Abstract
Background:
Allogeneic hematopoietic stem cell transplant (HCT) is a potentially curative therapy for patients with hematologic malignancies but is associated with acute kidney injury (AKI). Few studies have examined risk factors for AKI at engraftment, or its relationship with clinical outcomes.
Objective:
The objective of this study was to examine the incidence and risk factors for peri-engraftment AKI, as well as the association between AKI and overall survival and non-relapse mortality.
Methods:
We conducted a retrospective analysis of adult patients receiving reduced intensity conditioning (RIC) allogeneic HCT at the Dana-Farber Cancer Institute between 2012 and 2019. Peri-engraftment (day 0 to day 30) AKI incidence and severity was defined using modified Kidney Disease: Improving Global Outcomes criteria. Factors associated with peri-engraftment AKI risk were examined using Cox regression analysis. The impact of peri-engraftment AKI on overall survival and non-relapse mortality (defined as death without recurrent disease after HCT), was evaluated using Cox regression and Fine and Gray’s competing risk model, respectively. Kidney recovery, defined as a return of serum creatinine within 25% of baseline or liberation from kidney replacement therapy (KRT), was examined at day 90 in relation to HCT.
Results:
Peri-engraftment AKI occurred in 330 of 987 patients (33.4%) at a median of 13 days [IQR 4–30] post-transplant. Factors associated with a higher multivariable-adjusted risk of AKI were supratherapeutic rapamycin (HR: 1.56, 95% CI: 1.20–2.03; p<0.001), fludarabine/melphalan conditioning (HR: 1.35, 95% CI: 1.01–1.81; p=0.05; compared to fludarabine/busulfan and fludarabine, cyclophosphamide, total body irradiation), HCT-Comorbidity Index ≥4 (HR: 1.43, 95% CI: 1.14–1.79; p=0.002), albumin <3.4 g/dl (HR: 2.04, 95% CI: 1.33–3.12; p=0.001), hemoglobin ≤12 (HR 1.96, 95% CI 1.38–2.78; p<0.001), supratherapeutic tacrolimus (HR 1.45, 95% CI 1.07 – 1.95; p=0.02), and baseline serum creatinine >1.1 mg/dl (HR: 1.87, 95% CI: 1.48–2.35; p<0.001). Peri-engraftment AKI was associated with worse overall survival (HR 1.40, 95% CI: 1.16–1.71; p<0.001) and non-relapse mortality (subdistribution HR 2.10, 95% CI: 1.52–2.89; p<0.001). Kidney recovery occurred in 18%, 15%, and 30% of patients with stage 1, 2, and 3 AKI without KRT, respectively, and 4 of 16 (25%) patients were liberated from KRT.
Conclusion:
Peri-engraftment AKI is common among RIC allogeneic HCT recipients. We identified several important risk factors for peri-engraftment AKI. Peri-engraftment AKI is associated with worse overall survival and non-relapse morality, highlighting the importance of timely recognition and management of AKI.
Keywords: reduced intensity allogeneic HCT, acute kidney
Graphical Abstract
Introduction
Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative therapy for multiple hematologic malignancies, as well as severe blood disorders.1 HCT involves the administration of multiagent conditioning chemotherapy followed by the infusion of a donor stem cell graft based on human leukocyte antigen (HLA) compatibility.1 Conditioning regimens can be either myeloablative, reduced intensity or non-myeloablative, with the former carrying the highest risk for toxicity.1–3 Despite rapid developments in the field, HCT carries a high risk of GVHD requiring administration of immunosuppression for its prevention, as well as infection requiring potentially nephrotoxic antimicrobials.1 Thus, HCT carries a significant risk of organ toxicity, largely depending upon intensity of conditioning, as well as other patient-, disease-, and transplant-related factors.4
Acute kidney injury (AKI) is an important manifestation of organ toxicity from allogeneic HCT, occurring in around 52–64% of patients, depending on definitions used, and most frequently within the first 100 days following HCT.5, 6 The causes of AKI in HCT are variable, and include hypovolemia, sepsis, acute tubular necrosis, thrombotic microangiopathy, and medication-induced kidney injury.7–11 AKI is associated with worse overall survival and transplant-related mortality;5, 12–16 accordingly, identifying those at highest risk of AKI has the potential to improve clinical outcomes of HCT recipients. Engraftment is the process by which hematopoietic stem cells home to the bone marrow and proliferate in order to generate hematopoietic cell subsets.17 Data examining the incidence of peri-engraftment AKI, and its association with HCT outcomes, particularly among those receiving reduced intensity conditioning regimens, are overall lacking. Our objective was therefore to examine the incidence and risk factors associated with peri-engraftment AKI in patients who received reduced intensity conditioning-HCT, and to investigate the association between peri-engraftment AKI and both overall survival and non-relapse mortality.
