Phase 3 Trial of Intravenous Mannitol Use During Partial Nephrectomy Prior to Renal Ischemia and Impact on Renal Function Outcomes
Phase: PHASE3
Conditions: Renal Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

 
 
MEMORIAL SLOAN-KETTERING CANCER CENTER 
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Phase 3 Trial of Intravenous Mannitol Use During Partial Nephrectomy Prior to Renal 
Ischemia and Impact on Renal Function Outcomes 
 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator/Department: 
Jonathan Coleman, MD 
Dept. of Surgery- Urology Service 
Co-Principal 
Investigator(s)/Department: 
Karim Touijer, MD 
Paul Russo, MD 
Dept. of Surgery- Urology Service 
Dept. of Surgery- Urology Service 
Investigator(s)/Department: 
Bernard Bochner, MD 
Guido Dalbagni, MD 
S. Machele Donat, MD 
Harry Herr, MD Raul 
Parra, MD Behfar 
Ehdaie, MD Abraham 
Hakimi, MD 
Daniel Sjoberg, MA 
Sarina Lopez, PharmD 
Carlos Flombaum, MD 
Paul Dalecki, MD 
Massimiliano Spaliviero, MD 
Katie Murray, MD 
Hebert A. Vargas Alvarez, MD 
Dept. of Surgery- Urology Service 
Dept. of Surgery- Urology Service 
Dept. of Surgery- Urology Service 
Dept. of Surgery- Urology Service 
Dept. of Surgery- Urology Service 
Dept. of Surgery-Urology Service 
Dept. of Surgery-Urology Service 
Dept. of Biostatistics and 
Epidemiology 
Dept. of Pharmacy 
Dept. of Medicine- Nephrology 
Service 
Dept. of Anesthesiology 
Dept. of Surgery-Urology Service 
Dept. of Surgery-Urology Service 
Dept. of Radiology 
Consenting 
Professional(s)/Department: 
Bernard Bochner, MD 
Guido Dalbagni, MD 
S. Machele Donat, MD 
Harry Herr, MD 
Karim Touijer, MD Paul 
Russo, MD Jonathan 
Coleman, MD 
Raul Parra, MD 
Behfar Ehdaie, MD 
Abraham Hakimi, MD 
Dept. of Surgery- Urology Service 
Dept. of Surgery- Urology Service 
Dept. of Surgery- Urology Service 
Dept. of Surgery- Urology Service 
Dept. of Surgery- Urology Service 
Dept. of Surgery- Urology Service 
Dept. of Surgery- Urology Service 
Dept. of Surgery- Urology Service 
Dept. of Surgery- Urology Service 
Dept. of Surgery- Urology Service 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
 
 
 
 
Amended:  03/02/15 
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Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 3 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 3 
 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 3 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION............................................................ 8 
 
4.1 
Design............................................................................................................................. 8 
 
4.2 
Intervention ..................................................................................................................... 8 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 9 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ........................................................................... 9 
 
6.1 
Subject Inclusion Criteria................................................................................................. 9 
 
6.2 
Subject Exclusion Criteria ............................................................................................... 9 
 
7.0 
RECRUITMENT PLAN ..................................................................................................... 10 
 
8.0 
PRETREATMENT EVALUATION .................................................................................... 10 
 
9.0 
TREATMENT/INTERVENTION PLAN.............................................................................. 11 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ................................................. 11 
 
11.0 TOXICITIES/SIDE EFFECTS ........................................................................................... 12 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ..................... 13 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ..................................................................... 14 
 
14.0 BIOSTATISTICS .............................................................................................................. 14 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES15 
 
15.1 Research Participant Registration ................................................................................. 15 
 
15.2 Randomization .............................................................................................................. 16 
 
16.0 DATA MANAGEMENT ISSUES ....................................................................................... 16 
 
16.1 Quality Assurance ......................................................................................................... 16 
 
16.2 Data and Safety Monitoring ........................................................................................... 16 
 
17.0 PROTECTION OF HUMAN SUBJECTS .......................................................................... 17 
 
17.1 Privacy .......................................................................................................................... 17 
 
17.2 Serious Adverse Event (SAE) Reporting ....................................................................... 17 
 
17.2.1 ................................................................................................................................... 18 
 
18.0 INFORMED CONSENT PROCEDURES .......................................................................... 18 
 
19.0 REFERENCES ................................................................................................................. 19 
 
20.0 APPENDICES .................................................................................................................. 20 

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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
We propose a placebo controlled randomized study on the use of mannitol as an agent to 
protect against the effects of transient renal ischemia and its impact on renal function during 
the surgical procedure of partial nephrectomy. Patients undergoing partial nephrectomy for 
the treatment of kidney tumors will be randomized 1:1 to receive either intravenous mannitol 
or saline during their procedure, administered prior to renal vascular clamping. Changes in 
renal function following surgery will be monitored using calculated glomerular filtration rate 
(eGFR) and renal scan data obtained pre- and post-operatively, as part of routine standard of 
care. 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary endpoints: 
 
• 
Difference in eGFR at 6 months after surgery. 
Secondary endpoints: 
• 
Difference in eGFR at 6 weeks after surgery. 
• 
Difference in radionuclear scintigraphy renal scan at 6 months postoperatively. 
• 
Difference in rate of grade 3-5 complications within 30 days of surgery. 
• 
Difference in estimated blood loss. 
• 
Difference in ischemia time. 
 
