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. 2020 Feb 26;113(9):621–632. doi: 10.1093/qjmed/hcaa072

Incidence and mortality of acute kidney injury in patients undergoing hematopoietic stem cell transplantation: a systematic review and meta-analysis

S R Kanduri 1,✉, W Cheungpasitporn 1, C Thongprayoon 2, T Bathini 3, K Kovvuru 1, V Garla 4, J Medaura 1, P Vaitla 1, K B Kashani 2,5
PMCID: PMC7828586  PMID: 32101318

Abstract

Background

While acute kidney injury (AKI) is commonly reported following hematopoietic stem cell transplant (HCT), the incidence and impact of AKI on mortality among patients undergoing HCT are not well described. We conducted this systematic review to assess the incidence and impact of AKI on mortality risk among patients undergoing HCT.

Methods

Ovid MEDLINE, EMBASE and the Cochrane Databases were searched from database inceptions through August 2019 to identify studies assessing the incidence of AKI and mortality risk among adult patients who developed AKI following HCT. Random-effects and generic inverse variance method of DerSimonian–Laird were used to combine the effect estimates obtained from individual studies.

Results

We included 36 cohort studies with a total of 5144 patients undergoing HCT. Overall, the pooled estimated incidence of AKI and severe AKI (AKI Stage III) were 55.1% (95% confidence interval (CI) 46.6–63.3%) and 8.3% (95% CI 6.0–11.4%), respectively. The pooled estimated incidence of AKI using contemporary AKI definitions (RIFLE, AKIN and KDIGO criteria) was 49.8% (95% CI 41.6–58.1%). There was no significant correlation between study year and the incidence of AKI (P = 0.12) or severe AKI (P = 0.97). The pooled odds ratios of 3-month mortality and 3-year mortality among patients undergoing HCT with AKI were 3.05 (95% CI 2.07–4.49) and 2.23 (95% CI 1.06–4.73), respectively.

Conclusion

The incidence of AKI among patients who undergo HCT remains high, and it has not changed over the years despite advances in medicine. AKI after HCT is associated with increased short- and long-term mortality.

Introduction

Hematopoietic stem cell transplant (HCT) is being used for multiple malignant and non-malignant conditions.1–4 In the current era, indications have been extended to metabolic, immune-related, autoimmune and other inflammatory disorders.5 More than 50 000 patients undergo HCT every year, and its rate is increasing by 20–30% annually.6 Despite the widespread use of preventive measures, acute kidney injury (AKI) remains a substantial problem after HCT. AKI is associated with significant cost burden, morbidity and mortality.7,8 Survivors of AKI could sustain recurrent episodes of AKI, leading to multiple hospitalizations.9 In long-term survivors after HCT, chronic kidney disease is prevalent in up to 20% of the patients.10–12 They are at further risk for the development of hypertension, albuminuria and nephrotic range proteinuria.13,14 Severe AKI requiring renal replacement therapy (RRT) is associated with significant mortality of about 80%.15–18

Multiple steps are involved in successful hematopoietic stem cell transplantation.19 The process begins with the procurement of stem cells from the donor, while the recipient undergoes intensive chemotherapy (myeloablative)3,20 vs. less intensive chemo (non-myeloablative)21 depending on age and other comorbidities. The second stage includes the infusion of graft stem cells to the recipient (engraftment). Finally, the recipient receives immunosuppression to suppress rejection or graft vs. host disease. AKI can occur during any of the above-mentioned steps.22 AKI following HCT is traditionally defined as ‘Doubling of serum creatinine in the first hundred days’. However, in order to standardize AKI risk stratification, RIFLE, KDIGO and AKIN definitions were developed.18,23–27 The reported incidence of AKI after HCT varies widely from 12% to 66%.18,20,28–30 This wide variation is likely related to not using a standardized AKI definition, various conditioning regimens, allogeneic vs. autologous donor and retrospective nature of studies.25,26 It is reported that the incidence of AKI after autologous stem cell transplant is 12–50%, non-myeloablative allogeneic 29–54% and myeloablative allogeneic at 19–66%.

Given the variability in the reported incidence of AKI post-HCT, we performed a systematic review and meta-analysis of the existing cohort studies up to August 2019 to assess the pooled incidence of AKI and its associated mortality.

