Hematol Oncol Stem Cell Ther (2018) 11, 195– 205
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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 in nephrons leads to cast nephropathy, glomeru- of CRS deserves special attention in a field of haploidentical lonephritis, or less frequently, to amyloidosis. Also, hyper- HCT. In this instance, CRS complicates 87% of cases and 12% calcemia causes direct damage to the renal interstitium experience severe CRS, which correlates with markedly [24]. Other mechanisms of kidney injury in the course of higher mortality. Clinically significant renal failure was malignancy include: tumor lysis syndrome, cytokine release found in 14% of severe CRS [30]. Treatment options are ster- syndrome (CRS), infiltration by cancer cells, and obstructive oids and currently investigated anti-interleukin-6 therapies uropathy caused by lymphadenopathy. Iatrogenic injury via [30]. Engraftment syndrome presents similarly to CLS but chemotherapy and radiation also should not be overlooked it occurs mainly during neutrophil regeneration and is often [23]. Comorbidities such as diabetes mellitus, hypertension, accompanied by fever and rash with multiorgan dysfunction and arteriosclerosis also contribute to pretransplant kidney [31]. Kidney dysfunction in engraftment syndrome was insufficiency. Paradoxically, patients with cardiovascular found in 8% of alloHCT recipients [32] and 27% of autoHCT disease (coronary disease, cerebral atherosclerosis, dia- recipients [33]. Engraftment syndrome responds well to betes) and mild CKD have lower risk of AKI after alloHCT glucocorticoid treatment provided that the treatment is compared to patients with none of the above conditions implemented early [32]. [7,8,25]. The reason for this is not clear; cytoprotective effects of cholesterol and nephroprotective properties of statins and antihypertensive agents are postulated [25]. Conditioning CKD is not a firm contradiction for alloHCT, however RIC is preferred in this population of patients [26]. Studies con- Considering the variability and complexity of conditioning ducted among patients with mild to moderate CKD trans- regimens, it is difficult to assess the impact of particular planted after RIC did not show an increase in mortality agent or regimen on renal injury. What is more, renal injury [26]. Patients with myeloma with end stage renal failure may manifest with a delay, which is most significant in the on RRT undergo autoHCT with acceptable transplant- case of TBI use [18]. related mortality, but reduction of melphalan dose is required [24]. The transplant-related mortality rate of TBI those with renal impairment reaches 4%, compared to <1% TBI-induced kidney injury has a particular tendency to in patients without renal failure [24]. develop late, even several years after exposure. Animal 198 D. Jagus´ et al.
Table 2 Requirement for dose reduction of chemotherapeutics used in conditioning regimens [23,38,39]. Chemotherapeutic Clinical presentation Recommended dosage reduction Recommended dosage reduction for general population for HCT recipients Busulfan AKI, NO NO electrolyte disturbances, (hypomagnesemia, hypocalcemia, hypophosphatemia) Cyclophosphamide Hemorrhagic cystitisa Consider in moderate to severe Urinary-bladder fibrosis 25% for GFR < 10, 50% for HD renal impairment Fludarabine – 25% for GFR 10–50, 50% for GFR 20–25% in moderate to severe <10 and HD renal impairment Melphalan AKI 25% for GFR 10–50, 50% for GFR 100–140 mg/m2 in renal <10 and HD impairment and HD Carmustine AKI No data for GFR 10–50, avoid in GFR <10 and HD Clofarabine - 50% for GFR 30–60 Thiotepa Hematuria YES NO in moderate and severe renal Dysuria impairment. Urinary retention Etoposide Metabolic Acidosis 25% for GFR 10–50, 50% for GFR <10. HD: no reduction No data Note. AKI = acute kidney injury; GFR = estimated glomerular filtration rate (mL/min/m2); HCT = hematopoietic cell transplantation; HD = hemodialysis; MESNA = sodium 2-mercaptoethane sulfonate. a Risk significantly decreases with use of adequate hydration and prophylaxis with MESNA [29]. models and autopsy studies show features of glomeruloscle- Consequently, precise dosing is crucial for the efficacy and rosis, clots in the glomerulus vessels, and scarring of the safety of treatment, but the actual recommendations put kidney parenchyma. Clinical presentation varies from the same dose reduction for a wide range of GFR. There- asymptomatic course, proteinuria, to thrombotic microan- fore, current research concentrates on calculation of per- giopathy and end stage renal disease [34]. Fractionation of sonalized dosing, based on kidney function tests and body the radiation dosage into five to 12 