Introduction
Materials and methods
Patient selection and design
Inclusion criteria |
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• Age: 18 to 80 years, inclusive |
• Diagnosis: proven or suspected infection |
• Two out of four SIRS criteria of systemic inflammation [36] |
- Core temperature > 38° or < 36° Celsius |
- Heart rate > 90 beats/minute (unless the patient has a medical condition known to increase heart rate or is receiving treatment that would prevent tachycardia) |
- Respiratory rate > 20 breaths/minute, PaCO2 < 32 mmHg or the use of mechanical ventilation for an acute respiratory process |
- White-cell count > 12,000/mm3 or < 4,000/mm3 or a differential count showing > 10% immature neutrophils. |
• Acute Kidney Injury, defined as: |
• Rise in serum creatinine level to > 150 μmol/L (1.70 mg/dL) within the previous 48 hours, in the absence of primary underlying renal disease, OR |
• Minimally at Stage 1 Kidney Injury according to AKIN creatinine criteria: Increase in serum creatinine > 26.2 μmol/L (0.30 mg/dL) or increase to > 150% (> 1.5-fold) from baseline in the previous 48 hours in the absence of primary underlying renal disease and where baseline creatinine is less than 150 μmol/L (1.70 mg/dL)), OR |
• Minimally at Stage 1 Kidney Injury (AKIN) Urine Output criteria: Urine Output < 0.5 mL/kg/h for > 6 h and following adequate fluid resuscitation when applicable, in the absence of underlying primary renal disease and where baseline creatinine is less than 150 μmol/L (1.70 mg/dL). |
• Written informed consent obtained prior to any study intervention. In addition to the above, acute onset of end-organ dysfunction (other than renal failure) in the preceding 12 hours unrelated to the primary septic focus and not explained by any underlying chronic disease [15]may be present (not compulsory) for patient qualification for enrollment) |
Exclusion criteria
|
• Pregnant women or nursing mothers and fecund females not on effective contraception |
• Known HIV (sero-positive) patients |
• Patients already on RRT at entry |
• Patients receiving immunosuppressant therapy or on chronic high doses of steroids equivalent to prednisone 1 mg/kg/day |
• Patients expected to have rapidly fatal disease within 24 hours |
• Known confirmed gram-positive sepsis |
• Known confirmed fungal sepsis |
• Acute pancreatitis with no established source of infection |
• Any previous administration of exogenous AP |
• Participation in another investigational study within 90 days |
• Patients not expected to survive for 28 days due to other medical conditions such as end-stage neoplasm |
• Known allergy to dairy products including cow milk |
• Sepsis without renal failure as defined in Entry Criteria |
• History of chronic renal failure or history of persistent creatinine level equal or greater than 150 μmol/L (1.70 mg/dL) prior to entry for reasons other than the current sepsis condition |
Assays methodology
Statistics
Results
Baseline Parameter* | AP (n= 16) | Placebo (n= 19) | P= |
---|---|---|---|
Male: n (%)
| 13 (81) | 14 (74) | 0.7003† |
Age: mean (SD) years
| 65 (12) | 67 (15) | 0.7323‡ |
Height: mean (SD) cm
| 176 (10) | 174 (8) | 0.6275‡ |
Weight: mean (SD) kg
| 86 (12) | 80 (14) | 0.2207‡ |
Heart rate: mean (SD) bpm
| 103 (23) | 105 (22) | 0.8510‡ |
Systolic BP: mean (SD) mmHg
| 103 (26) | 110 (26) | 0.4140‡ |
Diastolic BP: mean (SD) mmHg
| 52 (13) | 55 (13) | 0.4035‡ |
Temperature: mean (SD) °C
| 37 (1) | 37 (1) | 0.5899‡ |
APACHE-II score: mean (SD)
| 24 (7) | 23 (8) | 0.5928‡ |
SOFA score: mean (SD)
| 10 (4) | 11 (5) | 0.9128‡ |
AKIN stage 1: %
| 44 | 58 | 0.0657† |
AKIN stage > 1: %
| 56 | 42 | |
Urine production: mean (SD) mL/kg/hour
| 0.6 (0.4) | 0.6 (0.7) | 0.9245‡ |
Serum creatinine: mean (SD) μmol/L
| 164 (48) | 214 (120) | 0.1108‡ |
Creatinine clearance: mean (SD) mL/minute
| 50 (27) | 40 (37) | 0.3984‡ |
(Nor)epinephrine: mean (SD; n) μg/kg/min
| 0.32 (0.25;13) | 0.40 (0.28;15) | 0.3418‡ |
Dopamine/dobutamine: mean (SD; n) μg/kg/min
| 1.50 (2.12;2) | 0.25 (0.35;2) | 0.4975‡ |
Renal variables
Secondary efficacy parameters
Urinary biomarkers of renal injury
Serum concentrations of inflammatory markers
Clinical management parameters
Safety results
AP | Placebo | ||
---|---|---|---|
All adverse events (AEs)
| n (%) | 130 (100) | 154 (100) |
Treatment-emergent AEs*
| n (%) | 124 (95) | 147 (96) |
Patients with treatment-emergent AEs
| n (%) | 15/16 (94) | 20/20 (100) |
Non-serious treatment-emergent AEs
a
: | n | ||
Atrial fibrillation | 3 | 6 | |
Diarrhea | 6 | 3 | |
Hypotension | 2 | 7 | |
Delirium | 2 | 5 | |
Decubitus ulcer | 1 | 4 | |
Abdominal pain | 3 | 2 | |
Pyrexia | 1 | 4 | |
Impaired gastric emptying | 3 | 2 | |
Tracheostomy | 1 | 3 | |
Constipation | 1 | 3 | |
Restlessness | 2 | 2 | |
Atrial flutter | 1 | 3 | |
All serious treatment-emergent AEs
| n | ||
Septic shock | 2 | 2 | |
Respiratory failure | 3 | 1 | |
Gastrointestinal necrosis | 2 | . | |
Hypotension | . | 2 | |
Hepatic necrosis | 1 | . | |
Gall bladder necrosis | 1 | . | |
Electrolyte imbalance | 1 | . | |
Azotemia | 1 | . | |
Cardiac arrest | . | 1 | |
Bradycardia | . | 1 | |
Electrocardiogram QT prolonged | . | 1 | |
Blood calcium decreased | . | 1 | |
Coma | . | 1 | |
Hyperlactacidemia | . | 1 | |
Depressed level of consciousness | . | 1 | |
Osteomyelitis | 1 | . | |
Brain neoplasm | . | 1 | |
Renal failure | . | 1 | |
Therapy cessation | 1 | . | |
Echocardiogram abnormal | 1 | . |
Discussion
Conclusions
Key messages
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Alkaline phosphatase is an endogenous enzyme that exerts detoxifying effects through dephosphorylation of endotoxins and pro-inflammatory extracellular ATP.
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Administration of bovine alkaline phosphatase to sepsis patients attenuates the urinary excretion of markers of tubular injury.
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In the present randomized, double-blind placebo-controlled phase 2 trial in patients with severe sepsis or septic shock with evidence of acute kidney injury treatment with alkaline phosphatase improved overall renal function as represented by three main clinical parameters: endogenous creatinine clearance, requirement and duration of dialysis.
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The results in renal parameters were supported by more pronounced reductions in circulating inflammatory markers and in the urinary excretion of markers of tubular injury in AP-treated patients relative to placebo.