3.0 
BACKGROUND AND RATIONALE 
 
The improved renal function outcomes that occur with nephron sparing surgery in patients 
with renal tumors amenable to partial nephrectomy has prompted a considerable increase in 
the number of partial nephrectomies performed for patients with small renal masses. 
Nationally, this trend has been notable, comprising less than 5% of cases in 1988, 15% of 
procedures by 2002 and roughly 25% of kidney surgery by 2008. Surgeons at Memorial 
Sloan Kettering have led the field in partial nephrectomy procedures consistently, publishing 
the initial papers describing the technique and now performing nephron sparing surgery in 
95% of patients surgically treated for small renal masses and over 80% for larger tumors ( 4 - 
7 cm) in contemporary experience.1, 2 With oncologic results that appear equivalent to radical 
nephrectomy, a fundamental goal of this procedure is to optimally preserve renal function. 
Several factors play a role in the loss of function which occurs as a result of surgery, some of 
which may be controlled for and studied in order to optimize the goals of oncologic surgical 
intent, minimize the risk of harm to the patient and ensure excellence in patient care while 
offering the best possible quality of life for our patients. Factors include cold and warm 
ischemia, limits of renal artery clamping time and the use of intraoperative mannitol as a 
renal protective medication prior to renal ischemia. Requirements of the surgery and patient 
variability limit the control that can be placed on many factors however, most would be 
evenly distributed in both arms of a randomized trial design which evaluates the factors that 
can be controlled. Our study aims to assess the significance of mannitol infusion prior to 
renal ischemia in partial nephrectomy in a randomized prospective manner. 

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the randomized groups when evaluating change in eGFR from 2 hrs to 7 days after surgery 
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Mannitol ‘s purported effects of increasing renal blood flow, decreasing intravascular cellular 
swelling, and increasing intravascular volume have been used as rationale for its use to 
ameliorate the damage to renal tissue caused by vascular insult to the kidney.3 During partial 
nephrectomy, renal ischemia occurs as a result of temporary renal artery occlusion to 
provide a bloodless field during the resection.4 Traditionally, mannitol has routinely been 
used during partial nephrectomy as a renal protective agent. Unfortunately, there is no level I 
or level II evidence supporting its use for this purpose in the surgical literature and, indeed, 
little evidence supporting its use in preventing the onset of renal dysfunction caused by other 
mechanisms of acute medical renal disease. Despite this, mannitol intravenously applied in 
this setting continues in contemporary surgical practice largely due to the legacy effect of its 
historic use based on limited preclinical data in animal models. There is mounting evidence, 
as the complex renal physiological milieu is elucidated, that mannitol may in fact be 
detrimental to kidney function.5 
 
Mannitol is an osmotic diuretic with a number of physiologic effects on the kidney as studied 
in preclinical models. Zager et al. showed that mannitol increases renal blood flow (RBF) in 
rats compared to sham controls (2 fold) when rats were given an intravenous bolus after 25 
minutes of renal artery occlusion.6 Corollary studies suggested that this increase in RBF was 
due possibly to prostaglandin mediated vasodilatory effect of mannitol7 and/or release of 
atrial natriuretic peptide.8 Physiologically, increased renal blood flow by mannitol in animal 
models can decrease intravascular hypoxic cell swelling9, 10 and increase intravascular 
volume with an associated decrease in hematocrit11. Intratubular casts may be flushed out by 
an increase in tubule flow rate as shown in rat models of progressive aortic clamping.12 
Mannitol may also play a role in mitochondrial protection after ischemia. Schrier et al 
demonstrated in a dog renal ischemia model that mannitol preserved renal cortical 
mitochondrial function.13 
 
There has been suggestion, however, that mannitol‘s effects may not be entirely beneficial 
and the response of increased renal blood flow a reflection, or cause, of severe hypoxic 
injury. As described by Gelman and colleagues, the vascular anatomy of the human kidney is 
remarkable for the magnitude of the relative difference in arteriovenous oxygen tension 
between the cortex and the medulla, creating a region of hypoxia within the outer medulla that 
is sensitive to ischemia and metabolic changes.5 The cortex receives 94% of renal blood flow 
whereas the medulla only receives 6%, with the portion of the outer medulla receiving its 
vascular supply as venous blood from the inner medulla. Because of this, the partial pressure 
of oxygen in the medulla is normally around 10 mm Hg versus 50 mm Hg in the cortex. The 
medulla, therefore, exists in a state of relative hypoxia, even in the presence of adequate 
RBF, and the prime region of risk during states of ischemia. The thick ascending limb of 
Henle’s loop is especially vulnerable to hypoxic injury.14 The decrease in RBF associated 
with oliguric renal failure and resultant reduction in GFR, has been postulated to act as a 
medullary protective mechanism by decreasing the metabolic demand required for solute 
reabsorption.10 Considering these physiologic findings, the adverse effects sometimes 
associated with mannitol use may be due to the selective increase in renal cortical RBF, 
filtration rate and resulting solute load, producing a shift in regional vascular flow while 
increasing the metabolic demand within the medulla and potentiating the effects of ischemia.5 
 
