficacy (Table 5 ). In patients with CKD, apixaban should primarily be considered, as it has the lowest renal elimination. It can be used at a reduced dose (2.5 mg bid) in subjects with eGFR 15-30 ml/min/1.73 m 2 [38] .

Prophylactic anticoagulation should be initiated for standard clinical indications (e.g. atrial fibrillation following standard guidelines) [144] . In patients receiving IMiD-based regimens, thromboprophylaxis with aspirin or LMWH for low-risk and LMWH for high-risk patients is recommended [145] . In addition, standard guidelines for thromboprophylaxis for venous thromboembolism for hospitalised and non-hospitalised medical patients should be followed [146] .

For patients with amyloidosis not falling into any of the populations addressed by guidelines, the decision on thromboprophylaxis relies on individual clinical judgement and experiences, the limited data on outcomes is confined to cohort studies. In one retrospective study of 450 patients with AL amyloidosis, 31, 15, 7, and 8% were on antiplatelet agents, and prophylactic doses of LMWH, VKA, and DOAC respectively [138] . In that study, antiplatelet agents were not protective against arterial and venous thrombotic events, whereas a prophylactic dose of LMWH was marginally associated with a lower risk of VTE. On the other hand, antiplatelet agents did not appear to increase the risk of bleeding, whereas those on anticoagulants had a marginally elevated risk of bleeding. Until additional data are available, the decision to initiate prophylactic anticoagulation needs to be individualised.

Malnutrition supportive care guidelines

The spectrum of clinical manifestations in amyloidosis can significantly affect the nutritional status of patients, due to an imbalance between nutrient supply, absorption, and demand. Overall, unintentional weight loss is common in systemic amyloidosis, being reported in 55 and 28% of AL and ATTR patients at diagnosis, respectively [105, 147] . However, due to the heterogeneity of the definitions of malnutrition, its exact prevalence in patients with systemic amyloidosis remains undetermined. For example, malnutrition rates range from 25 to 65% in AL amyloidosis [148] . From a clinical perspective, malnutrition risk is more common in the presence of GI and liver involvement, end-stage renal disease, nephrotic syndrome, and advanced CA, and is likely to be more severe when these conditions coexist. Poor nutritional status is known to negatively impact several clinical outcomes, including increased morbidity and complication rates, length of hospital stay, and healthcare costs [149] . Accordingly, malnutrition, weight loss, low body mass index (BMI), and impaired body composition have been associated with higher mortality [150, 151] . Notably, AL patients who received nutritional counselling had a lower risk of mortality than those who did not [152] . Malnutrition has been associated with poorer quality of life [150, 151, 153] and plays a role in patient selection for heart transplantation [154] .

Nutritional status assessment

This is a multi-step process that begins with nutritional screening to identify patients at risk for malnutrition. BMI and modified BMI (calculated by multiplying BMI by serum albumin level) should not be used alone as screening tools, due to their inaccuracy in evaluating body composition and nutritional status. This approach is consistent with the recent recommendations of the Global Leader Initiative on Malnutrition (GLIM), which rely on assessing multiple nutritional domains rather than using a single parameter, such as BMI or weight loss [155] . Nutritional screening in systemic amyloidosis should be performed with multidimensional validated screening tools [148] , the most common are summarised in Table 6 [156] [157] [158] [159] . Nutritional screening should be performed at diagnosis and repeated at regular intervals, with the frequency depending on the degree of malnutrition risk, but at least every three months in the outpatient setting and weekly in an inpatient service.

Following recent recommendations for cancer patients [156] , systemic amyloidosis patients at risk of malnutrition should be referred to a clinical nutrition service for further evaluation of nutritional status and early nutritional support. Body composition analysis, if available, and laboratory evaluation of biochemical nutritional indices should be performed. Bioimpedance analysis (BIA) is the only instrumental method for body composition assessment tested in patients with systemic amyloidosis [150] ; other methods, such as CT scans, have not been studied in this population. Body composition analysis allows the identification of muscle wasting, a common finding in amyloidosis which exacerbates exercise intolerance.