sessions and partial size measures or plasma concentration [41,42]. shielding of kidneys may decrease renal toxicity, however, it comes with the price of higher relapse rates [35,36]. Ani- GvHD prophylaxis mal studies and small cohort observations suggest a protec- tive role of angiotensin convertase inhibitors for kidney It is proven that some agents used to prevent and treat function during TBI, but further studies are needed to draw GvHD increase the risk of kidney injury. The list of poten- clear conclusions [34,37]. tially nephrotoxic agents is included in Table 3. CNIs deserve special attention because of multifactorial nephrotoxic Chemotherapy influence. This may result in reduction of GFR, secondary Table 2 lists chemotherapeutics used in conditioning regi- to vasoconstriction, which is reversible after dose reduction mens that are either nephrotoxic or eliminated by kidneys. or discontinuation of CNIs, as well as irreversible renal dys- Recommendations on dose modifications come from recom- function [43]. A systematic review of 19 studies of alloHCT mendations for the general population [38] and a document revealed a correlation of cyclosporine (CSA) treatment and issued by the American Society for Blood and Marrow Trans- AKI in one third of studies, with only some studies proving a plantation [39]. The second one is exclusively for recipients concentration-dependent effect [44]. Nevertheless, long- of HCT, but the majority of data come from small studies term CSA treatment is a significant risk factor for CKD and case reports. [20]. A recent study in RIC HCT revealed the correlation of Special attention is given to fludarabine, which is com- tacrolimus serum concentration and development of AKI monly used in RIC regimens dedicated to patients with [45]. Studies comparing protocols containing CSA or tacroli- comorbidities, including renal insufficiency. Fludarabine is mus did not show differences in nephrotoxicity and effec- not nephrotoxic, but since it is eliminated by the kidneys tiveness in GvHD prophylaxis [46]. Regarding that facts, there is a higher risk of neurotoxic adverse effects in cases emerging CNI-free regimens for prophylaxis of GvHD might of renal impairment [40]. Concentration and clearance of be a milestone also in preventing post HCT kidney injury, the active metabolite of fludarabine, F-Ara-A, correlate as was proven in a study comparing posttransplant with creatinine clearance, and it was proven that high cyclophosphamide with CNI-based regimens: 1 year after plasma concentration (parallel with low clearance) of HCT, creatinine concentration was comparable to the base- F-Ara-A, correlates with higher NRM in HCT recipients, while line level in a posttransplant cyclophosphamide group, its high clearance carries increased risk of GvHD [41]. while in a CNI-based group median fold change was 1.4 Kidney dysfunction after HCT—Etiology, management, and perspectives 199
Table 3 Nephrotoxic drugs that require dose adjustment to renal function [23,38]. Drug Potential nephrotoxicity Required adjustments Methotrexate Crystalluria (dose 1 g/m2) YES (when GFR <50 ml/min/m2)
Cyclosporine Vasoconstriction, interstitial nephritis, Guided by drug concentration Tacrolimus thrombotic microangiopathy, hypomagnesemia, hypophosphatemia
Cyclophosphamid Hemorrhagic cystitisa YES, guided by GFR Urinary-bladder fibrosis
Sirolimus [49] Proteinuria, glomerulonephritis NO
Vancomycin Acute tubular necrosis YES, guided by drug concentration
Aminoglycosides Acute tubular necrosis YES, guided by GFR and drug concentration
Penicillins, cephalosporins, Tubulointerstitial nephritis YES fluoroquinolones, macrolides
Trimethoprim-sulfamethoxazole Tubulointerstitial nephritis, proteinuria YES
Amphotericin B liposomal Vasoconstriction, damage of the kidney NO Amphotericin B colloidal tubules, hypokalemia, hypomagnesaemia, metabolic acidosis
Aciclovir, ganciclovir Crystalluria YES
Foscarnet Damage of the kidney tubules, electrolyte YES disturbances, proteinuria
Cidofovirb Damage of the kidney tubules, proteinuria Contraindicated when GFR <55 ml/min or proteinuria >100 mg/dl
Allopurinol, proton pump Tubulonterstitial nephritis NO inhibitors
Diuretics Prerenal kidney injury NO
Angiotensin converting enzyme Renal vascular dysregulation, polydipsia Contraindicated when mean inhibitors, angiotensin receptor [77] arterial pressure <60–65 mmHg, antagonists progressive AKI, CDK with GFR <25–30 ml/min Note. AKI = acute kidney injury; CKD = chronic kidney disease; GFR = glomerular filtration rate. a Risk significantly decreases with use of adequate hydration and prophylaxis with sodium 2-mercaptoethane sulfonate (MESNA) [29]. b Used with probenecid to limit nephrotoxicity.
