Acute kidney injury following HCT: incidence, risk factors and ... - Nature

Bone Marrow Transplantation (2011) 46, 1399–1408 & 2011 Macmillan Publishers Limited All rights reserved 0268-3369/11

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REVIEW

Acute kidney injury following HCT: incidence, risk factors and outcome JA Lopes and S Jorge Department of Nephrology and Renal Transplantation, Hospital de Santa Maria, Lisboa, Portugal

Acute kidney injury (AKI) is a common complication in haematopoietic cell transplantation (HCT) patients and it adversely affects outcome. Herein, we provide a comprehensive and contemporary discussion of the incidence, risk factors and outcome of AKI in patients undergoing HCT, focusing on the differences between the myeloablative and nonmyeloablative regimens. Bone Marrow Transplantation (2011) 46, 1399–1408; doi:10.1038/bmt.2011.46; published online 7 March 2011 Keywords: acute kidney injury; HCT; myeloablative; nonmyeloablative

Introduction Haematopoietic cell transplantation (HCT) is now used to treat several malignant (for example, multiple myeloma, leukaemias, lymphomas) and non-malignant haematological disorders (for example, aplastic anaemia, b-thalassaemia, immunodeficiency disorders, inborn errors of metabolism), as well as solid tumours (for example, breast cancer, neuroblastoma), which otherwise are incurable. There are at present two major HCT procedures taking into account the conditioning regimen used: myeloablative autologous and allogeneic HCT and nonmyeloablative HCT. Myeloablative HCT uses maximally tolerated dose of TBI with or without chemotherapy, or chemotherapy alone. On the contrary, nonmyeloablative HCT relies more on donor cellular immune effects and less on the cytotoxic effects of the preparative regimen to control the underlying disease.1–5 It uses a lower dose conditioning regimen and can be offered to older patients, to patients debilitated by other concomitant diseases (co-morbidities) or to high-risk, heavily pretreated patients, who would not tolerate myeloablative HCT, with an attendant decrease in regimen-related toxicity and treatment-related mortality.6–10 Patients undergoing HCT are prone to developing acute kidney injury (AKI). AKI itself adversely affects short- and long-term outcome of those patients. In fact, in patients

Correspondence: Dr JA Lopes, Department of Nephrology and Renal Transplantation, Hospital de Santa Maria, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal. E-mail: [email protected] Received 22 November 2010; revised 26 January 2011; accepted 27 January 2011; published online 7 March 2011

receiving HCT short- and long-term mortality are increased in AKI patients comparing with patients with no acute kidney impairment. Herein, we provide a comprehensive and contemporary discussion of the incidence, risk factors and outcome of AKI in patients undergoing HCT, focusing on the differences between the myeloablative and nonmyeloablative regimens.

Incidence of AKI following HCT Although AKI is a common complication in patients undergoing HCT and it usually occurs within the first 100 days after transplantation, reported incidence and timing of post-HCT AKI varies according to the conditioning regimen (myeloablative vs nonmyeloablative) used. Furthermore, the severity of AKI following HCT is quite different between myeloablative and nonmyeloablative procedures. Myeloablative HCT. The initial report of AKI following HCT was performed by Zager et al.,11 and included 272 patients with primarily haematologic malignancies who underwent myeloablative HCT (89% allogeneic, 11% autologous) at the Fred Hutchinson Research Center in Seattle, WA, USA. This study revealed that 53% of patients developed AKI defined as a doubling in serum creatinine (SCr) and the mean onset of renal impairment occurred at 14 days. The first study to specifically examine renal injury in autologous myeloablative HCT was performed at the University of Colorado and evaluated 232 patients with breast cancer with positive nodes or metastases. At 3 months after HCT, 21% of patients developed at least a doubling of baseline SCr and dialysis was required in 3% of patients.12 In the mid 1990s, a retrospective analysis of 275 myeloablative autologous and allogeneic HCT patients has been undertaken at Princesa Hospital, Autońoma University, Madrid, Spain, to ascertain the incidence, risk factors and impact on outcome of AKI after HCT. AKI was diagnosed in 72 patients (26%) and occurred in 81.9% within the first month. The prevalence was higher in allogeneic HCT (36%) than in autologous HCT (6.5%) (ref. 13). More recently, in the past decade, several studies addressing AKI in myeloablative HCT have been published14–22 (Table 1); most of them have evaluated patients receiving myeloablative allogeneic HCT.14–18 Three studies have analyzed the incidence of AKI in both myeloablative allogeneic and autologous HCT,19–21 and one prospective