To prescribe an appropriate nutritional treatment, biochemical laboratory evaluation should include albumin, prealbumin, iron, ferritin, transferrin, vitamin B12, folate, vitamin D-25OH, cholesterol, triglycerides, uric acid, electrolytes, renal and liver function tests, and glucose levels. Prealbumin is a serum marker of protein status with a short half-life (~2 days) and has been associated with short-term energy intake in patients with AL amyloidosis [159] . Elevated uric acid has been shown to predict mortality in patients with cardiac ATTR amyloidosis [157] and AL amyloidosis [160, 161] . In patients with clinical signs and symptoms of nutritional deficiency or malabsorption, other vitamins (e.g. vitamin A) and trace elements (e.g. zinc) should be measured periodically and replaced when low levels are detected. Preventive approaches based on liberal vitamin A, D, and calcium supplementation in ATTR amyloidosis patients with diarrhoea, and vitamin B12 supplementation in patients with small intestinal bacterial overgrowth have been described [162] .

Nutritional support strategies

Patients at risk of malnutrition or diagnosed with malnutrition should be treated promptly, to prevent further nutritional deterioration. Caloric and protein requirements should be adjusted based on patient's clinical condition, especially in the case of organ failure, according to international Clinical Nutrition societies' guidelines [163] . In patients without organ failure, caloric requirements can be reasonably estimated by formulas based on body weight (i.e. 25-35 kcal/kg/day) or by the Harris-Benedict formula [164] , if indirect calorimetry is not available. Similarly, protein requirements can be estimated in the range of 1.2-1.5 g/kg/day. However, to date, no clinical trial has specifically addressed the caloric and protein requirements of patients with systemic amyloidosis and the accuracy of prediction equations in this population. Clinicians should be aware of the limitations of weight-based formulas, which should only be used as a starting point for estimating requirements [163] . In patients with low BMI and muscle mass, combining nutritional intervention and physical therapy should be considered [61] .

Nutritional support can be aided by dietary counselling, which consists of individualised dietary advice aimed at modifying eating habits to satisfy the patient's energy and nutrient needs and to mitigate the catabolic effects of the disease or its treatment. For example, the following common dietary modifications may be suggested for amyloidosis patients:

1. In the presence of diarrhoea, total dietary fibre should be temporarily reduced, and fluid intake should be increased, preferably between meals; in selected cases (e.g. patients treated with bile acid sequestrants), a low-fat diet may be indicated in the presence of steatorrhoea; When food intake is inadequate, oral nutritional supplements can be prescribed to increase caloric and nutrient intake in the form of liquids, creams, or powders [165] . If total oral intake is inadequate, enteral and parenteral nutrition can be used to provide sufficient calories, macronutrients, and micronutrients [120] . In particular, enteral nutrition requires a functioning gastrointestinal tract and can be administered through nasal tubes (i.e. nasogastric tube or, in the case of gastroparesis, naso-jejunal tube) or stomies (i.e. gastrostomy or, in the case of gastroparesis, gastrostomy with jejunal extension or jejunostomy). Polymeric formulas are usually the first choice, with semi-elemental formulas to be used in case of intolerance. Parenteral nutrition via a dedicated central venous catheter should be used when the gastrointestinal tract is unsuitable for digestion and absorption of nutrients, as in severe GI involvement or intestinal pseudo-obstruction, or when oral and enteral intake are inadequate [165, 166] . A recent case report described the successful weaning from parenteral nutrition of a patient with GI involvement and intestinal failure with the use of teduglutide, a Glucagon-Like Peptide-2 analog [167] .

Management of symptoms of special interest

Fatigue is a common and often debilitating symptom of systemic amyloidosis. Managing fatigue involves the implementation of an individualised and gradual exercise program (including aerobic exercises, and strength training), education on energy conservation strategies (including pacing activities), prioritising tasks, optimising sleep hygiene, and incorporating psychosocial support through counselling, support groups, or other mental health interventions [168] .