In clinical practice, mannitol has been used and studied in a variety of settings involving 
acute renal dysfunction or the risk for progressive renal impairment.  In vascular surgery, 
three randomized controlled trials have been performed to assess the use of mannitol in 
reducing the incidence of renal failure in patients undergoing abdominal aortic aneurysm 
(AAA) repair for infrarenal aortic aneurysms.15 There were no significant differences between 

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with the exception of one study (Wijnen et al) which identified evidence of improved 
outcomes in the mannitol treated cases on post operative day 2 (p=0.047). 16-18 Early 
retrospective uncontrolled clinical studies of the effects of mannitol during interventional 
cardiology procedures suggested its renal protective effects against radiocontrast 
nephropathy 19, 20 Subsequent published RCT’s have since  demonstrated mannitol is not 
only ineffective in regard to renal protection, but also has potential for producing renal failure. 
21, 22 As a result of these trials mannitol is no longer used during interventional cardiology 
procedures. Other studies, including meta-analysis of renal protective agents for contrast 
induced nephropathy and Cochrane analysis of the use of perioperative renal protective 
agents have not identified a benefit to the use of mannitol for preserving renal function in 
these settings.23, 24 
 
The strongest arguments for the use of mannitol as a renal protective agent come from the 
transplant literature, although this model and the results of these studies may involve 
mechanisms dissimilar to those of partial nephrectomy patients. Collins and Green et al 
performed some of the early studies of unilateral normothermic renal ischemia in a rabbit 
model utilizing 1 hour of renal vascular occlusion 25 The right kidney served as an internal 
control for the clamped left kidney. Renal function was assessed immediately after 
unclamping by measuring creatinine excretion at intervals acutely (within 1 hour) and 
chronically (up to 7 days). Mannitol conferred a significant benefit in both the acute and 
chronic measurements. The same investigators further characterized the timing and dose of 
mannitol in a subsequent study, and found that 0.25 mg/kg of IV mannitol given 15 minutes 
before the onset of warm renal ischemia provided the greatest benefit at day 3. 26 Shilliday 
and Allison provide a summary of the animal models supporting mannitol ‘s beneficial role 
but conclude the “case for mannitol must remain, in the words of the Scottish legal verdict, 
‘Not proven’”.3 Weimar et al subsequently reported results from a prospective randomized 
trial in which 50 patients receiving cadaveric donor transplant were provided either 50 g IV 
mannitol or saline infusion just prior to graft revascularization. 27 They found a significant 
decrease in the incidence of ATN in the early postoperative period in the mannitol group 
although no effect was demonstrated at 3 months when eGFR was compared. 
 
In large part due to the results of mannitol use in the one-hour rabbit renal ischemia models 
by Collins and Green, intravenous mannitol at a dose of 12.5 gm has been provided as 
standard dosing during partial nephrectomy procedures as part of routine practice.25 The 
origin of this dosing level is uncertain and the use of mannitol during surgery remains up to 
the surgeon’s discretion. In a preliminary study, as yet unpublished, investigators at MSKCC 
performed a retrospective evaluation of the renal function outcomes in patients undergoing 
minimally invasive partial nephrectomy, segregating the cohort by use of mannitol (standard 
dosing regimen) during the procedure. In total, 164 patients received mannitol and 117 did 
not. Characteristics of the patients in each group are shown in Table 1 and were not notably 
favorable to the non-mannitol group.  Statistically, those who received mannitol tended to 
have better preoperative eGFR (median 68 vs 61 ml/min/1.73m2), were more likely to 
undergo ischemia (98% vs 88%) and had fewer comorbidities (42% vs 53% had an ASA 
score of 3 or 4) than those who did not receive mannitol. 

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Table 1. Patient characteristics, stratified by whether the patient received mannitol treatment.  All 
values are median (IQR) or frequency (proportion). 
 
