Introduction

The conditioning regimen is a critical element in the haematopoietic cell transplant (HCT) procedure. The purpose of the preparative regimen is to provide adequate immunosuppression to prevent rejection of the transplanted graft and to eradicate the disease for which the transplant is being performed. These goals have traditionally been achieved with myeloablative HCT by delivering maximally tolerated doses of multiple chemotherapeutic agents with non-overlapping toxicities, with or without radiation. Several novel approaches have been evaluated in an attempt to minimize toxicity. Reduced intensity conditioning (RIC) HCT is a recently developed procedure that is providing an effective therapy for malignant and non-malignant haematologic disorders,^{1, 2, 3} as well as in renal cell carcinoma⁴ and, more recently, in autoimmune diseases.⁵ RIC HCT relies more on donor cellular immune effects and less on the cytotoxic effects of the preparative regimen to control the underlying disease.^{4, 6, 7} 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 pre-treated patients, who would not tolerate myeloablative HCT, with an attendant decrease in regimen-related toxicity and treatment-related mortality.^{8, 9, 10, 11, 12}

Acute kidney injury (AKI) is a common complication after myeloablative HCT and is associated with mortality.^{13, 14, 15, 16, 17} In previous studies,^{18, 19} we employed the recently established classifications for AKI, an acronym of risk, injury, failure, loss of kidney function and end-stage kidney disease (RIFLE)²⁰ and the Acute Kidney Injury Network classification,²¹ in a group of patients who had undergone myeloablative HCT, and we found that AKI was frequent after HCT and increased short- and long-term mortality. RIFLE is a newly developed classification for acute renal failure that defines three grades of severity—risk (class R), injury (class I) and failure (class F) and two outcome classes (loss of kidney function and end-stage kidney disease).²⁰ The classification system includes separate criteria for creatinine and urine output. A patient can fulfil the criteria through changes in serum creatinine or changes in urine output, or both. The criteria that lead to the worst possible classification should be used. Class R is considered if there is an increase of serum creatinine X1.5 or a 6FR decrease >25% or an urinary output lower than 0.5 ml/kg/h for 6 h; class I if there is an increase of serum creatinine X2 or a 6FR decrease >50% or an urinary output lower than 0.5 ml/kg/h for 12 h and class F if there is an increase of serum creatinine X3 or a 6FR decrease >75% or in patients with serum creatinine higher than 4 mg per 100 ml if there is an acute rise in serum creatinine of at least 0.5 mg per 100 ml, or an urinary output lower than 0.3 ml/kg/h for 24 h, or anuria for 12 h (Table 1).

Table 1 - Risk, injury, failure, loss and end-stage kidney classification²⁰.

Full table

Given that patients eligible for RIC HCT are usually older and have more co-morbid conditions, it is expectable that AKI may occur more frequently compared to myeloablative HCT. However, taking into consideration that in RIC HCT less toxic conditioning regimens are used and a shorter period of neutropaenia occurs, infectious complications and organ failure will occur less frequently in this setting,²² which could have a positive impact on the incidence of AKI.²³ In fact, recent studies reported lower incidence of AKI after RIC HCT when comparing to that reported for myeloablative allogeneic HCT.^{24, 25, 26, 27}

In the current study, we evaluated the incidence of AKI, defined by RIFLE, in patients undergoing RIC HCT, and we also assessed the influence of AKI in long-term survival.

Patients and methods

We performed a retrospective analysis of the 82 patients aged 18–60 years (mean: 39.612.5 years) who underwent related (N=41) and unrelated (N=41) RIC HCT at the Department of Haematology of the Hospital de Santa Maria, Lisboa, Portugal, between January 1999 and December 2005. Data were collected from the Unit database and patient medical records. Patients gave their written consent and were treated according to protocols approved by the local Ethics Committee.

The following baseline variables were considered: age, gender, history of cardiovascular disease (CVD) (angina pectoris, myocardial infarction, cerebrovascular disease and diabetes mellitus), diagnosis of haematologic disease, malignancy risk (low-risk malignancy: acute leukaemia in first CR, CML in first chronic phase and untreated severe aplastic anaemia; high-risk malignancy: all other haematologic diseases), history of prior autologous HCT, conditioning regimen, graft source, infectious complications prophylaxis and GVHD prophylaxis and treatment.

Renal function was assessed by serum creatinine concentration determined on a daily basis. Estimated glomerular filtration rate (GFR) was calculated by the Modified Diet in Renal Disease (MDRD) equation (GFR (ml/min per 1.73 m²)=186 1.154 (PCr, plasma creatinine) 0.203 (age) 1.212 (if black), 0.742 (if female)).²⁸ Baseline serum creatinine was available for all patients. None of the patients were on maintenance dialysis or had received a renal transplant. RIFLE criteria were used to define and classify AKI (Table 1).²⁰ The RIFLE class was determined based on the worst GFR criteria. We used the change in serum creatinine level to classify patients according to the RIFLE criteria. The maximum RIFLE class (risk, injury or failure) of the first 100-day post transplant was considered. We assessed the recovery of renal function after AKI by using the minimum reported serum creatinine values between the determination of AKI and day 100. Follow-up serum creatinine before day 100 was available for all patients.

