Between January 2005 and December 2015, 209 patients diagnosed with leukaemia were submitted to allo-HSCT in our centre. Among these patients, 45 patients had at least one exclusion criteria and 164 patients were eligible for the study. Demographic and clinical patients’ characteristics are shown in table 1.
Table 1. Patients’ baseline characteristics and transplant related variables.
Patients Characteristics and transplant related variables
|
|
n (%)
|
P50
|
P25
|
P75
|
Category
|
|
Age at transplant (years)
|
|
|
39.1
|
28.1
|
50.4
|
Gender
|
Female
|
89(54.3)
|
|
|
|
Male
|
75 (45.7)
|
|
|
|
Race
|
Caucasian
|
150 (91.5)
|
|
|
|
non Caucasian
|
14 (8.5)
|
|
|
|
BMI (Kg/m2)
|
|
|
23.2
|
20.9
|
25.3
|
HCT-CI
|
0-1
|
140 (85.5)
|
|
|
|
≥2
|
24(14.5)
|
|
|
|
Hematologic Diagnosis
|
AML
|
91 (55.5)
|
|
|
|
ALL
|
55 (33.5)
|
|
|
|
CML
|
14 (8.5)
|
|
|
|
Others
|
4 (2.4)
|
|
|
|
Nr of previous cycles of therapy
|
|
|
3
|
2
|
4
|
Radiotherapy in the past
|
|
11 (6.7)
|
|
|
|
baseline eGFR
|
|
|
115
|
100
|
130
|
Chronic Kidney Disease
|
eGFR < 60
|
9 (5.5)
|
|
|
|
|
stage 3a
|
7 (4.3)
|
|
|
|
|
stage 3b
|
2 (1.2)
|
|
|
|
Induction Regimen
|
Non-myeloablative (RIC)
|
117(71.3)
|
|
|
|
Myeloablative
|
47(28.7)
|
|
|
|
Donor
|
Related donor
|
92(56.1)
|
|
|
|
Unrelated/panel donor
|
72(43.9)
|
|
|
|
Progenitor cells source
|
peripheral blood
|
142(86.6)
|
|
|
|
bone marrow
|
22(13.4)
|
|
|
|
Period of aplasia (days)
|
|
|
11
|
10
|
13
|
Sepsis
|
|
147(89.6)
|
|
|
|
Nephrotoxic drugs
|
|
136(82.9)
|
|
|
|
Hypovolemia
|
|
64(39.0)
|
|
|
|
Shock
|
|
41 (25.0)
|
|
|
|
ICU stay
|
|
13 (7.9)
|
|
|
|
GVHD *
|
|
117(71.3)
|
|
|
|
CMV
|
|
53(32.3)
|
|
|
|
TMA/ TLS/ VOOS
|
|
6(0.04)
|
|
|
|
At hospital admission day:
|
|
|
|
|
|
Haemoglobin (gr/dl)
|
|
|
11.3
|
9.4
|
12.9
|
Leukocytes (cells/mm3)
|
|
|
4330
|
2700
|
6340
|
Neutrophils (cells/mm3)
|
|
|
2110
|
1160
|
3520
|
Lymphocytes (cells/mm3)
|
|
|
1030
|
610
|
1600
|
Platelets (/μl)
|
|
|
150000
|
69000
|
2E+05
|
Urea (mg/dl)
|
|
|
31
|
25
|
40
|
Uric Acid (mg/dl)
|
|
|
4.9
|
3.7
|
5.6
|
Calcium (mg/dl)
|
|
|
9.3
|
8.8
|
9.7
|
Phosphate (mg/dl)
|
|
|
3.8
|
3.2
|
4.3
|
Reactive C Protein (mg/dl)
|
|
|
1
|
0.3
|
2.3
|
Lactate Dehydrogenase (U/L)
|
|
|
352
|
283
|
467
|
Alanine Transaminase (U/L)
|
|
|
31
|
19
|
47
|
Total Bilirubin (mg/dl)
|
|
|
0.5
|
0.4
|
0.7
|
Legend table 1: BMI - body mass index; RIC (reduced-intensity regimen); HCT CI - hematopoietic stem cell transplant comorbidity index; Nr – number; ICU - intensive care unit; GVHD* - Graft versus Host Disease during hospital stay for HSCT; CMV – cytomegalovirus; TMA/ TLS/ VOOS – Thrombotic microangiopathy/Tumor Lysis Syndrome/ Sinusoidal obstruction syndrome