Bone Marrow Transplantation

140

363

140

189

64

173

Parikh et al.17a

Kersting et al.18

Lopes et al.19

Ando et al.20b

Hosing et al.21d

Fadia et al.22

Type of HCT

Allo

CY/TBI

CY/TBI or CY/BU

CY/BU or BU/melphalan or CY/TBI or melphalan/TBI Etoposide/CY/TBI or thiotepa/TBI or BU/CY or BU/TBI or thiotepa/ carboplatin/CY/ATG/TBI or CY/TBI or fludarabine/melphalan or BU/CY/ATG or melphalan/ ATG/TBI or melphalan/TBI CY/TBI

Conditioning regı´men

Prospective, single centre

Auto

Retrospective, Allo (3%) multicentre Auto (97%)

Melphalan

CY/ATG/TBI or BU/CY/ATG

BU/CY or BU/CY/etoposide or BU/CY/melphalan or BCNU/ etoposide/cytarabibe/melphalan or melphalan or etoposide/melphalan/ carboplatin Retrospective, Allo (74.6%) Cytarabine/CY/TBI or BU/CY or single centre Auto (25.4%) BU/CY/TLI

Retrospective, Allo (64%) single centre Auto (36%)

Retrospective, Allo single centre

Retrospective, Allo single centre

Prospective, single centre

Retrospective, Allo single centre Retrospective, Allo single centre

Design

PBSC

PBSC (92%) BM (3%)

BM (53%) PBSC (37.6%) UCB (9.4%)

PBSC (58.6%) or BM (41.4%)

Not specified

BM (43%) or PBSC (57%)

Not specified

BM or PBSC or UCB BM (85%) UCB (13%) PBSC (2%)

Graft source

Median: 35 days (range 0–90)

49.5%

Overall incidence 21.5% Allo-HCT 27% Auto-HCT 12% Allo-HCT 66%/ 61.7%/66%c Auto-HCT 18.8%/10.4%/ 18.8%c

Overall incidence 14%

m 42 SCr m 42 SCr

m 41.5 SCr or m SCr X0.5 mg (if baseline SCr 44 mg/dL)/m SCr X0.3 mg/dL or m41.5 SCr or m SCr X0.5 mg (if baseline SCr 44 mg/dL)/m 42 SCr m SCr X0.3 mg/dL or m41.5 SCr or m SCr X0.5 mg (if baseline SCr 44 mg/dL) m1 mg/dL SCr or m 42 SCr to 1.5 mg/dL

21%

Not specified

73%

k 450% GFR+m 42 SCr

Median: 7 days (range –14–27)

Not tested


Not specified


36%

m 42 SCr

Not specified

Mean: 16 days

21%

69%

m42 SCr

Timing of AKI

AKI requiring dialysis

Incidence of AKI

Definition of AKI

k Baseline Cr clearance, involvement cardiac, melphalan dose, bacteraemia

Not specified

Not specified

Amphtotericin, hepatic VOD, k baseline SCr Myeloablative HCT, female, high-risk disease, co-morbidity Previous hypertension, admission to ICU Not tested

Lung toxicity, hepatic VOD Acute GVHD, hepatic VOD

Risk factors for AKI

Abbreviations: AKI ¼ acute kidney injury; ATG ¼ antithymocyte globulin; GFR ¼ glomerular filtration rate; HCT ¼ haematopoietic cell transplantation; ICU ¼ intensive care unit; SCr ¼ serum creatinine; UCB ¼ umbilical cord blood; VOD ¼ veno-occlusive disease. a This study compared the incidence and risk factors for AKI in patients receiving myeloablative or nonmyeloablative HCT. b This study compared the incidence of AKI in patients receiving myeloablative allogeneic HCT or myeloablative autologous HCT or nonmyeloablative HCT. c Incidence of AKI according to the definition used (m 41.5 SCr or m SCr X0.5 mg (if baseline SCr 44 mg/dL)/m SCr X0.3 mg/dL or m41.5 SCr or m SCr X0.5 mg (if baseline SCr 44 mg/dL)/m 42 SCr). d This study evaluated the incidence of AKI in patients with systemic sclerosis participating in three HCT trials in the United States who received myeloablative autologous or allogeneic HCT.

147

97

88

Hingorani et al.16

Hahn et al.