The following post transplantation variables were obtained: acute GVHD (aGVHD), chronic GVHD (cGVHD), CMV reactivation and CYA trough levels. aGVHD and cGVHD were diagnosed and classified according to the Seattle criteria.²⁹

Reduced intensity conditioning regimen and HCT procedure

The conditioning regimen for related HCT consisted of fludarabine (30 mg/m² per day for 5 days), thymoglobulin (2 mg/kg per day for 4–5 days, with i.v. continuous perfusion during 24 h), prednisone (2 mg/kg per day for 4–5 days) and melphalan (120 mg/kg per day on day -2). For patients undergoing unrelated-HCT melphalan (70 mg/m² per day) was given on days -3 and -2, and cytarabine (2 g/m² per day, with i.v. continuous perfusion during 12 h) was also given on day -8. The patients received haematopoietic cell grafts from HLA-matched related or unrelated donors derived from either peripheral blood or BM on day 0. All patients received GVHD prophylaxis with CYA and mycophenolate mofetil. CYA was started on day -1 at 5 mg/kg twice daily and continued until 3–6 months, followed by tapering if no GVHD was present. Trough levels of CSA were targeted at 180–380 ng/l. Mycophenolate mofetil was started and continued at 2 g twice daily until 1–3 months. GVHD treatment consisted of methylprednisolone and resumption of CSA, if already tapered. Infection prevention consisted of ciprofloxacin and fluconazol until granulocyte counts exceeded 500 cell per l, and fluconazol was given for 3 months, unless GVHD was diagnosed, in which case fluconazol was continued for at least 6 months. Cotrimoxazol 960 mg on alternate days was given for 12 months, and acyclovir 500 mg/m² three times a day was given on the first 30 days. Then, it was continued at 400–1600 mg twice daily for 6 months, unless GVHD was diagnosed, in which case acyclovir was continued for at least 12 months.

Statistical analysis

Continuous variables are expressed as means.d. and categorical variables as percentage of number of cases. Comparisons between RIFLE classes were performed using the analysis of variance and the ²-test for continuous and categorical variables, respectively. Patient follow-up was considered on 31 December 2007. We evaluated all-cause mortality and non-relapse mortality (NRM). NRM was defined as death occurring after HCT in the absence of progression or relapse of malignancy. As AKI is known to occur in the first 100 days after HCT and as we were looking for association between AKI and long-term survival, patients who survived less than 100 days after HCT were excluded from long-term survival analysis. Cumulative survival curves were determined by the Kaplan–Meier method, and log-rank test was employed to analyse statistically significant differences between survival curves. Cox regression was used to determine independent predictors of all-cause mortality and NRM. A two-tailed P-value less than 0.05 was considered significant. Analysis was performed with the statistical software package SPSS 15.0 for Windows.

Results

Acute kidney injury

In total, 44 patients (53.6%) developed AKI after HCT. Of which, 11 patients (25%) were on risk, 20 patients (45.5%) on injury and 13 patients (29.5%) on failure. Demographics and transplant characteristics of study patients are summarized on Table 2. AKI patients had lower baseline GFR (P=0.016), higher need of ventilatory support (P<0.0001) and multiple myeloma was more frequent in such patients (P=0.008). However, they did not differ from patients without AKI in terms of age, gender, race, history of CVD, other haematologic malignancies, high-risk disease, prior autologous HCT, related-donor HCT, graft source, aGVHD and cGVHD diagnosis, CMV reactivation or CSA toxicity. Mean time to AKI development was 37.326.8 days (4–95 days). The causes of AKI were as follows: sepsis in 26 patients (59.1%), aminoglycoside and amphotericin B nephrotoxicity in 8 patients (18.2%), CSA toxicity in 6 patients (13.6%), aGVHD with severe diarrhoea in 3 patients (6.8%) and haemolytic-uraemic syndrome in 1 patient (2.3%). Four patients (three patients on failure and one patient on injury) (9.1%) received renal replacement therapy; one patient (25%) received intermittent haemodialysis and three patients (75%) received continuous venovenous haemodiafiltration.

Table 2 - Demographics and transplant characteristics of study patients and post transplant renal function according to RIFLE²⁰.

