Acute Kidney Injury in Pediatric Patients Receiving Allogeneic Hematopoietic Cell Transplantation: Incidence, Risk Factors, and Outcomes

Accepted Manuscript Title: Acute Kidney Injury in Pediatric Patients Receiving Allogeneic Hematopoietic Cell Transplantation: Incidence, Risk Factors, and Outcomes Author: Kyung-Nam Koh, Anusha Sunkara, Guolian Kang, Amanda Sooter, Daniel A. Mulrooney, Brandon Triplett, Ali Mirza Onder, John Bissler, Lea C. Cunningham PII: DOI: Reference:

S1083-8791(17)30868-6 https://doi.org/10.1016/j.bbmt.2017.11.021 YBBMT 54878

To appear in:

Biology of Blood and Marrow Transplantation

Received date: Accepted date:

4-8-2017 18-11-2017

Please cite this article as: Kyung-Nam Koh, Anusha Sunkara, Guolian Kang, Amanda Sooter, Daniel A. Mulrooney, Brandon Triplett, Ali Mirza Onder, John Bissler, Lea C. Cunningham, Acute Kidney Injury in Pediatric Patients Receiving Allogeneic Hematopoietic Cell Transplantation: Incidence, Risk Factors, and Outcomes, Biology of Blood and Marrow Transplantation (2017), https://doi.org/10.1016/j.bbmt.2017.11.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Acute Kidney Injury in Pediatric Patients Receiving Allogeneic Hematopoietic Cell Transplantation: Incidence, Risk Factors, and Outcomes

Kyung-Nam Koh1,5*, Anusha Sunkara2, Guolian Kang2, Amanda Sooter1, Daniel A. Mulrooney3,7, Brandon Triplett1,7, Ali Mirza Onder4,6, John Bissler4,6, Lea C. Cunningham1,7*

1

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s

Research Hospital, Memphis, Tennessee 2

Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, Tennessee

3

Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee

4

Department of Pediatrics, St. Jude Children’s Research Hospital, Memphis, Tennessee

5

Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center

Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea 6

Division of Nephrology, Department of Pediatrics, The University of Tennessee Health Science

Center, Memphis, Tennessee 7

Department of Pediatrics, The University of Tennessee Health Science Center, Memphis,

Tennessee

1

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*

Correspondence and reprint requests:

Lea C. Cunningham, MD, Department of Bone Marrow Transplantation & Cellular Therapy, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, MS-310, Room I4308, Memphis, TN 38105 Tel: 901-595-6298; Fax: 901-595-3966; E-mail address: [email protected]

Kyung-Nam Koh, MD, PhD, Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea Tel: +82-2-3010-3386; Fax: +82-2-473-3725; E-mail address: [email protected]

Running title: Acute kidney injury in children receiving HCT Financial disclosure: The authors have nothing to disclose.

Highlights 

Acute kidney injury is common after hematopoietic cell transplant in children.



Survival is poor among patients with stage 3 acute kidney injury.



Survival is dismal in patients requiring renal replacement therapy.



Independent risk factors of acute kidney injury are suggested.



Acute kidney injury should be monitored on standardized criteria after hematopoietic cell transplants. 2

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ABSTRACT Acute kidney injury (AKI) is a common adverse event following hematopoietic cell transplantation (HCT). AKI is associated with early death or chronic kidney disease among transplant survivors. However, large-scale pediatric studies based on standardized criteria are lacking. We performed a retrospective analysis of 1057 pediatric patients who received allogeneic HCT to evaluate the incidence and risk factors of AKI according to AKI Network criteria within the first 100 days of HCT. We also determined the effect of AKI on patient survival. The 100-day cumulative incidences of all stages of AKI, stage 3 AKI, and AKI requiring renal replacement therapy (RRT) were 68.2 ± 1.4%, 25.0 ± 1.3%, and 7.6% ± 0.8%, respectively. Overall survival at 1 year was not different between patients without AKI and those with stage 1 or 2 AKI (66.1% vs 73.4% vs 63.9%), but it was significantly different between patients without AKI and patients with stage 3 AKI with or without RRT requirement (66.1% vs 47.3% vs 7.5%, P < .001). Age, year of transplantation, donor type, sinusoidal obstruction syndrome (SOS), and acute graft-versus-host disease (GVHD) were independent risk factors for stage 1 through 3 AKI. Age, donor, conditioning regimen, number of HCTs, SOS, and acute GVHD were independent risk factors for AKI requiring RRT. Our study revealed that AKI was a prevalent adverse event and severe stage 3 AKI, which was associated with reduced survival, was common after pediatric allogeneic HCT. All patients receiving allogeneic HCT, especially those with multiple risk factors, require careful renal monitoring according to standardized criteria to minimize nephrotoxic insults. Key Words: Acute kidney injury, Allogeneic hematopoietic stem cell transplantation, Children, Renal replacement therapy 3