Materials and Methods
Study Population
We conducted a cohort study of adults (aged ≥18 years) who underwent a reduced intensity conditioning allogeneic HCT at the Dana-Farber Cancer Institute (DFCI) between 2012 and 2019. We excluded patients undergoing myeloablative allogeneic HCT, cord blood allogeneic HCT, or allogeneic HCT for non-malignant conditions; those participating in clinical trials for GVHD regimens and/or conditioning regimens; second or subsequent allogeneic transplants; and patients with AKI in the 7 days preceding allogeneic HCT (defined as a 1.5-fold rise in serum creatinine [SCr]) from the start of conditioning at day −7 to the day of transplant, day 0). We identified the eligible cohort through the Organ Transplant Tracking Record (OTTR), which contains clinical data for patients receiving allogeneic HCT at DFCI. This study was approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board.
Data Collection
We extracted data on demographics, patient comorbidity index (HCT-CI),18, 19 and transplant factors (donor age and sex, ABO mismatch status, underlying malignancy, donor type and source, conditioning regimen, and GVHD prophylaxis regimen) from OTTR. We obtained laboratory data from the Research Patient Data Registry (RPDR), which is a clinical data warehouse of over 6.5 million individuals who receive their care from Mass General Brigham and DFCI providers in Massachusetts. Continuous variables (age, HCT-CI, estimated glomerular filtration rate [eGFR], serum albumin, serum bicarbonate, hemoglobin, platelet count, serum ferritin, SCr) were examined in clinically-relevant categories. We also extracted data on intravenous antibiotics commonly used for the treatment of sepsis, and that are known to be nephrotoxic (e.g., cefepime, ceftazidime, vancomycin, piperacillin-tazobactam, meropenem, and imipenem).
We confirmed supratherapeutic tacrolimus and rapamycin levels and kidney replacement therapy (KRT) by manual chart review of the electronic health record (EHR). We estimated the percentage of time patients were in the supratherapeutic range for tacrolimus and rapamycin within the peri-engraftment period, generating tacrolimus and rapamycin supratherapeutic indices. To do this, we projected the drug trough level curve for each patient onto the time axis and calculating the proportion of time that patients spent above the drug trough thresholds, using a value of 10 ng/mL for the tacrolimus threshold and 12 ng/mL for the rapamycin threshold (Supplemental Figure 1). For analyses, patients were categorized as having tacrolimus levels in the supratherapeutic range (yes vs. no) and rapamycin levels in the supratherapeutic range (yes vs. no).
Definition of AKI and Kidney Recovery
We defined peri-engraftment AKI as a ≥1.5-fold rise in SCr from baseline (where baseline SCr was the closest value prior to receipt of conditioning) or the receipt of KRT within the first 30 days post-transplant. We staged AKI severity according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria.20 Stage 1 was defined as 1.5 to less than 2-fold increase in SCr from baseline; stage 2 was defined as 2 to less than 3-fold increase in SCr from baseline; and stage 3 was defined as a ≥3-fold rise in SCr from baseline, SCr ≥4.0 mg/dL, or initiation of KRT.
Among patients with stage 1, 2, or 3 AKI not treated with KRT, kidney recovery was defined as a return of SCr within 25% of baseline at day +90 after HCT. For patients without a SCr value at 90 days after transplant, we utilized the SCr closest to day +90 (+/− 15 days). For those treated with KRT, kidney recovery was defined as liberation from KRT at any point in the 90 days following HCT.