No Mannitol 
N=117 
Mannitol 
N=164 
P value* for 
difference 
between groups 
Age at surgery (years) 
60 (49, 68) 
60 (51, 67) 
1 
Preoperative GFR 
61 (54, 71) 
68 (59, 75) 
0.032 
Male gender 
75 (64%) 
109 (66%) 
0.7 
Estimated blood loss 
150 (50, 300) 
200 (100, 350) 
0.0017 
White race 
106 (91%) 
143 (87%) 
0.3 
Ischemia 
103 (88%) 
161 (98%) 
0.001 
Ice slush 
4 (4%) 
6 (4%) 
Clamp time (in min) 
32 (23, 39) 
32 (25, 40) 
High grade 
32 (41%) 
38 (36%) 
0.5 
Pathologic Stage 
0.8 
T1 
87 (83%) 
130 (87%) 
T2A 
4 (4%) 
5 (3%) 
T2B+ 
14 (13%) 
15 (10%) 
ASA Score 
0.006 
1 
12 (10%) 
6 (4%) 
2 
43 (37%) 
89 (55%) 
3 
60 (51%) 
65 (40%) 
4 
2 (2%) 
1 (1%) 
Year of surgery 
<0.001 
2005 
3 (3%) 
27 (16%) 
2006 
5 (4%) 
18 (11%) 
2007 
5 (4%) 
48 (29%) 
2008 
30 (26%) 
25 (15%) 
2009 
49 (42%) 
24 (15%) 
2010 
25 (21%) 
22 (13%) 
*Fisher’s exact or Wilcoxon rank sum 
 
 
 
 
Overall renal function appears to transiently decrease following nephron sparing surgery in a 
manner which suggests delayed recovery. As demonstrated in Figure 1, the profile of renal 
function, as assessed by eGFR, appears comparable for patients managed with and without 
mannitol based on retrospective data. Overall, the recovery of renal function was very similar 
in both groups (p=0.8 for effect of mannitol from GEE model). The predicted eGFR for a 
typical patient 2 months after surgery was 62 ml/min/1.73m2 both for those given and not 
given mannitol; at 6 months the respective predicted GFR measurements were 63 and 64 
ml/min/1.73m2. It is notable that the mannitol group had a lower nadir and recovery of eGFR 
than the group who did not receive mannitol. In evaluating the open surgical experience in 
over 850 open partial procedures 34 did not receive mannitol, many of who did not require 
renal ischemia, limiting our evaluation of this cohort. 

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Frequency 
0 
50 
100 
150 
50 
55 
60 
65 
70 
75 
Estimated GFR (ml/min/m2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0 
2 
4 
6 
8 
10 
12 
 
Time from surgery,  in months 
 
Figure  1.  Population-averaged changes  in  GFR  (mL/min/1.73m2)  after  partial  nephrectomy for 
patients given mannitol (grey line) and not given mannitol (black line), adjusted for differences in 
preoperative GFR, age, gender, ASA score, estimated blood loss, and ischemia time. Dashed lines 
indicate 95% confidence intervals. The histogram shows the number of GFR measurements over 
time, excluding postoperative measurements taken within two days of surgery that were recorded for 
all patients. 
 
The clinical significance of 6 units of eGFR change is somewhat empiric though based on 
data considered clinically meaningful to prompt a change in clinical practice. For most 
clinicians informally questioned, detecting a 3 or 4 point difference between groups in post- 
operative eGFR was not felt clinically important. We further evaluated our retrospective 
dataset of 281 patients identifying an index patient as 60 yo, non-African American man with 
preoperative baseline eGFR of 65 cc/min/1.73m2. Using the CKD Epi calculator, this would 
correlate  to  a  serum  creatinine  of  1.2  mg/dL.  For  every  0.1  mg/dL  change  in  serum 
creatinine, up or down from this baseline, there would be a roughly consistent 6 unit change 
in  eGFR.  Finally,  we  noted  that  a  6  unit  decrease  from  the  median  value  of  65 
cc/min/1.73m2 would place a patient below the threshold of stage 3 chronic kidney disease 
which is clinically meaningful. For these reasons we felt that detecting a difference in 6 units 
of eGFR between the groups was an appropriate level at which to power the study. 
 
Other methods to describe the change in renal function by group would be to allow each 
patient to serve as their own control and use the change in eGFR experienced by the patient 
to serve as a metric. We will assess this outcome as a secondary endpoint and will also 
evaluate the relationship to the primary endpoint. This method will enable each patient’s 
preoperative eGFR to be used as their own individual control. The percentage changes in 
each patient’s postoperative eGFR compared to the preoperative baseline can then be used 
to compare the treatment and placebo arms of the trial. 

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In summary, the practice of intravenous mannitol use during partial nephrectomy procedures 
as a renal protective agent has not been appropriately investigated to prove its effectiveness. 
Our preliminary retrospective data suggests mannitol does not demonstrate a benefit in 
attenuating the effects of ischemia or in the recovery of renal function following partial 
nephrectomy. We propose a randomized prospective study to evaluate its use for this 
purpose. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This study is a prospective randomized double blind placebo controlled trial comparing renal 
function outcomes in patients undergoing partial nephrectomy for renal tumors. Patients will 
be randomized in 1:1 fashion to receive mannitol or saline provided intravenously within 30 
minutes prior to renal vascular clamping for performing partial nephrectomy. 
 
