Approach Considerations
The lack of currently available agents that directly target amyloid deposits mandates the use of agents that strongly suppress the inflammation caused by the primary disease. At present, the major therapeutic strategy in amyloid A (AA) amyloidosis is treatment of the primary inflammatory disease in order to reduce the circulating levels of the amyloid precursor protein, serum amyloid A (SAA). Intensive treatment that lowers SAA levels to less than 10 mg/L may halt disease progression and induce a slow progressive recovery of kidney function. Biologic agents, including tumor necrosis factor (TNF) inhibitors and interleukin-1 (IL-1) and IL-6 antagonists, are the main therapeutic options used for this purpose.,
The major consequence of renal amyloidosis is complete renal failure. Hospitalized inpatient care may be necessary for intercurrent infections or deterioration in kidney function, requiring acute dialysis or the initiation of chronic dialysis.
Medical Care
Accounts exist of the disappearance of the amyloid deposits associated with tuberculosis or chronically infected burns with appropriate treatment of the infection. Similarly, case reports exist of the disappearance of amyloid deposition associated with chronic inflammatory bowel disease after resection of the affected section of bowel. In general, early and aggressive therapy and treatment of the underlying inflammatory disease causing secondary AA amyloidosis helps treat and slow the progression of AA amyloidosis complications.
Colchicine
Colchicine is a plant-derived (colchicum autumnale) alkaloid that has been used for thousands of years to treat nonspecific arthritis. The use of colchicine (0.6 mg tid) by patients with familial Mediterranean fever (FMF) has been shown to reduce or eliminate the febrile episodes and to prevent the appearance of renal amyloidosis. [48] When started early and used at sufficient doses with good compliance, development of AA amyloidosis can be prevented, but established AA renal amyloidosis is much less responsive to colchicine treatment. In addition, beneficial effect in the other causes of AA amyloidosis has not been demonstrated. [49]
Alkylating agents
Data from a randomized prospective series of patients with juvenile chronic arthritis who were treated with chlorambucil or cyclophosphamide show that the occurrence of amyloidosis is markedly reduced. [50] The tradeoff for the aggressive use of alkylating agents is an increased incidence of leukemia.
Biologic agents
Biologic agents targeting proinflammatory cytokines such as tumor tumor necrosis factor–αnecrosis factor alpha (TNF-α), interleukin (IL)-1, and IL-6 have been tried in patients with AA amyloidosis. Treatment with TNF-α inhibitors and IL-1 inhibitors has proved effective in controlling the progression of renal amyloid in patients with inflammatory arthritides and hereditary periodic fevers. The rationale for using TNF inhibitors in secondary amyloidosis comes from the fact that these medications lower levels of serum IL-6, which is an important mediator of the acute phase inflammatory response, which can be measured through serum C-reactive protein (CRP) levels. Lowering of IL-6 levels results in reduced synthesis of acute-phase proteins, suppression of systemic inflammation, and lower SAA levels, leading to reduction of amyloid deposits. [51]
Anakinra, a recombinant form of IL-1 receptor antagonist, has shown favorable effects on dermatologic and rheumatic manifestations in patients with Muckle–Wells syndrome and familial cold autoinflammatory syndrome. This treatment also resulted in the resolution of AA amyloidosis in these patients. [52]
IL-6 is one of the pro-inflammatory cytokines playing a critical role in the induction of SAA genes, and inhibition of IL-6 results in dramatic suppression of SAA. Tocilizumab, a humanized monoclonal anti–IL-6 receptor antibody, has proved effective in the treatment of amyloidosis secondary to various rheumatic diseases. It binds to soluble and membrane-bound IL-6 receptors and down-regulates the synthesis of IL-6, with significant decrease in SAA levels. [53] A case report of a patient with AA amyloidosis secondary to rheumatoid arthritis describes reduction in inflammatory parameters and improvement in kidney function with tocilizumab treatment. [54]
A retrospective study that indirectly compared tocilizumab to TNF inhibitors, with a median treatment duration of 2 years, suggested a more favorable outcome with tocilizumab. Although IL-6 blockage seems to have the advantage of significantly reducing circulating SAA levels, its long-term impact on kidney function is not known. Moreover, switching between these agents is frequently necessary in inflammatory conditions due to adverse events and primary or secondary inefficacy. [55]
Surgical Care
Castleman disease, a rare group of lymphoproliferative disorders in which IL-6 is often the pathologic driver, can be complicated by AA amyloidosis. Surgical resection is effective for cases that involve a single region of enlarged lymph nodes (unicentric Castleman disease). In certain cases where surgery is not feasible or curative, the anti–IL-6 agent siltuximab may be effective. [21]
Although kidney transplantation is widely used for treating renal amyloidosis secondary to familial Mediterranean fever (FMF), some data suggest that patients with amyloidosis do not have as favorable a prognosis as patients transplanted for other forms of end-stage kidney disease. [56] Nonetheless, there have been reports of improving results and transplantation is a reasonable option. [57]
Recurrence of amyloidosis in the allograft, gastrointestinal intolerance, and fatal infections remain as major complications during the post-transplant period. Severe sepsis is the cause of 60% to 100% of all deaths with a functioning graft in kidney recipients with AA amyloidosis. [58]
In a multicentric retrospective survey to assess the graft and patient survival in 59 renal transplant recipients with AA amyloidosis, the recurrence rate of AA amyloidosis nephropathy was estimated at 14%. There was significant decrease in the 5-year and 10-year survival of patients in the AA amyloidosis group compared with the control group. [59]
Consultations
Worsening kidney function demands management by an experienced nephrologist, with particular emphasis placed on the eventual need for dialysis and the availability of transplantation. Nephrologic and surgical management of the chronic kidney disease requires a coordinated team approach for an optimal outcome. Cardiac complications at the time of transplantation seem to be more common in patients with amyloidosis than in those with other forms of kidney disease.
In AA amyloidosis that develops as a complication of a primary chronic infectious disease, consultations with an infectious diseases specialist concerning antibiotics, surgical services to discuss resection, and other diagnostic and therapeutic modalities are appropriate. For cases related to rheumatologic disease, consultation with a rheumatologist may be beneficial in guidance for choices for newer modes of anti-inflammatory treatment.
Diet
No specific dietary recommendations for patients with amyloid disease exist. Patients with chronic kidney disease should be managed by both a nephrologist and a nutritionist who has experience with such patients. Both will be able to guide the patient in maintaining appropriate levels of sodium and protein intake. As the kidney disease progresses, lower-potassium diets will often be recommended.
Occasionally, patients have significant gastrointestinal symptoms. In these cases, attention should be paid to maintaining caloric intake with minimal gastrointestinal distress.
Prevention
The use of colchicine prophylaxis in FMF has been previously mentioned, as has the need for aggressive anti-inflammatory treatment for the predisposing inflammatory disorders. The introduction of anti-inflammatory biological agents for the treatment of rheumatologic disorders may decrease the current rate of appearance of tissue AA deposition.
Long-Term Monitoring
Clinicians managing a patient with AA amyloidosis should take into account the organ systems involved. As with any patient with chronic kidney disease, kidney function should be monitored perioidically to assess progress and the possible ultimate need for dialysis or transplantation. Anemia of chronic disease often goes hand-in-hand with chronic kidney disease, and routine monitoring of hemoglobin, hematocrit, and iron studies should be performed. Overall, laboratory values to follow include a complete blood count, complete metabolic panel, and urinalysis (to monitor proteinuria). Other laboratory values that may be affected in chronic kidney disease, vitamin D and parathyroid hormone, should be followed by an experienced nephrologist. [60]