Mortality
In addition to evaluating the incidence and stage of AKI in the 30 days following HCT, we also examined its association with overall survival (OS) and non-relapse mortality (NRM). OS was defined as the time from stem cell infusion to death from any cause or until the date of last seen alive. NRM was defined as time from stem cell infusion to death from any cause other than relapse or until the date of last seen alive.
Statistical Analysis
Baseline characteristics were primarily reported descriptively. Since all AKI events occurred within 30 days of HCT, without loss of generality, these characteristics were compared using Fisher’s exact test, Chi-square test or Wilcoxon-Rank-Sum test, as appropriate. The cumulative incidence of peri-engraftment AKI was estimated in the competing risks framework treating death without AKI as a competing event. Univariable and multivariable Cox regression analyses were used to identify risk factors for peri-engraftment AKI. Variables for multivariable analyses were selected based on univariable associations, biological plausibility, and prior knowledge.6, 21, 22 A sensitivity analysis was performed to examine risk factors for stage 2 AKI or higher, and after adjusting for exposure to intravenous antibiotics. As only one death occurred within 30 days, the results from two types of regression analyses were similar. The impact of peri-engraftment AKI on OS and NRM was assessed using Cox model and the Fine and Gray competing risks model, respectively, treating AKI as a time-dependent variable. In the analysis of NRM, relapse was treated as a competing event. The difference between AKI and no AKI on OS and NRM was graphically presented using Simon-Makuch type curves.23, 24 A landmark analysis was performed at day 7, 14, 21 and 30 in relation to HCT, with log-rank test and Gray test used for comparisons of OS and NRM, respectively. All comparisons were two sided, with p<0.05 considered significant. Analyses were performed using SAS V.9.5 (SAS Institute, Cary, NC), and R version 3.2.2 (the CRAN project, www.cran.r-project.org).
Results
Patient Characteristics
There were 1324 patients who underwent reduced intensity conditioning allogeneic HCT during the study period, of whom 987 (74.5%) were included in the analysis (Figure 1). In the 30 days following HCT, 330 patients (33.4%) developed AKI. Patients with AKI were older and had a higher HCT-CI index, but had similar baseline eGFR compared to patients without AKI (Table 1). They were more likely to undergo matched unrelated donor (MUD) HCT, receive busulfan/fludarabine or melphalan/fludarabine conditioning, and receive a GVHD prophylaxis regimen that included tacrolimus and rapamycin (Table 1). Additional baseline characteristics are shown in Supplemental Table 1.
Figure 1. Flowchart.
Abbreviation: AKI, acute kidney injury; GVHD, graft versus host disease; HCT, hematopoietic stem cell transplant.
Table 1.
Baseline Characteristics
| Variable | All (n=987) |
AKI within 30 days | p-value | |
|---|---|---|---|---|
| No (n=657) |
Yes (n=330) |
|||
| Age, yrs | <0.001 | |||
| Median (range) | 63 (56, 68) | 63 (55, 68) | 65 (59, 68) | |
| ≥65 yrs, n (%) | 396 (40.1) | 237 (36.1) | 159 (48.2) | |
| <65 yrs, n (%) | 591 (59.9) | 420 (63.9) | 171 (51.8) | |
| Male sex, n (%) | 614 (62.2) | 410 (62.4) | 204 (61.8) | 0.89 |
| Race, n (%) | 0.66 | |||
