Chronic Kidney Disease
Conditions
Keywords
Contrast media, Kidney, Complication
Brief summary
The purpose of the present study is to assess the role of the RenalGuard System as compared to the optimal strategy (sodium bicarbonate infusion plus N-acetylcysteine (NAC)) in high and very-high risk patients to prevent contrast-induced acute kidney injury contrast induced acute kidney injury (CI-AKI). Consecutive patients with chronic kidney disease, referred to our institutions for coronary and/or peripheral procedures, will be randomly assigned to 1) prophylactic administration of sodium bicarbonate plus NAC (Systemic alone therapy group; n \> 133) and 2) RenalGuard System treatment (RenalGuard group; n \> 133). All enrolled patients must have an estimated glomerular filtration rate \<30 ml/min/1.73 m2 and/or a contrast nephropathy risk score ≥11). In all cases iodixanol (an iso-osmolar, non ionic contrast agent) will be administered. The primary end point is an increase of \>=0.3 mg/dL in the creatinine concentration 48 hours after the procedure. This study will give important answers on how to prevent CI-AKI in high and very-high risk patients undergoing contrast media exposure.
Detailed description
The strategy of volume supplementation by sodium bicarbonate plus N-acetylcysteine (NAC) seems to be the optimal pharmacological approach in preventing contrast induced acute kidney injury (CI-AKI) in patients at medium-to-high risk. Whether this prophylactic strategy is effective in high and very-high risk patients is unknown. In this subset of patients the potential protective effects and therapeutic advantage of a local delivery of protective compounds should be investigated. The RenalGuard™ System (PLC Medical Systes, Inc.) is a real-time measurement and real time matched fluid replacement device designed to accommodate the RenalGuard Therapy. The RenalGuard Therapy is based on the theory that creating and maintaining a high urine output is beneficial to patients undergoing imaging procedures where contrast agents are used. This should allow the body to rapidly eliminate contrast, reducing its toxic effects. The RenalGuard System seems to be ideal for the prevention of CI-AKI, by allowing an optimal urine flow rate \>150 ml/h (ideally \>300 ml/h). Preliminary data suggests that the RenalGuard System, by increasing the urine flow rate ≥ 300 ml/h, allows a quick renal first-pass elimination and therefore reduces the risk for contrast nephropathy. The potential benefits of RenalGuard Therapy are intended to reduce the incidence of CI-AKI via a combination of known physiological effects of high urine output including: a) lower concentration of contrast in the kidneys, b) more rapid transit of contrast through the kidneys, c) less overall exposure to toxic contrast, d) potential reduction of oxygen consumption in the medulla of the kidneys. No randomized study has been performed to assess the role of the RenalGuard System as compared to the optimal strategy (sodium bicarbonate infusion plus NAC) in high and very-high risk patients to prevent CI-AKI.
Interventions
DEVICERenalGuard system
The RenalGuard™ System (PLC Medical Systems, Inc.) is a real-time measurement and real time matched fluid replacement device designed to accommodate the RenalGuard Therapy. The RenalGuard Therapy is based on the concept demonstrated by clinical data that high urine output is beneficial to patients with impaired baseline renal function who receive intravascular iodinated contrast medio (CM). The RenalGuard System seems to be ideal for the prevention of CI-AKI, by allowing an optimal urine flow rate \>300 ml/h. It is known that excessive diuresis can cause dehydration which increases the risk to the kidneys from CM. The RenalGuard System should allow the patient to achieve high urine output safely by maintaining the intravascular blood volume and avoiding the risk of over-or-under-hydration.
