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1.
Risk factors for early onset acute kidney injury after allogeneic haematopoietic stem cell transplantation and the role of drug-drug interactions
Günay, A., Ünal, A., Demirpolat, E., Yerer, M. B.
European journal of hospital pharmacy : science and practice. 2023
Abstract
INTRODUCTION Acute kidney injury (AKI) is an important and life-threatening complication following allogeneic haematopoietic stem cell transplantation (allo-HSCT). This is therefore an active research area with studies aiming to understand the factors that cause this complication. MATERIALS AND METHODS We conducted a retrospective study to identify the factors that caused AKI in 100 patients who underwent allo-HSCT in the first 100 days after transplantation using logistic regression analysis. RESULTS The mean time of onset of AKI was 45.58 days (range 13-97) and the mean±SD maximum serum creatinine value was 1.53±0.78 mg/dL. In 47 patients, level 1 or higher AKI occurred in the first month of transplantation and 38 of these patients were diagnosed with a higher level of AKI 31-100 days after transplantation. According to multivariate analysis, use of cyclophosphamide (adjusted odds ratio (AOR) 4.01, p=0.012), mean ciclosporin blood levels ≥250 ng/mL (AOR 2.81, p=0.022) and ciclosporin blood levels ≥450 ng/mL in the first month of transplantation (AOR 3.30, p=0.007) were found to be potential factors for early onset AKI. Ciclosporin blood levels exceeded 450 ng/mL in 35% of those using posaconazole and voriconazole during administration route change of ciclosporin. Use of ≥2 nephrotoxic anti-infective drugs (AOR 3, p=0.026) and developing AKI in the first month of transplantation (AOR 4.14, p=0.002) were found to be potential factors in the development of advanced AKI. CONCLUSION Nephrotoxic drugs, cyclophosphamide use and ciclosporin blood levels are factors to be considered to prevent the development of AKI in patients undergoing allo-HSCT.
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2.
AKI treated with kidney replacement therapy in critically Ill allogeneic hematopoietic stem cell transplant recipients
Kim, H., Ali, R., Short, S., Kaunfer, S., Krishnamurthy, S., Durai, L., Yilmam, O., Shenoy, T., Monson, A. E., Thomas, C., et al
Bone marrow transplantation. 2023
Abstract
Acute kidney injury (AKI) is a frequent complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), but few studies have focused on AKI treated with kidney replacement therapy (AKI-KRT), particularly among critically ill patients. We investigated the incidence, risk factors, and 90-day mortality associated with AKI-KRT in 529 critically ill adult allo-HSCT recipients admitted to the ICU within 1-year post-transplant at two academic medical centers between 2011 and 2021. AKI-KRT occurred in 111 of the 529 patients (21.0%). Lower baseline eGFR, veno-occlusive disease, thrombotic microangiopathy, admission to an ICU within 90 days post-transplant, and receipt of invasive mechanical ventilation (IMV), total bilirubin ≥5.0 mg/dl, and arterial pH <7.40 on ICU admission were each associated with a higher risk of AKI-KRT. Of the 111 patients with AKI-KRT, 97 (87.4%) died within 90 days. Ninety-day mortality was 100% in each of the following subgroups: serum albumin ≤2.0 g/dl, total bilirubin ≥7.0 mg/dl, arterial pH ≤7.20, IMV with moderate-to-severe hypoxemia, and ≥3 vasopressors/inotropes at KRT initiation. AKI-KRT was associated with a 6.59-fold higher adjusted 90-day mortality in critically ill allo-HSCT vs. non-transplanted patients. Short-term mortality remains exceptionally high among critically ill allo-HSCT patients with AKI-KRT, highlighting the importance of multidisciplinary discussions prior to KRT initiation.
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3.
Clinical Features of AKI in the Early Post-Transplant Period Following Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation
Vergara-Cadavid, J., Johnson, P. C., Kim, H. T., Yi, A., Sise, M. E., Leaf, D. E., Hanna, P. E., Ho, V. T., Cutler, C. S., Antin, J. H., et al
Transplantation and cellular therapy. 2023
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.
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4.
Rationale for the evaluation of renal functional reserve in allogeneic stem cell transplantation candidates: a pilot study
Mancianti, N., Guarnieri, A., Lenoci, M., Toraldo, F., Salvo, D. P., Belluardo, M., Iadanza, E., Ferretti, F., Marotta, G., Garosi, G.