| White | 929 (94.1) | 615 (93.6) | 314 (95.1) | |
| Black | 25 (2.5) | 19 (2.9) | 6 (1.8) | |
| Asian | 16 (1.6) | 12 (1.8) | 4 (1.2) | |
| Other | 17 (1.7) | 11 (1.7) | 6 (1.8) | |
| Baseline eGFRa, ml/min per 1.73 m2, median (IQR) | 85.5 (71.9, 97) | 85.2 (71.4, 97.3) | 86.3 (72.3, 96.2) | 0.88 |
| KDIGO GFR category, n (%) | 0.97 | |||
| ≥90 | 402 (40.7) | 264 (40.2) | 138 (41.8) | |
| 60–89 | 470 (47.6) | 318 (48.4) | 152 (46.1) | |
| 30–59 | 93 (9.4) | 61 (9.3) | 32 (9.7) | |
| <30 | 22 (2.2) | 14 (2.1) | 8 (2.4) | |
| Median donor age (range) | 31 (25, 45) | 31 (25, 44) | 30 (25, 45) | 0.96 |
| Male Donor sex, n (%) | 646 (65.4) | 426 (64.8) | 220 (66.7) | 0.62 |
| Female pt & male donor, n (%) | 0.45 | |||
| Yes | 198 (20.1) | 127 (19.3) | 71 (21.5) | |
| No | 789 (79.9) | 530 (80.7) | 259 (78.5) | |
| ABO mismatch, n (%) | 0.59 | |||
| None | 607 (61.5) | 413 (62.9) | 194 (58.8) | |
| Major | 168 (17.0) | 109 (16.6) | 59 (17.9) | |
| Minor | 175 (17.7) | 110 (16.7) | 65 (19.7) | |
| Bi-directional | 37 (3.7) | 25 (3.8) | 12 (3.6) | |
| Disease, n (%) | 0.03 | |||
| Lymphoma/CLL | 304 (30.8) | 218 (33.2) | 86 (26.1) | |
| AML/ALL | 348 (35.3) | 219 (33.3) | 129 (39.1) | |
| MDS | 198 (20.1) | 136 (20.7) | 62 (18.8) | |
| MPD/CML | 111 (11.2) | 64 (9.7) | 47 (14.2) | |
| MM/PCD | 22 (2.2) | 18 (2.7) | 4 (1.2) | |
| Other Leukemia | 4 (0.4) | 2 (0.3) | 2 (0.6) | |
| HCT-CIb, n (%) | 0.002 | |||
| 0 | 193 (19.6) | 142 (21.6) | 51 (15.5) | |
| 1 | 120 (12.2) | 86 (13.1) | 34 (10.3) | |
| 2 | 158 (16.0) | 109 (16.6) | 49 (14.8) | |
| 3 | 167 (16.9) | 116 (17.6) | 51 (15.5) | |
| ≥4 | 349 (35.4) | 204 (31.1) | 145 (43.9) | |
| Donor type, n (%) | <0.001 | |||
| MRD | 209 (21.2) | 145 (22.1) | 64 (19.4) | |
| Haploidentical | 85 (8.6) | 73 (11.1) | 12 (3.6) | |
| MUD | 585 (59.3) | 362 (55.1) | 223 (67.6) | |
| MMUD | 108 (10.9) | 77 (11.7) | 31 (9.4) | |
| Cell source, n (%) | <0.001 | |||
| Bone marrow | 97 (9.8) | 81 (12.3) | 16 (4.8) | |
| PBSC | 890 (90.2) | 576 (87.7) | 314 (95.1) | |
| Conditioning agents, n (%) | <0.001 | |||
| Bu/Flu | 733 (74.3) | 478 (72.7) | 255 (77.3) | |
| Flu/Cy/TBI | 111 (11.2) | 99 (15.1) | 12 (3.6) | |
| Flu/Mel | 143 (14.5) | 80 (12.2) | 63 (19.1) | |
| GVHD prophylaxis, n (%) | <0.001 | |||
| PTCY-based regimenc | 125 (12.7) | 112 (17.0) | 13 (3.9) | |
| TAC/MTX | 256 (25.9) | 192 (29.2) | 64 (19.4) | |
| TAC/RAP | 145 (14.7) | 79 (12.0) | 66 (20.0) | |
| TAC/RAP/MTX | 461 (46.7) | 274 (41.7) | 187 (56.7) | |
Data are shown as median (range) and n (%). All data are complete. Only one patient died within 30 days of transplant. Abbreviations: AKI, acute kidney injury; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; Bu/Flu, busulfan + fludarabine; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; Cy, cyclophosphamide; eGFR, estimated glomerular filtration rate; Flu/Cy/TBI, fludarabine + cyclophosphamide + total body irradiation; Flu/Mel, fludarabine + melphalan; GVHD, graft versus host disease; HCT-CI, hematopoietic cell transplantation-specific comorbidity index; MDS, myelodysplastic syndromes; MM, multiple myeloma; MMF, mycophenolate mofetil; MMUD, mismatched unrelated donor; MPD, myeloproliferative disorders; MRD, matched related donor; MTX, Methotrexate; MUD, matched unrelated donor; PBSC, peripheral blood stem cells; PCD, plasma cell disorders; Pt, patient; Rap, rapamycin (Sirolimus); TAC, tacrolimus.