15

N

Studies reporting the incidence and risk factors for AKI in patients receiving myeloablative HCT

Parikh et al.14

Table 1

Acute kidney injury in HCT JA Lopes and S Jorge

1400


1401

study has addressed the development of AKI in patients undergoing a myeloablative autologous HCT.22 In the majority of cases, AKI occurring following HCT was captured within the first 3 months after transplantation, thus, providing evidence that 100 days is an appropriate ‘cut-off’ time for assessing most AKI events. The incidence of AKI within the first 100 days after myeloablative allogeneic HCT ranged from 21 to 73%. The reported incidence of AKI in patients receiving a myeloablative autologous HCT varied between 12 and 19%, which was much lower than that described for patients undergoing myeloablative allogeneic HCT. There are two major reasons for lower prevalence of AKI in myeloablative autologous HCT compared with that of myeloablative allogeneic HCT. First, the absence of GVHD in autologous HCT, which can contribute to renal lesion directly through cytokine- and immune-related injury, including glomerular deposits causing nephrotic syndrome, and tubulitis; or indirectly through nephrotoxicity induced by CYA used in prophylaxis against GVHD.23–25 In addition, severe GVHD with diarrhoea and dehydration, and CMV reactivation because of treatment of GVHD with high-dose prednisolone can also contribute to GVHDassociated nephrotoxicity.26,27 Second, because there are no foreign cells in myeloablative autologous HCT, more rapid engraftment occurs (resulting in less cytopenia, sepsis and nephrotoxicity induced by antimicrobials). AKI following myeloablative HCT occurred early (7–40 days), usually in the first month after transplantation. At this time, the patient is more vulnerable to multiple organ dysfunctions because of toxicities associated with the intense conditioning regimen, especially infections and hepatic veno-occlusive disease (VOD). Kersting et al.18 have reported a median time of 40 days to occurrence of AKI after HCT, which was longer than that described in the other studies. In this study, the one complication that was associated with a significantly shorter time to occurrence of AKI after HCT was hepatic VOD. In patients suffering from hepatic VOD, AKI developed within a median of 19 days after HCT, and, contrary to other studies,11,14 a relatively small number of patients (4.4%) suffered from hepatic VOD, which in part might explain the lengthened time of AKI occurrence, in this study. Nonmyeloablative HCT. Nonmyeloablative HCT is a recently developed procedure that is providing an effective therapy for malignant and nonmalignant haematologic disorders,28–30 as well as in renal cell carcinoma1 and, more recently, in autoimmune diseases.31 Nonmyeloablative HCT relies more on donor cellular immune effects and less on the cytotoxic effects of the preparative regimen to control the underlying disease.1–3 It uses a lower dose conditioning regimen and can be offered to older patients, to patients debilitated by other concomitant diseases (co-morbidities) or to high-risk, heavily pretreated patients, who would not tolerate myeloablative HCT, with an attendant decrease in regimen-related toxicity and treatment-related mortality.6–10 Given that patients eligible for nonmyeloablative HCT are usually older and have more co-morbid conditions, it was expected that AKI might

occur more frequently compared with myeloablative HCT. However, taking into consideration that in nonmyeloablative HCT less toxic conditioning regimens are used and a shorter period of neutropenia occurs, infectious complications and organ failure will occur less frequently in this setting,32 which could have a positive impact on the incidence of AKI.33 Recently, several studies have evaluated the incidence and time of occurrence of AKI in nonmyeloablative HCT15,17,20,26,27,34–38 (Table 2). The reported incidence of AKI following nonmyeloablative HCT ranged from 29 to 56%, and AKI usually occurred later than in the myeloablative regimens. In nonmyeloablative HCT studies, time to development of AKI ranged from 22 to 60 days and most of cases occurred in the second month after transplantation. Less frequent infectious complications and organ failure, especially hepatic VOD, could explain the lengthened time of AKI occurrence in nonmyeloablative HCT compared with myeloablative conditioning. Severe AKI has been shown to be more frequent in myeloablative HCT than in nonmyeloablative HCT,14,17,18,20,26,34 although both conditioning regimens have been associated with similar percentage of patients having at least some degree of AKI (mild, moderate or severe AKI) (Figures 1 and 2). The higher severity of AKI in myeloablative allogeneic HCT could be related to the higher intensity of radiochemotherapy used in this conditioning regimen, when compared with nonmyeloablative regimens, which can destroy stem cells that reside in adult renal papilla, and, therefore, can hamper renal repair in AKI. In vitro these cells proliferate during renal injury and are capable of incorporating into other parts of the renal parenchyma, including renal tubules.39