Patient randomization will be accomplished by the Clinical Research Database (CRDB) once 
eligible patients have been consented and registered in the Protocol Participant Registration 
system.  Pharmacy will be able to access the requisite information on the CRDB to ensure 
correct delivery of either mannitol or saline to the treatment or placebo arms respectively. 
The anesthesiologist, surgeon and patient will be blinded to the intervention. 
 
To avoid any compromise in the blinding process, mannitol input into CASIS will be deferred 
until after the trial has finished. At this time it will be entered into CASIS by the research 
assistant. 
 
An interim analysis half way through the trial when 88 patients have eGFR measurements at 
6 months. The O’Brien-Fleming stopping boundaries will be used. The significance levels for 
the interim and final analyses are 0.0031 and 0.049, respecitively. 
 
4.2 
Intervention 
 
In patients undergoing partial nephrectomy, fluid management will be uniform and 
standardized for all operative techniques (open, laparoscopic or robot assisted) using the 
fluid management guidelines recommended by the Department of Anesthesia summarized 
herein. Upon arrival to the operating room patients will be placed supine on the operating 
room table and intravenous lines connected to allow initiation of IV hydration with Normosol 
or Lactated Ringers. Before induction of general anesthesia, IV hydration may be provided 
by the anesthesia team as clinically indicated which should not exceed 500 cc, including IV 
antibiotics. Presurgical intravenous fluid use will be documented in the anesthesia operative 
record. Parameters for maintenance intravenous fluid rates will be according to standard 
institutional clinical practice as provided by the Department of Anesthesia. These guidelines 
are consistent with those recommended as standard hydration parameters for patients 
undergoing both open and laparoscopic surgical procedures28. After induction of general 
anesthesia Normosol or Lactated Ringers, at a target infusion rate of 10cc/kg (+/- 1cc/kg), 
will be administered over the first hour of surgery.  After the first hour of surgery IV fluid will 
be administered at 6cc/kg (+/- 1cc/kg) intended to maintain a minimum systolic blood 
pressure of 90-100mmHg and a minimum urine output of 0.5cc/kg/hour. 

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• 
Allergy to mannitol 
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The treatment arm will receive a standard dose of 12.5 grams of mannitol (200 cc of a 6.25% 
mannitol solution) intravenously completely infused through an existing intravenous access 
catheter within 30 minutes prior to renal artery clamping. The placebo arm will receive 200cc 
of normal saline completely infused within 30 minutes prior to renal artery clamping. The 
perioperative team, investigator and patient will be blinded to the intervention 
 
Intraoperative events related to fluid resuscitation will be documented in the record. 
Hypotension (systolic blood pressure less than 90 mm Hg) or low urine output will be treated 
with 250cc intravenous boluses of Normosol or Lactated Ringers solution. Episodes of 
hypotension not responsive to intravenous fluids may be treated with small doses of 
intravenous vasopressors (phenylephrine or ephedrine) as per current practice at MSKCC. 
Surgical blood loss may be replaced on a volume basis cc per cc with colloids, including 
albumin or 6% hetastarch solution.  Blood transfusion will be performed as per MSKCC 
Blood Bank guidelines. 
 
At the end of the procedure, all intravenous fluid provided during the surgery will be 
summarized and documented in the operative record as per Anesthesia institutional 
standards. Any events of total intravenous fluid volume outside of the ranges defined by the 
maintenance parameters above will be recorded as events. The randomized design would 
lead to the expectation that these events would be similarly distributed between the stratified 
arms of the study. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
Mannitol (US Brand Name: Osmitrol) is in the osmotic diuretic pharmacologic category 
according to the American Hospital Formulary Service (AHFS) database.29 MSKCC OR 
pharmacy prepares a 6.25% mannitol solution by combining a 50 ml vial (12.5 grams) of 
mannitol with 150 ml of normal saline. . 
 
Mannitol solutions >15% concentrations may crystallize when exposed to low temperatures 
therefore the solution is stored at room temperature (15-30 degrees Celsius).29 
 
Mannitol is injected by intravenous infusion using an administration set with a filter and 
infused over 5-10 minutes as a 6.25% solution. As per current institutional practice, a volume 
of 200 cc will be infused. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
Describe the characteristics of the patient/subject population. 
 
6.1 
Subject Inclusion Criteria 
 
• 
Age >18 years 
• 
Scheduled for partial nephrectomy at MSKCC (open or minimally invasive technique) 
during which renal ischemia is anticipated 
• 
Preoperative eGFR > 45 cc/min/1.73m2 as measured by the CKD-EPI study equation 
 
6.2 
Subject Exclusion Criteria 

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• 
Severe  renal  impairment  (stage  3B)  defined  as  eGFR  <  45  cc/min/1.73m2  as 
measured by the CKD-EPI calculation. 
• 
Combined major surgical cases that include a partial nephrectomy. 
 