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INTRODUCTION Acute kidney injury (AKI) is a well-described complication following hematopoietic cell transplantation (HCT), affecting 20% to 84% of transplant recipients1–4. HCT is a multistep process including many treatments that can cause renal insults, such as conditioning regimens comprised of intensive chemotherapy or radiation, nephrotoxic immunosuppressive agents, and prophylactic or therapeutic anti-infectious agents. In addition, many posttransplant adverse events contribute to renal injury during the course of transplantation. AKI is associated with mortality and increased risk of chronic kidney disease in transplant survivors1,2,4–7. In addition, AKI can limit the use of many medications, thereby complicating posttransplant management. Therefore, understanding the risk factors and incidence of AKI is important for improving transplant outcomes. Although several small studies have evaluated AKI after pediatric HCT, large-scale studies are lacking. Previous pediatric studies reported variable incidence rates and inconsistent risk factors. Small patient populations and heterogeneity of diagnoses and transplant strategies have hampered comprehensive analyses of AKI in pediatric HCT. In addition, most earlier studies did not use standardized criteria of AKI, such as the pediatric RIFLE (pRIFLE) criteria8, AKI Network (AKIN) criteria9, or Kidney Disease Improving Global Outcomes (KDIGO) classification system10. Therefore, additional large-scale studies based on standardized criteria are required to accurately determine the incidence, risk factors, and prognosis of AKI in pediatric HCT. We performed this retrospective study to establish the incidence and outcomes of AKI according to AKIN criteria and to determine the risk factors associated with AKI after allogeneic HCT in a large pediatric population. 4

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PATIENTS AND METHODS Patients This study included 1057 consecutive pediatric and adolescent patients who received allogeneic HCT from January 1991 to December 2015 at St. Jude Children’s Research Hospital (St. Jude). For patients who received multiple transplantations, the data from the most recent transplantation were used for the analysis. Data were collected and analyzed retrospectively by using a prospectively managed transplant database and electronic medical records maintained by the Department of Bone Marrow Transplantation and Cellular Therapy at St. Jude. Demographics, year of transplantation, transplant characteristics (e.g., type of donor, graft source, HLA matching, method for graft-versus-host disease [GVHD] prophylaxis, and number of HCTs), indications for HCT, conditioning regimen, acute GVHD, sinusoidal obstruction syndrome (SOS), transplant-associated thrombotic microangiopathy (TA-TMA), hemorrhagic cystitis, renal replacement therapy (RRT), and survival outcomes were retrieved from the transplant database. Because serum creatinine values were unavailable in the database, they were extracted from electronic medical records to evaluate AKI. This study was approved by the St. Jude institutional review board. As this study was retrospective in nature, the requirement for informed consent was waived.

Definitions AKI within the first 100 days after transplantation was graded according to the AKIN classification system (Table 1), which was modified from its original version9. Baseline creatinine was defined as the most recent serum creatinine level recorded immediately before the 5

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conditioning regimen was started. An optimal state of hydration, which is stipulated in the original AKIN criteria, was not considered in this study because it could not be readily assessed in a retrospective medical record review. Urine output data were not used to define AKI because these data were not readily available from the database. Requirement of RRT (e.g., hemodialysis, peritoneal dialysis, or continuous renal replacement therapy) was considered a secondary outcome parameter. To evaluate the effect of the severity of AKI on outcomes, we defined the maximum stage of AKI as the highest stage observed within the first 100 days after transplantation. Conditioning regimens were defined as myeloablative when they contained oral/intravenous equivalent busulfan ≥ 9 mg/kg or total-body irradiation (TBI) with fractionated doses of ≥ 8 Gy, or melphalan doses ≥ 150 mg/m2. Acute GVHD was graded according to the standard criteria11. The diagnosis and severity of SOS was defined according to the modified Seattle criteria12. Both acute GVHD and SOS were considered valid variables if they developed only before AKI and were included in our analysis to evaluate their effect on AKI.

Statistical analysis The primary endpoint of this study was the cumulative incidence and severity of AKI within 100 days post transplant and survival outcome according to AKI. Secondary endpoints included the cumulative incidence of requirement of RRT. Descriptive statistics for patients with and without AKI were provided, and compared using t-test or Wilcoxon rank sum test for continuous variables depending on the normality testing and chi-square test or fisher exact test for categorical variables.