Full table

Outcome

In the first 100 days after HCT, 18 patients died and 17 of them (94.5%; P<0.0001) had AKI: 2 patients (11.8%) were on risk, 6 patients (35.3%) on injury and 9 patients (52.9%) on failure. The causes of death among AKI patients were sepsis in 13 patients (76.5%), relapse in 2 patients (11.7%), aGVHD in 1 patient (5.9%) and thrombotic thrombocytopaenic purpura in 1 patient (5.9%); sepsis was the cause of death in the patient with no AKI. In addition, all AKI patients who received renal replacement therapy died during this period.

In all, 64 patients (mean age: 38.912.8 years; 37 men; 32 undergoing related HCT) survived after 100 days of post transplant and were available for long-term survival analysis. Acute kidney injury occurred in 27 patients (42.2%): 9 patients (33.4%) were on risk, 14 patients (51.8%) were on injury and 4 patients (14.8%) were on failure. In total, 21 out of the 27 AKI patients who survived had complete renal function recovery and the remaining 6 patients (22.2%) had partial renal function recovery.

Mean follow-up of the 64 patients who survived after 100 days of post transplant was 3926 months (3–98 months). At follow-up 28 patients (43.7%) died. The causes of death among AKI patients (N=16) were sepsis in seven patients (43.7%), relapse in four patients (25%), aGVHD in one patient (6.2%), pulmonary complications in one patient (6.2%), fulminant hepatitis B in one patient (6.2%), upper gastrointestinal haemorrhage in one patient (6.2%) and secondary neoplasm in one patient (6.2%); relapse (N=7; 58.3%), cGVHD (N=3; 25%) and sepsis (N=2; 16.7%) were the causes of death among patients who did not develop AKI (N=12).

Patients with AKI experienced poorer long-term survival. A 5-year overall cumulative survival of AKI patients was 41.6% as compared with 67.1% for those who did not develop AKI (P=0.028; Figure 1). Moreover, overall survival decreased according to AKI severity, which was as follows: 5-year survival (no AKI, 67.1%; risk, 55.6%; injury plus failure, 33.3%; P=0.045; Figure 2). In addition, 5-year NRM was higher among AKI patients (no AKI, 16.9%; AKI, 53.5%; P=0.003; Figure 3), and increased according to AKI severity (risk 37.5%; injury plus failure 73.3%; P=0.006; Figure 4).

Figure 1.

Overall cumulative survival according to acute kidney injury (AKI); log-rank test, P=0.028.

Full figure and legend (17K)

Figure 2.

Overall cumulative survival according to risk, injury, failure, loss and end-stage kidney disease (RIFLE) classes; log-rank test, P=0.045.

Full figure and legend (19K)

Figure 3.

Non-relapse mortality according to acute kidney injury (AKI); log-rank test, P=0.003.

Full figure and legend (16K)

Figure 4.

Non-relapse mortality according to risk, injury, failure, loss and end-stage kidney disease (RIFLE) classes; log-rank test, P=0.006.

Full figure and legend (19K)

After adjusting for age, history of CVD, high-risk disease and cGVHD, AKI emerged as independent predictor of 5-year all-cause mortality (AKI: AHR 2.36, 95% CI: 1.03–5.37; P=0.041) and of 5-year NRM (AKI: AHR, 6.2, 95% CI: 1.76–21.6; P=0.004; Table 3). Moreover, moderate and severe AKI (injury plus failure) was also associated with an increased 5-year all-cause mortality (injury plus failure: AHR, 1.64, 95% CI: 1.06–2.54; P=0.024) and 5-year NRM (injury plus failure: AHR, 2.7, 95% CI: 1.4–5.2; P=0.003; Table 4).

Table 3 - Adjusted association of AKI with all-cause mortality (N=64).

Full table

Table 4 - Adjusted association of RIFLE classes²⁰ with all-cause mortality (N=64).

Full table

Discussion

We conducted a retrospective study to analyse the incidence of AKI after RIC HCT and its impact on long-term survival. For this purpose, we used the new recently released classification for AKI, the RIFLE, which has been established by the Acute Dialysis Quality Initiative (ADQI) group to standardize the definition of AKI and its categorization in various levels of severity.²⁰ RIFLE criteria have been shown to reflect the phenomenon of increasing mortality with increasing renal dysfunction and to characterize well the risk for in-hospital mortality both in hospitalized patients in general and in the intensive care unit setting.^{30, 31, 32} Traditionally, a grading system for acute renal dysfunction has been employed in studies evaluating ARF after HCT.^{15, 16, 17, 24, 25, 26, 27} This classification considers baseline and post transplant serum creatinine and GFR changes and is similar to RIFLE as follows: grade 1 corresponds to risk, grade 2 corresponds to injury and grade 3 corresponds to patients with grade 2 but requiring dialysis.

We found that 53.6% of the patients developed AKI within the first 100 days after RIC HCT, 40% had more than double of the baseline serum creatinine and 4.8% of the patients required dialysis.