7.0 
RECRUITMENT PLAN 
 
Patients will be recruited from the practices of the Division of Urology, Department of 
Surgery. The study will be introduced to every patient scheduled for partial nephrectomy by 
the participating consenting physicians from the Department of Surgery and consent 
obtained prior to surgery. Candidate patients will be provided time to consider the study, to 
read the informed consent document at their convenience, and discuss with family and 
others, as desired. Once the participant is ready to provide informed consent, this will occur 
in-person with written informed consent.. 
 
Estimated Breakdown of target population by race/ethnicity (derived from CAISIS generated 
data for numbers of partial nephrectomies performed from 2002-2010 at MSKCC, N=1426 
patients): 
 
• 
Male 
64% 
• 
Female 
36% 
--------------------------------------------- 
• 
Native American/Alaskan 
0.1% 
• 
Asian/Pacific Islander 
2.5% 
• 
Black Non-Hispanic 
4.0% 
• 
Hispanic 
0.9% 
• 
White Non-Hispanic 
91% 
• 
Other 
1.5% 
 
8.0 
PRETREATMENT EVALUATION 
 
This protocol does not require any additional pretreatment evaluations other than those 
which are part of current clinical care standards for a patient undergoing a partial 
nephrectomy at MSKCC. These include: 
• 
Baseline radionuclear scintigraphy renal scan within 6 months of surgery 
• 
Routine history and physical examination to include documentation of any 
comorbidities, medications (including complementary and alternative medications), 
family history, social history (alcohol and tobacco usage), height, body weight, 
Karnofsky performance status within 30 days of surgery 
• 
Abdominal and pelvic CT scan and/or renal ultrasound within 3 months of surgery 
• 
Chest X-ray or Chest CT scan within 3 months of surgery 
• 
Preoperative laboratory investigations: CBC, basic chemistry panel, urinalysis 
(dipstick, microalbumin, creatinine, microscopic evaluation if indicated), urine culture if 
indicated within 30 days of surgery 
• 
Baseline creatinine values will be converted to eGFR using the CKD-EPI equation. 
o This value will be recorded from the MSKCC pre-surgical testing blood work 
mandatory for all patients undergoing surgery at MSKCC 

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9.0 
TREATMENT/INTERVENTION PLAN 
 
Patients will be randomized to receiving 12.5 g of mannitol versus placebo as an intravenous 
infusion to be initiated and be completely infused within 30 minutes prior to vascular 
occlusion of the renal artery in patients undergoing partial nephrectomy for a renal mass. 
 
CAISIS fields will be added to the standardized kidney surgery reporting form, currently used 
for all such cases, to record the binary variables of: Mannitol (or placebo) infusion prior to 
clamping (Y/N), Clamping of renal vessels within 30 minutes of mannitol infusion completion 
(Y/N).  If negative responses are recorded, details will be required. Currently, CAISIS fields 
for details of nephrectomy are extensive and include duration of ischemia time and 
proportion of kidney tissue preserved during surgery. 
 
The technique of surgery (open, laparoscopic, robot assisted laparoscopic) will be at the 
discretion of the surgeon and patient. None of the techniques utilized in the study are 
considered experimental and all are considered standard therapeutic options for a patient 
with a renal mass amenable to partial nephrectomy. Since patients will be randomized as 
stratified by approach (laparoscopic or open) any impact from physiologic differences 
between the 2 approaches are expected to be equally distributed between the 2 arms. The 
decision for renal hypothermia during surgery will be at the discretion of the surgeon and 
patient. Patient medications will be recorded from the home medications list and managed 
perioperatively per institutional standards. 
 
The operating team will consist of surgeons on faculty at the MSKCC Department of Surgery, 
Urology Service. The procedures are performed under general anesthesia with standard 
intraoperative vital sign monitoring. This will include blood pressure, 4-lead ECG, heart rate, 
pulse oximetry, temperature and urine output. Intravenous fluid use during surgery will be 
provided by the anesthesiology team as clinically indicated. Total volume of fluids provided 
as well as estimated blood loss will be recorded. 
 