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The cumulative incidence of renal events was estimated by the Kalbfleisch-Prentice method13 and compared with Gray tests14. In the estimation of cumulative incidence of AKI and RRT, deaths without renal events were considered competing events. The Fine-Gray regression model was used to evaluate the associations between cumulative incidence and all other covariates. Univariate analysis was performed to identify variables that were significantly associated with AKI. The parameters associated with outcomes in univariate analyses at a nominal level of 0.1 were included in their respective multivariate analyses according to a step-wise model selection strategy using the Fine-Gray regression model. The rate of overall survival (OS) was estimated by using Kaplan-Meier methods and compared by using log-rank tests. Risk factors considered included age at transplant, gender, year of transplantation (1991–1999 vs 2000–2015), race, indication for HCT (malignant vs nonmalignant diseases), type of progenitor cell source (bone marrow vs peripheral blood vs cord blood), donor (matched related vs mismatched related vs unrelated), conditioning regimen (myeloablative vs reduced intensity vs no conditioning), receipt of more than 8 Gy TBI, total lymphoid irradiation, method for GVHD prophylaxis (calcineurin inhibitor-based vs ex vivo T-cell depletion), receipt of multiple HCTs (1 vs 2 or more), SOS, and acute GVHD (grades II to IV). TA-TMA and hemorrhagic cystitis were not used for risk factor analysis because data on those complications were inconsistently collected in our registry. All reported P values were 2-sided and considered significant if less than 0.05. Statistical analyses were performed with SAS software, version 9.4 (SAS Institute, Cary, NC).

RESULTS We determined the clinical characteristics of 1057 patients who received HCT (Table 2). The median age at the time of transplant was 9.9 years (range, 0.1 to 27.2 years). AKI developed in 7

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721 (68.2%) patients within 100 days of HCT. Among these patients, AKI developed in 555 (52.5%) within 1 month post transplant. The median time between HCT and AKI was 14 days (range, 0 to 99 days). Of the 721 patients who experienced AKI, 158 (22.0%) had stage 1 AKI, 299 (41.4%) had stage 2 AKI, and 264 (36.6%) had stage 3 AKI. Among the 264 patients with stage 3 AKI, 80 (30.3%) required RRT. The 100-day cumulative incidences of all stages of AKI, stage 3 AKI, and AKI requiring RRT were 68.2% ± 1.4%, 25.0% ± 1.3%, and 7.6% ± 0.8%, respectively (Figure 1A). In the early cohort (1991–1999), the 100-day cumulative incidence of all stages of AKI, stage 3 AKI, and AKI requiring RRT were 81.3% ± 2.1%, 35.5% ± 2.6%, and 5.1% ± 1.6%, respectively (Figure 1B). In the late cohort (2000–2015), the 100-day cumulative incidence of all stages of AKI, stage 3 AKI, and AKI requiring RRT were 62.2% ± 1.8%, 20.1% ± 1.9%, and 8.7% ± 1.5% (Figure 1C). The 1-year OS of the patients without AKI and patients with stage 1, stage 2, stage 3 not requiring RRT, and stage 3 requiring RRT was 66.1%, 73.4%, 63.9%, 47.3%, and 7.5%, respectively (Figure 2A). The OS among patients without AKI and those with stage 1 or 2 AKI was not different, but OS was significantly reduced for patients with stage 3 AKI with or without the requirement of RRT (P < .001) when compared with that of patients without AKI. In addition, patients with stage 3 AKI requiring RRT had significantly diminished OS than did patients with stage 3 AKI not requiring RRT (P < .001). The 1-year OS of the patients in the early cohort (1990–1999) without AKI and patients with stage 1, stage 2, stage 3 not requiring RRT, and stage 3 requiring RRT AKI was 67.7%, 61.1%, 64.6%, 38.6%, and 0%, respectively (Figure 2B). The 1-year OS of the patients in late cohort (2000–2015) without AKI and patients with stage 1, stage 2, stage 3 not requiring RRT, and stage 3 requiring RRT AKI was 65.7%, 77.1%, 63.4%, 57.8%, and 9.5%, respectively (Figure 2C). OS rates were significantly greater in the late cohort 8