Materials and methods

Search strategy

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) statement31 was followed in conducting this systematic review. Ovid MEDLINE, EMBASE and the Cochrane Databases were systematically searched from database inceptions through August 2019 to identify studies fulfilled the following inclusion criteria: (i) clinical trials or observational studies published as original articles or conference abstracts; (ii) studies that assessed the incidence of AKI or AKI-associated mortality among patients undergoing HCT; (iii) adult patient population (age ≥ 18 years old). The primary outcome was AKI post-HCT. Mortality risk was also assessed among the studies that reported AKI-outcome. Two investigators (S.K. and K.K.) performed independent literature search using the search terms of ((‘bone morrow’ OR ‘stem cell’) AND (‘transplant’ OR ‘transplantation’)) AND (‘acute kidney injury’ OR ‘acute renal failure’ OR ‘renal replacement therapy’). Supplementary Data S1 provide information on the detailed search strategy. The data for this meta-analysis are publicly available through the Open Science Framework (URL: <seurld>https://osf.io/qfgj9/</seurld>). Language restriction was not applied. Potentially related studies were manually reviewed using the references. Gray literature was additionally searched for further relevant information.

Study selection

Observational studies and clinical trials providing 95% confidence intervals (CI) data on the incidence of AKI and mortality risk of AKI in adult patients undergoing HCT were included in the meta-analysis. Two investigators (S.K. and K.K.) independently reviewed retrieved articles for eligibility. A third reviewer (W.C.) solved inconsistencies by collective agreement. AKIN,32 RIFLE33 and KDIGO34 definitions of AKI were used for subgroup analysis.

Data collection

The collected data from individual studies included title, name of authors, year of the study, publication year, the country where the study was conducted, patient characteristics, AKI definition, the incidence of AKI and severe AKI requiring RRT and finally reported death rate among patients with AKI following HCT.

Statistical analysis

Meta-analysis was performed using Comprehensive Meta-Analysis software version 3.3.070 (Biostat Inc., NJ, USA). Adjusted point estimates of included studies were incorporated by the generic inverse variance method of DerSimonian–Laird, which assigned the weight of individual study based on its variance.35 Due to the probability of between-study variance, we applied a random-effects model to pool outcomes of interest, including the incidence of AKI and mortality risk. Cochran’s Q test (P < 0.05 for a statistical significance) and I2 statistic (≤25% represents insignificant heterogeneity, 26–50% represents low heterogeneity, 51–75% represents moderate heterogeneity and ≥75% represents high heterogeneity) were used to assess statistical heterogeneity.36 Publication bias was assessed by funnel plot and the Egger test.37

Results

The search yielded a total of 1818 articles for initial screening. Four hundred seventy-eight duplicates were removed, and 1262 articles were excluded for the following reasons: in vitro studies, pediatric patient population, animal studies, case reports, correspondences or review articles. Full-length reviews of 90 studies were performed. Twenty-six studies were not observational studies and 28 studies were excluded due to not providing the outcome of interest; thus, 36 cohort studies15–18,20,25,26,38–65 with a total of 5144 patients undergoing HCT were enrolled. Figure 1 outlines the flowchart of paper selection for inclusion. Table 1 provides details of the included studies.

Figure 1.

Figure 1.

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Outlines the flowchart of paper selection for inclusion.

Table 1.

The main characteristic of studies included in this meta-analysis of AKI incidence and mortality among patients with hematopoietic stem cell transplantation

Study Year Country Patients Indication for HCT Number AKI definition AKI incidence Mortality
Merouani et al.38 1995 Colorado, USA, 1991–1994 Autologous hematopoietic cell transplant Breast cancer 232

  • Grade 0: <25% decline in GFR,

  • Grade 1: >25% decrease in GFR <2-fold rise in serum creatinine,

  • Grade 2: >fold rise in creatinine, no HD

  • Grade 3: need for dialysis

  • Overall AKI = 130/232 = (56%)

  • Severe AKI/needing RRT = 7/232 = (3%)

  • 60-day AKI mortality 12/130 (9%)

