Risk factors for acute kidney injury after hematopoietic stem cell transplantation in children: a single-center retrospective study

Abstract

Objective

To analyze the clinical characteristics and risk factors of acute kidney injury (AKI) after hematopoietic stem cell transplantation (HCT) in children.

Methods

The clinical data of children who underwent HCT at our hospital from August 2016 to December 2023 were retrospectively analyzed, including age, sex, primary disease, mode of transplantation, conditioning regimen, serum creatinine (SCr) before transplantation, and the highest value of SCr from the beginning of conditioning to 100 days after transplantation. AKI was diagnosed and staged according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria, primarily based on changes in SCr. We performed univariate and multivariate logistic regression analyses to determine the risk factors for AKI, including the time of AKI onset, transplantation-related complications (sepsis, acute graft-versus-host disease (aGVHD), thrombotic microangiopathy (TMA), hepatic sinusoidal gap obstruction syndrome, hemorrhagic cystitis, cytomegalovirus infection, and Epstein-Barr virus infection). Cumulative incidence competing risk analysis was used to assess AKI incidence, with death as a competing event. Risk factors were analyzed using multivariable Cox proportional hazards regression with time-dependent covariates for post-transplantation complications.

Results

A total of 299 patients were included. The cumulative incidence of AKI was 73.6% (220/299), with 131, 62, and 27 cases at Stage I, II, and III, respectively. The median time to AKI onset was 24 days (range: −4 to +91 days). Multivariable analysis showed that human leukocyte antigen (HLA) mismatch, hepatic sinusoidal obstruction syndrome (SOS), aGVHD, TMA, and cytomegalovirus/Epstein-Barr virus (CMV/EBV) infection were independent risk factors for AKI (P < 0.05). AKI was significantly associated with worse overall survival (Log-rank test, P < 0.001).

Conclusions

AKI is a common complication of HCT in children. HLA mismatch and post-transplantation complications are independent risk factors. Severe AKI is closely associated with poor prognosis. Early monitoring and management of AKI are crucial for improving outcomes.

Introduction

The rapid development of pediatric hematopoietic stem cell transplantation (HCT) in China has increased the availability of various donor sources, including haploidentical donors (HIDs), unrelated donors, matched related donors (MRDs), and cord blood transplantation (CBT). The proportion of HID HCT in allogeneic HCT increased from 29.6% (313/1,062) in 2008 to 48.8% (1,939/3,975) in 2015 and reached 51.7% (1,157/2,237) (Xu et al., 2017) in the first half of 2016. Consequently, survival rates and quality of life for patients have improved. However, the increase in transplantation procedures has been accompanied by a rise in transplantation-related complications, among which renal complications are significant as they directly affect patient prognosis (Hingorani, 2016; Parikh & Coca, 2006). Currently, there is a scarcity of data on HCT-related acute kidney injury (AKI) in children in China, and international studies are also limited. This lack of evidence leads to inconsistencies in the diagnosis and management of AKI in this population. Therefore, this study aimed to assess the incidence of AKI and analyze its risk factors in children undergoing HCT, to provide a basis for early diagnosis, prevention, and treatment, thereby potentially reducing overall mortality.

Subjects and Methods

Subjects

We enrolled children aged 0–18 years who underwent allogeneic HCT at our Hospital between August 2016 and December 2023. The study was approved by the Institutional Review Board of Wuhan Children’s Hospital (Ethics Review Number: 2021R039-E01). Informed consent was waived due to the retrospective nature of the study. Patients were excluded if they had incomplete clinical data or were lost to follow-up within 100 days post-transplantation without a documented AKI event. Initially, 303 patients were screened, and 299 were included in the final analysis, with four excluded due to loss of follow-up.

Data collection and definitions

Clinical data were retrospectively collected, including demographic characteristics, primary disease, transplantation details (donor type, human leukocyte antigen (HLA) matching), conditioning regimen, and post-transplantation complications.