[47]. In the same study, the incidence of hemorrhagic cysti- of endothelium and coagulation that results in obstruction tis was 27% all cases were associated with BK virus reactiva- of hepatic sinuses and consequently portal hypertension tion (see section ‘BK virus and adenovirus’). Another, [50]. The mechanism of kidney injury is analogical to relatively rare complication is sirolimus-associated protein- hepato-renal syndrome [51], but the pathophysiology of uria, observed both in HCT and solid organ transplant recip- hepato-renal syndrome also remains puzzling. Currently, it ients, especially after conversion from CNI. This is thought to be a result of hypoperfusion of kidneys, sec- complication, potentially leading to chronic renal failure, ondary to splanchnic vasodilatation and reduced effective is usually mild and reduced by treatment with antagonists blood volume. Kidney specimens typically show no struc- of the renin-angiotensin-aldosterone system (RAAs) and tural changes, which confirms the above hypothesis [52]. reversible after discontinuation of sirolimus [48,49]. Clinical presentation of AKI secondary to VOD/SOS is olig- uria, ascites, peripheral edema, low mean arterial pressure Veno-occlusive disease/sinusoidal obstruction with a relatively high pulse pressure, and tachycardia. In syndrome laboratory testing, creatinine concentration may be inade- quately normal or only slightly increased. Other findings The veno-occlusive disease/sinusoidal obstruction syn- include hyponatremia, hyperkalemia, urine sodium exertion drome (VOD/SOS) is the effect of pathological activation less than 10 mEq/L and urine osmolality greater than plasma 200 D. Jagus´ et al. osmolality [52]. Treatment is based on fluid and sodium of hypertension, calcium blockers are considered the safest restriction, albumin infusion together with vasoconstrictors, option for injured kidneys while diuretics are the drugs of preferably terlipressin, and in severe cases RRT [52]. Apart choice for management of fluid retention [62]. Some from the above symptomatic measures, defibrotide is con- authors highlight the role of angiotensin convertase inhibi- sidered as an effective causative treatment [29,50]. tors and sartans in the prophylaxis of TAM, but data is scarce [37]. There is no universally approved approach to specific GvHD treatment of TAM. The EBMT recommends replacing CNIs in GvHD prophylaxis with other immunosuppressive agents Apart from the obvious risk of prerenal AKI in the course of as an initial step [29]. Since some patients respond to such gastrointestinal GvHD, moderate and severe presentations management, it is possible to identify TAM caused by CNIs. of both acute and chronic GvHD are correlated with AKI and Plasmapheresis is another therapeutic option, the early use CKD. Evidence suggests that glomerulonephritis and protein- of which, in combination with withdrawal of CNIs, gives 27– uria are associated with chronic GvHD [7,9,53]. Undoubtedly, 80% response rates. Several case reports demonstrated good the damage to kidneys in GvHD is propelled by excessive effects of plasmapheresis in combination with rituximab in release of proinflammatory cytokines such as tumor necrosis patients with antibodies against complement factor H. How- factor-a, interleukin-6, and transforming growth factor-b ever, the most promising drug today is eculizumab—the mon- [53]. The evidence of the direct cytotoxic response against oclonal antibody targeting complement factor C5, with kidney tissue in GvHD is missing, but that could be explained proven effectiveness in patients with increased serum con- by the fact that kidney biopsies are performed rarely in this centration of C5b-9 [63]. Other therapeutic options are group of patients. Animal studies showed infiltration of under investigation, including defibrotide. Development of CD3+, CD4+, CD8+ lymphocytes, and macrophages in kidney TAM is correlated with lower overall survival of transplant tissues of transplanted rats and mice [54,55]. recipients (approximately 30% during the 1st year) and the mortality rate of TAM with multiorgan