  • Non-AKI mortality = 4/102(3.9%)
Gruss et al.39 1995 Madrid, Spain Allogeneic and autologous BMT AL, CML, AA, other 275 Doubling of serum creatinine or creatinine > 2 mg/dl or AKI requiring HD

  • Overall AKI—72/275 = (26%)

  • AKI requiring HD = 17/275 = (6.18%)

  • 90-day mortality

  • AKI mortality = 33/72, (45.8%)

  • Non-AKI mortality 36/203 = (17.7%)
Parikh et al.40 2002 Colorado, USA Allogeneic hematopoietic cell transplant Hematological malignancy 88

  • Grade 0: <25% decline in GFR,

  • Grade 1: > 25% decrease in GFR, <2-fold rise in serum creatinine,

  • Grade 2: > fold rise in creatinine, no HD,

  • Grade 3: need for dialysis

  • Overall AKI = 81/88 = (92%)

  • Severe AKI = 29/88 = (32.9%)

  • Six-month AKI mortality = 48/81 (59%)

  • Non-AKI mortality 3/7 = (42%)
Schrier et al.53 2005 New Haven, CT, USA Autologous HCT Breast cancer 232

  • Grade 0: <25% decline in GFR;

  • Grade 1: >25% decrease in GFR, <2-fold rise in serum creatinine;

  • Grade 2: > fold rise in creatinine, no HD

  • Grade 3: need for dialysis

  • Overall AKI = 130/232 = (56%)

  • Severe AKI = 17/232 (7%)

  • 60-day mortality

  • AKI mortality = 12/130 = (9%)

  • Non-AKI mortality = 4/102 = (4%)
Lopes et al.54 2006 Portugal Autologous and allogeneic HCT Hematological malignancy 140 RIFLE

  • Overall AKI = 53/140 = (38%)

  • Severe AKI = 20/140 = (14.3%)

 N/A
Parikh et al.41 2004 Colorado, USA, 1998–2001 Non-myeloablative HCT CML ALL 253

  • Grade 0: <25% decline in GFR;

  • Grade 1: >25% decrease in GFR, <2-fold rise in serum creatinine;

  • Grade 2: >fold rise in creatinine, no HD;

  • Grade 3: need for dialysis

  • Overall AKI = 228/253 = (90%)

  • Severe AKI needing RRT = 11/253 = (4%)

 N/A
Caliskan et al.20 2006 Turkey, 2001–2003 Myeloablative allogeneic and autologous Hematological malignancy 47

  • Grade 0: <25% decline in GFR;

  • Grade 1: >25% decrease in GFR, <2-fold rise in serum creatinine;

  • Grade 2: >fold rise in creatinine, no HD;

  • Grade 3: need for dialysis

  • Overall AKI-33/47 = (70%)

  • Severe AKI 7/47 = (14.8%)

  • 100-day

  • AKI mortality 8/33 = (24%)

  • Non-AKI mortality = 1/14 = (7%)
Liu et al.42 2007 China, 2002–2005 Non-myeloablative peripheral blood stem cell transplant CML 26

  • Grade 0: <25% decline in GFR;

  • Grade 1: >25% decrease in GFR, <2-fold rise in serum creatinine;

  • Grade 2: >2-fold rise in creatinine, no HD;

  • Grade 3: need for dialysis

  • Overall AKI = 10/26

  • (38%)

  • Severe AKI 1/26 = (3.8%)

  • 100-day

  • AKI mortality 4/10 = (40%)

  • Non-AKI mortality = 1/16 = (6.25%)
Kersting et al.43 2008 Netherlands Non-myeloablative HCT CML, AA 150

  • Grade 1: decrease in glomerular filtration rate > 25% and <doubling in serum creatinine; Grade 2: >doubling in serum creatinine;

  • Grade 2 plus: tripling in serum creatinine.