Macroglossia, an enlargement of the tongue, is not an uncommon manifestation in patients with AL amyloidosis due to the deposition of amyloid fibrils in the tongue. Speech therapy may help individuals adapt to changes in speech patterns and articulation resulting from macroglossia. In some patients, dental appliances or prosthetics can be used to optimise oral function and prevent complications, such as dental malocclusion. Maintaining good oral hygiene and artificial saliva usage are essential to prevent secondary infections and enhance oral health. In severe cases where macroglossia significantly impairs function or causes discomfort, surgical interventions, such as partial glossectomy may be considered, weighing the potential risks and benefits in the context of the patient's overall health and treatment plan [169] . If macroglossia obstructs the airway in the supine position, CPAP use at night is recommended. Nutritional supplements, dietary modifications, and percutaneous endoscopic gastrostomy should be considered in severe cases [170] . Low-dose steroid administration may help in reducing inflammation associated with macroglossia [171] .

Xerostomia, a sensation of dry mouth, is a common symptom across the various amyloidosis types, typically from amyloid deposition in the salivary glands leading to reduced saliva production. The management of xerostomia includes frequent sips of cold water and ice chips, eating foods with high water content, stimulating saliva by chewing sugar-free gum or sugar-free candy, use of artificial saliva or biotin, and maintaining good oral hygiene [172] . Coffee, tobacco, and alcohol (including alcohol-containing mouthwash) can exacerbate xerostomia and should be avoided.

Dysgeusia, an alteration in taste perception, can be seen in amyloidosis, either as a direct effect of amyloid deposition in the tongue and oro-pharynx, complications related to the disease (such as B12 or zinc nutritional deficiencies, poor oral hygiene, end-stage renal disease), or as a side effect of therapy (corticosteroid-or chemotherapy-induced dysgeusia). The management of dysgeusia includes the identification of the underlying cause(s) and correction when possible. Additional measurements to consider are the consumption of cold foods or foods that are associated with less dysgeusia (such as poultry, fish, eggs, and cheese), avoiding foods that are more likely to cause dysgeusia (spicy or very sweet foods), and eating less tolerable foods in the morning hours where dysgeusia is often less severe [173] .

Amyloid arthropathy is a rare manifestation of systemic amyloidosis. Topical application of nonsteroidal antiinflammatory drugs, systemic low-dose corticosteroids, physical therapy for maintaining joint function and mobility, joint aspiration to relieve symptoms of effusion or inflammation, and orthopaedic interventions, such as joint replacement surgery or laminectomy may be considered (but carefully weighed against the risks associated with surgery) [174] .

Dermatological symptoms of AGel amyloidosis require various skin lifting procedures and ophthalmologic manifestations may need corneal transplantation and eyelid surgery to restore eyelid function [175] . Other supportive measures for improving symptoms in AGel amyloidosis include protective corneal lenses, botulinum injections, wedge resection of the upper and lower lips, genioplasty, and carpal tunnel release surgery.

Management of side effects of amyloid-related therapies

Management of side effects of plasma cell-directed therapies in AL amyloidosis

Plasma cell-directed treatments play a crucial role in AL amyloidosis by targeting the underlying plasma cell dyscrasia responsible for the amyloidogenic light chain production. While these therapies aim to halt the progression of the disease, their use may be accompanied by potential adverse events. Strategies to manage treatment-related toxicities or prevent potential common complications associated with their use include: (1) antiviral medications to prevent herpes zoster and herpes simplex reactivation while receiving bortezomib and/or daratumumab [176] ; (2) the use of Pneumocystis jiroveci prophylaxis in patients receiving corticosteroid dose equivalent to ≥20 mg of prednisone daily for > 1 month or if undergoing autologous stem cell transplantation [177] ; (3) the use of antiemetics, prokinetics, laxatives, and anti-diarrheal agents for bortezomib-or alkylator-induced gastrointestinal adverse events [178] ; anticholinergic drugs may also be used to manage gastrointestinal side effects but require extra caution; (4) H 2 blockers or proton-pump inhibitors to reduce dyspepsia/peptic ulcer disease and gastrointestinal (GI) bleeding associated with the use of corticosteroids and alkylators [179] ; (5) morning single dose of lower corticosteroid dose and sleep aid for corticosteroids-related insomnia [180] ; (6) adjusted doses of diuretics to minimise fluid retention enhanced by corticosteroid use. Additionally, vigilant monitoring and adjustment of treatment regimens and doses can help alleviate side effects and improve treatment tolerability. For instance, lower doses of corticosteroids (e.g. dexamethasone ≤20 mg weekly) are important for patients above the age of 65-70 or those presenting with significant peripheral edoema or heart failure. (7) Bortezomib dose attenuation (and possibly its omission from the selected regimen) should be considered in patients with pre-existing peripheral or autonomic neuropathy or patients with advanced heart failure. (8) Several treatments in AL amyloidosis, particularly daratumumab-based treatment, are associated with a higher degree of hypogammaglobulinemia. We recommend that intravenous globulin (IVIG) replacement be considered for patients with severe or recurrent infections and serum IgG < 400 mg/dL [176] .