Baseline eGFR was calculated based on Chronic Kidney Disease-Epidemiology Collaboration equation.
HCT-CI is a comorbidity index that comprises 17 different categories of organ dysfunction. Positive findings are summated into a total score. The HCT-CI provides information regarding the overall as well as non-relapse mortality risk a patient is likely to experience after hematopoietic cell transplantation. Among patients with HCT-CI ≥4, 1 patient received a score of 2 for a serum creatinine >2.
Post-transplant cyclophosphamide-based regimens (PTCY). Most patients (n=108) received PTCY with TAC and MMF but a subset (n=17) received PTCY with Rap and MMF.
Risk Factors for Peri-Engraftment AKI
Of the 330 patients with peri-engraftment AKI, 199 (60.3%) had stage 1, 88 (26.7%) had stage 2, and 43 (13.0%) had stage 3 AKI, of whom 16 received RRT (Figure 2a). AKI occurred at a median of 13 days (IQR: 4–30), and rates of AKI were highest in the 22–30 days following HCT (Figure 2b) (Supplemental Figure 2).
Figure 2. Incidence of AKI.
a.Highest AKI staging among those who developed AKI within 30 days.
b.Cumulative incidence of AKI within 30 days post-transplant according to each stage and overall. Median time to onset of AKI is 13 days (Range, −4 to 30)
AKI stages are defined by Kidney Disease: Improving Global Outcomes criteria.
Abbreviations: AKI, acute kidney injury.
In multivariable analyses, serum albumin <3.4 vs. ≥3.4 g/dl (HR 2.04, 95% CI 1.33–3.12; p=0.001), baseline hemoglobin ≤12 vs. >12 g/dl (HR 1.96, 95% CI 1.38–2.78; p<0.001), baseline SCr > 1.1 vs. <1.1 mg/dl (HR 1.87, 95% CI 1.48 – 2.35; p<0.001), any time spent vs. no time spent with rapamycin in the supratherapeutic range (HR 1.56, 95% CI 1.20 – 2.03; p<0.001), any time spent vs. no time spent with tacrolimus in the supratherapeutic range (HR 1.45, 95% CI 1.07 – 1.95; p=0.02), and HCT-CI score ≥4 vs. <4 (HR 1.43, 95% CI 1.14 – 1.79; p=0.002) were each associated with a higher risk of peri-engraftment AKI (Figure 3). When limited to AKI stage 2 or higher in multivariable analyses, any time spent with rapamycin in the supratherapeutic range remained associated with peri-engraftment AKI (Figure 3). In addition, the use of melphalan in the conditioning regimen, baseline serum bicarbonate <22 mEq/L, and CD34+ cell dose > 12×106 cells/kg in the stem cell graft were each associated with peri-engraftment AKI. Age, peripheral blood stem cell source, and any time spent with tacrolimus in the supratherapeutic range were not associated with peri-engraftment AKI after limiting to patients with stage 2 AKI or higher (Supplemental Figure 3). Exposure to nephrotoxic IV antibiotics was associated with stage 2 AKI or higher in univariable analyses (HR 1.67, 95% CI 1.18–2.36; p=0.004), but not in multivariable analyses (HR 1.50, 95% CI 1.00–2.27; p=0.053) (Supplemental Figure 4).
Figure 3. Risk Factors for 30-Day AKI.
