Efficacy and safety of forced diuresis and guided fluid replacement
therapy on contrast media induced nephropathy; a feasibility study

Contrast media are frequently used in diagnostic and therapeutic procedures.
The total number of procedures with contrast media amounts approximately 1
million/year in the Netherlands and is expected to increase in the nearby
future.
Although replacement of high osmolar iodinated contrast media by low osmolar
non-ionic contrast media has reduced the number of adverse events,
acute renal failure is still a regular and severe complication seen after
intravascular administration of iodinated contrast media.
This contrast-induced nephropathy (CIN), defined as a rise of serum creatinine
> 25% within 48 to 72 hours after administration of contrast media, is
associated with marked morbidity and mortality.
It is therefore important to recognize the patients at risk and to take
appropriate preventive measures.

Patients with pre-existing chronic kidney disease who receive high volume of
(intra-arterial) contrast media are at highest risk of this contrast-induced
nephropathy (CIN).

Although the exact mechanisms remain unknown, intravenous hydration before the
catheterization procedure is the only current treatment that has shown to
reduce the incidence of CIN.
However in patients with baseline impairments in renal or cardiac function,
hydration is not without risk and preformed at a slow rate due to fear of
overhydration and pulmonary edema.
Previous studies have used diuretics to increase urine output en prevent
overhydration.
In addition to the benefit of increased urine flow, loop diuretics, such as
furosemide, should be expected to provide benefit against another potential
mechanism of CIN, medullary ischemia, as they reduce sodium reabsorption and
consequentially oxygen consumption of the kidney.

However a number of studies have shown that the use of furosemide is associated
with an increased risk of CIN. This was most likely the consequence of
insufficient fluid replacement. (Renal failure was also associated with weight
loss in the furosemide-treated group.)

A prospective randomized trial of prevention measures in patients with a high
risk for CIN (PRINCE Study) demonstrated that inducing diuresis with a single
dose of diuretic, while attempting to prevent dehydration by balancing urine
output with matched intravenous fluid replacement, provided an protective
benefit against CIN. More importantly it showed that no patient with a mean
urine flow rate above 150ml/hour developed CIN with the need for dialysis.
In this trail matching fluid replacement and urine output started after the
procedure. Thus, it can be possible that some patients were intravascular
dehydrated prior to the start of matched fluid replacement.

The real-time measurement and matched fluid replacement design of the
RenalGuard system is intended to ensure that a high urine flow is maintained
before, during and after these procedures and that the risk of over-or-under
hydration is minimized while preventing CIN.

Previous animal and human studies were performed by using both the RenalGuard
system and by manually replacing urine output with a matched amount of saline,
conform this concept. With promising results.

A recent animal study extended the PRINCE methodology of continuous matching of
urine output and hydration to maintain intravascular volume starting
pre-catheterization and maintained for up to 4 hours after the last dose of
radio contrast material. In these animals with pacing-induced heart failure to
put the kidneys at risk for CIN, the investigators found that maintenance of
urine output greater than the equivalent of 150 ml/hour prior to and during the
4 hour period with maintenance of intravascular volume reduced the incidence of
radio contrast injury to the kidney by 80% compared to the control group.

A human study was also performed, with manual fluid balancing, to test this
concept. Ten patients with renal impairment and at risk for CIN, who were
scheduled to undergo elective cardiac catheterization, were treated with the
therapy. The inclusion and exclusion criteria were aimed at identifying
patients who would be expected to have a 20-30% risk of developing CIN.
Patients were given an initial 250cc IV bolus of normal saline and then an IV
bolus of 1mg/kg of furosemide. After this, urine volumes were measured at 15 -
30 minute intervals and an infusion pump was adjusted to replace the measured
urine output ml for ml (plus an additional 50ml/hr) of normal saline. Urine
rates ranged from 631 - 2163 ml/hr (mean = 1139+440 ml/hr). Of the 10 patients
treated, only one developed CIN (as defined as a 25% increase of serum
creatinine over baseline) with a 28% increase of serum creatinine over
baseline. There were no serious or unanticipated adverse events including any
clinically significant changes in electrolytes. Any protocol or therapy
related events were minor, and did not result in any significant clinical
sequelae.