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than in the early cohort for patients with stage 3 AKI not requiring RRT (57.8% vs 38.6%, P = .011) and stage 3 requiring RRT (9.5% vs 0%, P < .001). We performed univariate cumulative incidence analyses of patients with and without stage 1 through 3 AKI considering death without developing AKI as a competing event, and provided the results of hazard ratios in Table 2. Patients who experienced AKI were significantly older than those who did not (median age, 11.2 vs 7.1 years, P < .001). Among demographic and clinical variables, age at transplantation, year of transplantation, indication for HCT, progenitor cell source, type of donor, intensity of conditioning regimen, use of more than 8 Gy TBI, and method for GVHD prophylaxis were associated with stage 1 through 3 AKI. Among posttransplant events, SOS was associated with stage 1 through 3 AKI, whereas acute GVHD (grades II to IV) was marginally associated. In multivariate analyses, age, year of transplantation, type of donor, SOS, and acute GVHD (grades II to IV) were independent risk factors for stage 1 through 3 AKI (Table 3). Older age groups (6–10 years, 11–15 years and > 16 years) were at higher risk of AKI. Patients in the early cohort (1991–1999) were at higher risk of AKI. The use of matched related donors lowered risk when compared with that of unrelated donors but was not lower than that of mismatched related donors (MMRD). Overall comparisons of conditioning regimens revealed modest differences, but myeloablative conditioning regimens were more highly associated with stage 1 through 3 AKI than were no conditioning regimens. We also performed univariate cumulative incidence analyses of patients with and without developing AKI with requirement of RRT and provided the hazard ratios in Table 2. By univariate cumulative incidence analysis, we found that patients who required RRT were significantly older than those who did not (median age, 15.0 vs 9.3 years, P < .001) (Table 2). Among demographic and clinical variables, age at transplantation, type of donor, intensity of 9

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conditioning regimen, and number of HCTs were associated with AKI requiring RRT. Year of transplantation was marginally associated with AKI requiring RRT. Among posttransplant events, SOS and acute GVHD (grades II to IV) were associated with AKI requiring RRT. By multivariate analysis, we found that age (older age), donor type (MMRD and unrelated donors), conditioning regimens, number of HCTs (≥ 2), SOS, and acute GVHD (grades II to IV) increased the cumulative incidence of AKI requiring RRT (Table 3). Myeloablative conditioning regimens were associated with a higher risk of AKI requiring RRT but were not different than reducedintensity regimens. Notably, SOS was highly associated with AKI. Among 259 patients with SOS, 238 (91.8%) subsequently experienced various stages of AKI (13 with stage 1, 84 with stage 2, and 141 with stage 3). The median time between SOS and AKI was 3 days (range, 0 to 73 days). All 24 patients who were reported to experience TA-TMA also experienced variable degrees of AKI, including 5 (20.8%) with stage 1 AKI, 3 (12.5%) with stage 2 AKI, 4 (16.6%) with stage 3 AKI without RRT, and 12 (50.0%) with stage 3 AKI requiring RRT. For the 78 patients who were reported to experience hemorrhagic cystitis, 28 (35.9%) did not experience AKI, 10 (12.8%) had stage 1 AKI, 18 (23.1%) had stage 2 AKI, 15 (19.2%) had stage 3 AKI without RRT, and 7 (9.0%) had stage 3 AKI requiring RRT.

DISCUSSION This retrospective analysis is the largest single-center study of AKI in pediatric patients receiving allogeneic HCT to date. We found that the incidence of AKI within 100 days of HCT was 68.2%, suggesting that development of various degrees of AKI is prevalent after allogeneic HCT in children. OS was poor among patients with stage 3 AKI and dismal in patients who 10

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required RRT. Although survival improved for patients with stage 3 AKI either with or without the requirement of RRT in the late cohort, the mortality rate for patients requiring RRT was quite high. Therefore, we determined the independent risk factors for stage 1 through 3 AKI and stage 3 AKI requiring RRT. The reported incidence of AKI among pediatric HCT recipients varies widely from 21% to 84%3,15–18. This difference among studies is most likely due to differences in patient characteristics and populations and also by the use of nonstandardized definitions of AKI. Specifically, earlier studies defined AKI as simply the doubling of serum creatinine without further grading of AKI, thereby excluding early-stage AKI15,16,18,19. We found the incidence of AKI is comparable with that in a recent study from Minnesota, which investigated AKI according to the pRIFLE criteria and reported that AKI was detected in 173 of 205 pediatric patients (84%) within the first 100 days post transplant3. Our findings confirm those of the Minnesota study, indicating that AKI is a prevalent adverse event during the early steps of HCT. Previous studies showed that application of the pRIFLE, AKIN, and KDIGO criteria resulted in differences in the reported incidence and staging of AKI in hospitalized children, but all 3 definitions provided excellent interstage discrimination20–22. In a study of adult patients receiving HCT, the RIFLE criteria were more sensitive than the AKIN criteria for identifying patients with posttransplant AKI23. However, a comparative study of the pRIFLE and AKIN criteria for determining AKI after HCT in pediatric patients is lacking. We observed that using either the pRIFLE criteria (stages R and I) from the Minnesota study or the AKIN criteria (stages 1 and 2) from our study to determine early stage AKI did not affect survival outcomes in pediatric patients. To adopt a single, universal definition for future prospective studies, criteria that are