  • Overall AKI = 141/150 = (94%)

  • Severe AKI = 14/150 = (9.3%)

 NA
Kersting et al.44 2007 Netherlands, 1993–2004 Allogeneic myeloablative AML, ALL, CML, OTHERS 363

  • Grade 0: <25% decline in GFR;

  • Grade 1: >25% decrease in GFR, <2-fold rise in serum creatinine;

  • Grade 2: >fold rise in creatinine, no HD;

  • Grade 3: need for dialysis

  • 90 days post-Tx Overall AKI = 339/363 = (93%)

  • Severe AKI

  • 4/363 = 1.1%

  • Six-month mortality

  • AKI mortality

  • 58/339 = 17%
Lopes et al.17 2008 Portugal, 1999–2005 Reduced-intensity conditioning, HCT AML, CML 82 KDIGO

  • Overall AKI: 44/82 (53.6%)

  • Severe AKI: 13/82 = (15.8%)

  • 100-day AKI mortality = 17/44 (38%)

  • Non-AKI mortality 1/38 = 2.6%
Yakushijin et al.55 2009 Tokyo, Japan Reduced-intensity stem cell transplant AML, ALL, CML, MDS 286

  • Grade 0: <25% decline in GFR;

  • Grade 1: >25% decrease in GFR; <2-fold rise in serum creatinine,

  • Grade 2: >fold rise in creatinine, no HD;

  • Grade 3: need for dialysis

  • Overall AKI = 220/286 = (76.9%)

  • Severe AKI = 9/286 = (3.14%)

 N/A
Tokgoz et al.56 2009 Turkey, 2007–2008 Allogeneic myeloablative AML, ALL 39

  • Grade 1: increase in creatinine >2 times

  • Grade 2: increase in serum creatinine >3 times;

  • Grade 3: Grade 2 along with needing dialysis

 Overall AKI = 20/39 = (51.3)

  • 100-day mortality

  • AKI mortality = 2/20 = (10%)

  • Non-AKI mortality = 1/19 = (5.2%)
Ando et al.25 2010 Japan, 2004–2007 Autologous and allogeneic HCT Hematological malignancy 249 AKIN

  • Overall AKI = 116/249 (46%)

  • Severe AKI: 25/249 (10%)

  • AKI mortality

  • 60/116 = (51.7)

  • Non-AKI mortality

  • 32/133 = 24%
Lui et al.18 2010 China, 2002–2007 Non-myeloablative HCT CML, ALL, CLL 62 AKIN

  • Overall AKI = 18/62 = 29%

  • Severe AKI = 1/62 = 1.6%

  • OR = 3.3; 95% CI 1.0–11.1

  • AKI/mortality = 11/18 (61%)

  • Non-AKI mortality = 6/44 (13.6%)
Yu et al.66 2010 China, 2003–2008 Allogeneic HCT Hematological malignancy 96

  • Grade 0: <25% decline in GFR;

  • Grade 1: >25% decrease in GFR, <2-fold rise in serum creatinine;

  • Grade 2: >fold rise in creatinine, no HD;

  • Grade 3: need for dialysis

  • Overall AKI = 28/96 = (29.2%)

  • Severe AKI/RRT = 2/96 = (2.1%)

 NA
Irazabal et al.57 2011 Rochester, USA, 1997–2009 Autologous stem cell transplant Light chain amyloidosis 29 AKIN

  • Overall AKI = 28/29 = (96.5%)

  • Severe AKI/RRT = 7/29 = 24.1%

 100-day AKI mortality = 2/28 = (7.1%)
Helal et al.45 2011 France Hematopoietic stem cell transplant AML, ALL, CML, MM 101 Requiring RRT AKI requiring RRT: 12/101 = (11.8%) N/A
Morito et al.47 2011 Japan Allogeneic HCT Hematological malignancy 40 RIFLE

  • Overall AKI = 28/40

  • (70%)

  • Severe AKI = 4/40 = 10%

  • 100-day AKI mortality

  • 4/28 = (14%)
Bao et al.46 2011 China, 2003–2008 Allogeneic hematopoietic stem cell transplant CML, ALL, MDS, MM 143 RIFLE

  • Overall AKI = 70/143 (48.9%)

  • Severe AKI = 12 /143 (8.4%)

  • 100-day AKI mortality =

  • OR: 6.984, 95%

  • CI: 1.227–39.762

  • P = 0.029
Kagoya et al.58 2011 Tokyo Autologous and allogeneic Hematological malignancy 207 RIFLE

  • Overall AKI = 158/207 = (76.3%)

  • Severe AKI = 92/207 = 44.4%

 3-year AKI mortality, 24/158 (16.6%)
Durate et al.59 2012 Brazil, 2008–2011 Autologous BMT

