DISCUSSION

Advancements in the treatment of the hematological disorders underlying the amyloid production have dramatically improved outcomes in AL amyloidosis, leading to an increase in the survival of affected patients. Current guidelines recommend monitoring hematological parameters to assess treatment response in this disease [11]. However, kidney and cardiac involvement are critical determinants of the prognosis of AL amyloidosis and may not always align with hematological response. Therefore, in clinical practice, assessment of organ-specific response to ACT is routinely performed [9, 14]. While the role of troponins in assessing cardiac response is well established, the criteria for kidney response and its prognostic value remain less clearly defined.

In our cohort of patients with AL amyloidosis and kidney involvement, we have reported that traditional criteria for kidney response are associated with an improvement in kidney survival. Notably, this kidney response consistently occurred after hematologic response, which was observed exclusively in those patients under ACT. Indeed, untreated patients experienced an accelerated kidney function impairment and higher rates of ESKD (50%) compared to treated patients (7% and 46%, respectively). However, these findings should be interpreted with caution. Untreated patients in our cohort had worse baseline kidney function and a higher burden of comorbidities at diagnosis, and in multivariable models, treatment status was no longer independently associated with kidney survival. Additional sensitivity analyses including baseline comorbidities yielded similar results, and exploratory histological models did not identify independent associations between baseline kidney lesions and kidney survival. These findings suggest that baseline kidney severity, rather than treatment exposure alone, may explain the differences observed between treated and untreated patients.

Nevertheless, once hematologic control is achieved, previous studies and our own cohort suggest that deeper hematologic responses are closely linked to subsequent renal improvement. In that way, Leung et al. reported that, among a group of patients with AL amyloidosis and kidney involvement treated with ASCT, those who achieved a complete hematologic response showed a reduction in proteinuria >75% in 73.7% of cases and >95% in 52.6%. In contrast, only 25% of patients with partial hematologic response achieved >75% reduction in proteinuria, and none with less than very good partial response attained >95% reduction. Remarkably, our cohort showed a significant improvement in kidney response rates over time, reaching 60% response in the most recent decade (2010–24) compared to only 16% in the 1990s. It is noteworthy that patients who achieved kidney response had a significantly higher prevalence of ASCT (43%) compared to those without response (7%). These findings likely reflect improvements in therapeutic strategies, earlier diagnosis, and more accurate selection of candidates for intensive therapies.

However, patients in our study showed a significant delay between hematological and kidney response. In this way, whereas hematological response occurred relatively quickly after treatment initiation (median of 4.58 months), complete kidney response was observed at a median follow-up of 16.5 months (P = .03). Similar delays in the kidney response after ACT have been previously reported [8, 15–17].

The lag in kidney response relative to hematological response likely reflects the slow clearance of amyloid deposits from kidney tissue and subsequent functional recovery, often manifested as persistent proteinuria with stable kidney function. Indeed, the persistence of kidney amyloid deposits after hematological response has been well documented in repeated biopsy studies [17–20]. In addition, chronic structural lesions, such as glomerular sclerosis and interstitial fibrosis, in patients experiencing a delayed renal response, could contribute to persistent proteinuria, even after the resolution of amyloid deposits [21]. In this context, in patients with complete hematologic response without partial kidney response after one year of treatment, repeat kidney biopsy may provide additional information by identifying chronic damage or persistent amyloid deposits. Although these findings may be useful to predict kidney outcomes, their role in guiding treatment decisions despite hematological response remains uncertain [21].

In this study we stratified our patients according to the time to achieve kidney response (0–6 months, 6–12 months, and >12 months). We found no significant differences in their baseline characteristics that could predict a shorter or longer time to response. However, the patients with a late kidney response presented a more delayed hematological response compared to those with very early kidney response (3 months vs. 9 months). Remarkably, contrary to previous reports, in which an early response was associated with a better prognosis, the kidney outcomes were similar in the three groups [13].

Notably, patients with a delayed kidney response underwent more lines of ACT, which extended the time to hematological treatment by up to 24 months, despite the hematological response being achieved after a median of 9 months. Furthermore, among patients who achieved very early hematological response, those with late kidney response received significantly more ACT lines than those with very early and early kidney response. Although current guidelines do not recommend the use of organ-specific biomarkers beyond hematological response to guide ACT, our findings suggest that, in the clinical practice, the absence of kidney response despite hematologic control was associated with longer or more intensive hematological treatment administered to patients with primary amyloidosis. Although our retrospective data support association rather than causality, this treatment pattern may reflect attempts to improve kidney outcomes in patients without renal remission [21]. Nevertheless, as discussed above, most of these patients probably present with either established or chronic kidney damage or “old” AL amyloid deposits that have not yet been removed. Therefore, kidney response should be interpreted cautiously when used to guide treatment duration or intensity in clinical practice. However, prospective studies evaluating toxicity and relapse data are needed to clarify whether prolonged therapy is beneficial or potentially unnecessary.

The main limitations of our study include its retrospective nature, leading to heterogeneous treatment approaches, the lack of repeated kidney re-biopsies, and the long study period, during which response criteria evolved. In addition, the relatively small sample size, particularly within subgroup analyses according to time to renal response, may have limited the statistical power of our comparisons and these findings should therefore be interpreted cautiously. Accordingly, subgroup analyses based on timing of kidney response should be considered exploratory because of the small sample sizes However, the strengths of this study lie in the substantial patient cohort (76 individuals) and the extended, close clinical follow-up.

In summary, treatment advances in AL amyloidosis have improved kidney outcomes in patients with kidney involvement. The time to kidney response is significantly longer than the time to hematologic response, reflecting the slow clearance of amyloid deposits from kidney tissue. Nonetheless, kidney response is associated with good kidney outcomes, regardless of the time to achieve it. The absence of kidney response after hematological response may indicate a delayed kidney response or the presence of irreversible chronic damage. In our cohort, the delay in kidney remission was associated with prolonged/more intensive treatment. However, kidney response alone should be interpreted cautiously when guiding treatment decisions, as the absence of response may simply reflect delayed organ recovery rather than ongoing disease activity. Further prospective studies are needed to determine the optimal role of kidney response in guiding therapy duration.