DRUGSystemic alone therapy
Patients allocated to the Systemic alone therapy group will receive 154 mEq/l of sodium bicarbonate in dextrose and H2O, according to the protocol reported by Merten et al. The initial intravenous bolus was 3 ml/kg per hour for 1 hour immediately before contrast injection. Following this, patients will receive the same fluid at a rate of 1 ml/kg per hour during contrast exposure and for 6 hours after the procedure. All patients will receive NAC (Fluimucil, Zambon Group SpA, Milan, Italy) orally at a dose of 1200 mg twice daily on the day before and on the day of administration of the contrast agent (total of 2 days)
Sponsors
Clinica Mediterranea
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age \>=18 years 2. Chronic kidney disease (estimated glomerular filtration rate \<=30 ml/min/1.72 m2) and/or 3. Risk score for contrast nephropathy ≥11 (according to the Mehran score; J Am Coll Cardiol 2004; 44: 1393-1399)
Exclusion criteria
1. Pregnancy 2. Heart failure (NYHA functional class III-IV) 3. Acute pulmonary edema 4. Acute myocardial infarction 5. Recent (\<=2 days) contrast media exposure 6. Patients enrolled in concomitant studies 7. Administration of theophylline, dopamine, mannitol and fenoldopam. 8. End-stage CKD (patients on chronic dialysis) 9. Systemic hypotension (systolic blood pressure \< 100 mg/dl). 10. Multiple myeloma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Contrast-induced Acute Kidney Injury | at 48 hours following contrast exposure | The primary outcome measure will be the rate of development of CI-AKI in the 2 study arms (number of participants). CI-AKI is defined as an increase in the serum creatinine concentration \>=0.3 mg/dL from the baseline value at 48 hours after administration of the contrast media or the need for dialysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in the Serum Cystatin C Concentration at 24 and 48 Hours After Contrast Exposure | 7 days | Cystatin C is an alternative biomarker of kidney damage. Cystatin C seems to be superior to serum creatinine an identifying kidney function and damage. |
| Changes in the Urine and Serum NGAL Concentration After Contrast Exposure | 7 days | NGAL is a new biomarker which seems to be very promising in detecting kidney injury. prelimiary data suggest that urine and serum NGAL increase very early (within few horurs) after the occurrence og acute kidney damage. Therefore, NGAL may be a real marker of acute kidney injury. |
| Rate of Kidney Injury and Major Adverse Events | 7 days | an increase in the serum creatinine concentration \>=0.25% and \>=0.5 mg/dl at 48 hours after contrast exposure |
| The Rate of In-hospital Major Adverse Events (i.e. Acute Myocardial Infarction, c) Renal Failure Requiring Dialysis, and d) Acute Pulmonary Edema) | 1 month | Assessment of the rate of in-hospital major adverse events (i.e. acute myocardial infarction, c) renal failure requiring dialysis, and d) acute pulmonary edema) will give important informantion on the clinical relevance of prophylactic strategies in preventing CI-AKI |
| The Cost-effectiveness Ratio. | 1 month | Assessement of the cost-effectiveness ratio is important when testing a new strategy of both therapy and prophylaxis. The Renalguard system is more expensive than the conventional hydration regimen. The cost of RenalGuard system is approximately 800 $. This cost will be justified only if the system is more effective in preventing CI-AKI and improving the clinical outcome, expecially reducing the lenght of ospedalization and the rate of dialysis. |
| the Rate of Acute Renal Failure Requiring Dialysis | 1 month | occurrence of renal failure requiring dialysis represents the haard endpoint of the study. Actually this represents the worst clinical consequence of CI-AKI. |
Countries
Italy
Participant flow
Recruitment details
All patients with CKD scheduled for coronary and/or peripheral angiography/angioplasty from January 2009 to December 2011 were screened for inclusion/exclusion criteria. The trial was conducted in across 4 interventional cardiology centers in Italy, according to the principles of the Declaration of Helsinki and Good Clinical Practice
Pre-assignment details
Two enrolled patients did not finally undergo the scheduled treatment due to the occurrence fever or gastrointestinal bleeding
Participants by arm
| Arm | Count |
|---|---|
| Systemic Alone Therapy Group Systemic alone therapy grou will be treated by intravenous sodium bicarbonate plus NAC administration. Patients allocated to the Systemic alone therapy group will receive 154 mEq/l of sodium bicarbonate in dextrose and H2O, according to the protocol reported by Merten et al. (9) The initial intravenous bolus was 3 ml/kg per hour for 1 hour immediately before contrast injection. Following this, patients will receive the same fluid at a rate of 1 ml/kg per hour during contrast exposure and for 6 hours after the procedure. All patients will receive NAC (Fluimucil, Zambon Group SpA, Milan, Italy) orally at a dose of 1200 mg twice daily on the day before and on the day of administration of the contrast agent (total of 2 days. Additional NAC dose (1.2 g) will be administered i.v. during the procedure. | 147 |