Management of side effects of ATTR-related therapies

Tafamidis, the first approved therapy for cardiac ATTR has a very favourable side-effect profile [181] . In the ATTR-ACT clinical trial, there was no difference in the reported side effects between tafamidis and placebo, nor any meaningful difference in the toxicities between higher and lower doses of tafamidis. Clinical experience with tafamidis has confirmed that the drug is well tolerated and rarely associated with side effects. A new TTR stabiliser, acoramidis, was investigated in a phase III study in cardiac ATTR, and the overall incidence of adverse events was similar between the acoramidis and the placebo group [182] . It has been approved by the FDA for the treatment of ATTR cardiomyopathy in November 2024. More recently, vutrisiran, a subcutaneously administered RNA interference therapeutic agent, was tested in a phase III study, and no difference in the overall adverse events compared to placebo was noted [183] . The approved drugs for hereditary ATTR (ATTRv) polyneuropathy are tafamidis (only by the European Medicine Agency), patisiran, inotersen (removed from the US market in September 2024), eplontersen, and vutrisiran. Except for tafamidis and acoramidis, all the other agents reduce vitamin A levels and regular use of vitamin A supplements is mandatory at the daily recommended dose of 2500-5000 IU (750-1500 mcg) [184] . Regular monitoring of serum vitamin A levels is recommended. A referral to ophthalmology should be made if suggestive ocular symptoms develop, such as corneal xerosis and ulceration, a decrease in visual acuity, or night blindness. In addition, infusion-related reactions were reported especially for patisiran and are characterised by flushing, body aches or pain, including pain in the back, neck, or joints, nausea, and epigastric pain [185] . All symptoms can be managed with a temporary hold of the infusion. The use of patisiran can also be associated with respiratory infections and nasal congestion [185] . The most frequent serious adverse events described in the inotersen group of the registration clinical trials were glomerulonephritis and thrombocytopenia (frequency < 5%) [186] . Therefore, all patients treated with inotersen should receive close monitoring of blood platelet count and blood chemistry. In addition, hypersensitivity reaction to inotersen was reported with symptoms that may include headache, chills, flushing, chest pain, hypertension, dysphagia, palmar erythema, eosinophilia, arthralgia, myalgia, and flu-like symptoms. These symptoms typically develop within 2 h of administration and require permanent discontinuation of the treatment. No specific safety signals were noticed with vutrisiran [187] and eplontersen [188] . Another less-used option for the treatment of ATTRv polyneuropathy is diflunisal [189] . This drug showed a good safety profile, but gastrointestinal bleeding and renal dysfunction were reported and require close monitoring and proper selection of patients for this treatment.