involvement is Transplant-associated microangiopathy reported to be as high as 90%, therefore new therapeutic approaches are urgently needed [59]. Transplant-associated microangiopathy (TAM) is a complex and not fully understood disorder, which resembles atypical Infective factors hemolytic uremic syndrome. It is thought that damage of Sepsis vascular endothelium triggers platelet aggregation in the microvasculature and excessive activation of the comple- Sepsis is characterized by a combination of factors, both ment leading to thrombosis and fibrin deposition [56]. Risk hemodynamic and inflammatory, that coalesce to cause factors include high dose radiation, viral infections (cyto- renal failure [65]. 75% of transplanted patients who require megalovirus, adenovirus), GvHD, VOD/SOS, and treatment treatment in an intensive care unit develop AKI and the with CNIs [57,58]. Most commonly, TAM presents as hemoly- death rate in those who require RRT is 95% [2]. Therefore, tic anemia (with schistocytes in the blood smear, increased early diagnosis and treatment of infections is crucial for pre- lactate dehydrogenase, and decreased level of hap- vention of AKI. In cases of sepsis-associated AKI, optimiza- toglobin), thrombocytopenia, neurological symptoms, and tion of fluid therapy and withdrawal of nephrotoxic drugs organ failure. Kidneys are affected most often and autopsy are essential. Early initiation of RRT before development studies confirm features of TAM also in patients with normal of fluid overload may improve treatment outcomes [66]. creatinine level [57,59]. Diagnostic criteria of TAM are not unified. Considering kidney function tests, the Blood and BK virus and adenovirus Marrow Transplant Clinical Trials Network consensus BK virus and adenovirus deserve special attention in the includes twofold creatinine rise or at least 50% drop of context of kidney injury. Both viruses are found in asymp- GFR [60]. The International Working Group of the EBMT does tomatic carriers and immunosuppression may cause their not include renal function test in the criteria [61]. Since all reactivation in HCT recipients, leading to hemorrhagic cys- criteria used in the guidelines are not specific and are often titis and, less commonly, interstitial nephritis [67–69]. met due to the underlying disease, toxicity of conditioning, Hemorrhagic cystitis manifests as hematuria or microscopic infection, or medications, it is recommended to verify the hematuria, sometimes accompanied by dysuria. Massive diagnosis of TAM with kidney biopsy, whenever feasible. hematuria may lead to obstruction of the urinary tract by Noninvasive tests include assessment of complement com- clots and to urinary retention, causing postrenal AKI [29]. ponents, antibodies against factor H of complement, and Diagnosis is confirmed by the quantitative measurement of findings specific to affected organs, such as pulmonary the virus copies in the plasma or urine. It has been shown hypertension or abnormalities in the central nervous sys- that being an asymptomatic carrier of BK virus after HCT tem. When gut is affected, intestinal biopsy is an option is a risk factor for AKI, especially when viremia is detectable [62]. In addition, it is suggested to consider TAM in cases [70]. The first line of treatment is based on adequate hydra- of newly diagnosed microalbuminuria and hypertension tion, bladder irrigation with normal saline, and reduction of [63]. Negative prognostic factors are AKI, proteinuria >30 the immunosuppressive therapy. Trials with cidofovir were mg/dL and increased concentration of the C5b-9 comple- undertaken in cases that did not improve with symptomatic ment complex [63,64]. measures. It is efficient in 60–100% of the cases caused by Treatment of TAM is based on aggressive management of the BK virus, however, it is associated with renal toxicity triggering factors and supportive care. In the management in 9–50% of treated individuals and is contraindicated in Kidney dysfunction after HCT—Etiology, management, and perspectives 201 patients with renal dysfunction [71]. Other therapies