Incidence, presentation criteria and severity of AKI
AKI cumulative incidence (CI) considering death as a competing event was 58.5% at day 30 and 63.4% at day 100 after HSCT. (Fig. 1)
Considering only AKI patients: on the first day of AKI onset, 76.9% presented SCr criteria, 15.4% presented UO criteria and 7.7% presented both criteria. According to the severity of AKI on the first day of AKI onset, 80.8% of patients presented with stage 1, 16.4% presented with stage 2, and 2.9% of patients presented with stage 3. As AKI developed, the highest severity stage reached was stage 1 in 61.8% of AKI patients, stage 2 in 21.6% of AKI patients, and stage 3 in 16.7% of AKI patients.
Analysis of the association between patients’ baseline characteristics and transplant related variables with AKI incidence
The univariable analysis considering death as a competing risk is presented in Table 2. In this analysis variables associated with AKI incidence were: HCT-CI>2 (HR:1.79;95%CI:1.14-2.80;p=0.011), radiotherapy in the past (HR:2.22;95%CI:1.21-4.05;p=0.009), leucocytes count at hospital admission (HR:1.02;95%CI:1.01-1.03;p<0.001 considering each increase of 1000 leucocytes/L), lymphocytes count at hospital admission (HR:1.02;95%CI:1.02-1.03;p<0.001 considering each increase of 1000 lymphocytes/L), serum lactate dehydrogenase at hospital admission (HR:1.60;95%CI:1.27-2.02;p<0.001 considering each increase of 1000 units/L), sepsis (HR:3.82;95%CI:1.30-11.2;p=0.015), mechanical ventilation (HR:1.96;95%CI:1.30-2.95;p=0.001), ICU stay (HR:2.30;95%CI:1.38-3.83;p<0.001).
Table 2. Competing risks regression. Univariable analysis for AKI
Patients Characteristics
|
Hazard ratio estimate
|
|
p-value
|
95% confidence interval
|
lower limit
|
upper limit
|
Age at transplant (years)
|
0.98
|
0.68
|
1.44
|
0.940
|
Gender (reference category female)
|
1.18
|
0.81
|
1.72
|
0.380
|
Race
|
0.64
|
0.35
|
1.18
|
0.150
|
BMI (Kg/m2)
|
1.03
|
0.98
|
1.07
|
0.230
|
HCT-CI ≥2
|
1.58
|
1.14
|
2.80
|
0.011
|
Hematologic Diagnosis:
|
|
|
|
|
AML comparing ALL
|
0.70
|
|
|
0.099
|
AML comparing CML
|
0.96
|
|
|
0.923
|
AML comparing Others
|
2.4
|
|
|
0.098
|
ALL comparing CML
|
0.73
|
|
|
0.360
|
CML comparing Others
|
0.40
|
|
|
0.127
|
Nr of previous cycles of therapy
|
1.06
|
0.97
|
1.14
|
0.210
|
Radiotherapy in the past
|
2.22
|
1.21
|
4.05
|
0.009
|
baseline eGFR
|