  • Hodgkin lymphoma,

  • Non-Hodgkin’s lymphoma,

  • Multiple myeloma

 70 AKIN

  • Overall AKI = 7/20 = (35%)

  • Severe AKI = 4/20 = (20%)

 N/A
Mori et al.48 2012 Japan, 2004–2009 Allogeneic hematopoietic stem cell transplant ALL, CML, ATL, MDS, MM 289 AKIN

  • Overall AKI = 180/289 = (62.2%)

  • Severe AKI = 46/289 (15.9%)

  • 100 days AKI mortality = 82/180 = (45%)

  • Non-AKI mortality = 28/109 (25%)
Canet et al.60 2014 Paris, France, 2007–2011 Allo—HCT ALL, AML and lymphoma 75 KDIGO

  • Overall AKI = 49/75 = (65%)

  • Severe AKI = 25/75 = (33%)

 N/A
Chapchap et al.61 2016 Brazil, 2007–2014 Allogeneic HCT Hematological malignancy 111 Requiring RRT RRT = 20/111 = (18.3%) N/A
Esposito et al.62 2016 Pavia, Italy, 2013–2015 Allogeneic HCT Hematological malignancy 57

  • Grade 1: creatinine ≥ 2 times from the baseline;

  • Grade 2: creatinine ≥3 times from the baseline;

  • Grade 3: creatinine ≥ 4 times from the baseline.

  • Overall AKI = 18/57 = (31.6%)

  • Severe AKI = 1/57 = (1.8%)

 N/A
Liu et al.26 2017 China, May 2013–June 2014

  • Haplo stem cell transplantation

  • AL, ALL, MDS

  • Leukemia (20%), lymphoma (36%),

  • MM (28%)

 353

  • Grade 0–3

  • Grade 1: <1.5-fold rise in baseline creatinine;

  • Grade 2: ≥2-fold rise;

  • Grade 3: ≥3-fold rise.

  • Overall AKI = 152/353 = 43%

  • Severe AKI = 23/353 = 6.5%

 N/A
Myhre et al.63 2017 Norway, 2004–2016 Non-myeloablative allogeneic Lymphoma 108 RIFLE Overall AKI = 75/108 = (69.4%) N/A
Pinana et al.52 2017 Spain, 2008–2015 Allo- HCT

  • AML

  • MDS

 186 KDIGO

  • Overall AKI = 81/186 = 44%

  • Severe AKI = 31/186 = 16.6%

 Grade 2 KDIGO = HR 2.8; P = 0.05, Grade 3 KDIGO (HR 6.6; P < 0.001).
Sehgal et al.49 2017 India, 2008–2014 Hematopoietic stem cell transplant MM, leukemia, lymphoma, aplastic anemia 65 RIFLE

  • Overall AKI = 49/65 = (75.4%)

  • Severe AKI/needing dialysis = 4/65 (6.1%).

  • Three-month AKI mortality = 14/49 (28.5%)

  • Non-AKI mortality

  • 6/17 = (35%)
Deger et al.50 2017 Turkey, 2009–2011 Allogeneic HCT Hematological malignancies 50 AKIN

  • Overall AKI = 19/50 (38%)

  • Severe AKI = 2/50 (4%)

 NA
Cekdemi et al.64 2018 Turkey, 2010–2017 Autologous and allogeneic Hematological malignancy 155 AKIN Overall AKI = 78/155 = (50.3%) N/A
Khalil et al.51 2019 Jordan, 2002–2016 Hematopoietic stem cell transplant CML, MM, ALL, AML, HL, NHL 60 RIFLE

  • Overall AKI = 19/60 = (31.6%)

  • Severe AKI = 2/60 = (3.3%)

  • 90-day AKI mortality = 8/19 = (42%)

  • Non-AKI mortality = 7/41 = (17%)
Pereira et al.65 2018 Brazil, 2010–2014 Hematopoietic stem cell transplant Multiple myeloma 132 Rise in serum creatinine >0.3 mg/dl Overall AKI = 21/132 = (16%) N/A
Andronesi et al.15 2019 Romania, 2016–2017 Autologous stem cell transplant Multiple myeloma 185 KDIGO