Univariable (UV) and multivariable (MV) Cox regression models were performed to identify predictors of peri-engraftment AKI. Tacrolimus and Rapamycin supratherapeutic levels (> 10 ng/mL for tacrolimus and >12 ng/mL for rapamycin) were manually verified by 3 researchers. We calculated estimate of time (in days) spent in the supratherapeutic range for each medication (Calculated Tacrolimus and Calculated Rapamycin)
Abbreviations: 95% CI, 95% Confidence interval; AKI, acute kidney injury; Bu/Flu, busulfan + fludarabine; CMV, cytomegalovirus; Flu/Cy/TBI, fludarabine + cyclophosphamide + total body irradiation; Flu/Mel, fludarabine + melphalan; GVHD PPX, graft versus host disease prophylaxis; HCT-CI, hematopoietic cell transplantation-specific comorbidity index; HLA, human leukocyte antigen; MMUD, mismatched unrelated donor; MRD, matched related donor; MUD, matched unrelated donor; PBSC, peripheral blood stem cells; Rap, rapamycin (sirolimus); SCr, serum creatinine.
There were 125 patients who received post-transplant cyclophosphamide. Among patients who received post-transplant cyclophosphamide but did not receive a haploidentical stem cell transplant (n=40), 4 patients (10%) developed BK viruria, and 3 (7.5%) developed hemorrhagic cystitis (Supplemental Figure 5). None of the patients with BK viruria or hemorrhagic cystitis in this subgroup of patients developed AKI. Among patients who received a haploidentical stem cell transplant (all with post-transplant cyclophosphamide as GVHD prophylaxis), 15 patients (18%) developed BK viruria and 16 (19%) hemorrhagic cystitis. BK viruria was associated with peri-engraftment AKI in unadjusted analyses (p=0.006), but there was no association between development of hemorrhagic cystitis and peri-engraftment AKI (p=0.23) (Supplemental Table 2).
We further explored the association of time spent with individual supratherapeutic drug trough levels with peri-engraftment AKI among patients who received a haploidentical HCT, as the combination of rapamycin and tacrolimus is not used in this subgroup. A total of 85 of 987 patients (8.6%) underwent a haploidentical HCT in our cohort (Table 1), of whom 12 (14.1%) developed AKI, including nine with stage 2 AKI or higher. Due to the small incidence rate of AKI, only univariable analyses were conducted. We found that factors associated with peri-engraftment AKI included any time spent with rapamycin in the supratherapeutic range (HR 27.77, 95% CI 5.13 – 150.36; p<0.001), peripheral blood stem cell source (HR 7.05, 95% CI 1.68–29.66; p<0.01), HCT-CI score ≥ 4 (HR 4.49, 95% CI 1.37–14.77; p=0.013), albumin <3.4 g/dl (HR 7.05, 95% CI 1.96–25.34; p<0.01), and male patients with female donors (HR 3.45, 95% CI 1.05–11.34; p=0.04) (Supplemental Table 3).
Kidney Recovery
Of the patients with stage 1, 2, and 3 AKI not treated with KRT, 18%, 15%, and 30% had kidney recovery, respectively (Supplemental Figure 6). Of the 16 patients treated with KRT, 4 (25%) were liberated within 90 days of HCT.
Peri-Engraftment AKI and Overall Survival and Non-relapse Mortality
Peri-engraftment AKI by day 30 post-HCT was associated with worse overall survival (HR 1.51, 95% CI: 1.26–1.81; p<0.001) (Figure 4, Supplemental Table 4). Additionally, as AKI severity increased, there was a decrease in overall survival (p<0.0001) and an increase in non-relapse mortality (p<0.001) (Figure 5A–B, Supplemental Figure 7A–B). After multivariable adjustment, peri-engraftment AKI was associated with lower overall survival (HR 1.40, 95% CI: 1.16–1.71; p<0.001) and higher non-relapse mortality (HR 2.10, 95% CI: 1.52–2.89; p<0.001) (Supplemental Table 4). Peri-engraftment AKI at any time point from days 0 to 30 was associated with worse overall survival and an increase in non-relapse mortality (Supplemental Figures 8 & 9).
Figure 4. Association of AKI with Overall Survival and Non-Relapse Mortality.
a. Simon-Makuch curves for overall survival. AKI occurrence was treated as a time-dependent variable
b. Simon-Makuch curves for non-relapse mortality. AKI occurrence was treated as a time-dependent variable
Abbreviations: AKI, acute kidney injury.