Clinical kidney journal. 2023;16(6):996-1004
Abstract
BACKGROUND The main purpose of our study was to evaluate the ability of renal functional reserve (RFR) to stratify the risk of acute kidney injury (AKI) occurrence within 100 days of hematopoietic stem cell transplantation (HSCT) and to predict any functional recovery or the onset of chronic kidney disease. A secondary aim was to identify the clinical/laboratory risk factors for the occurrence of AKI. METHODS The study design is prospective observational. We enrolled 48 patients with normal basal glomerular filtration rate (bGFR) who underwent allogenic HSCT. A multiparameter assessment and the Renal Functional Reserve Test (RFR-T) using an oral protein load stress test were performed 15 days before the HSCT. RESULTS Different RFRs corresponded to the same bGFR values. Of 48 patients, 29 (60%) developed AKI. Comparing the AKI group with the group that did not develop AKI, no statistically significant difference emerged in any characteristic related to demographic, clinical or multiparameter assessment variables except for the estimated GFR (eGFR). eGFR ≤100 mL/min/1.73 m(2) was significantly related to the risk of developing AKI (Fisher's exact test, P = .001). Moreover, RFR-T was lower in AKI+ patients vs AKI- patients, but did not allow statistical significance (28% vs 40%). In AKI patients, RFR >20% was associated with complete functional recovery (one-sided Fisher's exact test, P = .041). The risk of failure to recover increases significantly when RFR ≤20% (odds ratio = 5.50, 95% confidence interval = 1.06-28.4). CONCLUSION RFR identifies subclinical functional deterioration conditions essential for post-AKI recovery. In our cohort of patients with no kidney disease (NKD), the degree of pre-HSCT eGFR is associated with AKI risk, and a reduction in pre-HSCT RFR above a threshold of 20% is related to complete renal functional recovery post-AKI. Identifying eGFR first and RFR second could help select patients who might benefit from changes in transplant management or early nephrological assessment.
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5.
Impact of antimicrobial drug-drug interactions on acute kidney injury after allogeneic hematopoietic cell transplantation
Wada, F., Arai, Y., Jo, T., Mizumoto, C., Kanda, J., Kitawaki, T., Nishikori, M., Yamashita, K., Takaori-Kondo, A.
Transplantation and cellular therapy. 2023
Abstract
Acute kidney injury (AKI) is one of the major complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Use of multiple antimicrobials is one of the major causes of post-transplant AKI, due the potential nephrotoxicity of each agent and drug-drug interactions (DDI). No satisfactory reports on DDI have appeared in the field of allo-HSCT, and we performed a retrospective analysis to compare the incidence of AKI within 100 days. In total, 465 transplant cases (416 patients) were included, and cumulative incidence of AKI was 40.0%. Incidence of AKI significantly reduced overall survival (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.95-3.55, p<0.01) and increased transplant-related mortality (HR 4.77, 95%CI 2.90-7.88, p<0.01). A higher incidence of AKI was significantly associated with the use of ciprofloxacin, cefepime, tazobactam/piperacillin, meropenem, vancomycin, liposomal amphotericin B, ganciclovir, and foscarnet. Among them, combinations with vancomycin plus tazobactam/piperacillin (HR 2.23. p=0.09 for interaction), ganciclovir plus cefepime (HR 5.93, p=0.04), and ganciclovir plus meropenem (HR 2.63, p=0.12) synergistically increased the risk of AKI, whereas combinations involving teicoplanin did not. This is the first report dealing with DDIs after allo-HSCT, and such combinations should be avoided so as to preserve renal function and to reduce AKI-related morbidity and mortality.
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6.
