RESULTS

Baseline characteristics

Seventy-six patients with AL amyloidosis and kidney involvement were included in the study. Baseline characteristics are shown in Table 1. The main etiology of AL amyloidosis was monoclonal gammopathy of kidney significance IgG λ (MG IgGλ) (37%), followed by multiple myeloma IgGλ (MM IgGλ) (25%). Cardiac biomarkers were assessed in all patients and only seven had cardiac involvement expressed by an increase in their NT-proBNP.

 | Patients included in the study | Patients receiving hematologic treatment | Patients not receiving hematologic treatment | P
N(%) | 76 (100%) | 58 (76%) | 18 (24%) | 
Types of AL amyloidosis N (%) | MG IgG λ | 28 (37%) | 17 (29%) | 11 (61%) | .27
 | MM IgG λ | 19 (25%) | 17 (29%) | 2 (11%) | 
 | MG IgG k | 9 (12%) | 6 (10%) | 3 (16%) | 
 | MM IgG k | 5 (6%) | 5 (9%) | 0 | 
 | MG IgM k | 6 (8%) | 5 (9%) | 1 (6%) | 
 | MG IgA λ | 1 (1%) | 1 (2%) | 0 | 
 | MG IgA k | 1 (1%) | 1 (2%) | 0 | 
 | MM IgA λ | 7 (10%) | 6 (10%) | 1 (6%) | 
Age at the diagnosis of kidney amyloidosis, M ± SD (years) | 65 ± 12 | 65 ± 11 | 64 ± 15 | .12
Male/woman, N (%) | 40/36 (53/47%) | 34/24 (59/41%) | 6/12 (33/67%) | .06
HTA, N (%) | 12 (16%) | 9 (15%) | 3 (17%) | .91
DM, N (%) | 11 (14%) | 6 (10%) | 5 (28%) | .07
Biochemical characteristics
SCr, mg/dl | 1.09 (0.87–1.77) | 1.02 (0.81–1.72) | 1.29 (0.97–2.26) | .07
eGFR, ml/min/1.73 m2 | 76.36 (40.25–96.21) | 71.36 (40.25–98.75) | 56.34 (31.33–80.76) | .05
Serum albumin, g/dl | 2.9 (2.2–3.6) | 2.91 (2.17–3.8) | 3.01 (2.17–3.01) | .37
Proteinuria, g/day | 5.01 (3.30–8.02) | 4.81 (2.96–6.7) | 7.05 (3.90–10.25) | .07
Kidney clinical manifestations at baseline
AKI, N (%) | 31 (41%) | 21 (36%) | 10 (56%) | .14
Nephrotic syndrome, N (%) | 44 (58%) | 33 (57%) | 11 (61%) | .75
Histological characteristics at baseline
Glomerular amyloid deposits | 76 (100%) | 58 (100%) | 18 (100%) | –
Vascular amyloid deposits | 30 (40%) | 19 (33%) | 11 (61%) | 0.03
Glomerular sclerosis, |  |  |  | 
- Number patients N (%) | 32 (45%) | 21 (36%) | 6 (33%) | 0.61
- Mean number of sclerosed glomeruli | 10 (0–20) | 10 (3.77–17.5) | 10 (0–20) | 
Interstitial fibrosis | 23 (31%) | 16 (27%) | 7 (39%) | 
- Mild | 14 (18%) | 11 (19%) | 3 (17%) | 
- Moderate | 6 (8%) | 3 (5%) | 3 (17%) | 0.45
- Severe | 3 (5%) | 2 (3%) | 1 (5%) | 

The mean age at diagnosis of kidney amyloidosis was similar between patients who received hematologic treatment (65 ± 11 years) and those untreated (64 ± 15 years), P = .12. The mean age at the diagnosis of the hematologic disease was 65 ± 11 years for patients under ACT and 64 ± 14 years for cases without it (P = .19). Therefore, 70% of patients were diagnosed with renal amyloidosis and the hematologic disorder simultaneously, while in 30% the diagnosis of renal involvement was delayed. The median time to the diagnosis of renal amyloidosis in these patients was 248 days (117–1018).

Patients who received anti-plasma cell therapy exhibited better kidney function, with a difference that approached statistical significance. Median SCr in patients with and without ACT was 1.02 (0.81–1.72) mg/dl and 1.29 (0.97–2.26) mg/dl, (P = .07). Median eGFR was 71.36 (40.25–98.75) ml/min/1.73 m2 and 56.34 (31.33–80.76) ml/min/1.73 m 2, P = .05.