Summary

The field of amyloidosis has witnessed a significant expansion in diagnostic testing and treatment options, leading to improved outcomes for amyloidosis patients over the past few decades. The relevance of prompt initiation of therapy upon diagnostic confirmation (including accurate typing) cannot be overemphasised, as early recognition and treatment are the best paths to achieve improvement in affected organ(s) function and ease in symptom burden. Care of patients with amyloidosis should be done in a multidisciplinary approach given the complexity of multi-organ involvement or the presence of comorbidities, which may challenge the provision of optimal care. Care should be provided (or at least guided by) in specialised amyloidosis centres to enhance patient outcomes and optimise supportive care as long as patients are affected by the disease, which is typically life-long. Finally, providing patients and their caregivers and families with psychological and spiritual support is an important aspect of the care, especially for those with advanced disease with heightened symptom burden and poor prognosis. Patients and caregivers are encouraged to participate in support groups, education sessions, and seminars on amyloidosis to share their experiences and acquire better knowledge about their disease. This should enhance informed decision-making by patients, and their adherence to treatments and lifestyle changes to further improve symptom management and outcomes in this disease.

Disclaimer

These recommendations are meant to assist clinicians in making decisions regarding the treatment of patients with amyloidosis. Adherence to these recommendations will not ensure successful treatment in every situation. Furthermore, these recommendations should not be interpreted as setting a standard of care or be deemed inclusive of all proper methods of care nor exclusive of other methods of care reasonably directed to obtaining the same results. The ultimate judgement regarding the propriety of any specific therapy must be made by the physician and the patient in light of all the circumstances presented by the individual patient, and the known variability and biological behaviour of the disease. These recommendations reflect the best available data at the time this document was prepared. The results of future studies may require revisions to the recommendations in this document to reflect new data.

|Thrombotic complications|Thrombotic complications primarily arise due to end-organ dysfunction associated with amyloidosis and| |---|---|

||certain amyloid-directed therapies.|

|Prevention and treatment of thrombotic|indications for preventing and treating thrombosis vary based on clinical circumstances. The choice of|

|complications|antithrombotic agents depends on the extent of underlying organ dysfunction and potential drug|

||interactions with amyloid-directed therapy.|

|Nutrition||

|Nutritional screening|Amyloidosis can significantly affect nutritional status due to imbalances in nutrient supply, absorption,|

||and demand. Patients should undergo nutritional screening using multidimensional validated tools at|

||diagnosis and at regular intervals.|

|Referral for evaluation||

|||Starting dose and|||| |---|---|---|---|---|---|

||Route|max dose|Bioavailability|duration of effect|Comments|

|Loop diuretics||||||

|||max daily dose: 600 mg|max daily dose: 600 mg|max daily dose: 600 mg|mean 51%|

||||||bioavailability|

|||max daily dose: 200 mg|max daily dose: 200 mg|max daily dose: 200 mg||

|||max daily dose: 10 mg|max daily dose: 10 mg|max daily dose: 10 mg||

|Thiazides||||||

|Chlorthalidone|Po|Starting dose: 12.5-25 mg|65%|72 h||

|||max daily dose: 100 mg|max daily dose: 100 mg|max daily dose: 100 mg||

|||max dose: 200 mg|max dose: 200 mg|max dose: 200 mg||

|||max daily dose: 20 mg|max daily dose: 20 mg|max daily dose: 20 mg||

||||||azotaemia and electrolyte|

||||||imbalance, should be used in|

||||||combination with loop diuretics|

||||||in patients who do not respond|

||||||to moderate to high-dose loop|

||||||diuretics|

|Potassium-sparing diuretics||||||

|Spironolactone|Po|Starting dose: 12.5-25 mg|90%|2-3 days||

|||max daily dose: 50 mg|max daily dose: 50 mg|max daily dose: 50 mg||

|Triamterene|Po|Starting dose: 50-100 mg|30-70%|7-9 h||

|||max daily dose: 300 mg|max daily dose: 300 mg|max daily dose: 300 mg||

||||||spironolactone|

|SGLT2 inhibitors||||||

||||||All SGlT2 inhibitors carry the risk of|

||||||dehydration, urinary tract|

||||||infection, and diabetic|

||||||ketoacidosis|

|Empagliflozin|Po|Starting dose: 10 mg|Starting dose: 10 mg|Starting dose: 10 mg||

|||max daily dose: 25 mg|max daily dose: 25 mg|max daily dose: 25 mg||

|||max daily dose: 400 mg|max daily dose: 400 mg|max daily dose: 400 mg||

|SGlT2: sodium-glucose co-transporter 2.||||||

|medication|indication|mechanism of action|Starting and maximum dose|Adverse events| |---|---|---|---|---|