Analysis of risk factors for fatal renal complications after allogeneic hematopoietic cell transplantation
Yanagisawa, R., Koyama, H., Yakushijin, K., Uchida, N., Jinguji, A., Takeda, W., Nishida, T., Tanaka, M., Eto, T., Ohigashi, H., et al
Bone marrow transplantation. 2023
Abstract
Various complications can influence hematopoietic cell transplantation (HCT) outcomes. Renal complications can occur during the early to late phases of HCT along with various factors. However, studies focusing on fatal renal complications (FRCs) are scarce. Herein, we analyzed 36,596 first allogeneic HCT recipients retrospectively. Overall, 782 patients died of FRCs at a median of 108 (range, 0-3,440) days after HCT. The cumulative incidence of FRCs was 1.7% and 2.2% at one and five years, respectively. FRCs were associated with older age, male sex, non-complete remission (non-CR), lower performance status (PS), and HCT comorbidity index (HCT-CI) associated with renal comorbidity in multivariate analysis. The risk factors within 100 days included older age, multiple myeloma, PS, and HCT-CI comorbidities (psychiatric disturbance, hepatic disease, obesity, and renal disease). Older age and male sex were risk factors between 100 days and one year. After one year, HCT-CI was associated with the presence of diabetes and prior solid tumor; total body irradiation was identified as a risk factor. Non-CR was a common risk factor in all three phases. Furthermore, acute and chronic graft-versus-host disease, reactivation of cytomegalovirus, and relapse of underlying disease also affected FRCs. Systematic follow-up may be necessary based on the patients' risk factors and post-HCT events.
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7.
CYP3A5 influences oral tacrolimus pharmacokinetics and timing of acute kidney injury following allogeneic hematopoietic stem cell transplantation
Seligson, N. D., Zhang, X., Zemanek, M. C., Johnson, J. A., VanGundy, Z., Wang, D., Phelps, M. A., Roddy, J., Hofmeister, C. C., Li, J., et al
Frontiers in pharmacology. 2023;14:1334440
Abstract
Introduction: Polymorphisms in genes responsible for the metabolism and transport of tacrolimus have been demonstrated to influence clinical outcomes for patients following allogeneic hematologic stem cell transplant (allo-HSCT). However, the clinical impact of germline polymorphisms specifically for oral formulations of tacrolimus is not fully described. Methods: To investigate the clinical impact of genetic polymorphisms in CYP3A4, CYP3A5, and ABCB1 on oral tacrolimus pharmacokinetics and clinical outcomes, we prospectively enrolled 103 adult patients receiving oral tacrolimus for the prevention of graft-versus-host disease (GVHD) following allo-HSCT. Patients were followed in the inpatient and outpatient phase of care for the first 100 days of tacrolimus therapy. Patients were genotyped for CYP3A5 *3 (rs776746), CYP3A4 *1B (rs2740574), ABCB1 exon 12 (rs1128503), ABCB1 exon 21 (rs2032582), ABCB1 exon 26 (rs1045642). Results: Expression of CYP3A5 *1 was highly correlated with tacrolimus pharmacokinetics in the inpatient phase of care (p < 0.001) and throughout the entirety of the study period (p < 0.001). Additionally, Expression of CYP3A5 *1 was associated with decreased risk of developing AKI as an inpatient (p = 0.06). Variants in ABCB1 were not associated with tacrolimus pharmacokinetics in this study. We were unable to discern an independent effect of CYP3A4 *1B or *22 in this population. Conclusion: Expression of CYP3A5 *1 is highly influential on the pharmacokinetics and clinical outcomes for patients receiving oral tacrolimus as GVHD prophylaxis following allo-HSCT.
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8.
Occurrence and influencing factors of cyclosporine A on the kidney injury following allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis
Lu, R., Shi, Y., Yang, M., Yang, N., He, S., Xin, L., Qin, Y., Li, H., Zeng, L., Zou, K., et al
International immunopharmacology. 2023;122:110633
Abstract
OBJECTIVE Whether cyclosporine A (CsA) is a risk factor of kidney injury after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has not been determined. We aim to comprehensively review the correlation and influencing factors between CsA and kidney injury in patients following allo-HSCT. METHODS We searched PubMed, Embase (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), CNKI, VIP, Wanfang and CBM Database from inception to March 2022. Two researchers independently conducted literature screening, data extraction and quality assessment. Qualitative and quantitative methods were combined to analyze the data. RESULTS We included a total of 30 studies. Meta-analyses of total incidence of kidney injury related to CsA was 37.0% [95% CI (25.4%, 48.6%); n = 15]. The proportion of CsA-related acute kidney injury to total acute kidney injury following allo-HSCT was 59.7% [95% CI (49.1%, 70.3%); n = 9]. One study found that AKI had a significant association with CsA in multivariate analysis [RR = 6.173; 95% CI (4.032, 9.434)]. With respect to cyclosporine combination and nephrotoxicity, 6/9 studies demonstrated that the concomitant medications for CsA (especially aminoglycoside antibiotics and amphotericin B) had negative effect on kidney functions related to CsA in allo-HSCT patients. No consensus was reached for "dose of CsA", "duration of CsA use", "comorbidities" and "CsA levels" across studies. CONCLUSIONS CsA may be a risk factor for kidney injury in patients following allo-HSCT, especially the concomitant use of CsA and nephrotoxic medications.