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more clinically relevant for predicting chronic kidney disease and survival outcomes for pediatric HCT recipients should be elucidated. Previous reports have described some risk factors for AKI in HCT recipients6,24. In pediatric studies, transplant characteristics such as donor and race; nephrotoxic agents such as cyclosporine, amphotericin B, and foscarnet; and posttransplant events such as SOS were inconsistently described as risk factors for AKI3,15–18. This inconsistency among pediatric studies is due to the vast number of possible risk factors in comparison with the small size and heterogeneity of the study populations. In our study, we describe independent risk factors for all stages of AKI and severe AKI requiring RRT, which we based on a large population size. In particular, our study population included a relatively large number of patients who received transplants from MMRDs, reduced-intensity conditioning, and multiple transplantations, thereby permitting evaluation of the effect of various risk factors on AKI in children. Age was not determined to be a risk factor of AKI in previous pediatric studies3,15–18, except by a study by Rajpal et al. that reported older age (11 to 21 years vs 0 to 10 years) as a predictor of AKI requiring dialysis25. Older age at treatment was reported to be an important risk factor of renal adverse events in multivariate analyses of pediatric patients with cancer who received chemotherapy26. We also found that older ages were independently predictive of all stages of AKI and severe AKI requiring RRT, suggesting that older children are more vulnerable to renal injury during allogeneic HCT. We found that the use of unrelated donors for HCT was an independent risk factor for all stages of AKI and AKI requiring RRT. HCTs from unrelated donors are associated with more posttransplant events, such as infection, GVHD, and organ toxicities27–29. Such posttransplant adverse events may also contribute to AKI, and the nephrotoxic agents used to prevent or treat 12

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such complications also cause AKI. Notably, use of MMRDs did not increase risk of stage 1 through 3 AKI but was associated with a higher risk of AKI requiring RRT. This may be because St. Jude clinicians frequently use reduced-intensity conditioning regimens and intensive T-cell– depletion strategies (thereby minimizing calcineurin inhibitor exposure) for many transplants from MMRDs, and the MMRD group was most likely to include patients who had refractory or advanced disease or received multiple transplantations. By multivariate analyses, we found that conditioning intensity was a risk factor for all stages of AKI and stage 3 AKI requiring RRT, and only the absence of a conditioning regimen was predictive of less AKI. This suggests that conditioning radio-chemotherapy can influence the occurrence of AKI regardless of its intensity. In adult studies, severe AKI was more frequent in myeloablative transplants than in nonmyeloablative transplants24. However, the independent effect of conditioning regimens is difficult to evaluate because the choice of conditioning regimen relies largely on the indication of HCT, disease status, comorbidities, and type of donor. Many posttransplant events such as lung toxicity, sepsis, cardiac involvement, admission to an intensive care unit, SOS, and acute GVHD are previously described risk factors for renal events in various pediatric and adult studies1,2,24. Among them, SOS is a repeatedly described risk factor16,17,26,30–32. We found that hepatic SOS is an independent predictor of all stages of AKI and severe AKI requiring RRT. Studies in adults revealed that 50% to 80% of patients with SOS also experience severe AKI2, although few pediatric studies have evaluated the incidence of AKI and SOS in large pediatric cohorts. We found that more than 90% of patients with SOS experienced various stages of AKI, and notably 54% of these patients experienced severe stage 3 AKI. Although the pathophysiology of AKI in the context of SOS is not fully understood, AKI