• •AKI definition and staging: AKI was diagnosed and staged according to the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines (Khwaja, 2012), based on an increase in serum creatinine (SCr). Specifically, AKI was defined as an increase in SCr by ≥0.3 mg/dL (≥26.5 µmol/L) within 48 h or an increase to ≥1.5 times the baseline level within 7 days. Urine output criteria were not used due to inconsistent monitoring in our retrospective dataset, which is a limitation of this study. AKI staging was as follows: Stage I: 1.5−1.9 times baseline or ≥0.3 mg/dL increase; Stage II: 2.0−2.9 times baseline; Stage III: ≥3.0 times baseline or initiation of renal replacement therapy.
• •Baseline SCr: The lowest SCr value measured within 7 days before the start of the conditioning regimen was used as the baseline.
• •Conditioning regimens: The majority of patients received a busulfan (BU) plus cyclophosphamide (CY) based myeloablative regimen. Other commonly used agents included fludarabine (Flu), etoposide (VP-16), semustine (CCNU), and anti-thymocyte globulin (ATG). The drug dosages were BU, 12.8 mg/kg/d −7 to +4; CY, 120 mg/kg/d −3 to −2; ATG, 4.5 mg/kg/ d−2 to −l; VPl6, 200 mg/m2/d −5 to −4; CCNU, 250 mg/m2/d −5, and Flu, 40 mg/m2/d −6 to −4.
• •Definitions of Complications:
  • ⇒Acute graft-versus-host disease (aGVHD) was diagnosed and graded according to the Chinese Expert Consensus (Stem cell Application Group, Society of Hematology, Chinese Medical Association, 2020), which is consistent with international standards (Penack et al., 2020).
  • ⇒Transplant-associated thrombotic microangiopathy (TA-TMA) was diagnosed using the criteria proposed by Jodele et al. (2016) (Table 1).
  • ⇒Sinusoidal obstruction syndrome (SOS) was diagnosed based on the European Society for Blood and Marrow Transplantation (EBMT) criteria (Mohty et al., 2015). Any one of the following criteria needed to be met if disease onset occurred 21 days after HCT. (1) Disease onset occurred 21 days after HCT and other criteria were met according to the Baltimore criteria. (2) Pathological evidence of liver biopsy showed that the early manifestations were terminal hepatic vein intimal edema, centrilobular congestion, and hepatocyte necrosis. In the late stage, centrilobular fibrosis, terminal hepatic vein wall thickening, and luminal stenosis or occlusion could be seen. (3) Hemodynamic and/or ultrasonographic evidence revealed slow or reversed portal blood flow, hepatomegaly, and ascites; in addition, patients were required to have met at least two of the following four criteria—serum bilirubin ≥ 20 mg/L, hepatomegaly with pain, weight gain >5%, and ascites.
  • ⇒Hemorrhagic cystitis (HC), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) infections were diagnosed using standard clinical and laboratory criteria (Petca et al., 2021; Ljungman et al., 2017; Ru et al., 2020).
• •Chronic kidney disease (CKD) definition: For follow-up, CKD was defined as the presence of kidney damage or a glomerular filtration rate (GFR) of <60 mL/min/1.73 m² for more than 3 months, according to KDIGO guidelines.

Table 1. Diagnostic criteria for transplantation-associated thrombotic microangiopathy (TA-TMA).

Tissue biopsy showed evidence of microthrombus or met five of the following seven laboratory or clinical criteria:
① Lactate dehydrogenase (LDH) exceeding the upper limit of normal values
② Proteinuria (random urine protein exceeding the upper limit of normal values or random urine protein/creatinine ≥2 mg/mg)
③ Hypertension
④ New thrombocytopenia (platelet count <50 ×109 per liter or ≥ 50% reduction in platelet count from baseline)
⑤ New anemia (hemoglobin level below the lower limit of the normal reference value or increased transfusion requirements)
⑥ Evidence of microangiopathy (presence of schistocytes in peripheral blood) or pathological findings of tissue specimens suggestive of microangiopathy)
⑦ Terminal complement activation (plasma sC5b-9 levels above the upper limit of normal in healthy individuals)

Notes.

sC5b-9

Soluble complement membrane attack complex

① ② ③

TA-TMA should be considered and closely monitored

②+⑦

The prognosis is poor, and early intervention should be considered

Statistical analysis

Statistical analyses were performed using R software (version 4.3.2; R Core Team, 2023) and SPSS 20.0. Continuous variables were described as mean ± standard deviation or median (interquartile range) as appropriate, and compared using Student’s t-test or Mann–Whitney U test. Categorical variables were described as counts (percentages) and compared using the Chi-squared test or Fisher’s exact test.