  • One-month post-TX

  • Overall AKI: 19/ 185 (10.3%)

  • Severe AKI = 1/185 = (0.5%)

  • 90-day mortality after AKI

  • 1/19 = (5.2%)

  • 90-day mortality in patients with no AKI

  • 1/166 = (0.6%)
Mima et al.16 2019 Japan, 2006–2016 Hematopoietic stem cell transplant AML, ALL, CML, MM, AA 108 KDIGO

  • Overall AKI (17/108 = 15.7%)

  • Severe AKI = 4/108 = (3.7%)

 N/A
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AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; AKIN, acute kidney injury network; KDIGO, Kidney Disease Improving Global Outcomes; RIFLE, Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease; BMT, bone marrow transplant; HCT, hematopoietic stem cell transplantation; RRT, renal replacement therapy; GFR, glomerular filtration rate; HD, hemodialysis; CML, chronic myelogenous leukemia; CLL, chronic lymphocytic leukemia; AML, acute myeloid leukemia; ALL, acute lymphocytic leukemia; MDS, myelodysplastic syndrome; MM, multiple myeloma; ATL, adult T-cell leukemia/lymphoma; HL, Hodgkin’s lymphoma; NHL, non-Hodgkin’s lymphoma; TX, transplant; NA, not applicable; USA, United States of America.

Incidence of AKI among patients undergoing HCT

Overall, the pooled estimated incidence of AKI and severe AKI among patients undergoing HCT were 55.1% (95% CI 46.6–63.3%, I2 = 96%, Figure 2) and 8.3% (95% CI 6.0–11.4%, I2 = 92%, Figure 3), respectively. The pooled estimated incidence of AKI using standard AKI definitions was 49.8% (95% CI 41.6–58.1%, I2 = 93%, Supplementary Figure S1). The pooled estimated incidence of RRT among patients undergoing HCT was 7.2% (95% CI: 4.0–12.5%, I2 = 83%, Figure 3).

Figure 2.

Figure 2.

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Forest plots of the included studies evaluating incidence rates of AKI among patients undergoing HCT.

Figure 3.

Figure 3.

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Forest plots of the included studies evaluating incidence rates of severe AKI among patients undergoing HCT.

Subgroup analyses were performed according to AKI definitions. The pooled estimated incidence rates of AKI by RIFLE, AKIN and KDIGO criteria were 59.2% (95% CI 44.5–72.5%, I2 = 93%, Supplementary Figure S1), 48.2% (95% CI 37.4–59.1%, I2 = 86%, Supplementary Figure S1) and 34.1% (95% CI 16.7–57.2%, I2 = 96%, Supplementary Figure S1), respectively.

Meta-regression of all studies using standard AKI definitions showed that the year of the study did not significantly affect the incidence of AKI (P = 0.12, Supplementary Figure S2A) and severe AKI (P = 0.97, Supplementary Figure S2B).

Mortality risk of AKI in patients after HCT

Data on mortality risk from included studies are shown in Table 1. The pooled odds ratios (ORs) of 3-month mortality and 3-year mortality among patients undergoing HCT with AKI were 3.05 (95% CI 2.07–4.49, I2 = 19%, Figure 4A) and 2.23 (95% CI 1.06–4.73, I2 = 82%, Figure 4B), respectively.

Figure 4.

Figure 4.

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Forest plots of the included studies evaluating (A) mortality risk of AKI within 3 months and (B) mortality risk of AKI within 3 years after HCT.

Evaluation for publication bias

The funnel plot (Supplementary Figure S3) and Egger’s regression asymmetry tests were performed to assess publication bias in analysis evaluating the 3-month mortality of AKI in patients undergoing HCT. We found no significant publication bias in the meta-analysis evaluating the mortality risk of patients after HCT with AKI (P = 0.30).

Discussion

In this systematic review and meta-analysis, we found that the incidence of overall AKI and severe AKI requiring RRT after HCT is very high. Overall, the pooled estimated incidence of AKI and severe AKI among patients undergoing HCT are 55.1% and 8.3%, respectively. The pooled estimated incidence of AKI using standard AKI definition (KDIGO, RIFLE and AKIN) is 49.8%. Our findings showed significant increased short- and long-term mortality among patients with AKI after HCT. Meta-regression analyses showed that the year of the study did not significantly affect the incidence of AKI after HCT among included studies (published between years 1995 and 2019).

