How To Deal With Secondary Renal Amyloidosis

Secondary (AA) amyloidosis is secondary to excessive deposition of insoluble serum amyloid A (SAA) and can involve multiple organs, but the kidney is the most severely affected, and most patients will progress to end-stage renal disease. At present, the disease is becoming more and more common all over the world, and compared with chronic kidney disease (CKD) caused by other causes, the clinical manifestations, examination methods, pathological features, and treatment options of patients with AA renal amyloidosis have certain differences. difference. Therefore, the latest guidelines are needed to guide clinical diagnosis and treatment.

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On February 10, 2023, France published practical guidelines for the diagnosis and management of AA amyloidosis. This article mainly selects the clinical manifestations and characteristics, diagnosis, treatment, and follow-up of AA renal amyloidosis in the guidelines for the readers.

Clinical manifestations and diagnostic criteria

1 Clinical manifestations

AA amyloidosis can present as a variety of chronic diseases, such as chronic inflammation, but it is most prominently manifested as progressive glomerulonephropathy. Its typical clinical manifestations are similar to other CKD, namely proteinuria and decreased estimated glomerular filtration rate (eGFR). However, kidney disease caused by AA amyloidosis is significantly different from CKD caused by other causes in three points:

① CKD caused by AA amyloidosis usually has no hypertension, and hypotension is more common, while CKD caused by other etiologies is more common hypertension;

②The kidney volume of patients with CKD caused by AA amyloidosis is usually normal or enlarged;

③The kidney involvement caused by AA amyloidosis may be isolated or related to other organ involvement, such as the digestive tract, spleen, liver, thyroid, etc.

2 Diagnostic criteria

Measurement of proteinuria and renal function (eg, estimated glomerular filtration rate [eGFR]) in patients with chronic inflammation or infectious disease is the most common method for detecting AA renal amyloidosis. Proteinuria was more common than decreased eGFR. AA amyloidosis may also be found on renal biopsy in patients with low or normal biomarkers of chronic inflammation who have symptoms of renal involvement. In conclusion, the etiology of patients with proteinuria and decreased eGFR may be AA amyloidosis.

A biopsy is a gold standard for the diagnosis of AA amyloidosis. However, unlike other CKDs, if AA amyloidosis is suspected in a patient, renal biopsy should not be the first choice because the kidney is a more susceptible tissue for AA amyloidosis invasion. The preferred biopsy location should be tissues with a low risk of AA amyloidosis invasions, such as salivary glands, periumbilical fat, and digestive tract biopsies. A kidney biopsy can only be performed after no AA amyloidosis is detected in these tissues.

Typically, biopsy samples are stained with Congo red and green birefringence can be seen under polarized light. In addition, immunofluorescence can clarify the extent and severity of SAA deposition and rule out other types of amyloidosis. Renal involvement is common in AA amyloidosis, but in the biopsy sequence, tissues at lower risk of AA amyloid invasion should be taken first, such as salivary glands, periumbilical fat, gastrointestinal biopsies where AA amyloid was not detected After denaturation, a kidney biopsy can be performed.

Treatment programs

The main therapeutic goal of AA amyloidosis is to normalize the serum concentrations of C-reactive protein (CRP) and SAA to prevent further amyloidosis. At present, the management and treatment of AA amyloidosis are divided into cause treatment and symptomatic treatment. Treatment for the cause of amyloidosis is focused on controlling and managing chronic inflammation and treating the cause of amyloidosis. Symptomatic treatment is mainly to delay the progression of kidney disease and provide renal replacement therapy, such as hemodialysis, peritoneal dialysis, and kidney transplantation, if necessary.

1 to cause treatment

Currently, the first-line therapy for the cause of the disease is no longer potent immunosuppressants, which are nonspecific and have short- and long-term adverse effects. The current first-line therapy is biological therapy, including anti-TNF, anti-IL-1, and anti-IL-6R. Patients' short- and medium-term responses to these drugs were assessed by inflammatory markers, while long-term assessments were by renal markers (eg, proteinuria and eGFR). It is worth noting that if early detection, early intervention, early treatment, early control of inflammation levels, and complete disappearance of inflammation, nephrotic syndrome can be completely relieved, and renal function may return to normal.