• •AKI incidence: The cumulative incidence of AKI was calculated using a competing risk analysis, with death without AKI treated as a competing event. Results were presented as cumulative incidence curves.
• •Risk factor analysis: Univariable analysis was first performed. Variables with P < 0.1 in univariable analysis were included in the multivariable analysis. To account for the timing of events, a time-dependent Cox proportional hazards model was used for post-transplantation complications (e.g., aGVHD, SOS, thrombotic microangiopathy (TMA), infections). In this model, complications were included as time-varying covariates, meaning a patient was considered unexposed until the complication occurred. Pre-transplantation factors (e.g., HLA matching, primary disease) were included as fixed covariates.
• •Survival analysis: The association between AKI stage and overall survival was assessed using the Kaplan–Meier method, and differences between groups were compared with the log-rank test.

Results

A total of 299 children were included, with a mean age of 8.5 years (range: 8 months to 15.11 years). The baseline characteristics of patients with and without AKI are summarized in Table 2. The cumulative incidence of AKI at 100 days post-transplantation was 73.6% (220/299). Among the AKI patients, 131 (59.5%), 62 (28.2%), and 27 (12.3%) were classified as Stage I, II, and III, respectively. The median time to AKI onset was 24 days (4 days + 91 days): with an AKI I period of 28 days, AKI II period of 23.5 days, and AKI III period of 19 days; of these, seven cases occurred during the pre-transplantation conditioning phase, and the rest occurred within the first 100 days of transplantation. There were 155 cases of aGVHD, 40 cases of TMA, 32 cases of SOS, 53 cases of hemorrhagic cystitis, 83 cases of CMV, and 41 cases of EBV. Regarding prognosis, two cases we followed showed septic shock, six cases converted to CKD, three cases were in AKI Stage III, one case in AKI Stage II, and two cases in AKI Stage I. The renal function of the remaining children returned to normal within 100 days.

Table 2. Clinical indicators of AKI and No Acute Kidney Injury (NAKI) in children after hematopoietic stem cell transplantation.

	NAKI group	AKI group			AKI vs. NAKI
		AKI stage I	AKI stage II	AKI stage III
Number of cases	79	131	62	27	Z/chi square	P
Age (years)	4.67 (0.86–12.83)	4.33 (0.85–14.9)	4.58 (0.73–13)	7.33 (1.08–13.58)	0.220	0.826
Male/female	40/39	74/57	40/22	17/10	1.866	0.170
Median time to AKI (days)	–	28	23.5	19	–	–
Source (allogeneic/autologous)	72/7	131/0	61/1	27/0	#	0.142
Degree of HLA match (perfect match/incomplete match)	46/33	31/100	19/43	10/17	#	<0.001
(related/unrelated donor correlation)	44/35	96/35	42/20	18/9	#	0.024
Pretreatment-method (myeloablative/non-myeloablative)	78/1	131/0	61/1	27/0	#	0.142
Diseases
Aplastic anemia	22	36	20	6	0.230	0.631
Acute lymphoblastic leukemia	5	12	5	3	0.575	0.448
Acute myeloid leukemia	26	32	14	2	1.343	0.247
Myelodysplastic syndromes	5	6	3	1	#	>0.99
β-Thalassemia	6	12	2	0	#	0.268
Hemophagocytic syndrome	0	5	2	5	#	0.041
Other	16	29	18	6	0.0003	0.987
Transplant complications
aGVHD	28	74	35	18	11.562	<0.001
SOS	3	14	9	6	5.356	0.021
TMA	2	18	11	9	10.900	<0.001
EBV infection	4	20	11	6	6.788	0.009
CMV infection	9	44	18	12	14.342	<0.001
Hemorrhagic cystitis	8	22	14	9	4.251	0.039
Sepsis	77	128	62	27	#	0.610
Related medications for treatment
Meropenem	74	126	58	26	#	0.552
Vancomycin	65	115	53	24	1.201	0.273
Voriconazole	77	123	56	25	#	0.171
Methotrexate	36	68	35	10	0.781	0.377
Cyclosporin	69	121	59	24	#	0.054
Tacrolimus	1	2	2	3	#	>0.99

Notes.

^#Fisher’s exact-probability method.

We analyzed HCT AKI for risk factors of AKI with respect to sex, age, degree of HLA matching, donor correlation, diseases, and complications after transplantation and drug use. First, the risk factors for AKI were screened using univariate logistic regression analysis (Table 3).

Table 3. Single-factor regression analysis.