Figure 5. Association of AKI with Overall Survival and Non-Relapse Mortality, Stratified by Stage.
a. Simon-Makuch curves for overall survival. AKI occurrence was treated as a time-dependent variable
b. Simon-Makuch curves for non-relapse mortality. AKI occurrence was treated as a time-dependent variable
Abbreviations: AKI, acute kidney injury
Discussion
In this large cohort study of RIC allogeneic HCT adult recipients, we found that peri-engraftment AKI is common, occurring in approximately one-third of patients. We identified key patient factors associated with risk of peri-engraftment AKI, including baseline kidney dysfunction, higher HCT-CI index, lower baseline hemoglobin, and hypoalbuminemia. Additionally, transplant-related factors such as conditioning with fludarabine and melphalan, along with GVHD prophylaxis with tacrolimus and rapamycin (particularly when rapamycin levels were supratherapeutic), were each independently associated with risk of peri-engraftment AKI. Importantly, AKI was associated with both worse overall survival and non-relapse mortality.
While rapamycin alone has not been associated with AKI in other studies,25 its combination with tacrolimus is known to be associated with an increased risk of HCT-associated thrombotic microangiopathy and AKI.26 In our cohort, we found that supratherapeutic rapamycin levels (e.g., >12 ng/mL) were associated with AKI, particularly when rapamycin was used in combination with tacrolimus. In patients undergoing haploidentical transplantation, where the combination of tacrolimus and rapamycin is not used, any time with a supratherapeutic rapamycin trough level remained associated with a higher risk of peri-engraftment AKI. The latter association must be interpreted with caution, however, because rapamycin is substituted for tacrolimus in haploidentical transplantation when there is a higher perceived baseline risk of AKI.
Our findings are in general agreement with a recently published single center retrospective study that identified certain GVHD prophylaxis regimens as risk factors for AKI within 100 days of HCT,5 as well as with another study that found an association between melphalan-based conditioning and tacrolimus exposure with AKI post HCT.25 In the former study, however, the association of tacrolimus or rapamycin with peri-engraftment AKI was not evaluated, while in the latter, rapamycin exposure was not associated with the development of AKI in the first 2 years post-HCT. As there are many potential etiologies for AKI within the first 2 years post-HCT, it is possible that the effect of rapamycin exposure on post-HCT AKI was better evaluated in the peri-engraftment period. Additionally, the present study included manual verification of tacrolimus and rapamycin levels, which has rarely been incorporated in studies of large patient cohorts. Overall, our findings underscore the importance of minimizing supratherapeutic levels of rapamycin, especially when used in combination with tacrolimus.
Our results also suggest that physicians should exercise caution with fludarabine/melphalan conditioning and tacrolimus/rapamycin for GVHD prophylaxis when patients carry other risk factors for peri-engraftment AKI, specifically hypoalbuminemia, elevated HCT-CI scores, and baseline kidney dysfunction. Recent studies have shown that lower baseline eGFR and higher baseline SCr are each independently associated with HCT-AKI.27 Hypoalbuminemia is common in patients with cancer, due to malnutrition and cachexia, and may be a predictor of both AKI and other cancer outcomes.28 Among haploidentical stem cell transplant patients receiving post-transplant cyclophosphamide, we also found an association between BK viruria and peri-engraftment AKI in unadjusted analyses, suggesting that these patients may benefit from closer monitoring in the peri-transplant period. However, this analysis comprised a small number of patients, and larger studies are needed to evaluate the association between BK viruria and AKI post-HCT.
We found that peri-engraftment AKI was associated with reduced overall survival and non-relapse mortality, and that the risk increased with AKI severity. Our findings align with the results of single-center studies that found an association between AKI and worse overall survival and progression-free survival after HCT.5, 6, 16 However, our findings add to the literature by focusing specifically on the peri-engraftment period, and we show that AKI during this time period may independently associate with worse outcomes.