A pilot study was conducted under IDE G060190.13 The study was designed to
preliminarily investigate the safety and performance of the RenalGuard* System
in up to 40 subjects. The study was approved at 4 clinical sites and enrolled
23 subjects. The RenalGuard System was used on patients undergoing a previously
scheduled cardiac or peripheral catheterization procedure. The protocol
involved connecting the patient to the RenalGuard System using a Foley catheter
and a standard peripheral i.v. catheter. The system was then set to deliver a
250 cc bolus of normal saline over 30 minutes. When the bolus was completed,
the patients received 0.5 mg/kg of furosemide to induce high urine flow and the
system continued to balance infusion input to urine output. Patients were kept
on the system for approximately two hours prior to their catheterization
procedure, throughout the procedure and for four hours after the procedure.
Urine rates for these patients averaged approximately 550 ml/hr at the time of
first contrast dose.
No patient experienced hypotension or significant impairment of vital organ
function during the RenalGuard Therapy.
No subjects required renal replacement therapy or experienced symptomatic
hypervolemia/pulmonary edema. One patient had clinically significant
arrhythmias, which was determined to be due to the catheterization procedure.
One subject remained hospitalized overnight, at the decision of the
investigator, to monitor the subject*s potassium levels due to the large volume
of urine output achieved. The subject was discharged the following morning and
experienced no clinical sequelae. There were no infections recorded during the
study.
The system was shown to match effectively in- and output. Two of twenty-one
evaluable subjects showed a creatinine increase of >25%. An additional
secondary endpoint was the percent of patients that reached the target urine
output of 300 ml/hr or greater over at least 2 hours of treatment. Only one
patient did not meet this endpoint, and this was thought to be due to the
subject*s chronic diuretic use.

After this pilot study FDA approval was obtained to begin the pivotal trial for
renal guard therapy: The Mythos study
Preliminary results:
The trial has enrolled 105 chronic kidney disease (CKD) patients undergoing
elective or urgent percutaneous coronary interventions (PCI). Approximately 14%
of the patients in the control group were determined to have acquired
contrast-induced nephropathy (CIN), whereas only 4% of those who were treated
with RenalGuard acquired CIN. Dr. Marenzi also reported that the incidence of
in-hospital complications in the control group was 18%, compared to only 6% in
the RenalGuard group, a statistically significant difference (p=0.05)

The rationale of diuresis-guided fluid replacement therapy is evident and the
first data look promising. Before embarking on controlled clinical trials, a
feasibility study is needed to assess the safety of this treatment , its
applicability, and its potential advantages. This is the primary object of this
study.

A secondary objective of this study is to obtain blood and urine samples that
will allow
identification and evaluation of biomarkers for the early detection of CIN.
The hypothesis is that different serum and urine markers can predict kidney
injury better than
the conventional serum creatinine and proteinuria.
Cystatine C, NGAL, alfamicroglobuline and L-FABP are investigated in a number
of small
studies.
We would like to store blood en urine samples to investigate these, or possible
new
biomarkers (with proteomic techniques) in the future.


This study aims;
1.To evaluate the feasibility of RenalGuard for diuresis-guided fluid
replacement therapy (in our hospital)
2.To evaluate the safety of forced diuresis and fluid replacement therapy
3.To evaluate the potential benefits of forced diuresis and fluid replacement
therapy
4.To obtain blood and urine samples that will allow identification and
evaluation of
biomarkers for the early detection of CIN in the future

2.1 Primary Objective:
To evaluate the feasibility of RenalGuard for diuresis-guided fluid
replacement therapy
(ability to match in and output) (time to desired diuresis>200ml/hour)
To evaluate the safety of forced diuresis and fluid replacement
therapy
(adverse events)
To evaluate the potential benefits of forced diuresis and fluid
replacement therapy
(incidence CIN)

2.2 Secondary Objective(s):
To obtain blood and urine samples that will allow identification and
evaluation of
biomarkers for the early detection of CIN

Feasibility Study

The treatment consists of induced diuresis with matched hydration therapy,
using the RenalGuard System. The purpose of matched fluid replacement is to
provide sterile replacement solution to a patient in an amount matched
(millilitre for millilitre) to the volume of urine produced by the patient.

