Hematol Oncol Stem Cell Ther (2018) 11, 195– 205 Available at www.sciencedirect.com ScienceDirect journal homepage: www.elsevier.com/locate/hemonc REVIEW Kidney dysfunction after hematopoietic cell transplantation—Etiology, management, and perspectives Dorota Jagus´a, Karol Lis b, Longin Niemczyk a, Grzegorz W. Basak b,* a Department of Nephrology, Dialysis and Internal Medicine, Medical University of Warsaw, Warsaw, Poland b Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland Received 4 February 2018; received in revised form 26 April 2018; accepted 12 July 2018 Available online 29 July 2018 KEYWORDS Abstract Acute kidney injury; Kidney dysfunction is a common complication of hematopoietic cell transplantation (HCT) with Chronic kidney disease; proven negative impact on early and long-term mortality. Causes of this complication are Hematopoietic cell diverse, usually overlapping, and poorly understood. Therefore, management implicates multi- transplantation directional investigations and simultaneous treatment of suspected causes. The etiology is fre- quently unconfirmed due to a lack of specific markers and prevalence of contraindications to renal biopsy among HCT recipients. Herein, we provide a summary of etiology and propose an algorithm for evaluation of kidney injury after HCT. We also map out the most urgent areas for research that aim to identify patients at risk of severe renal injury and develop nephropro- tective strategies. Ó 2018 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc- nd/4.0/). Contents Introduction . 196 Etiology . 197 Kidney injury before HCT . 197 Prerenal AKI. 197 * Corresponding author at: Department of Hematology, Oncology and Internal Medicine, Medical University of Warsaw, 1A Banacha Street, 02-097 Warsaw, Poland. E-mail address: [email protected] (G.W. Basak). https://doi.org/10.1016/j.hemonc.2018.07.004 1658-3876/Ó 2018 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 196 D. Jagus´ et al. Conditioning. 197 TBI.................................................................... 197 Chemotherapy . 198 GvHD prophylaxis . 198 Veno-occlusive disease/sinusoidal obstruction syndrome. 199 GvHD.................................................................... 200 Transplant-associated microangiopathy . 200 Infective factors . 200 Sepsis . 200 BK virus and adenovirus . 200 Nephrotoxic drugs . 201 Management of kidney dysfunction after HCT . 201 Prevention of kidney injury . 202 Personalized drug dosing. 202 Nephroprotective agents . 202 Summary . 203 Conflict of interest . 203 References . 203 Introduction days, Shingai et al. [14] proved that development of AKI before engraftment is an indicator of significantly lower Annually, over 50,000 hematopoietic cell transplantations overall survival within 100 days after HCT, compared to (HCTs) are performed around the globe. According to the postengraftment AKI, at 56% versus 90%, respectively. European Society for Blood and Marrow Transplantation Diagnosis of AKI after HCT may be challenging. Serum (EBMT) statistics, both the number and life expectancy of concentration of creatinine depends on muscle mass, hydra- transplant recipients have been rising recently [1]. Even tion, and increases with latency: 1–3 days after injury of a though prevalence of acute kidney injury (AKI) and chronic nephron has occurred. Similarly, GFR estimation based on kidney disease (CKD) after HCT has been decreasing in the creatinine level is prone to errors. Comparisons of esti- recent years [2,3], the kidney injury remains a significant mated GFR and GFR measured via radioisotopic methods complication of HCT that affects the quality of life and mor- (involving iohexol, Tc-99m-diethylenetriaminepentaacetic tality of transplanted patients. Identification of risk factors, acid) showed significant differences among patients quali- understanding causes, early diagnosis, and treatment of kid- fied for HCT [15,16]. In consequence, under- and overesti- ney injury are important to develop safer transplantation mation of GFR carry a risk of toxic or inadequate dosage procedures. of chemotherapeutics, as well as delayed AKI diagnosis. AKI after HCT is usually defined as a doubling of base- Since radioisotopic methods are expensive and time con- line serum creatinine and/or decline in glomerular filtra- suming, new more sensitive and specific markers of kidney tion rate (GFR) of at least 50% within the first 100 days function are urgently needed. A useful tool for prediction after HCT. This stands for Stage 2 of AKI according to of AKI is HCT comorbidity index (HCT-CI). It was proven that Acute Kidney Injury Network (AKIN) and Kidney Disease: HCT-CI 1–2 is associated with a 2.4-fold higher risk of sev- Improving Global Outcomes (KDIGO) criteria or stadium ere AKI, while HCT-CI 3 increases the risk almost fivefold of Injury in Risk, Injury, Failure, Loss, End-Stage (RIFLE) [17]. 