Risk factors for AKI following HCT Myeloablative conditioning itself has shown to be an independent risk factor for the development of AKI.17 In myeloablative studies, hepatic VOD,14–16 lung toxicity,14 female sex,17 high-risk disease,17 co-morbidity,17 previous hypertension,18 admission to intensive care unit,18 acute GVHD15 and amphotericin16 were statistically associated with increased risk for AKI. Furthermore, in one study evaluating patients who underwent a myeloablative autologous HCT for AL amyloidosis, cardiac involvement, melphalan dose and bacteraemia were significantly associated with the occurrence of AKI after transplantation.22 In nonmyeloablative HCT, requirement for mechanical ventilation,34 previous autologous HCT, absence of vascular disease, low baseline SCr, elevated baseline glomerular filtration rate (GFR), acute GVHD, CMV reactivation,26 incomplete HLA-matched transplant and sepsis,38 as well as MTX, more than three lines of therapy before HCT and diabetes mellitus37 significantly increased the risk for the development of AKI. Conflicting results were associated with baseline renal function in HCT. In two studies,16,26 low baseline SCr was an independent risk factor for AKI development while in other study22 low baseline Cr clearance was independently associated with greater probability for the occurrence of AKI after myeloablative HCT. It is conceivable that the Bone Marrow Transplantation


82

253

Lopes et al.27

Parikh et al.34 Liu et al.35

62

188

358

Retrospective, Fludarabine/ATG/ single centre prednisone/melphalan or melphalan/cytarabine Retrospective, TBI or TBI/fludarabine multicentre Retrospective, Fludarabine/BU/CY or single centre Fludarabine/BU/CY/ATG Retrospective, TBI or TBI/fludarabine single centre Retrospective, Fludarabine/BU/or single centre fludarabine/melphalan or fludarabine/CY or fludarabine/TBI Retrospective, Fludarabine/BU/CY or multicentre Fludarabine/BU/CY/ATG

Retrospective, TBI or TBI/fludarabine single centre

PBSC

PBSC (98%) or BM (2%) PBSC (94%) BM (6%)

PBSC (95.7%) or BM (4.3%) PBSC

BM (72%) or PBSC (28%)

Not specified

BM 71.6% PBSC 17.4% UCB 11%

PBSC (93%) or BM (7%)

Graft source 47%

48.3%/ 40%/ 48.3%c

k 450% GFR+m 42 SCr m 41.5 SCr or m SCr X0.5 mg (if baseline SCr 44‘mg/dL)/m SCr X0.3 mg/ dL or m41.5 SCr or m SCr X0.5 mg (if baseline SCr)/ m 42 SCr m 42 SCr

53.6%

40.4% 38% 56% 42%

29%

m 41.5 SCr or m SCr X0.5 mg (if baseline SCr 44 mg/dL) m 42 SCr k 425% GFR+m o2 SCr m 42 SCr or requirement of dialysis k X25% GFR

m SCr X0.3 mg/dL or m41.5 SCr or m SCr X0.5 mg (if baseline SCr 44 mg/dL)

33%

Incidence of AKI

Definition of AKI

Prior auto-HCT, absence of vascular disease, k baseline SCr, m baseline GFR, acute GVHD, CMV reactivation Not tested

Myeloablative HCT, female, high-risk disease, comorbidity Not specified

Risk factors for AKI

Not specified

Median: 22 days (3–99) Median: 31 days (range 0–320)

MTX, 43 lines of therapy before HCT, diabetes mellitus, acute GVHD grade III–IV Incomplete HLA-matched HCT, acute GVHD, hepatic VOD, sepsis

Not specified

Requirement for mechanical ventilation Mean: 33±4 days Not specified

Median: 60 days

Mean: 37 days (4–95)


Not specified

Not specified

Timing of AKI

Abbreviations: AKI ¼ acute kidney injury; ATG ¼ antithymocyte globulin; GFR ¼ glomerular filtration rate; HCT ¼ haematopoietic cell transplantation; ICU ¼ intensive care unit; SCr ¼ serum creatinine; UCB ¼ umbilical cord blood; VOD ¼ veno-occlusive disease. a This study compared the incidence and risk factors for AKI in patients receiving myeloablative or nonmyeloablative HCT. b This study compared the incidence of AKI in patients receiving myeloablative allogeneic HCT or myeloablative autologous HCT or nonmyeloablative. c Incidence of AKI according to the definition used (m 41.5 SCr or m SCr X0.5 mg (if baseline SCr 44 mg/dL)/m SCr X0.3 mg/dL or m41.5 SCr or m SCr X0.5 mg (if baseline SCr 44 mg/dL)/m 42 SCr).