with are CNIs, antibiotics, allopurinol, and proton pump inhibi- high efficacy and acceptable safety profile include lefluno- tors [76]. Importantly, despite a proven nephroprotective mide [72] and hyperbaric oxygen [73]. Benefits of role of antagonists of RAAs, in certain clinical scenarios they immunoglobulin infusions have been shown among kidney also appear nephrotoxic. Antagonists of RAAs may cause transplant recipients [74]. Ongoing studies explore the util- more harm than good when used in cases of dehydration, ity of ciprofloxacin and levofloxacin in the treatment and hypotension, hyperkalemia, progressing AKI, and advanced prophylaxis of BK virus reactivation, but available data is CKD, as well as in combination with nonsteroidal antiinflam- ambiguous [75]. Cases of massive hematuria, flank pain, matory drugs [77]. Recent studies note an increased risk of fever, and AKI, as well as high viral load, are suggestive of AKI in patients treated with RAAs blockers in cases of sepsis nephritis, which may be confirmed by renal biopsy, and [78]. guide a decision of more aggressive treatment, involving cidofovir or leflunomide [68,69]. Management of kidney dysfunction after HCT
Nephrotoxic drugs Fig. 1 and Table 4 show a proposed algorithm for the man- agement of AKI after HCT, based on three basic clinical find- Establishing diagnosis of drug nephrotoxicity may be chal- ings: hydration status, blood pressure, and possible lenging in HCT recipients treated with numerous agents. infections, as well as basic blood and urine tests and ultra- Table 3 illustrates frequently used drugs with their possible sound. First and foremost, in cases of AKI, nephrotoxic nephrotoxic effects. Tubulointerstitial nephritis deserves drugs should be withdrawn or reduced, fluid and electrolyte special attention. It is caused by immunological reactions balance restored, and infection aggressively managed. At to drugs. Apart from AKI, it presents with pyuria, eosinophil- the same time, rare but life-threatening conditions such ia, and eosinuria, and sometimes skin rash, therefore it may as TAM or VOD/SOS should not be overlooked. A significant be misdiagnosed as urinary tract infection or GvHD. Medica- obstacle in evaluating the cause of kidney dysfunction after tions most often associated with tubulointerstitial nephritis HCT is the fact that kidney biopsies are rarely performed
Nephrotoxic: discontinue if possible Drugs Metabolized by kidney: adjust the dose to GFR
Excessive intake Inadequate intake (diarrhea, nausea, vomiting) Hydration status VOD/SOS Diuretics Dehydration Fluid overload Poliuria (i.e. hypercalcemia) ES, CLS
Heart failure CNI Hypertension Hypotension TAM Blood pressure Sepsis
Fever, signs of Present • Cultures infecion • Imaging studies
INCREASE IN CREATININE CONCENTRATION (≥0.3 mg/dL in 48h or ≥ 1,5x in 7 d) or OLIGURIA (diuresis <0,5ml/kg/h for 6 h)
ULTRASOUND URINE TEST Drugs BLOOD TESTS
Crystaluria TLS Hyperuricemia Urinary obstruction Renal vein thrombosis High specific gravity VOD/SOS Hyperphosphatemia
Pyuria (leukocyturia) Hypocalcemia UTI
Neoplasm infiltration Low specific gravity Hyperkalemia Interstitial on urinary tract nephritis PCR for BKV Proteinuria Hyperbillirubinemia and adenovirus Billirubin (serum and urine) GvHD, Hypoalbuminemia GN Erytrocytes in urine , Thromoboytopenia Hemorrhagic cystitis hematuria TAM Schistiocytes Increased LDH
Consider KIDNEY BIOPSY
Fig. 1 Suggested strategy of clinical workup in acute kidney injury (AKI) after hematopoietic cell transplantation (HCT). The dotted line boxes show possible causes of AKI; the shaded boxes show suggested additional tests. Note. BKV = BK virus; CLS = capillary leak syndrome; CNI = calcineurin inhibitors; d = day; ES = engraftment syndrome; GFR = glomerular filtration rate; GN = glomerulonephritis; GvHD = graft versus host disease; LDH = lactate dehydrogenase; PCR = polymerase chain reaction; TAM = transplant-associated microangiopathy; TLS = tumor lysis syndrome; UTI = urinary tract infection; VOD/SOS = veno-occlusive disease/sinusoidal obstruction syndrome. 202 D. Jagus´ et al.