Mannitol solution of 12.5 gm in 200 cc of saline or placebo will be available in the OR at the 
time of surgery initiation. It will be administered intravenously and will be completely infused 
within 30 minutes prior to renal artery clamping. During the surgery, vascular occlusion will 
be provided using vascular bulldog or Satinsky clamp of the renal artery. If multiple primary 
renal vessels are encountered, selective occlusion of the vessels can be provided at the 
surgeon’s discretion and the details regarding number of arterial vessels and number of 
clamped vessels recorded. Clamping or non-clamping of the renal vein will also be recorded. 
Patients who do not undergo clamping of the renal artery will still receive either the mannitol 
or placebo since kidney surgery for partial nephrectomy is intrinsically damaging to the 
kidney and the effects of dissection of the kidney have unknown effects on renal perfusion for 
which mannitol may have potential benefit. 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
This protocol does not require any additional evaluations after the patient is admitted for 
surgery other than those routinely part of clinical care for a patient undergoing a partial 
nephrectomy. These will include: 
• 
ASA classification, assigned by the anesthesiologist 
• 
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• 
Type of anesthesia: general, epidural, combination 
• 
Duration of anesthesia and of surgery 
• 
Duration of warm or cold ischemia time 
• 
Estimated blood loss 
• 
Use of intraoperative fluids (crystalloid, colloid, blood products) 
• 
Postoperative day 1 and postoperative day 2 serum creatinine measurement. For 
patients discharged before post-operative day 2, serum blood testing will be ordered 
as an outpatient test. 
• 
Follow up visit serum creatinine measurements (6 weeks +/- 4 weeks and 6 months 
+/- 2 months) 
• 
6 month +/- 2 months follow up radio nuclear scintigraphy renal scan, which is a 
routine postoperative investigation for patients who have undergone a partial 
nephrectomy. 
• 
Patients may be concurrently enrolled on protocol 89-076 for collection of tissue and 
blood for tissue banking. 
 
11.0 TOXICITIES/SIDE EFFECTS 
 
There are minimal side effects to the use of mannitol in the dosages prescribed for this study. 
The AHFS warnings/ precautions relate to excess amounts (>100 g of intravenous mannitol 
in a 24 hour period).29 12.5 g of mannitol is considered the “test dose” in adult populations 
when mannitol is used for other therapeutic effects. Nonetheless, concerns related to 
adverse effects listed are: 
 
• 
Fluid/electrolyte loss: excess mannitol infusion can lead to profound diuresis with fluid 
and electrolyte loss; close medical supervision is required 
o The anesthesia and PACU teams routinely monitor urine output, vitals and 
volume status and therefore this concern is minimal. 
• 
Nephrotoxicity: may cause renal dysfunction especially in high doses therefore 
caution is required in patients taking nephrotoxic agents or have pre-existing renal 
disease 
o Patients are excluded from participating if their eGFR identifies them as 
having  pre-existing Stage 3b or greater chronic kidney disease. All 
nephrotoxic agents are closely monitored/discontinued routinely in all partial 
nephrectomy patients. 
o Severe clinical complications from mannitol use in the literature are 
exceedingly rare and only follow massive doses of mannitol, in the range of 
400-900 g/day.30 
 
 
• 
Cardiovascular: may lead to chest pain, tachycardia, hypotension, hypertension, 
dyspnea due to congestive heart failure or overload 
• 
espiratory: Pulmonary edema 
• 
Central Nervous System: Pyrexia, headache, confusion, vertigo 
• 
Dermatological: Urticaria 
• 
Gastrointestinal: Nausea, emesis, xerostomia 
 
Surgical complications will be assessed prospectively and retrospectively reviewed using the 
institutional standard for complications reporting for all surgical patients as followed by the 
Department of Surgery. Standardized graded complications and adverse events at MSKCC 
utilize the five point modified Clavien system. Grade I include complications requiring 

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monitoring but no intervention, Grade II requires bedside or medical treatment; grade III 
constitutes adverse events require surgical or procedural intervention with return to normal 
functioning; grade IV includes disabling, life-threatening complications with resulting 
functional loss and grade V is the death of the patient. This is a modification of the Clavien 
system for reporting complications with defined, categorized, and classified events that will 
be segregated into time periods of </= 30 days, 31 - 90 days and > 90 days after surgery and 
includes medication related complications following NCI CTCAE version 3 guidelines.31 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
As an intent-to-treat study, patients will be evaluated for the primary endpoint if they are 
registered on study, brought to the operating room for surgery, and begin anesthesia for the 
procedure. Because the role of mannitol as a protective agent in regard to kidney function is 
not entirely clear and its mechanism of action may be mediated through its effects on the 
contralateral kidney, all patients will be evaluated for the primary endpoint even if the 
ipsilateral kidney is not clamped during the procedure. If the surgery is aborted for any 
reason before attempted excision of the mass or if intravenous infusion fails for any reason 
the patient will be dropped from the study and replaced. Based on past experience these 
issues are rare events. 
 
Estimated glomerular filtration rate (eGFR) will be estimated according to the CKD-EPI 
formula. 
 
Perioperative complications are defined as any complication graded in the MSKCC grading 
system occurring during the intraoperative and postoperative period up to 30 days. 
 
Immediate perioperative morbidity is defined as any complication graded in the MSKCC 
grading system occurring during the initial hospital stay. 
 
The intraoperative period is defined as the period from anesthesia induction to final skin 
closure. 
 
The postoperative period is defined as the period from final skin closure to the study endpoint 
at 6 months +/- 2 months. 
 
Renal hypothermia will be defined as induced cooling of the kidney by externally applied ice- 
slush or cold crystalloid infusion via catheter of the renal pelvis or intravascularly. 
 
Warm ischemia will be defined as no kidney cooling during renal artery occlusion. 
 