Liu et al.38

Parikh et al.36 Pinãna et al.37

150

Kersting et al.26

26

60

Ando et al.20b

Retrospective, CY/fludarabine single centre

Retrospective, TBI or TBI/fludarabine single centre

128

Parikh et al.17a

Conditioning regı´men

Design

Studies reporting the incidence and risk factors for AKI in patients receiving nonmyeloablative HCT

N

Table 2


1402


1403 300 250

AKI grades 2 and 3 AKI grade 1 Grade 0

200

102

150 100 50 0

126 61 20 7

25

Myeloablative allogeneic HCT (N =88)

Nonmyeloablative HCT (N =253)

Figure 1 Incidence and severity of AKI between myeloablative allogeneic HCT14 and nonmyeloablative HCT.34 Grade 0, defined by a decrease in baseline GFR o25%; grade 1, defined by a decrease in baseline GFR higher than 25% but an increase in baseline SCr o200%; grade 2, defined by a decrease in baseline GFR 425% and an increase in baseline SCr 4200%, but there was no requirement for dialysis; and grade 3, defined by a decrease in baseline GFR 425% and an increase in baseline SCr 425%, but there was dialysis requirement.

400

AKI grades 2 and 3

350

AKI grade 1 Grade 0

300

independent risk factor for the occurrence of AKI after nonmyeloablative conditioning,38 although VOD is an extremely rare complication associated with nonmyeloablative HCT. VOD is a hepatorenal-like syndrome because of hepatic sinusoidal obstruction syndrome, and is a frequent cause of AKI in HCT.42,43 Up to 80% of patients with VOD develop AKI, which usually begins after the onset of the hepatic disease (as manifested by progressive hyperbilirubinemia) and a superimposed event, such as sepsis, often triggers the onset of AKI.44 Hepatic VOD is almost exclusively seen in the setting of HCT, and is more commonly associated with myeloablative allogeneic HCT than with myeloablative autologous HCT, which may due to the absence of MTX because GVHD is not a concern in autologous HCT; the occurrence of VOD is extremely rare with nonmyeloablative regimens, probably because of the much lower intensity of the chemoradiotherapy.45 The risk of VOD is probably increased when donor BM is mismatched or obtained from an unrelated source and the risk of VOD may be reduced in patients receiving PBSCs compared with BM.46 The exact mechanism(s) by which the hepatic disease might cause AKI is still unclear, but decreased hepatic clearance of endotoxins absorbed from the gut may have a role.42 The prognosis of hepatic VOD can in part be predicted by renal function. In a retrospective analysis, the mortality rate was 17% in patients with a normal SCr, 37% in those with a doubling of SCr and 84% in those with AKI requiring dialysis.42

180

250 200 150 49

100

159 92

50 0

24

9

Myeloablative allogeneic HCT (N =363)

Nonmyeloablative HCT (N =150)

Figure 2 Incidence and severity of AKI in myeloablative allogeneic HCT18 and nonmyeloablative HCT.26 Grade 0, defined by a decrease in baseline GFR o25%; grade 1, defined by a decrease in baseline GFR 425% but an increase in baseline SCr o200%; grade 2, defined by a decrease in baseline GFR 425% and an increase in baseline SCr 4200%, but there was no requirement for dialysis; and grade 3, defined by a decrease in baseline GFR 425% and an increase in baseline SCr 425%, but there was dialysis requirement.

association between low baseline SCr and AKI development has been in part an artefact of the definition used (at least a doubling of baseline SCr) because the absolute change required to meet the criterion is less for a person with a low baseline level than a higher one. In fact, preexisting chronic kidney disease (CKD), which is common among patients who develop AKI, decisively contributes to a greater probability for the occurrence of AKI.40,41 Veno-occlusive disease. VOD is a major risk factor and has shown to consistently predict AKI in myeloablative allogeneic HCT. One study has also reported VOD as an