The incidence of AKI at baseline was 36% and 56% (P = .14) in patients treated with and without hematologic therapy, respectively. However, the most frequent kidney involvement in these patients was nephrotic syndrome, which was observed in 44 (58%) of the included patients, without differences between treated and untreated populations (57% vs. 61%, P = .75).

Regarding histologic findings, the prevalence of glomerular and interstitial fibrosis was similar in both groups, with a median of 10 sclerosed glomeruli (P = .61) and a percentage of fibrosis of 27% and 39% in treated and untreated patients (P = .45). The presence of vascular amyloid deposits was significantly higher in patients who did not receive ACT (33% vs. 61% respectively, P = .03).

Treatment

Fifty-eight (76%) of the included patients underwent hematologic-targeted treatment. The most common therapeutic strategy used was ASCT (26%), although a substantial proportion of patients received dexamethasone- and bortezomib-based combination regimens (DexBor and related protocols). The type of treatment received by each patient is displayed in Supplementary Table S1. Of the remaining 18 patients, 15 cases (83%) were not eligible for ACT due to advanced age, significant comorbidities, frailty, or poor functional status at diagnosis, as determined by the treating physician. In some cases, advanced disease stage and impaired kidney function also contributed to the decision not to initiate therapy. Three patients (17%) died before the initiation of hematologic therapy.

Outcomes

Thirty-four (59%) patients who received treatment in our cohort achieved hematologic response, and 30 (52%) achieved kidney response. The median time to hematologic response was 4.58 (1–9.38) months, while the median time to partial kidney response was 9 (6–18) months. Time to complete kidney response was 16.5 (9–25) months. None of the patients without ACT achieved hematologic or kidney response, showing at last follow-up a significantly lower eGFR and a higher proteinuria, compared to patients under hematologic treatment. This resulted in a higher need for KRT in untreated patients (50%) compared to treated patients (7%) (P = .01), Table 2. Time to ESKD was significantly longer in the treated group (P = .01), as is reflected in Figure 1. However, after adjustment for baseline kidney function, proteinuria, and AKI, treatment status was no longer significantly associated with kidney survival (Supplementary Table S2). In a sensitivity analysis additionally including hypertension and diabetes mellitus, the results remained unchanged, with baseline eGFR being the only variable independently associated with kidney survival (Supplementary Table S3). Likewise, in an exploratory multivariable model including baseline histological variables, none of the histological parameters evaluated were independently associated with kidney survival (Supplementary Table S4).

Figure 1:: Kidney survival rate among patients receiving hematologic treatment and patients not receiving hematologic treatment. (Log-rank test: χ² = 2.31, P = .01).

 | Patients included in the study | Patients receiving hematologic treatment | Patients not receiving hematologic treatment | P
N (%) | 76 (100%) | 58 (76%) | 18 (24%) | –
Time of follow up, months | 60 (9–131) | 64.5 (9–120) | 32.5 (9.75–312) | .70
SCr, mg/dl | 1.90 (0.98 -4.22) | 1.38 (0.90–2.77) | 2.5 (2.5–5.7) | .01
eGFR, ml/min/1.73 m2 | 41.83 (18.31–88.25) | 44.01 (44.01–89.24) | 22.86 (8.30–39.78) | .02
Proteinuria, g/day | 1.5 (0.22–5.01) | 1.12 (0.19–4.35) | 3.45 (1.39–9.48) | .02
Serum albumin, mg/dl | 3.60 (2.70–4.10) | 3.90 (2.85–4.12) | 3.07 (2.50–3.55) | .08
Hematologic response, N (%) | 34 (45%) | 34 (59%) | 0 | .01
Kidney response, N (%) | 30 (40%) | 30 (52%) | 0 | .01
Time to hematologic response, months | 4.58 (1–9.38) | 4.58 (1–9.38) | No response | .01
Time to partial kidney response | 9 (6–18) | 9 (6–18) | No response | .01
Time to complete kidney response | 16.5 (9–25) | 16.5 (9–25) | No response | .01
ESKD, N (%) | 17 (22%) | 4 (7%) | 9 (50%) | .05
Time to ESKD months, | 21 (4.5–138) | 58.5 (4.75–171) | 10 (3–94) | .01
Death, N (%) | 30 (40%) | 27 (46%) | 14 (78%) | .02
Time to death, months | 13 (4–44) |  | 25 (7.5–62.75) | 

As shown in Supplementary Table S5, when the year of disease diagnosis was stratified by decade, the rate of kidney response increased significantly from 16% in 1990–2000 to 60% in 2010–24 (P = .02). This increase paralleled a marked rise in the proportion of patients receiving ACT over time (42% in 1990–2000 vs. 95% in 2010–24, P = .01), suggesting that advances in therapeutic strategies may have contributed to improved renal outcomes. In contrast, the time to achieve kidney response did not differ significantly between groups (P = .85), a finding that was further confirmed in sensitivity analyses. Specifically, in a Cox regression model adjusted for era of diagnosis, era was not independently associated with time to kidney response (HR 0.97, P = .95).