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9.
Incidence and Risk Factors for Acute Kidney Injury after Allogeneic Stem Cell Transplantation: A Prospective Study
Andronesi, A., Sorohan, B., Burcea, A., Lipan, L., Stanescu, C., Craciun, O., Stefan, L., Ranete, A., Varady, Z., Ungureanu, O., et al
Biomedicines. 2022;10(2)
Abstract
(1) Background: Acute kidney injury (AKI) is a serious complication of hematopoietic stem cell transplantation (HSCT). (2) Methods: The aim was to identify the incidence, severity, and risk factors for AKI during the first 100 days after allo-HSCT; we performed a prospective observational study on 135 consecutive patients. (3) Results: The mean age was 38.3 ± 11.9 years (50.6% females), AKI developed in 93 patients (68.9%), the median time of appearance was 28 days, and the mean serum creatinine at the time of AKI was 1.8 ± 0.8 mg/dL. A total of 36 (38.7%) patients developed stage 1 AKI, 33 (35.5%) patients developed stage 2, and 24 (25.8%) patients developed stage 3; eight (8.6%) patients required temporary hemodialysis, and the mortality rate in these patients was 87.5%. Death was twice as frequent in the AKI subgroup, without statistical significance. Cyclosporine overdose (HR = 2.36, 95% CI: 1.45-3.85, p = 0.001), tacrolimus overdose (HR = 4.72, 95% CI: 2.22-10.01, p < 0.001), acute graft-versus-host disease (aGVHD) (HR = 1.96, 95% CI: 1.13-3.40, p = 0.01), and CRP level (HR = 1.009, 95% CI: 1.007-1.10, p < 0.001) were independent risk factors for AKI. Sepsis (HR = 5.37, 95% CI: 1.75-16.48, p = 0.003) and sinusoidal obstruction syndrome (HR = 5.10, 95% CI: 2.02-12.85, p = 0.001) were found as independent risk factors for AKI stage 3. (4) Conclusions: AKI occurs with high incidence and increased severity after allo-HSCT. Careful monitoring of calcineurin inhibitors and proper management of sepsis may reduce this risk.
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10.
Predictors of kidney complications and analysis of hypertension in children with allogeneic hematopoietic stem cell transplantation
Gurbanov, A., Gülhan, B., Kuşkonmaz, B., Okur, F. V., Ozaltin, F., Düzova, A., Çetinkaya, D. U., Topaloglu, R.
Pediatric nephrology (Berlin, Germany). 2022
Abstract
BACKGROUND This study aimed to determine incidence of kidney complications in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) patients. METHODS Pediatric allogeneic HSCT patients were included. Post-transplantation urinary system complications were collected from medical records and glomerular filtration rates at last visit compared with clinical parameters. Additionally, 24-h ambulatory blood pressure monitoring was performed. RESULTS The study included 165 pediatric patients. Acute kidney injury (AKI) developed in 125 (75.8%) patients of whom 54 (43.2%) had stage 1, 36 (28.8%) stage 2, and 35 (28%) stage 3 AKI. Primary malignant disease and viral infection post-HSCT were associated with increased risk of AKI (OR: 4; 95%CI: 1.2-13, p = 0.022 and OR: 2.9; 95%CI: 1.2-6.8, p = 0.014, respectively). Mean duration of post-HSCT follow-up was 4.4 ± 2.5 years, during which time 8 patients had chronic kidney disease (CKD) (stage 1, 4 patients; stage 2, 3 patients; stage 3, 1 patient). CKD incidence was higher in patients in whom stem cell product was bone marrow + cord blood and mobilized peripheral blood, compared to bone marrow alone (40-37.5% versus 5.1%, p = 0.002). Based on 24-h ABPM, 14.7% and 7.4% of patients with normal office blood pressure had pre-hypertension and hypertension, respectively. In patients with albuminuria/severe albuminuria, daytime and nighttime systolic SDS scores were higher than those without albuminuria/severe albuminuria (p = 0.010 and p = 0.004, respectively). CONCLUSIONS Incidence of AKI is higher in pediatric HSCT patients with primary malignant disease and those with documented viral infection. Our study highlights the beneficial role of 24-h ABPM as a routine part of standard care of pediatric HSCT recipients.