Acute CYA nephrotoxicity. The major culprit for AKI in nonmyeloablative HCT is CYA insult alone or in association with other aetiologies, such as sepsis, nephrotoxicity or GVHD.27,34,37 CYA is used in prophylaxis against GVHD both in myeloablative allogeneic and nonmyeloablative HCT. Nephrotoxicity is one of the most common and serious complications associated with CYA, which is manifested both as AKI (largely reversible after reducing the dose), or as chronic progressive renal disease, which is usually irreversible. Therefore, CYA nephrotoxicity has both a reversible haemodynamic component and an irreversible (structural) component. The haemodynamic component is mediated by acute renal vasoconstriction of the afferent and efferent glomerular arterioles with consequent reduction in renal blood flow and GFR.47–50 The vasoconstriction may be due to impairment of endothelial cell function, leading to reduced production of vasodilators (prostaglandins and nitric oxide) and enhanced release of vasoconstrictors (endothelin and thromboxane), increased sympathetic tone, increased production of transforming growth factor b-1, endothelin-1, reactive oxygen and nitrogen species.51,52 Other renal effects of the CYA include tubular dysfunction, and rarely a haemolytic uremic syndrome. Acute GVHD. Acute GVHD is a common aetiology and independently increases the risk for the occurrence of AKI both in myeloablative and nonmyeloablative settings.15,26,37,38 GVHD can contribute to renal lesion directly through cytokine- and immune-related injury, including glomerular deposits causing nephrotic syndrome, and tubulitis; or indirectly through nephrotoxicity induced by Bone Marrow Transplantation


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CYA in prophylaxis against GVHD.23–25 In addition, severe GVHD with diarrhoea and dehydration, and CMV reactivation because of treatment of GVHD with high-dose prednisolone can also contribute to GVHD-associated nephrotoxicity.26,27 CMV reactivation itself increased the risk for the occurrence of AKI in nonmyeloablative HCT.26

Impact of AKI following HCT on outcome Progression for chronic kidney disease. Chronic kidney disease after myeloablative and nonmyeloablative HCT is likely to be common, with reported incidence ranging from 3.6 to 89%. The wide range may be related to variability in the definitions of CKD and populations that have been studied.53 Overall patients who underwent HCT experienced a fall in their GFR by at least 25 ml/min/1.73 m2, irrespective of age. The majority of GFR decrement occurred during the first 12 months with less decline in renal function after 1 year;53 this fall is more than expected in the general population where an average yearly decline in GFR is 0.75 ml/min/1.73 m2 (ref. 54). Nonetheless, HCT survivors who develop CKD may be at a greater risk for death and cardiovascular events because of the increased risk conferred by CKD.55,56 Reported risk factors for CKD after HCT are sex, age, previous renal impairment, type of HCT (autologous vs allogeneic), TBI exposure, acute or chronic GVHD, development of VOD, post transplant exposure to nephrotoxic medications (aminoglycosides, amphotericin B and vancomycin), post transplant hypertension, post-HCT AKI and long-term use of CYA; the most common causes of CKD following HCT are chronic CYA nephrotoxicity and thrombotic microangiopathy.53,57–63 Chronic CYA therapy can cause nephrotoxicity similar to that seen in other settings, such as solid organ transplantation. Long-term complications are, however, unusual in HCT because CYA is given in full doses to stable patients for only several months. However, the characteristic vascular and interstitial changes of CYA nephrotoxicity, such as obliterative arteriolopathy, ischaemic collapse or scarring of the glomeruli, vacuolization of the tubules, global and focal segmental glomerulosclerosis, and focal areas of tubular atrophy and interstitial fibrosis (producing a picture of ‘striped’ fibrosis) can occur with prolonged therapy for GVHD.63 The factors responsible for chronic CYA nephrotoxicity are not well understood. The development of interstitial fibrosis is associated with increased expression of osteopontin,64 chemokines65 and transforming growth factor-b.66,67 Underlying genetic factors that increase CYA concentrations in the kidney68 and increased apoptosis69 may also contribute to chronic CYA nephrotoxicity. The aetiology of thrombotic microangiopathy in HCT is most likely due to a combination of factors that damage endothelium, including calcineurin inhibitors, chemotherapy, GVHD and/or TBI.45,70 CY use may also be pathogenetically important,71 and it is possible that infection is an initiating or contributing factor for thrombotic microangiopathy in HCT.72 The most common clinical presentation is a subacute or chronic thrombotic microangiopathy that first becomes apparent 20 and Bone Marrow Transplantation