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may contribute to hepatorenal syndrome. Moreover, endothelial damage may cause both hepatic and renal damage during SOS. The contribution of acute GVHD to AKI is described in several adult studies33–35 but not in pediatric studies. Acute GVHD may be associated with either cytokine-mediated inflammation affecting the tubules/glomeruli or the use of nephrotoxic medications such as calcineurin inhibitors1. In addition, gastrointestinal GVHD can cause mucosal damage and fluid loss, which can contribute to prerenal azotemia. Although our study provides a large-scale and comprehensive analysis of AKI from HCT, it was limited by several factors. First, we could not collect glomerular filtration rate and urine output data because of the retrospective nature of our study. Serum creatinine may remain low despite a marked reduction in glomerular filtration rate because of poor creatinine biosynthesis from reduced muscle mass in patients receiving HCT for prolonged, complex illnesses. Therefore, potential flaws in the applicability of the AKIN criteria should be considered for these patients. Second, we could not collect other potential variables that may have influenced the occurrence of AKI but were not present in the database. Third, because our analysis covered a relatively long time span, the conditioning regimens and supportive care strategies varied over the course of the study. Fourth, we could not collect data reporting the progression to chronic kidney disease from each stage of AKI, which should be elucidated in future studies. In conclusion, AKI was a prevalent adverse event affecting more than two thirds of pediatric recipients receiving allogeneic HCTs. Notably, 25% of patients experienced severe stage 3 AKI according to the AKIN criteria, which greatly affected survival outcomes. Therefore, all patients who receive allogeneic HCT should be carefully monitored for AKI based on standardized criteria, especially for patients who receive transplantations at an older age, stem cells from 14

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unrelated or mismatched donors, or multiple transplants. Because AKI was highly associated with the preceding posttransplant adverse events SOS and acute GVHD, meticulous renal care is necessary for patients who experience these adverse events. Further study is needed to identify other variables or biomarkers to predict AKI and improve its timely diagnosis.

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Ando M, Mori J, Ohashi K, et al. A comparative assessment of the RIFLE, AKIN and conventional criteria for acute kidney injury after hematopoietic SCT. Bone Marrow Transplant. 2010;45:1427-1434.

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Hahn T, Rondeau C, Shaukat A, et al. Acute renal failure requiring dialysis after allogeneic blood and marrow transplantation identifies very poor prognosis patients. Bone Marrow Transplant. 2003;32:405-410.

Figure 1. Cumulative incidence analysis for acute kidney injury (AKI), considering deaths without developing AKI as competing risk, within 100 days posttransplant in the overall cohort (A), early cohort (1991–1999) (B), and late cohort (2000–2015) (C). Figure 2. Overall survival by severity of acute kidney injury in the overall cohort (A), early cohort (1991–1999) (B), and late cohort (2000–2015) (C).

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TABLES Table 1 The AKIN classification modified for this study Stage Criteria Stage 1

Increase in serum creatinine levels to 1.5- to 2.0-fold from baseline

Stage 2

Increase in serum creatinine to > 2- to 3- fold from baseline

Stage 3

Increase in serum creatinine to > 3 fold from baseline or need for renal replacement therapy

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Table 2 Demographic/Clinical Characteristics and Univariate Analysis of Acute Kidney Injury Variables

All patients (N = 1057)

Median age at 9.9 (0.1–27.2) transplantation, year (range) Age group

AKI stage 1–3 vs no AKI AKI stage 1–3 (N = 721)

No AKI (N = 336)

11.2 (0.2–27.2)

7.1 (0.1–25.2)

HR (95% CI)

RRT vs no RRT P < .001

RRT (N = 80)

No RRT (N = 977)

HR (95% CI)

15.0 (0.5–22.9) 9.32 (0.1–27.2)

< .001

< .001

0–5 years

305 (28.8)

170 (55.7)

135 (44.3)

1

6–10 years

228 (21.6)

151 (66.2)

77 (33.8)

1.58(1.10–2.27)

11–15 years

247 (23.4)

185 (74.9)

62 (25.1)

> 15 years

277 (26.2)

215 (77.6)

62 (22.4)

< .001 9 (3.0)

296 (97.0)

1

.014

9 (3.9)

219 (96.1)

1.35 (0.54-3.40)

.500

2.05 (1.43–2.93)

< .001

23 (9.3)

224 (90.7)

3.28 (1.52-7.10)

.003

2.26 (1.59–3.23)

< .001

39 (14.1)

238 (85.9)

5.08 (2.47-10.45)

< .001

Sex

.758

.361

Male

609 (57.6)

413 (67.8)

196 (32.2)

1

50 (8.2)

559 (91.8)

1

Female

448 (42.4)

308 (68.6)

140 (31.4)

1.02 (0.88–1.18)

30 (6.7)

418 (93.3)

0.81 (0.52–1.27)

< .001

Year of transplantation

0.051

1991-1999

332 (31.4)

270 (81.3)

62 (18.7)

1.70 (1.46-1.97)

17 (5.1)

315 (94.9)

2000-2015

725 (68.6)

451 (62.2)

274 (37.8)

1

63 (8.7)

662 (91.3)

Race

0.59 (0.34-1.00)

.602

White

757 (71.6)

512 (67.6)

245 (32.4)