||approved)|approved)|agonist; increases peripheral|max 40 mg/day|

|||vascular resistance|vascular resistance|vascular resistance|

||approved)|approved)|longer-acting increase in|longer-acting increase in|

|||norepinephrine release|norepinephrine release|norepinephrine release|

|||and water reabsorption and|max 300 ug/day|hypertension, hypokalaemia,|

|||potassium losses from the renal||headaches, heart failure|

|||distal tubules and enhances the|||

|||sensitivity of α-adrenoreceptors|||

|Pyridostigmine|Postural hypotension (off-label) Acetylcholinesterase inhibitor;|Postural hypotension (off-label) Acetylcholinesterase inhibitor;|Postural hypotension (off-label) Acetylcholinesterase inhibitor;|30 mg b.i.d.-t.i.d.|

|||enhances cholinergic transmission|max 180 mg/day|nausea, urinary urgency,|

|||in autonomic ganglia|in autonomic ganglia|in autonomic ganglia|

|||||sweating|

|Atomoxetine|Postural hypotension (off-label) Norepinephrine reuptake inhibitor|10 mg b.i.d.-t.i.d.|Headache, insomnia, nausea,||

||||max 54 mg/day|supine hypertension, urinary|

|||||urgency, mood swings,|

|||||tachycardia|

||postprandial hypotension|splanchnic vasodilation|splanchnic vasodilation|splanchnic vasodilation|

||(off-label)||max 1.6 mg/kg Qid|cramps, diarrhoea, cholelithiasis,|

|||||hyperglycaemia, supine|

|||||hypertension|

||(off-label)|digestion and absorption of|max 300 mg/day|flatulence, cramps diarrhoea),|

|||carbohydrates, reduces splanchnic||skin rash, hepatotoxicity,|

|||vasodilation|vasodilation|vasodilation|

|disorder|PT|PTT|TT|RT|VWF:Ag|VWF activity assays|Plasma VWF| |---|---|---|---|---|---|---|---|

||||||||multimers|

||||||||distribution|

|||||||reduced compared to|absent, loss of|

|||||||VWF:Ag|HmWm|

|VKdF deficiency|Prol|Prol|Nl|Nl|Nl|Nl|Nl|

|Hyperfibrinolysis|Nl|Nl|Nl|Nl|Nl|Nl|Nl|

||Enoxaparin Fondaparinux|Warfarin|dabigatran|Rivaroxaban|Apixaban|Edoxaban|| |---|---|---|---|---|---|---|---|

|Route|Subcutaneous|||oral||||

|Absorption|||Gastric/prox-ileum|Gastric/duodenum Gastric/prox-ileum|distal ileum|Prox-ileum||

|TTP (h)|3-5|2-3|2-8|2|2-4|2-4|2-4|

|monitoring|Anti-Xa|Anti-Xa|iNR|N/A a|N/A b|||

|T½ (h)|5|17-21|20-60|12-14|5-9|8-15|10-14|

||||metabolism,||degradation (30%|o-demethylation|oxidation by CyP|

||||biotransformation||CyP CyP3A4/5,|15% CyP CyP3A4/5,|3A4 and|

||||> 90% of inactive||metabolism)|metabolism|hydrolysis|

||||metabolites (CyP||66% renal excretion|2/3 fecal excretion|1/2 biliary excretion|

||||2C9)||28% fecal excretion|1/3 renal excretion|1/2 renal excretion|

|iNR: international normalized ratio; prox: proximal; TTP: time to peak concentration; h: hours; T½: half-life of drug.||||||||

|a monitoring not generally indicated typically prolongs activated partial thromboplastin time and thrombin time.||||||||

|Screening tool|Components|Preferred usage| |---|---|---|

|PG-SGA|Weight history, oral intake,|Patients capable of|

|(patient-generated|symptoms, mobility|self-completion of|

|subjective global||a questionnaire|

|assessment) [156]|||

|mUST (malnutrition|Bmi, weight history, acute|Community/|

|universal screening|illness, or impossibility|non-hospitalised|

|tool) [157]|to eat|to eat|

|mNA (mini-nutritional|Gi symptoms, weight|Gi symptoms, weight|

|assessment) [158]|history, mobility,|history, mobility,|

||neuro-psychological||

||aspects, acute disease||

|NRS-2002 (nutritional risk|Bmi, weight history, food|Hospitalised patients|

|screening-2002) [159]|intake, disease severity||

|Bmi: body mass index; Gi: gastrointestinal.|Bmi: body mass index; Gi: gastrointestinal.||