There are several limitations of this study. First, this is a single-center study with mostly White patients, potentially limiting the generalizability of our findings. Second, the retrospective nature of this study limits inferences related to causality. Third, there may have been selection bias with respect to how physicians choose conditioning and GVHD prophylaxis regimens. Fourth, we could not adjudicate thrombotic microangiopathy, as we did not collect data on soluble c5b-9 levels or hemolysis labs. Fifth, we did not collect information on disease-specific factors such as number and type of prior lines of therapy, and overall disease burden at the time of transplant. Sixth, we could not examine the effects of different therapeutic troughs depending on whether tacrolimus was used in combination with rapamycin or not, as this does not reflect current practice at our institution. While these limitations impact the generalizability of our findings, this study is nevertheless the largest to comprehensively evaluate peri-engraftment AKI using standardized criteria in a well-curated group of patients. Moreover, the present study included patients receiving haploidentical HCT as well as those receiving tacrolimus and/or rapamycin for GVHD prophylaxis—patients who have been underrepresented in prior studies.5, 16 Finally, prior studies have focused primarily on AKI in the first 100 days post-HCT as opposed to the peri-engraftment period,5, 16 a period that may more accurately reflect the effect of conditioning and GVHD prophylaxis regimens and is less likely to be confounded by the presence of acute or chronic GVHD.29, 30
In conclusion, we identified a high incidence of peri-engraftment AKI among RIC allogeneic HCT recipients. We identified key risk factors associated with peri-engraftment AKI, including baseline kidney dysfunction, lower baseline hemoglobin, higher HCT-CI score, hypoalbuminemia, and type of conditioning and GVHD prophylaxis regimen. We demonstrated an association of peri-engraftment AKI with worse overall survival and non-relapse mortality. Our findings underscore the importance of preventing and managing peri-engraftment AKI to potentially improve the clinical outcomes of RIC allogeneic HCT recipients. Identifying patients at the highest risk for peri-engraftment AKI could aid oncologists and nephrologists in risk stratification, dose adjustments of potentially nephrotoxic medications, and guide monitoring of kidney function. Prospective studies are needed to further elucidate the relationship of transplant-related factors with risk of peri-engraftment AKI.
Supplementary Material
Highlights.
Peri-engraftment acute kidney injury (AKI) occurred in 33% of RIC allogeneic transplant recipients
Peri-engraftment AKI was associated with worse survival and non-relapse mortality
Fludarabine/melphalan conditioning was associated with peri-engraftment AKI
Supratherapeutic GVHD prophylaxis dosing was associated with peri-engraftment AKI
Funding:
NIDDK K23DK125672 (S. Gupta) and P01CA229092 (H. Kim, R. Soiffer)
Footnotes
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Disclosures: P. Connor Johnson reports consulting with AstraZeneca, Seagen, and ADC Therapeutics and research funding from Medically Home. D. Leaf reports funding from NIH grants R01HL144566, R01DK125786, and R01DK126685, as well as grant funding from BioPorto Diagnostics, BTG Specialty Pharmaceuticals, and Metro International Biotech. C. Cutler reports consulting with Mallinckrodt, Sanofi, CSL Behring, CTI Biopharma, Equillium, BMS, Janssen, Incyte, Deciphera, Editas, Pfizer, and CareDx, educational consulting with Omeros and Jazz, Scientific Advisory Board for Cimeio and Oxford Immune Algorithmics, and Data Safety and Monitoring Boards with Allovir, Da Volterra, BioLineRx, Pluristem, and Angiocrine. A. Kelkar reports research funding from CareDx. J. Koreth reports Scientific Advisory Board for Cugene and Therakos (Mallinckrodt), consulting with Equillium, Gentibio, Cue Biopharma, Biolojic Design, and TR1x, research support from Amgen, Clinigen, BMS, Miltenyi Biotec, Regeneron, and Equillium, and legal with Abbvie. S. Gupta reports research support from the NIH, NIDDK K23DK125672, BTG International, and GE Healthcare. She is a member of GlaxoSmithKline’s Global Anemia Council, a consultant for Secretome and Proletariat Therapeutics, and founder of the American Society of Onconephrology. The other authors have no disclosures to report.
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