Patients with and without kidney response

Table 3 shows the baseline characteristics of patients with and without kidney response. The prevalence of ASCT was 43% in the group of patients with kidney response and 7% in patients without response (P = .01). There were no other baseline differences between both groups. Median follow-up was significantly longer in patients who achieved kidney response compared with those without response [91.5 (60–123) vs. 16.5 (3.5–105) months, P = .01], mainly reflecting the higher mortality observed in the non-response group. Table 4 displays the outcomes between patients who achieve and not kidney response. Patients who achieved kidney response demonstrated superior kidney function at the end of follow-up: better eGFR, 76 (32.06–95.45) vs. 34.27 (7.29–59.8) (P = .03), lower levels of creatinine, 1.22 (0.80–2.66) vs. 2.50 (1.25–5.70) (P = .04), and lower levels of proteinuria, 0.38 (0.14–1.5) vs. 3.50 (0.85–6.03) (P = .01). The need for KRT was significantly lower in patients who achieved kidney response (0% vs. 15%) (P = .03), as was mortality (28% vs. 69%) (0.01). A multivariate analysis was performed to assess whether kidney response was independently associated with kidney survival, Supplementary Table S6. The variables analyzed included achievement of hematologic response, achievement of kidney response, eGFR at diagnosis, baseline proteinuria, and age at disease diagnosis. Both kidney response (HR 0.15, P = .02), and higher eGFR at diagnosis (HR 0.96, P < .05) were independently associated with improved kidney survival.

 | Treated patients | Patients with kidney response | Patients without kidney response | P
N (%) | 58 | 30 (52) | 28 (48) | –
Age, M ± SD (years) | 65.69 ± 11.67 | 63.71 ± 11.96 | 64.20 ± 11.37 | .33
Male/woman, N (%) | 34/24 (59/41) | 15/15 (50/50) | 19/9 (68/32) | .17
HTA, N (%) | 9 (15) | 4 (13) | 5 (18) | .63
DM, N (%) | 6 (10) | 2 (7) | 4 (14) | .45
Biochemical characteristics
SCr, mg/dl | 1.02 (0.81–1.72) | 0.96 (0.72–1.42) | 1.16 (0.80–1.95) | .35
eGFR, ml/min/1.73 m2 | 71.36 (40.25–98.75) | 89.50 (51.92–100.57) | 60.73 (38.19–97.35) | .15
Serum albumin, g/dl | 2.91 (2.17–3.8) | 3.30 (2.25–3.45) | 2.70 (2.12–3.45) | .06
Proteinuria, g/day | 4.81 (2.96–6.7) | 4.81 (2.99–7.02) | 4.82 (1.62–6.55) | .61
Kidney clinical manifestations at baseline
AKI, N (%) | 21 (36) | 8 (27) | 13 (46) | .12
Nephrotic syndrome, N (%) | 33 (57) | 17 (57) | 16 (57) | .19
Histological characteristics at baseline
Glomerular amyloid deposits | 58 (100) | 30 (100) | 26 (100) | –
Vascular amyloid deposits | 19 (33) | 11 (36) | 8 (29) | .51
Glomerular sclerosis, |  |  |  | .14
- Number patients N (%) | 21 (36) | 13 (43) | 8 (29) | 
- Mean number of sclerosed glomeruli | 10 (3.77–17.5) | 9 (0–15) | 10.5 (9.25–29.5) | 
Interstitial fibrosis | 16 (27) | 11 (36) | 5 (18) | 
-Mild | 11 (19) | 8 (27) | 3 (11) | .19
-Moderate | 3 (5) | 1 (3) | 2 (7) | 
-Severe | 2 (3) | 2 (6) | 0 | 

 | Patients with kidney response | Patients without kidney response | P
N (%) | 30 (52) | 28 (48) | –
SCr at last follow-up, mg/dl | 1.22 (0.80–2.66) | 2.50 (1.25–5.70) | .04
eGFR at last follow-up, ml/min/1.73 m2 | 76.00 (32.06–95.45) | 34.27 (7.29–59.8) | .03
Proteinuria, g/day | 0.38 (0.14–1.5) | 3.50 (0.85–6.03) | .01
Serum albumin, mg/dl | 3.62 ± 0.79 | 3.28 ± 1.11 | .22
End stage kidney disease, N (%) | 0 | 4 (15) | .03
Death rate, N (%) | 8 (26) | 18 (64) | .01
Time of follow up, months | 91.5 (60–123.02) | 16.5 (3.51–105.01) | .01