100 days after HCT.45,72,73 Affected patients present with the gradual onset of microangiopathic haemolytic anaemia along with thrombocytopenia, a urinalysis that may be relatively normal or show mild proteinuria and/or haematuria, and a moderate elevation in SCr. Histologic examination of the kidney reveals mesangiolysis with necrotizing arteriolar and glomerular lesions, and intraglomerular and renal arteriolar thrombi.44,45,72,73 As thrombotic microangiopathy is often associated with calcineurin toxicity, discontinuation of CYA is essential. Contrary to classic thrombotic thrombocytopenic purpura, in postHCT thrombotic microangiopathy plasma infusion or exchange is usually ineffective.72 The efficacy of angiotensin-converting enzyme inhibitors is uncertain, but it seems prudent to preferentially use an angiotensin-converting enzyme inhibitor in patients who become hypertensive. AKI after HCT portends an increased risk for subsequent development of CKD both in myeloablative and nonmyeloablative HCT. A retrospective cohort study has been carried on to describe the incidence and risk factors for CKD occurring after nonmyeloablative HCT. For this purpose, 122 patients from the University of Colorado Health Sciences Center, Denver, CO, USA, the Fred Hutchison Cancer Research Center and the University of Washington Medical Center both in Seattle, WA, USA were evaluated.57 In this study, CKD was defined as a decrease in the GFR of at least 25% from baseline during the 6 months, 9 months or 12 months of follow-up. In all, 55% of patients showed evidence of renal dysfunction at day 180, 50% at day 270 and 45% at day 365. Altogether, 66% had development of CKD within 1 year of receiving the nonmyeloablative HCT. In total, 22% of patients at day 180 showed a reduction of GFR of at least 50% from baseline. Multivariate analysis revealed that AKI during the first 100 days post transplant was associated with development of CKD (adjusted odds ratio 32.8 with 95% confidence interval 4.3–250). A cross-sectional and retrospective study in 158 adults who received myeloablative allogeneic HCT for lymphohaematologic malignancies have recently been conducted.74 Chronic kidney disease was defined as a sustained decrease in GFR or persistent proteinuria for a period 43 months. Chronic kidney disease was classified according to the National Kidney Foundation CKD staging.75 Proteinuria was defined as positive dipstick test 4 or ¼ 1 þ . The prevalence of proteinuria was found in 36 out of 158 patients (22.8%). The prevalence of patients with CKD 4 or ¼ stage 3 was 17%, and initiation of chronic dialysis treatment or transplant was performed in seven CKD stage-5 patients (4.4%) at a mean of 11 years after HCT. Multivariate analysis identified AKI following HCT (odds ratio, 9.920; 95% confidence interval, 2.084–39.68; P ¼ 0.0051) as being associated with the presence of CKD 4 or ¼ stage 3. To clearer understand the causes of CKD after HCT a cohort of 1635 adult and paediatric patients who received a myeloablative or nonmyeloablative HCT at the Fred Hutchinson Cancer Research Center from 1991 to 2002 have been studied.76 Chronic kidney disease was defined as two or more estimates of a GFR of 60 ml/min/1.73 m2, calculated using the modification of diet in renal disease equation for adults77 and the Schwartz formula78 for


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children. AKI was defined as at least one elevated SCr value (42.0 mg/dL in men, 41.8 mg/dL in women, 41.0 mg/dL in children aged 2–16 years and 40.6 mg/dL in children aged o2 years) or a doubling of baseline SCr in the first 100 days after transplant. A total of 376 patients (23%) developed CKD at a median of 191 days post transplant (range 131–516 days). After adjusting for other covariates, an increased risk of CKD was associated with AKI (adjusted hazard ratio 1.7, 95% confidence interval 1.3–2.1). After an episode of AKI, it is likely that there is failure to resolve renal structure and function adequately.79–81 AKI itself may increase the risk of subsequent events and decrease kidney reserve leading to an increased risk for CKD.82,83 In addition, AKI following HCT is associated with increased risk for hypertension, which could also contribute to CKD development.84 Chronic kidney disease itself with subsequent hypertension, proteinuria and increased cardiovascular disease has been appointed as a possible cause of poor longterm outcome among AKI patients.85 Impact of AKI on short- and long-term mortality. AKI is a risk factor for short- and long-term mortality, and there is a graded relationship between severity of AKI and increased mortality.86–92 The mechanism by which AKI contributes to increased mortality is not completely understood. Volume overload, coagulation abnormalities, an increased incidence of sepsis with multi-organ failure, and cytokine or immune-mediated major organ dysfunction are other possible explanations for poor survival among AKI Table 3

patients. The permanent injury to other vital organs caused by AKI, although the potential reversible nature of clinical AKI, in which SCr can return to baseline after the acute episode, could account for decreased long-term survival of patients who developed AKI.93–95 Moreover, CKD disease with subsequent hypertension, proteinuria and increased cardiovascular disease has been appointed as a possible cause of poor long-term outcome among AKI patients.85 Specifically, in the setting of HCT, AKI can also interfere with dosing of immunosuppressive drugs including calcineurin inhibitors, and may lead to the development of GVHD. Several studies have recently documented an increased short- and long-term overall and nonrelapse mortality in patients who develop AKI following myeloablative and nonmyeloablative HCT14,15,18,20,22,26,28,34–38,96 (Table 3). Furthermore, many of these studies have also demonstrated an increased association of various organ toxicities, mainly hepatic and pulmonary, and sepsis with AKI after both conditioning regimens.14–16,22,38 Therefore, the distant effects of renal injury to other organs could account for increased morbidity and mortality in patients who develop AKI after nonmyeloablative and myeloablative HCT.