1

African American

164 (15.5)

112 (68.3)

52 (31.7)

1.00 (0.82–1.22)

Asian

18 (1.7)

10 (55.6)

8 (44.4)

Other

118 (11.2)

87 (73.7)

31 (26.3)

.384 51 (6.7)

706 (93.3)

1

.975

17 (10.4)

147 (89.6)

1.55 (0.90–2.67)

.114

0.79 (0.40–1.56)

.493

1 (5.6)

17 (94.4)

0.83 (0.11–6.25)

.860

1.13 (0.92–1.41)

.259

11 (9.3)

107 (90.7)

1.39 (0.73–2.65)

.320

Indication for HCT

< .001

.062

Malignant

852 (80.6)

604 (70.9)

248 (29.1)

1

71 (8.3)

781 (91.7)

1

Nonmalignant

205 (19.4)

117 (57.1)

88 (42.9)

0.69 (0.57–0.84)

9 (4.4)

196 (95.6)

0.52 (0.26–1.03)

Donor cell source

P

< .001

.058

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Variables

All patients (N = 1057)

AKI stage 1–3 vs no AKI AKI stage 1–3 (N = 721)

No AKI (N = 336)

HR (95% CI)

RRT vs no RRT P

RRT (N = 80)

No RRT (N = 977)

HR (95% CI)

46 (6.6)

646 (93.4)

1

P

Bone marrow

692 (65.5)

526 (76.0)

166 (24.0)

1

Peripheral blood

338 (32.0)

175 (51.8)

163 (48.2)

0.51 (0.043–0.61)

< .001

29 (8.6)

309 (91.4)

1.29 (0.81–2.05)

.284

27 (2.6)

20 (74.1)

7 (25.9)

1.04 (0.65–1.68)

.869

5 (18.5)

22 (81.5)

2.90 (1.17–7.16)

.021

Cord blood Donor

< .001

MRD

265 (25.1)

185 (69.8)

80 (30.2)

1

MMRD

358 (33.9)

196 (54.7)

162 (45.3)

0.65 (0.53–0.79)

UD

434 (41.1)

340 (78.3)

94 (21.7)

1.30 (1.09–1.55)

Conditioning regimen

5 (1.9)

260 (98.1)

1

< .001

31 (8.7)

327 (91.3)

4.70 (1.82–12.11)

.001

.004

44 (10.1)

390 (89.9)

5.60 (2.21–14.17)

< .001

< .001

Myeloablative

716 (67.7)

542 (75.7)

174 (24.3)

1

Reduced intensity

326 (30.8)

178 (54.6)

148 (45.4)

0.57 (0.48–0.67)

15 (1.4)

1 (6.7)

14 (93.3)

0.05 (0.01–0.35)

No conditioning

.001

TBI ≥ 8 Gy

< .001 51 (7.1)

665 (92.9)

1

< .001

29 (8.9)

297 (91.1)

1.25 (0.79–1.96)

.339

.003

0

15 (100)

NE

< .001

< .001

.557

No

505 (47.8)

276 (54.7)

229 (45.3)

1

41 (8.1)

464 (91.9)

1

Yes

552 (52.2)

445 (80.6)

107 (19.4)

2.02 (1.74–2.34)

39 (7.1)

513 (92.9)

0.88 (0.57–1.36)

TLI

.686

.587

No

993 (93.9)

676 (68.1)

317 (31.9)

1

74 (7.5)

919 (92.5)

1

Yes

64 (6.1)

45 (70.3)

19 (29.7)

1.06 (0.79–1.43)

6 (9.4)

58 (90.6)

1.26 (0.55–2.86)

< .001

GVHD prophylaxis

0.831

CNI-based

946 (89.5)

670 (70.8)

276 (29.2)

2.01 (1.52-2.66)

72 (7.6)

874 (92.4)

1.08 (0.53-2.21)

Ex vivo T-cell depletion

111 (10.5)

51 (45.9)

60 (54.1)

1

8 (7.2)

103 (92.8)

1

Number of HCTs 1 ≥ 2 SOS*

.593

< .001

974 (92.1)

669 (68.7)

305 (31.3)

1

65 (6.7)

909 (93.3)

1

83 (7.9)

52 (62.7)

31 (37.3)

0.92 (0.68–1.24)

15 (18.1)

68 (81.9)

2.90 (1.65–5.07)

< .001

< .001

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Variables

No Yes Acute GVHD

All patients (N = 1057)

AKI stage 1–3 vs no AKI AKI stage 1–3 (N = 721)

No AKI (N = 336)

HR (95% CI)