Patients classified according to time to kidney response

The baseline characteristics and outcomes of the patients with very early (0–6 months), early (6–12 months), and late (>12 months) kidney response are shown in Table 5. There were no differences in laboratory or histological baseline characteristics among the three groups. In exploratory analyses, baseline histological lesions were not associated with time to kidney response, including glomerulosclerosis (Spearman ρ = −0.21, P = .38), interstitial fibrosis (Kruskal-Wallis test, P = .16), and vascular amyloid deposits (Mann-Whitney test, P = .79). Time to hematological response was longer in the late kidney response group [9.75 (3.87–13.5) months] compared with early response group [3 (1–6.10) months], P = .02. None of the patients who achieved kidney response progressed to ESKD and kidney function and proteinuria at the end of follow-up were similar in the three groups. Regarding treatment, the proportion of patients who received two or three lines of ACT was higher in the late kidney response group, although the difference was non-significant. However, when the three groups were stratified by time to hematological response and the number of hematologic treatment lines was analyzed, it was shown that patients with very early hematological response (0–6 months) and late kidney response received significantly more lines of ACT than those with very early hematological response and very early or early kidney response groups, Supplementary Table S7. No other differences were found. The duration of ACT was also longer in the late kidney response group [24.5 (10.9–43.57) months] than in the early response group [9 (6–15.7) months], P = .02.

 | Very early response0–6 months | Early response6–12 months | Late response>12 months | P
Baseline characteristics
N (%) | 7 (23) | 13 (43) | 10 (34) | 
Age at the diagnosis of kidney amyloidosis, M ± SD (years) | 71.14 ± 10.18 | 63.62 ± 11.35 | 60.1 ± 12.74 | .17
SCr, mg/dl | 1.05 (0.7–1.5) | 0.94 (0.61–1.61) | 0.95 (0.79–1.59) | .82
eGFR, ml/min/1.73 m2 | 80 (44.27–96.45) | 89 (40.24–191.21) | 90 (83.78–101.90) | .69
Serum albumin, g/dl | 3.5 (3–3.9) | 3.6 (2.25–4.15) | 2.9 (2.07–4.02) | .74
Proteinuria, g/day | 6.55 (3.30–8.9) | 4.4 (2.2–6.15) | 5.05 (2.8–7.89) | .29
AKI, N (%) | 2 (28) | 5 (38.5) | 1 (10) | .31
Nephrotic syndrome, N (%) | 3 (43) | 8 (61) | 6 (60) | .70
Glomerular amyloid deposits | 7 (100) | 13 (100) | 10 (100) | –
Vascular amyloid deposits | 3 (43) | 4 (31) | 4 (40) | .83
Glomerular sclerosis, |  |  |  | 
- Number patients N (%) | 4 (31) | 7 (54) | 2 (20) | .38
- Mean number of sclerosed glomeruli | 12 (6–12) | 9 (5–12) | 5 (0–42) | .59
Interstitial fibrosis |  |  |  | 
- Mild | 3 (43) | 4 (31) | 1 (10) | .35
- Moderate | 1 (14) | 0 | 0 | 
- Severe | 0 | 1 (8) | 1 (10) | 
Treatment
Number of hematologic treatment lines, N (%) |  |  |  | 
- 1 line of treatment | 4 (57) | 9 (69) | 0 | .23
- 2 lines of treatment | 3 (43) | 3 (23) | 6 (60) | 
- 3 lines of treatment | 0 | 1 (8) | 4 (40) | 
Treatment time, months | 9 (1.5–24) | 9 (6–15.7) | 24.5 (10.9–43.57)a | .07
Time to hematologic response, months | 4 (1.38–18.65) | 3 (1–6.10) | 9.75 (3.87–13.5)a | .07
N patients with hematologic treatment after hematologic response | 4 (57) | 7 (53) | 7 (70) | .60
Kidney outcomes
End stage kidney disease, N (%) | 0(0%) | 0(0%) | 0(0%) | .9
SCr, mg/dl | 1.29 (0.68–3.42) | 1.02 (0.81–2.99) | 1.39 (0.83–2.45) | .87
eGFR, ml/min/1.73 m2 | 81 (20.31–98.03) | 77 (43.81–92.39) | 44.61 (31.55–90.11) | .65
Proteinuria, g/day | 0.38 (0.17–1.80) | 0.48 (0.12–1.43) | 0.35 (0.18–2.92) | .86
Serum albumin, mg/dl (M ± SD) | 3.9 (3.25–4) | 3.85 (2.22–4.02) | 4.2 (3.92–4.35) | .57