2 criteria, as it was proven that AKI of at least this stage CKD is defined as a decrease in GFR below 60 mL/min/m , is a negative predictor of long-term mortality [4]. Such which persists for at least 3 months. CKD was reported to defined AKI occurs in 12–21% of patients undergoing autol- occur in up to 4.5% of patients within 5 years post HCT, 7% ogous HCT (autoHCT) [4–6] and varies depending on the of whom progressed to end stage renal failure and required type of conditioning after allogeneic HCT (alloHCT): 36– RRT [18]. The frequency of CKD increases with time after 56% after myeloablative and 7–46% after reduced- HCT and differs substantially between allogeneic (14%) and intensity conditioning (RIC) [4,7–11]. The percentage of autologous transplantation recipients (4%) [18,19]. Identified patients with AKI that require renal replacement therapy risk factors include AKI in the early posttransplantation per- (RRT) is reported at a rate of 7%, 20–33%, and 4%, respec- iod, total body irradiation (TBI) as a conditioning regimen, tively [12]. However, AKI is variably defined in the HCT lit- presence of graft-versus-host disease (GvHD), and prolonged erature, which along with heterogenicity of analyzed use of calcineurin inhibitors (CNIs) [19,20]. Albuminuria groups, make comparisons between studies problematic. defined as urinary albumin to creatinine ratio (ACR, Independently from definitions and laboratory methods 30–300 mg/g) is a negative prognostic marker for survival, used to asses kidney function, AKI is correlated with progression of CKD, occurrence of GvHD, and bacteremia increased all cause mortality (ACM) and nonrelapse mortal- [21]. There is a linear correlation between the level of ACR ity (NRM) [4,7,9,10,13]. Interestingly, while the median and NRM during the first 100 days after HCT: mortality rises time of AKI occurrence varies between 20 days and 40 about 10% on every 100 mg/g ACR increase [21,22]. Kidney dysfunction after HCT—Etiology, management, and perspectives 197 Table 1 Etiology of kidney dysfunction after Hematopoietic Cell Transplantation (HCT) [23]. Prerenal Intrarenal Post-renal Decreased renal blood flow following Acute tubular necrosis (sepsis, Crystal nephropathy heavy fluid loss (vomiting, diarrhea, nephrotoxic drugs, contrast agents, Retroperitoneal fibrosis associated dehydration, mucosal damage, CRS, ES, VOD/SOS) with radiotherapy bleeding) Interstitial nephritis (induced by: Tumor infiltration of urinary tract Septic shock drugs, infections such as BK virus, Hemorrhagic cystitis CLS adenovirus, fungal infection) ES TAM VOD/SOS Complex origin: GvHD Tumor lysis syndrome Note. CLS = capillary leak syndrome; CRS = cytokine release syndrome; ES = engraftment syndrome; GvHD = graft versus host disease; SOS = sinusoidal obstructive syndrome; TAM = transplant-associated microangiopathy; VOD = veno-occlusive disease. Etiology Prerenal AKI Kidney injury after HCT most often has complex origins. Prerenal AKI may occur at any time during and after HCT. Table 1 shows possible causes of renal injury in relation to This may be a result of fluid loss caused by chemotherapy- its pathophysiology. The most important issues are dis- induced vomiting or diarrhea, iatrogenic fluid overload, cussed below. and tumor-lysis syndrome in cases when remission was not achieved before conditioning [15,27]. Kidney injury before HCT Two other complications that cause AKI in the early post- transplant period are capillary leak syndrome (CLS) and engraftment syndrome. Both are caused by release of proin- Patients qualified for HCT frequently have impaired kidney flammatory cytokines and may manifest after autoHCT and function prior to transplantation. This may be caused by alloHCT as fluid retention and noninfectious fever. The underlying diseases, comorbidities, or both. Glomeru- mechanism of kidney injury is prerenal—secondary to lonephritis develops in many hematological malignancies intravascular volume depletion and possibly also direct as a paraneoplastic syndrome and resolves with remission impact of inflammation on kidney tissue [28]. CLS often pre- of the underlying disease [23]. In multiple myeloma and sents within 2 weeks post HCT as peripheral edema and ser- other plasma-cell dyscrasias, accumulation of monoclonal osal effusion resistant to diuretics [29]. CLS as a component protein