798 (75.5)

483 (60.5)

315 (39.5)

259 (24.5)

238 (91.9)

21 (8.1)

RRT vs no RRT RRT (N = 80)

No RRT (N = 977)

HR (95% CI)

1

28 (3.5)

770 (96.5)

1

2.62 (2.25–3.06)

52 (20.1)

207 (79.9)

6.19 (3.91–9.80)

†

P

.055

P

.024

No

820 (77.6)

548 (66.8)

272 (33.2)

1

54 (6.6)

766 (93.4)

1

Yes

237 (22.4)

173 (73.0)

64 (37.0)

1.18 (1.00–1.40)

26 (11.0)

211 (89.0)

1.71 (1.07–2.73)

Data presented are n (%) unless otherwise indicated. AKI indicates acute kidney injury; CI, confidence interval; CNI, calcineurin inhibitor; GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation; HR, hazard ratio; NE, not estimable; MMRD, mismatched related donor; MRD, matched related donor; RRT, renal replacement therapy; SOS, sinusoidal obstruction syndrome; TBI, total body irradiation; TLI, total lymphoid irradiation; UD, unrelated donor. * SOS before AKI was considered a valid variable. † Acute GVHD (grades II–IV) before AKI was considered a valid variable.

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Table 3 Multivariable analysis for AKI compared to no AKI and RRT compared to no RRT AKI stage 1–3 vs no AKI Variables HR (95% CI) P Age group

RRT vs no RRT HR (95% CI)

< .001

P < .001

0–5 years

1

6–10 years

1.38 (1.10–1.72)

.005

1.52 (0.62–3.71)

.361

11–15 years

1.77 (1.44–2.18)

< .001

3.16 (1.49–6.69)

.003

> 15 years

1.71 (1.38–2.11)

< .001

4.19 (2.07–8.50)

< .001

Year of transplantation

1

0.009

0.067

1991-1999

1.27 (1.06-1.53)

0.54 (0.28-1.04)

2000-2015

1

1

Indication for HCT Malignant Nonmalignant

.732 1

1

0.96 (0.75–1.22)

0.88 (0.40–1.94)

Donor cell source Bone marrow

.755

.477 1

.315 1

Peripheral blood

0.84 (0.63–1.13)

.260

0.67 (0.31–1.45)

.308

Cord blood

1.12 (0.63–1.99)

.703

1.67 (0.61–4.61)

.320

Donor MRD

.002 1

.005 1

MMRD

0.90 (0.70–1.17)

.443

4.64 (1.62–13.29)

.004

UD

1.29 (1.07–1.55)

.007

4.75 (1.83–12.32)

 .001

Conditioning regimen Myeloablative Reduced intensity No conditioning

< .001

.055 1 0.88 (0.68–1.14) 0.10 (0.01–0.73)

TBI ≥ 8 Gy

1 .278 .024

1.04 (0.59–1.85) NE

*

1

–

Yes

1.17 (0.90–1.53)

–

Number of HCT

< .001

1

–

1

≥ 2

–

3.05 (1.58–5.90)

GVHD prophylaxis

Ex vivo T-cell depletion

0.285 1.20 (0.86-1.66)

–

1

–

†

SOS

No

< .001

.250

No

CNI-based

.882

< .001 1

< .001 1

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AKI stage 1–3 vs no AKI HR (95% CI)

Variables Yes Acute GVHD

P

2.30 (1.95–2.71) ‡

RRT vs no RRT HR (95% CI)

P

5.87 (3.56–9.68) .001

.016

No

1

1

Yes

1.31 (1.11–1.54)

1.85 (1.12–3.05)

AKI indicates acute kidney injury; CI, confidence interval; CNI, calcineurin inhibitor; GVHD, graft-versus-host disease; HCT, hematopoietic cell transplantation; HR, hazard ratio; NE, not estimable; MMRD, mismatched related donor; MRD, matched related donor; RRT, renal replacement therapy; SOS, sinusoidal obstruction syndrome; TBI, total body irradiation; TLI, total lymphoid irradiation; UD, unrelated donor. *  Not estimable due to zero events in that particular category. † SOS before AKI was considered a valid variable. ‡ Acute GVHD (grades II–IV) before AKI was considered a valid variable.

26

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Figure 3.

27

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28

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Figure 4.

29

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30

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fig1A_bestsetConverted.png

31

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fig1B_bestsetConverted.png

32

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fig1C_bestsetConverted.png

33

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fig2A_bestsetConverted.png

34

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fig2B_bestsetConverted.png

35

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fig2C_bestsetConverted.png

36

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