First author: Basset et al
Review: Journal of the American Society of Nephrology
Reference : DOI : 10.1681/ASN.0000000000000339
Link to article: https://pubmed.ncbi.nlm.nih.gov/38512269/
Introduction:
Inflammatory amyloidosis is a rare disease secondary to the deposition of serum amyloid A (SAA) protein in the form of insoluble amyloid fibrils, causing predominantly renal damage and dysfunction that may progress to end-stage renal disease requiring dialysis. Renal involvement is almost constant in all cases of AA amyloidosis at the time of diagnosis, while cardiac involvement is uncommon. Unlike the more common forms of systemic amyloidosis, particularly AL and ATTR, AA amyloidosis has not yet been the subject of prospective studies.
Thanks to their ability to accurately predict prognosis without the need for invasive and expensive tests, stratification systems based on biomarkers are playing a well-established role in the management of patients with systemic amyloidosis. For example, stratification systems for overall survival and renal failure have been validated for AL amyloidosis. More recently, two overall survival stratification systems have been validated for transthyretin amyloidosis (ATTR). However, AA amyloidosis has not yet had a validated system for stratifying the risk of renal progression of the disease. In this study, the authors developed and validated a stratification system for overall survival and renal failure in patients with newly diagnosed AA amyloidosis.
Methods :
Patients included.
The databases of the Amyloidosis Research and Treatment Centre in Pavia, Italy, and the Amyloidosis Centre in Heidelberg, Germany, were used. Four hundred and seventy-six consecutive patients with newly diagnosed AA amyloidosis, including 233 in Pavia between 1991 and 2020 and 243 in Heidelberg between 1975 and 2020, were included in the study.
In the absence of a specific consensus on the definition of organ involvement in AA amyloidosis, the authors chose to use the criteria for organ involvement in AL amyloidosis: glomerular filtration rate (eGFR), B-type natriuretic peptide (BNP) and N-terminal BNP (NT-proBNP).
The Italian cohort was used as the test population and the German series as the validation cohort in the analysis.
Statistical analysis
ROC analyses based on survival, death and dialysis of patients with AA amyloidosis at 24 months were used to identify biomarker thresholds, which according to the Youden index, best discriminate between overall survival and renal failure. Median follow-up was estimated using the inverse Kaplan-Meier method. Overall survival was calculated from diagnosis to death (event) or last contact with the living patient.
The stratification system developed in the Pavia cohort was applied to the Heidelberg cohort. Given the good discrimination and calibration, the authors combined the two cohorts for subsequent analyses, in order to make effective use of the information contained in the risk categories and to increase the precision of the associated HR estimates.
Results:
A total of 476 patients were evaluated during the study period (233 in Pavia and 243 in Heidelberg), most of whom (>95%) were diagnosed after 2000 (Table 1). Renal involvement was present in 95% of cases; 33 Italian (14%) and 47 German (19%) patients were already on dialysis at the time of diagnosis respectively.
Differences were observed between the two cohorts: serum albumin levels were higher and German patients were younger than Italian patients. Differences were also observed in the underlying causes of chronic inflammation, with a higher proportion of recurrent infections and idiopathic AA in Italy and more autoinflammatory diseases in Germany. t .
The median follow-up of patients was 67 months in Italy and 36 months in Germany. In the Italian cohort, 58 (25%) patients died and 51 (21%) in the German cohort. No difference in overall survival was observed between the two cohorts (Log-rank test p=0.28).
Among patients who were not on dialysis at the time of diagnosis, 68 (32%) progressed to end-stage renal disease in the Pavia group and 56 (29%) in the Heidelberg cohort.
Identification of biomarker thresholds that best discriminate between overall survival and renal failure
The most discriminating thresholds for overall survival at 24 months in the Pavie test cohort were
- eGFR 45 ml/min/1.73 m2
- 3.0 g/dL for serum albumin
- 40 mg/L for SAA
- 130 ng/L for BNP
- 1000 ng/L for NT-proBNP
The most discriminating thresholds for dialysis at 24 months were
- GFR at 35 ml/min/1.73 m2
- 3.0 g/dL for serum albumin
- 25 mg/L for SAA
- 3 g/24h for 24-hour proteinuria
Prediction of overall survival and stratification system (Table 2)
The stratification system calculated as the sum of the simplified coefficients ranged from 0 to 3. Because of the low number of deaths in certain categories, the authors grouped score 0 with score 1 (low-risk category). This stratification system identified three groups of patients with significantly different survival.
Overall survival at 5 years was 94% (95% CI: 87-98%) in the low-risk category, 80% (95% CI: 62-90%) in the intermediate-risk category and 46% (95% CI: 21-68%) in the high-risk category.
Discussion and conclusion:
This is the first study to propose a stratification system based on non-invasive biomarkers for overall survival and renal failure in AA amyloidosis.
Older age at diagnosis, 24h proteinuria, proteinuria/creatinuria ratio
were confirmed as poor prognostic factors for survival and progression to renal failure.
In conclusion, the authors propose these biomarkers for stratifying overall survival and renal failure with the aim of improving the management of patients with AA amyloidosis by identifying the most severe cases.
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