Variables		OR	95% CI	P
Sex (male vs. female)		0.69	0.41, 1.16	0.171
Type of disease (vs. all other diseases)
Aplastic anemia	0.83	0.39, 1.80	0.633
Acute lymphoblastic leukemia	1.92	0.57, 9.19	0.313
Acute myeloid leukemia	0.63	0.29, 1.41	0.258
Bone marrow dysplasia syndrome	0.91	0.16, 7.56	0.917
β-thalassemia	0.45	0.10, 2.09	0.296
Hemophagocytic syndrome	6.57	1.25, 163	0.038
Myeloablative Regimen		–	–	-
HLA match (incomplete vs. full)		2.89	1.66, 5.06	<0.001
Donor correlation		1.74	0.97, 3.06	0.056
Complications (vs. none)
SOS	3.84	1.31, 16.39	0.030
aGVHD	2.48	1.47, 4.28	0.001
TMA	8.03	2.38, 50.17	0.005
CMV infection	3.94	1.95, 8.86	<0.001
EBV infection	3.79	1.45, 12.98	0.014
Hemorrhagic cystitis	2.28	1.07, 5.44	0.043
Sepsis	1.87	0.24, 11.54	0.494
Related medications
MTX	1.26	0.75, 2.12	0.377
Vancomycin	1.47	0.71, 2.93	0.275
Meropenem	1.41	0.43, 4.13	0.535
Antifungal agents	0.33	0.05, 1.20	0.147
CNI (ring spore element A and tacrolimus)	1.71	0.58, 4.83	0.463

Notes.

MTX

Methotrexate

CNI

Calcineurin inhibitors (including Cyclosporin and Thacrolimus)

Univariate logistic regression analysis showed that HLA matching degree, primary disease (hemophagocytic syndrome), and complications after transplantation (aGVHD, SOS, TMA, EBV/CMV infection, hemorrhagic cystitis) (P < 0.05) were risk factors for AKI. The above selected factors then underwent multivariate logistic regression analysis (Table 4).

Table 4. Multivariable cox proportional hazards regression analysis for AKI.

Variable		Hazard ratio (HR)			95% Confidence interval (CI)		P
Diseases (vs. all other diseases)
Hemophagocytic syndrome	2.75		0.44, 53.64		0.362
HLA matching (not total vs. total)	2.23		1.22, 4.09		0.009
Complications (yes vs. no)
SOS	3.92	1.24, 17.52		0.037
aGVHD	1.98	1.08, 3.65		0.027
TMA	8.50	2.31, 55.44		0.006
CMV infection	2.64	1.22, 6.21		0.018
EBV infection	4.66	1.66, 16.76		0.007
Hemorrhagic cystitis	2.03	0.88, 5.15		0.110

Multivariate cox regression analysis showed that HLA incompatibility and complications including SOS, aGVHD, TMA, and CMV/EBV infection were independent risk factors for AKI (P < 0.05).

During the follow-up period, six patients (2.0%) developed CKD. The Kaplan–Meier survival curve demonstrated that patients who developed AKI, particularly those with Stage II/III AKI, had significantly worse overall survival compared to those without AKI (Log-rank test, P < 0.001) (Fig. 1).

Figure 1. Kaplan–Meier survival curves by AKI stage.

Discussion

This study, employing advanced statistical methods such as competing risk analysis and time-dependent Cox modelling, confirms that AKI is a common and serious complication following allogeneic HCT in a large single-center pediatric cohort. We found that the cumulative incidence of AKI within 100 days post-transplantation was 73.6%, and its occurrence was significantly associated with worse overall survival. Multivariable analysis further identified HLA mismatch, SOS, aGVHD, TMA, and CMV/EBV infection as independent risk factors for AKI.

A key strength of this study lies in the application of more rigorous statistical methodologies. Unlike many previous studies that used logistic regression, we calculated the incidence of AKI using competing risk analysis, which avoids overestimation by accounting for competing events such as early death (Wanchoo et al., 2019; Koh et al., 2018). More importantly, we utilized a time-dependent Cox model for post-transplantation complications, ensuring the correct temporal sequence between risk factors (e.g., aGVHD) and the outcome (AKI), thereby providing hazard ratio (HR) estimates with greater causal inference value (Koh et al., 2018). Our findings are consistent with studies such as Koh et al. (2018) but highlight characteristics of the Chinese pediatric population, namely an earlier median time to AKI onset (24 days) and a more rapid progression to severe AKI (Stage III, median 19 days). This may be attributed to children’s heightened susceptibility to nephrotoxic drugs and poorer compensatory mechanisms for fluid balance, particularly when gastrointestinal aGVHD occurs, which can easily lead to pre-renal AKI due to volume depletion from diarrhea and vomiting (Koh et al., 2018; Krishnappa et al., 2016; Amin et al., 2020). We also demonstrated that a notable proportion of children developed CKD after HCT, though our observed rate was lower than the nearly 5% within five years reported in the literature (Wu et al., 2021).