Table 4 Suggested Management Options of AKI after hematopoietic cell transplantation (HCT). Dehydration Hydration guided by fluid balance and electrolyte concentration VOD/SOS Albumins RRT defibrotide
ES, CLS Steroids, diuretics
Heart failure Diuretics, vasopressors, inotropes, specific cardiologic treatment
Tumor lysis syndrome Hydration, allopurinol, rasburicase, febuxostat, RRT
TAM Consider discontinuation of CNI Plazmapheresis Rituximaba Eculizumaba
Hemorrhagic cystitis Urinary bladder irrigation, Cidofovira Leflunomid Immunoglobulin infusionsa Hyperbaric oxygena
Obstruction in urinary tract Urethral and ureteral catheterization Nephrostomy
Interstitial nephritis Discontinue drugs, steroids
GVHD, GN Immunosuppression Note CLS = capillary leak syndrome; CNI = calcineurin inhibitors; CRS = cytokine release syndrome; ES = engraftment syndrome; GN = glomerulonephritis; GvHD = graft versus host disease; RRT = renal replacement therapy; TAM = transplant-associated microangiopathy; VOD/SOS = veno-occlusive disease/sinusoidal obstruction syndrome. a Experimental treatment options.
due to a high risk of bleeding complications. We suggest per- 38% when the second dose of cyclophosphamide is guided forming kidney biopsies after careful consideration of the by measurement of the concentration of its metabolites in risks and impact of histological findings on treatment [67]. plasma after the first dose. Importantly, personalized cyclophosphamide dosing did not affect overall survival Prevention of kidney injury and relapse rate, despite an overall reduction in total cyclophosphamide dose [79]. Also, polymorphism of genes involved in the metabolism of chemotherapeutics may be Simple measures including strict control of fluid-electrolyte helpful in adjusting therapy [41,80]. Polymorphism in the balance seem to be a key to prevent kidney injury. There- gene encoding CYP2B6 has been correlated with a significant fore regular observation of weight, fluid balance, blood increase of hemorrhagic cystitis, VOD/SOS, and overall pressure, electrolytes, and creatinine should be a standard survival [80]. practice in transplantation units. Nephrotoxic drugs should be used with great caution. Since identification of risk fac- Nephroprotective agents tors, early diagnosis, and treatment of AKI is crucial for favorable outcomes, high expectations are put on research Compounds able to limit nephrotoxicity are the subject of on new markers of kidney injury. They should enable early promising studies in modern oncology. For example, supple- diagnosis and precise assessment of kidney injury. Also, mentation of selenium, magnesium, and vitamin E was detection of subclinical kidney dysfunction prior to HCT found to be effective in the reduction of cisplatin nephro- may guide clinicians to choose less nephrotoxic conditioning toxicity in patients with cancer. Also, caffeine, oxytocin, and GvHD prophylactic regimens. and antioxidants significantly reduced the nephrotoxicity of cisplatin in animal models [81–83]. Microelements and Personalized drug dosing antioxidants may be beneficial for HCT recipients, but there is not enough data to draw a clear conclusion. By contrast, Studies on personalized drug dosing based on calculations of acetylcysteine failed to show nephroprotective effects in body measurements, kidney function tests, and quantifica- the early period after HCT [84]. Ongoing studies focus on tion of plasma concentrations of drug metabolites, bring a nephroprotective role of drugs acting on the renin–angio hope to limit the toxicity of conditioning [41,42,79]. tensin–aldosterone system in patients after TBI or taking McCune et al. [79] showed that the rate of AKI after TBI CNIs [85,86]. However, so far, none of the nephroprotective and cyclophosphamide conditioning may be decreased by agents was approved for standard use. Kidney dysfunction after HCT—Etiology, management, and perspectives 203
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