| RenalGuard System Group Prophylactic controlled hydration with saline (0.9%) plus N-acetylcystein (NAC; 6 g in total). In the RenalGuard group, an initial bolus (priming) of 250 ml will be administered. In case of left ventricular dysfunction (ejection fraction ≤30%) and/or unstable hemodynamic conditions the bolus will be reduced to 150 ml. Following the initial bolus, furosemide (0.25 mg/kg) will be administered in order to achieve the optimal urine flow (≥300 ml/h). The hydration will be continued throughout the duration of the procedure and will last 4 hours following the procedure. Additional doses of furosemide are allowed in case of decrease of urine flow \<300 ml/h. | 147 |
| Total | 294 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | RenalGuard System Group | Systemic Alone Therapy Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 133 Participants | 128 Participants | 261 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 19 Participants | 33 Participants |
| Age, Continuous | 76 years STANDARD_DEVIATION 8 | 75 years STANDARD_DEVIATION 9 | 75 years STANDARD_DEVIATION 8 |
| Region of Enrollment Italy | 147 participants | 147 participants | 294 participants |
| Sex: Female, Male Female | 57 Participants | 43 Participants | 100 Participants |
| Sex: Female, Male Male | 90 Participants | 104 Participants | 194 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 146 | 3 / 146 |
| serious Total, serious adverse events | 10 / 146 | 14 / 146 |
Outcome results
Primary
Number of Participants With Contrast-induced Acute Kidney Injury
The primary outcome measure will be the rate of development of CI-AKI in the 2 study arms (number of participants). CI-AKI is defined as an increase in the serum creatinine concentration \>=0.3 mg/dL from the baseline value at 48 hours after administration of the contrast media or the need for dialysis.
Time frame: at 48 hours following contrast exposure
Population: all consecutive patients with chronic kidney disease scheduled for coronary and/or peripheral angiography and/or angioplasty with an estimated glomerular filtration rate (eGFR) ≤30 ml/min/1.73 m2 and/or a risk score ≥11 were considered eligible for the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Systemic Alone Therapy Group | Number of Participants With Contrast-induced Acute Kidney Injury | 146 participants |
| RenalGuard System Group | Number of Participants With Contrast-induced Acute Kidney Injury | 146 participants |
Secondary
Changes in the Serum Cystatin C Concentration at 24 and 48 Hours After Contrast Exposure
Cystatin C is an alternative biomarker of kidney damage. Cystatin C seems to be superior to serum creatinine an identifying kidney function and damage.
Time frame: 7 days
Secondary
Changes in the Urine and Serum NGAL Concentration After Contrast Exposure
NGAL is a new biomarker which seems to be very promising in detecting kidney injury. prelimiary data suggest that urine and serum NGAL increase very early (within few horurs) after the occurrence og acute kidney damage. Therefore, NGAL may be a real marker of acute kidney injury.
Time frame: 7 days
Secondary
Rate of Kidney Injury and Major Adverse Events
an increase in the serum creatinine concentration \>=0.25% and \>=0.5 mg/dl at 48 hours after contrast exposure
Time frame: 7 days
Secondary
The Cost-effectiveness Ratio.
Assessement of the cost-effectiveness ratio is important when testing a new strategy of both therapy and prophylaxis. The Renalguard system is more expensive than the conventional hydration regimen. The cost of RenalGuard system is approximately 800 $. This cost will be justified only if the system is more effective in preventing CI-AKI and improving the clinical outcome, expecially reducing the lenght of ospedalization and the rate of dialysis.
Time frame: 1 month
Secondary
the Rate of Acute Renal Failure Requiring Dialysis
occurrence of renal failure requiring dialysis represents the haard endpoint of the study. Actually this represents the worst clinical consequence of CI-AKI.
Time frame: 1 month
Secondary
The Rate of In-hospital Major Adverse Events (i.e. Acute Myocardial Infarction, c) Renal Failure Requiring Dialysis, and d) Acute Pulmonary Edema)
Assessment of the rate of in-hospital major adverse events (i.e. acute myocardial infarction, c) renal failure requiring dialysis, and d) acute pulmonary edema) will give important informantion on the clinical relevance of prophylactic strategies in preventing CI-AKI
Time frame: 1 month