The pathogenesis of HCT-related AKI is multifactorial, involving conditioning regimens, nephrotoxic drugs, and post-transplant complications (Lopes, Jorge & Neves, 2016; Kaya, 2021). Our analysis provides clear insights into the independent risk factors. HLA mismatch, as a strong fixed risk factor, likely confers risk by necessitating more intensive immunosuppressive regimens (e.g., calcineurin inhibitors) to prevent and control aGVHD. These drugs possess direct nephrotoxicity and can indirectly damage the kidneys by causing hypertension and TMA (Wanchoo et al., 2019; Lewis et al., 2020; Dvorak, Higham & Shimano, 2019; Mori et al., 2012). The identified complications (SOS, aGVHD, TMA, CMV/EBV infection) represent critical intermediate pathways. AKI engendered by SOS is primarily a pre-renal AKI generated by liver injury that reduces renal blood perfusion (Kaya, 2021; Lewis et al., 2020). The primary causes of AKI in aGVHD are the release of cytokines, immune damage, and nephrotoxic drugs, which can produce acute tubular necrosis; in severe cases, diarrhea and dehydration result in reduced circulating blood volume, leading to pre-renal AKI (Koh et al., 2018; Krishnappa et al., 2016; Amin et al., 2020). TMA can precipitate vascular endothelial injury, leading to AKI, and is often associated with drugs like cyclosporine and cyclophosphamide (Dvorak, Higham & Shimano, 2019; Mori et al., 2012). Furthermore, AKI induced by EBV/CMV infection is also closely related to the nephrotoxicity of antiviral drugs such as ganciclovir and foscarnet sodium (Zavras et al., 2020). For hemorrhagic cystitis, AKI is related to BK virus infection and high-dose cyclophosphamide, and if urinary tract obstruction occurs, it can lead to postrenal AKI (Zavras et al., 2020; Ruderfer et al., 2021). Therefore, proactive prevention, early detection, and effective management of these complications are paramount to reducing the risk of AKI (Lopes, Jorge & Neves, 2016; Sawinski, 2014).

Of particular importance, our Kaplan–Meier survival analysis confirmed that the development of AKI, especially severe AKI, is associated with significantly increased mortality. This finding elevates AKI from a mere laboratory abnormality to a key clinical event impacting the overall prognosis of pediatric HCT recipients, underscoring the critical importance of enhanced renal monitoring and management. For high-risk children (e.g., those with HLA mismatch or primary diseases such as hemophagocytic lymphohistiocytosis Aulagnon et al., 2015; Bae et al., 2016), risk assessment should begin pre-transplantation, with attention to controlling the use of nephrotoxic drugs and selecting a reasonable myeloablative regimen (Aulagnon et al., 2015). Close monitoring of volume status and renal function throughout the peri-transplant period is essential.

This study has several limitations. First, its retrospective, single-center design may introduce selection bias, and the generalizability of the findings requires validation through multi-center studies. Second, the diagnosis of AKI relied solely on serum creatinine without urine output criteria, potentially leading to under-recognition of non-oliguric AKI, a common limitation in retrospective datasets. Furthermore, despite adjusting for numerous confounders, residual confounding from unmeasured factors may persist. Future prospective studies incorporating novel renal biomarkers are needed to enable earlier and more accurate diagnosis of AKI and to elucidate its underlying pathophysiological mechanisms more clearly (Sawinski, 2014; Krishnappa et al., 2016).

Conclusions

In conclusion, this study demonstrates that AKI is a common and serious complication following HCT in children. The use of appropriate statistical methods confirms that HLA mismatch and specific post-transplantation complications are significant risk factors. Most importantly, the development of AKI, particularly severe AKI, is strongly associated with increased mortality. These findings highlight the necessity for vigilant monitoring, early identification, and proactive management of modifiable risk factors to improve the survival and quality of life of pediatric HCT recipients.

Funding Statement

Funding was provided by the Construction Project of Research Division of Children’s Kidney Disease of Wuhan Children’s Hospital (2022FEYJS003), and the Knowledge and Innovation Project of Wuhan Science and Technology Bureau (2023020201010197). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.