Conclusions In summary, AKI is a frequent complication following myeloablative and nonmyeloablative HCT and the majority of cases occur within the first 3 months after

Studies reporting the impact of AKI following myeloablative and nonmyeloablative HCT on short- and long-term mortality Type of transplant

Follow-up

Overall mortality (AKI vs non-AKI)

Nonrelapse mortality (AKI vs non-AKI)

Parikh et al.14 Hahn et al.15

Myeloablative Myeloablative Myeloablative Myeloablative

Fadia et al.22

Myeloablative

3 years

Lopes et al.96

Myeloablative

3 years

Ando et al. Kersting et al.26

Nonmyeloablative Nonmyeloablative

Lopes et al.27

Nonmyeloablative

1000 days 6 months 1 year 5 years

Parikh et al.34

Nonmyeloablative

Liu et al. 35 Parikh et al.36 Pinana et al.37

Nonmyeloablative Nonmyeloablative Nonmyeloablative

65.5 vs 40.7% (Po0.01) 90 vs 18% (Po0.001) 100 vs 53% (Po0.001) 63.7 vs 36.3% (P ¼ 0.002) Allo-HCT 53.8%/54%/53.8% Auto-HCT 11.1%/20%/11.1%b Mortality was higher among patients with AKI (percentage or absolute number of patients not specified) 48.8 vs 23% (Po0.001) AHR 3.3 (P ¼ 0.006) 48.3%/50%/48.3%b 30.6 vs 7.9% (P ¼ 0.01) 36.7 vs 15.8% (P ¼ 0.006) 58.5 vs 32.9% (P ¼ 0.028) AHR 2.36 (P ¼ 0.041) 29.4 vs 16.5% (Po0.05) 42.1 vs 28.5% (Po0.05) 40 vs 6% (Po0.001) AHR 1.57 (P ¼ 0.01) Not specified Not specified

Not specified Not specified

Kersting et al.18 Ando et al.20a

6 months 100 days 70 months 6 months 1000 days

Liu et al.38

Nonmyeloablative

20a

6 months 1 year 100 days 5 years 100 days 1 year

1 year

61.1 vs 13.6 % (P ¼ 0.001) AHR 3.3 (P ¼ 0.054)

70.8 vs 29.2% (P ¼ 0.027) Not specified Not specified

Not tested Not specified Not specified 20.4 vs 5.9% (P ¼ NS) 53.5 vs 16.9% (P ¼ 0.003) AHR 1.64 (P ¼ 0.004) Not specified Not specified AHR 1.72 (P ¼ 0.07) 25 vs 5% (P ¼ 0.002) AHR 3.4 (P ¼ 0.005) 35 vs 14% (P ¼ 0.002) AHR not tested Not specified

Abbreviations: AHR ¼ adjusted hazard ratio; AKI ¼ acute kidney injury; HCT ¼ haematopoietic cell transplantation; NS ¼ nonsignificant; SCr ¼ serum creatinine. a This study compared the impact of AKI on outcome in patients receiving myeloablative or nonmyeloablative HCT. b Mortality rates according to the definition used for AKI (m 41.5 SCr or m SCr X0.5 mg (if baseline SCr 44 mg/dL)/m SCr X0.3 mg/dL or m41.5 SCr or m SCr X0.5 mg (if baseline SCr 44 mg/dL)/m 42 SCr). Bone Marrow Transplantation


1406

transplantation. AKI is usually more severe in myeloablative HCT than in the nonmyeloablative HCT. Multiple factors account for the burden of AKI following HCT; VOD is a major and consistent risk factor for AKI in the setting of myeloablative HCT, and the major culprit for AKI associated with the nonmyeloablative regimen is CYA used for GVHD prophylaxis. Furthermore, acute GVHD is a common aetiology and independently increases the risk for the occurrence of AKI both in myeloablative and nonmyeloablative settings. AKI itself is an important risk factor for subsequent CKD development, and is associated with increased short- and long-term mortality following HCT. Therefore, strategies to preserve renal function in patients receiving HCT should be implemented and could have a positive impact on patient outcome.

12

Conflict of interest

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11

13

14

The authors declare no conflict of interest.

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