0.99
|
0.98
|
1.01
|
0.460
|
Induction Regimen (reference category myeloablative)
|
1.27
|
0.84
|
1.95
|
0.260
|
Donor (reference category related donor)
|
0.99
|
0.67
|
1.46
|
0.940
|
Progenitor cells source (reference category bone marrow)
|
1.47
|
0.68
|
0.86
|
0.160
|
GVHD prophylaxis (reference category methotrexate)
|
1.27
|
0.84
|
1.95
|
0.260
|
Period of aplasia (days)
|
1.01
|
0.99
|
0.96
|
0.610
|
Sepsis
|
3.82
|
1.3
|
11.2
|
0.015
|
Nephrotoxic drugs
|
1.50
|
0.97
|
2.32
|
0.067
|
Hypovolemia
|
1.44
|
0.99
|
2.08
|
0.055
|
Shock
|
2.07
|
1.41
|
3.02
|
<0.001
|
Mechanical Ventilation
|
1.96
|
1.30
|
2.95
|
0.001
|
ICU stay
|
2.3
|
1.38
|
3.83
|
<0.001
|
GVHD *
|
1.04
|
0.7
|
1.54
|
0.850
|
CMV infection
|
1.37
|
0.94
|
2.00
|
0.100
|
TMA/ TLS/ VOOS
|
1.73
|
0.75
|
4.00
|
0.200
|
At hospital admission day:
|
|
|
|
|
Haemoglobin (gr/dl)
|
1.03
|
0.94
|
1.12
|
0.560
|
Leukocytes (cells/mm3)*
|
1.02
|
1.01
|
1.03
|
<0.001
|
Neutrophils (cells/mm3)*
|
1.01
|
0.99
|
0.95
|
0.740
|
Lymphocytes (cells/mm3)*
|
1.02
|
1.02
|
1.03
|
<0.001
|
Platelets (/μl)*
|
1.01
|
0.99
|
0.98
|
0.470
|
Urea (mg/dl)
|
0.99
|
0.97
|
1.01
|
0.540
|
Uric Acid (mg/dl)
|
1.1
|
0.97
|
1.25
|
0.130
|
Calcium (mg/dl)
|
1.08
|
0.79
|
1.48
|
0.630
|
Phosphate (mg/dl)
|
1.01
|
0.80
|
1.28
|
0.910
|
Reactive C Protein (mg/dl)
|
1
|
0.95
|
1.06
|
0.920
|
Lactate Dehydrogenase (U/L)
|
1.6
|
1.27
|
2.02
|
<0.001
|
Albumin (gr/dl)
|
1.12
|
0.86
|
1.46
|
0.400
|
Alanine Transaminase (U/L)
|
0.99
|
0.99
|
1
|
0.130
|
Total Bilirubin (mg/dl)
|
0.85
|
0.51
|
1.39
|
0.520
|
Legend table 2: BMI - body mass index; RIC (reduced-intensity regimen); HCT CI - hematopoietic stem cell transplant comorbidity index; HSCT - hematopoietic stem cell transplant; AML – Acute Myeloid Leukaemia; ALL – Acute Lymphoblastic Leukaemia; CML - Chronic Myeloid Leukaemia; ICU - intensive care unit; GVHD* - Graft versus Host Disease during hospital stay for HSCT; CMV – cytomegalovirus; TMA/ TLS/ VOOS – Thrombotic microangiopathy/Tumour Lysis Syndrome/ Sinusoidal obstruction syndrome.
Variables independently associated with a higher incidence of AKI are shown in Table 3 and included: HCT-CI>2 and radiotherapy in the past with almost a double risk of AKI (HR: 1.88; 95% CI:1.13-3.11) and (HR: 2.07; 95% CI:2.07-1.06), respectively, shock (HR: 1.57; 95% CI:1.57-2.39), LDH with a 51% increase in the risk of AKI for each increment of 1000 units/L (HR: 1.51; 95% CI:1.03-2.21), and sepsis with an approximately three-fold higher risk (HR: 3.36; 95% CI:1.22-9.24).