Parikh et al.²⁴ found in a multi-centre study on non-myeloablative HCT that 90% of the patients had AKI, 40% of patients had at least more than twofold rise in serum creatinine, and 4% of patients needed dialysis. These figures are similar to those reported by the same author in a single-centre study.²⁵ Kersting et al.,²⁶ in a large single-centre cohort of recipients of non-myeloablative HCT, reported that 61% of patients developed AKI, 33% of patients developed at least an increase more than double in serum creatinine and none of the patients required dialysis. In these studies, the RIC regimen consisted of fludarabine followed by TBI or TBI alone, which has a lower intensity compared to those used in our cohort. We hypothesize that differences between the incidences may be due to baseline patient characteristics. It is important to remember that in the studies of Parikh et al.,^{24, 25} patients were considered for non-myeloablative HCT if they were either too old or had co-morbidities that would make them ineligible for myeloablative HCT. In the multi-centre study of Parikh et al.,²⁴ the mean patient age was 51.6 years, mean baseline GFR was 91.631 ml/min per 1.73 m², and pre-existing diabetes, pre-existing hypertension and pre-existing cardiomyopathy were present in 6.3, 11.46 and 1.6% of all patients, respectively. Similarly, in the study of Kersting et al.,²⁶ mean patient age was 56.5 years, mean baseline GFR was 82 ml/min per 1.73 m², and hypertension and vascular disease were present in 37.3 and 11.3% of patients, respectively. In contrast, in the present study, patients were younger (mean age 39.612.5 years), had lower incidence of co-morbidity (only 7.3% had prior CVD) and higher mean baseline GFR value (11431 ml/min per 1.73 m²).

We also found an association between AKI and AKI severity, stratified by RIFLE, and increased all-cause and NRM. Furthermore, classes injury and failure were independently associated with long-term mortality. In our study, the development of AKI within the first 100 days after HCT was associated with an increased overall mortality by 25.5% on follow-up. In addition, the association of AKI with NRM was even higher, contributing to 36.6% increase in events after HCT. At 5 years of follow-up, AKI patients had 2.36-fold risk of all-cause death and sixfold of NRM. Moreover, severity of AKI also influenced long-term mortality of patients undergoing HCT, and even mild AKI had a detrimental impact on long-term outcome. When compared to patients with no acute renal function deterioration, risk patients had increased 5-year all-cause mortality and 5-year NRM by 11.5 and 20.6%, respectively. This brings out an important point that even small changes in serum creatinine have important implications on short- and long-term outcome, as it has been shown after cardiothoracic surgery³³ and in critically ill patients.³⁴

To our knowledge, this is the second study that reports long-term outcomes of AKI after 5 years following non-myeloablative HCT. Recently, Parikh et al.²⁷ reported that AKI within first 100 days after non-myeloablative HCT was associated with an increased overall mortality by 57% and NRM by 73% at 5 years of follow-up. Additionally, after controlling for potential confounders, the adjusted odds ratio of AKI grade 2 for overall mortality and NRM was 1.57 and 1.72, respectively. Recently, we have also demonstrated a detrimental effect of AKI on long-term survival of patients receiving myeloablative HCT.¹⁹ In this study, we showed that post transplant AKI decreased 3-year survival by 25.8%.

The mechanism by which AKI contributes to decreased long-term survival is not completely understood. Chronic kidney disease with hypertension and increased cardiovascular disease has been appointed as a possible cause of poor long-term outcome among AKI patients.³⁵ Although AKI is a strong risk factor for chronic kidney disease after non-myeloablative HCT,³⁶ we do not have serial serum creatinine values after 100 days of transplant and blood pressure readings to confirm this hypothesis.

Volume overload, coagulation abnormalities, an increased incidence of sepsis with multi-organ failure, and cytokine or immune-mediated major organ dysfunction are possible explanations for poor long-term survival among AKI patients.^{37, 38} It is important to remember that, in the present study, almost 50% of NRM was caused by sepsis, and pulmonary and gastrointestinal injury were also appointed as causes of death.

On the other hand, AKI can also interfere with dosing of immunossupressive drugs including calcineurin inhibitors, and may lead to the development of GVHD. In our study, however, GVHD incidence did not differ between AKI patients and patients with no deterioration of renal function.

Finally, it is also possible that AKI is merely a surrogate of premature mortality. AKI may occur in older patients or patients with more severe co-morbidity and, thus, in patients with poor survival. However, in our study, no differences in age and co-morbidity were found between AKI patients and those who did not develop acute renal function impairment.

In summary, RIFLE allowed us to identify 53.6% of patients as having some degree of AKI within the first 100 days after RIC HCT. Moreover, RIFLE criteria provided an effective prognostic stratification of such patients. AKI appears to negatively influence long-term survival of patients receiving RIC HCT, and this effect is particularly relevant in moderate and severe AKI. As such, strategies to preserve renal function in patients receiving RIC HCT could have a positive impact on patient outcome.

References

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