Acknowledgments

Summary of main recommendations by clinical domains.

The pathophysiology of haemorrhage in amyloidosis may involve deficiencies in vascular, platelet, or clotting factors. Comprehensive laboratory investigations are crucial, including plasma-based and potentially more specialised platelet testing. monitoring asymptomatic patients Asymptomatic patients with coagulation defects may be monitored, but they might require prophylaxis before invasive procedures or treatment of haemorrhage. Patients at risk of malnutrition should be referred to a clinical nutrition service for further evaluation of nutritional status and early nutritional support. Body composition and laboratory analysis Perform body composition assessment via bioimpedance analysis and laboratory evaluation of biochemical nutritional indices. Calorie and protein requirements Adjust Calorie and protein requirements based on the patient's clinical condition, especially in the case of organ failure, according to international Clinical Nutrition Societies' guidelines. dietary counselling Begin nutritional support with dietary counselling. if food intake is inadequate, prescribe oral nutritional supplements to increase calorie and nutrient intake. Enteral and parenteral nutrition if total oral intake is inadequate, use enteral and parenteral nutrition to provide sufficient calories, macronutrients, and micronutrients. Management

Continued.

Summary of diuretic drug classes, dosing, and duration of activity for heart failure and nephrotic syndrome management.

Pharmacological treatment options for orthostatic hypotension.

Typical laboratory test results in acquired bleeding disorders.

Pharmacology of anticoagulants. monitoring generally not indicated, anti-Xa assays are available which need to be calibrated with the drug being assayed.

Nutritional screening tools.

Funding

Disclosure statement

EM received a consultation fee from Protego (a fee paid to the institution). MG received research support and/or consulting/advisory board from Alnylam, AztraZeneca, Novo-Nordisk, Pfizer, Janssen, BridgeBio (Eidos), and Intellia. FS received speaking fees from Pfizer, Alnylam Pharmaceuticals, Janssen, and consulting fees from Pfizer, Alnylam Pharmaceuticals, and Bayer. MWC received honorarium from FoldRx, Ionis, Pfizer, Alnylam, PTC, and AstraZeneca for travel expenses related to presentations at medical meetings, for acting as a principal investigator in clinical trials, and as a consultant member. YM received research funding from Alnylam and Pfizer. ASC has received a consultation fee from Alnylam and research funding from Pfizer. VS served as a consultant for Pfizer, Janssen, Attralus, GateBio, AbbVie, and BridgeBio and served on advisory board for Proclara, Caelum, AbbVie, Janssen, Regeneron, Protego, Pharmatrace, Telix, Prothena, AstraZeneca, Nexcella, and Alexion. PM received honoraria from Jannsen, Siemens, Prothena, Pfizer, and research grant from Pfizer. RC reports consulting and lecture fees from Astellas; Akern; Baxter; B-Braun; Bristol-Myers Squibb; Boehringer Ingelheim; Eli Lilly; Fresenius Kabi; Lionhealth; Nestle' Health Science; Novartis; Nutrisens; MSD; Nutricia; Pfizer; Roche; Servier; Takeda; Viatris. VDP reports lecture fees from Baxter, Fresenius Kabi, and Takeda. FB received lecture fees from Amgen, Janssen, GSK, Lilly, and Sanofi and served on the advisory boards of Attralus, Novartis, and AstraZeneca.

The remaining authors declare no relevant financial interests.

References

引用 / 出处

2025 ISA指南：系统性淀粉样变性的支持治疗. 2025.