Table 3. Competing risks multivariable regression analysis for AKI
Patients and transplant related Characteristics
|
Hazard ratio estimate
|
95% confidence interval
|
p-value
|
|
|
|
lower limit
|
upper limit
|
|
|
HCT≥2
|
1.88
|
1.13
|
3.11
|
0.015
|
|
|
Radiotherapy in the past
|
2.07
|
1.06
|
4.03
|
0.034
|
|
|
Shock
|
1.57
|
1.02
|
2.39
|
0.039
|
|
|
Sepsis
|
3.36
|
1.22
|
9.24
|
0.019
|
|
|
LDH at admission*
|
1.51
|
1.03
|
2.21
|
0.035
|
|
|
c-index = 0.635; 95% CI = (0.576; 0.694)
Legend table 3: HCT CI - hematopoietic stem cell transplant comorbidity index; LDH – Lactate dehydrogenase; *considering each 1000 units/L increment
We summarized in a flow chart the study design and the AKI Incidence, presentation criteria, severity, and risk factors. (Fig. 2) .
AKI prognostic impact in patients’ overall survival
Considering the first 5 years following allo-HSCT, 106 (64,6%) patients died. The median overall survival was 12.11 months (P25=3.96; P75=59.13)
Analysing overall survival, the univariable analysis showed that the variables with an impact on lower overall survival during this period were AKI (HR:1.85;95%CI:1.21-2.82;p=0.004), severe AKI (HR:3.26;95%CI:1.95-5.44;p <0.001), sepsis (HR:3.19;95%CI:1.57-2.39;p=0.039), shock (HR:4.63;95%CI:3.06-7.00;p<0.001), relapse (HR:1.62;95%CI:1.09-2.40;p=0.016), leucocytes count (HR considered for each rise of 1000 leucocytes:1.03:95%CI:1.01-1.05;p=0.001), and serum lactate dehydrogenase (HR for each 1000 units/L increment:4.35, 95%CI:2.15-8.80;p<0.001). Multivariable analysis identified variables with an independent impact on overall survival and results are shown in Table 4.
Table 4. Multivariable Cox regression for mortality.
Patients and transplant related Characteristics
|
Hazard ratio estimate
|
95% confidence interval
|
p-value
|
|
|
lower limit
|
upper limit
|
|
Leucocytes at admission
|
1.02
|
1.01
|
1.05
|
0.009
|
|
LDH at admission
|
3.73
|
2.00
|
6.95
|
<0.001
|
|
Severe AKI in the first 100 days
|
1.76
|
1.03
|
3.00
|
0.037
|
|
Shock
|
4.48
|
2.84
|
7.06
|
<0.001
|
|
Relapse in the first 13 months of HSCT
|
2.00
|
1.33
|
3.02
|
0.001
|
|
Relapse after 13 months of HSCT
|
14.39
|
5.92
|
34.99
|
<0.001
|
|
Legend Table 4: LDH – lactate dehydrogenase; AKI – Acute Kidney Injury; HSCT – Hematopoietic Stem Cell Transplant
Accordingly, patients with severe AKI had almost a double risk (HR:1.76, 95% CI:1.03-3.00) (Fig. 3), shock was associated with approximately a four-fold risk of AKI (HR:4.48, 95%CI:2.84-7.06), relapse presented a higher risk after 13 months of HSCT than before this time (HR in the first 13 months of HSCT:2.00, 95%CI:1.33-3.02 and HR after 13 months of HSCT:14.39, 95%CI:5.92-34.99), leucocytes count (for each 1000 leucocytes increment there is an increase of 2%: HR:1.02, 95%CI:1.01-1.05) and serum lactate dehydrogenase was associated with a 32% increase in the risk for each 1000 units/L increment (HR:1.32;95% CI:2.15-8.80).
Considering the disease-free survival, variables with an impact on time until relapse were radiotherapy in the past with almost a three-fold higher risk of relapsing (HR: 2.92, 95%CI:1.25-6.83; p=0.013) and serum Alanine transferase with a 1% increase in the risk of relapse for each unit increment of this enzyme (HR:1.01, 95%CI:1.00-1.01;p=0.011).