The etiology and mechanism of acute renal failure after HCT remain complex and multifactorial. Multiple risk factors are linked to the incidence of AKI after HCT. Major risk factors include diabetes,67 hypertension,44 preexisting chronic kidney disease,68 nephrotoxic medications including amphotericin B,10 acyclovir for viral prophylaxis,69 aminoglycosides,70 calcineurin inhibitors for prophylaxis of graft vs. host effect,71 intravenous immune globulin,28 underlying sepsis,18 admission to intensive care unit,44 use of mechanical ventilation,41 preexisting lung toxicity,43 incomplete human leukocyte antigen (HLA) matched transplant,18 female sex, weight gain > 10% and cytomegalovirus infections (Table 2).28

Table 2.

Risk factors linked to incidence of AKI after HCT.

Risk factors linked to incidence of AKI after HCT

  1. Diabetes mellitus67

  2. Hypertension44

  3. Chronic kidney disease68

  4. Nephrotoxic agents
    1. Amphotericin B10
    2. Acyclovir69
    3. Amino glycosides70

  5. CaIcineurin inhibitor use for GVH prophylaxis71

  6. Intravenous immunoglobulin28

  7. Sepsis18,28

  8. Intensive care unit stay44

  9. Mechanical ventilation41

  10. Preexisting lung toxicity43

  11. HLA mismatch18

  12. Female sex44

  13. Weight gain >10%18

  14. Cytomegalovirus infection28
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In general, the etiology of AKI varies based on the different phases of HCT.10,72–74 Tumor lysis syndrome and marrow intoxication syndrome manifest between 0–5 days of the pre-conditioning phase. Tumor lysis syndrome is rare in patients following HCT, as most are in the remission phase.75–77 The incidence of tumor lysis is <1 in 400 patients.5 Marrow intoxication syndrome is specifically seen in patients after HCT. Dimethyl sulfoxide (DMSO) is used as a freezing solvent to store stem cells and could contribute to RBC and granulocyte lysis.76 With modified stem cell storing options and limiting the amount of DMSO, the incidence of marrow intoxication syndrome has reduced.78

In the early phase between 1 and 4 weeks, the etiology of AKI is attributed to chemo-induced volume loss, pre-renal AKI,79, ischemic acute tubular necrosis (ATN), septic ATN,80,81 engraftment syndrome,82 hepatic veno-occlusive disease,83–87 use of nephrotoxic medications including69 aminoglycosides,70,88 amphotericin10 and acyclovir.5,89 Acute graft vs. host disease (GVHD) can be seen first 100 days post-HCT. Acute GVHD post-HCT is associated with significant renal dysfunction and rejection episodes post-transplant.6 Viral infections, including adenovirus and BK virus leading to AKI post-HCT, are worth mentioning. Calcineurin inhibitors play a significant role in causing renal vasoconstriction, tubular toxicity contributing to AKI post-HCT.28,71 Transplant thrombotic microangiopathy, chronic calcineurin inhibitor nephrotoxicity and chronic GVHD are being noticed after 6–12 months post-transplant and could lead to chronic kidney disease.1,19,78,79,90–94

Our meta-analysis included some limitations. This systematic review was based on cohort studies. Thus, it is not identifying any causal relationship between AKI and death rate, but it reports associations. The missing data from the included studies related to the novel AKI biomarkers may be another limitation. Due to the presence of statistical heterogeneities among the studies, subgroup analyses were performed using standardized definitions of AKI (RIFLE, AKIN and KDIGO) to mitigate the risk of bias.

As demonstrated in our meta-analysis, AKI post-HCT is associated with increased risk of mortality especially if RRT is needed. Despite medical advances, the overall incidence has not decreased since 1995. Our effort is to increase awareness about the continued high incidence of AKI in hopes that identifying at risk patients and implementing naive preventive measures through continued research might mitigate some AKI-associated poor outcomes.

Supplementary material

Supplementary material is available at QJMED online.

Conflict of interest: None declared.

Supplementary Material

hcaa072_Supplementary_Data
Click here for additional data file. (156.8KB, docx)

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