2 Symptomatic treatment

At present, the symptomatic treatment of AA renal amyloidosis is quite different from that of some CKD patients, which needs to be paid attention to by doctors. The renal-related symptomatic treatment of AA renal amyloidosis can be divided into 3 categories, namely drug therapy, renal replacement therapy, and dietary intervention.

① drug treatment

All patients with abnormal renal function should take non-specific renal protection measures. For patients with urine protein > 300 mg/24h, angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) may be used. The effectiveness of the above therapies has been tested in patients with diabetic nephropathy and certain forms of primary glomerulonephritis (IgA nephropathy, membranous nephropathy), but no studies have looked at patients with AA amyloidosis. In addition, studies have found that losartan can significantly improve proteinuria in patients with AA amyloidosis, but whether the drug can improve the renal function of AA amyloidosis in the long term requires further study.

However, nephrologists need to consider other symptoms in patients with AA amyloidosis, such as cardiovascular disease and diarrhea, when prescribing medications. AA amyloidosis can also affect the cardiovascular system, often causing symptoms of hypotension, while ACEi and ARB can lead to lower blood pressure, so they need to be used with caution. Diarrhea can lead to dehydration and a further decrease in blood pressure. If the patient develops diarrhea, ACEi/ARB should be discontinued. In addition, patients can also use diuretics to treat edema caused by nephrotic syndrome.

② Renal replacement therapy

If the patient progresses to end-stage renal disease, peritoneal dialysis or hemodialysis can be used, but peritoneal dialysis may increase the risk of hypoproteinemia. The prognosis of patients with AA amyloidosis is poor, with an average survival time ranging from 20 to 50 months. Of note, biologic therapy appears to have limited benefit in hemodialysis patients. In terms of kidney transplantation, although kidney transplantation can improve the survival period of patients with AA amyloidosis, compared with kidney transplantation patients caused by other etiologies, the improvement is not obvious, and the survival rate of transplanted organs is lower.

③Diet intervention

Unlike nephrotic syndrome caused by other causes, patients with AA amyloidosis do not need to consume a low-protein diet. On the contrary, patients need to consume more than 1.2g/kg of protein per day. This is because patients with AA amyloidosis are extremely prone to hypoproteinemia. In addition, sodium intake does not need to be strictly restricted as in other kidney diseases. Experts recommend restriction only if there is edema. If the patient develops diarrhea or adrenal damage, sodium supplementation should be given.

3 Diagnosis and treatment process

For patients suspected of having AA amyloidosis, the overall diagnosis and treatment process is shown in the figure below (Figure 1):

Follow up

The follow-up of patients with AA amyloidosis mainly focused on the cause and symptomatic treatment, while the follow-up on the cause of treatment mainly focused on serum albumin and SAA levels. For patients with renal involvement, it is necessary to screen patients for CKD complications, including but not limited to anemia, metabolic acidosis, calcium, phosphorus, and potassium levels, vitamin levels, skeletal system lesions, and the risk of cardiovascular events. In the later stage of the patient, if he progresses to end-stage renal disease, he should be prepared to receive renal replacement therapy, such as hemodialysis, peritoneal dialysis, and kidney transplantation. At this time, the nephrologist should focus on discussing dialysis access with the patient, because the vessels in patients with AA amyloidosis may be more difficult to fistula, and the possibility of poor postoperative recovery is higher.

When the disease progresses to GFR<30ml/min, the feasibility of renal replacement therapy, such as hemodialysis, peritoneal dialysis, and kidney transplantation, should be evaluated, with the specific frequency being twice a year. Other examinations, such as tumor markers, rheumatic immune markers, and imaging examinations, need to be determined according to the etiology of the patient.

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