Approximately 90 minutes prior to the planned catheterization procedure, the
RenalGuard system will be set up as instructed in the User*s manual.

A standard peripheral i.v. catheter (minimum of 20G; pink) will be inserted for
hydration. The system requires the use of a standard Foley catheter, which will
be inserted to allow the measurement of urine produced by the patient.
As the system requires the use of a Foley catheter, if it is unable to be
placed the subject will be withdrawn from the study and the patient will
undergo their cardiological procedure using standard (hydration) hospital
protocols.

A blood sample is taken and serum potassium, sodium, ureum and creatinine, Hb,
Ht, albumine are measured.
When the potassium level is
<3,0 : the subject will be withdrawn from the study
3,0-4,0: 20mmol/L Kaliumchloride in every litre of NaCl 0,9% will be
substituted
>4,0 : 10 mmol/L Kaliumchloride in every litre of NaCl 0,9% will be substituted

Subjects may partake oral hydration up to the point of the procedure.
The RenalGuard system will be started in *Replacement Mode* and also will be
set to deliver a pre-hydration bolus of 250ml of normal saline solution over a
time period of 30 minutes.
The system continues to operate in *Replacement Mode* until 4 hours after the
last dose of contrast.

Once the initial bolus hydration is complete, and prior to entering the
catheterization lab, the patient will receive 0,5 mg/kg-1.0mg/kg of furosemide
intravenously. (depending on GFR) (See Appendix 1)
When the urine flow rate is >150ml/hour,the patient may receive the first dose
of contrast media.
Additional doses may be given if during catheterization and/or up to 4 hours
post catheterization, if the calculated urine output falls below 200ml/hour.
The additional doses are 0,5-1.0 mg/kg furosemide intravenously (according to
initial doses), but no more than every hour. The maximum total amount of
furosemide that may be given is 3 mg/kg.

Data will be collected at frequent intervals (see Table 2) a nurse practitioner
will be available throughout the treatment period to record the data and to
monitor the patient for any adverse events, particularly signs and symptoms of
fluid overload.
Patient vital signs (heart rate, blood pressure, pulse oximetry) will be
recorded every 60 minutes until the discontinuation of therapy.
All intake (iv, oral) and output (urine, emesis, diarrhea) will be recorded
every 30 minutes.
The time of the first contrast dose and last contrast dose as well as the total
dose of contrast will be collected.
In all patients, we will take blood samples at baseline, after 2 hours,
between four and six hours after administration of contrast, daily for the time
they remain in the hospital, and one sample between 48 and 72 hours after
contrast. These samples will be analysed and stored for future analysis of
biomarkers.
In all patients we will collect urine samples, a baseline sample,
one sample 0-2 hours after contrast, 2-4 hours after contrast, 4-6 hours after
contrast. These samples will be analysed and stored for future analysis of
biomarkers.

Physical examination will be preformed prior to the catheterization procedure
and again 3-6 hours post procedure.

All results will be recorded on the appropriate Case Report Form (s).

Patients may be exposed to the risk of adverse effects as a consequence of
their participation in this study. Many of these risks are substantially
minimized by increased subject monitoring before, during, and after treatment.
An adverse effect is defined as any undesirable clinical event occurring in a
patient after treatment in this study. This includes adverse effects that are
related to the use of the System (device related adverse effect), the Therapy
(therapy related adverse effect as over- or underhydration,
elektrolytdisturbances), those which occur during the study but are related to
the patient*s underlying disease (adverse effect due to pre-existing
condition), and those which occur during the study but are related to the
planned cardiovascular catheterization procedure (adverse effect related to
cardiovascular cath procedure).
(see 8.2 Adverse and serious adverse events)

Potential Benefits
No benefits can be guaranteed to the study participant. However, there may be
direct and indirect benefits to the patient for their participation in the
study. The presence of radio contrast-induced renal impairment is associated
with problems ranging from transient impairments in renal function to the
occurrence of end-stage renal disease and the need for dialysis. The patient
may benefit from a complete or partial prevention of impairment of renal
function. In addition, there is the added benefit of close patient monitoring
that may be more than the standard of care before, during and after the
patient's cardiovascular catheterization procedure. Finally, the information
learned from this study may help in the evaluation and further development of
this therapy that may be helpful in treating patients in the future.