Ischemia time will be defined as the time elapsed from renal artery occlusion by a vascular 
clamp to removal of the vascular clamp. Re-clamping of the vessels will be recorded as an 
event and total duration of ischemia recorded as the sum duration of occlusion. 
 
Blood loss is defined as the estimate accounted from the suction device and absorptive 
sponges during the surgical procedure, and will be noted in the anesthesia record per 
institutional standard. 

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Intraoperative complications are defined as any complications related to either surgical or 
clinical aspects during the procedure, as described by the surgeon and covered by the 
institutional guidelines. 
 
Any patient who does not undergo renal ischemia by vascular clamping will during their 
procedure will be recorded as a zero ischemia time. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
Patients will be withdrawn from the study if they express a desire to do so, if it is determined 
to be in the patient’s best interest to do so, or if they do not undergo initiation of their surgical 
procedure as stipulated in section 12.0. Patients who are not evaluable for the study primary 
endpoint by failure to obtain data for the primary endpoint will be excluded from the analysis 
and replaced. 
 
 
14.0 
BIOSTATISTICS 
 
14.1 Primary Aim 
 
The primary aim is to establish the difference in eGFR 6 months after surgery between the 
mannitol group and the placebo group. The difference will be assessed with an ANCOVA 
model with eGFR 6 months after surgery (+/- 2 months) as the outcome and treatment group, 
surgical technique, and preoperative eGFR as covariates. We will report a two-tailed p-value 
and a 95% confidence interval for the difference between groups. If a patient does not have 
an eGFR measurement between 5-7 months after surgery and has both a measurement 
between 3-5 months and 7-12 months after surgery, then the 6 month eGFR measurement 
will be linearly interpolated. 
 
Based on historical data, patients not receiving mannitol have a mean eGFR of 60 
cc/min/1.73m2 6 months after surgery. The observed correlation between the preoperative 
eGFR and eGFR 6 months was 0.6. The standard deviation is 14.4.  Using bootstrap 
methods, the 75th percentile of the standard deviation was estimated to be 14.9. This 
inflated standard deviation was used in the sample size calculation. To detect the minimal 
clinical significant difference of 6 units of eGFR, a trial with 90% power and 5% alpha 
requires 83 patients per treatment arm.  Because of the loss of power in the interim analysis, 
a total of 88 patients are required per treatment arm. The trial will accrue until it is anticipated 
that 88 patients per treatment arm will have evaluable eGFRs at 6 months. We expect that, 
due to drop out, this will involve accruing approximately 105 patients per treatment arm. 
Sensitivity analyses will be performed to assess the effect of patient withdrawal on the 
primary analysis. 
 
We expect to reach our target sample size within 2 years, given that nearly 200 patients per 
year are eligible to enroll. We expect to enroll 8 patients per month to reach accrual in 2 
years. 

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14.2 Secondary Aims 
 
An ANCOVA model will be used to compare the difference in eGFR between treatment 
groups at 6 weeks (+/- 4 weeks) after surgery with postoperative eGFR as the outcome, and 
treatment group, surgical technique, and preoperative eGFR as covariates. 
 
We will also use the ANCOVA on the absolute level of eGFR because this has the greatest 
statistical power. However, the estimate produced by ANCOVA – a mean difference in eGFR 
levels – is of incomplete clinical interpretability. We will therefore present estimates in two 
other ways for the purposes of illustrating the results in clinical terms. We will first give 
percentage change separately by group, along with a difference between groups. We will 
also report the percentage of patients in each treatment group that have postoperative eGFR 
less than 60 ml/min/1.73 m2, as this is generally considered to represent a clinical level of 
kidney dysfunction. 
 
ANCOVA will be used to compare 6 month (+/- 2 months) postoperative radionuclear 
scintigraphy renal scan with treatment group, baseline postoperative radionuclear 
scintigraphy renal scan, and randomization stratum as covariates.  ANCOVA will also be 
used to compare estimated blood loss and ischemia time with treatment group and 
randomization stratum as covariates. 
 
Multivariable logistic regression will be used to assess the difference in the rate of grade 3-5 
complications between treatment groups. The multivariable model will include treatment 
group and randomization stratum as covariates. 
 
We will report a two-tailed p-value and a 95% confidence interval for the difference between 
groups for all secondary outcomes.  Summary statistics will be calculated by group for age, 
sex, race, BMI, serum hemoglobin, serum albumin, ASA, and Karnofsky Performance Scale. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/). The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 

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15.2 
Randomization 
 
Randomization will be accomplished by the method of random permuted block, and patients 
will be stratified by preoperative eGFR (<60 v. >=60 ml/min/1.73 m2) and surgical technique 
(open versus minimally invasive).  This ensures adequate numbers of patients above and 
below the K/DOQI chronic kidney disease classification (i.e. <60 ml/min/1.73 m2) in the final 
study patient population. Also, we do not believe that surgical approach plays a role in the 
putative mechanism of action. To control for any such effects, randomization of cases will be 
stratified by minimally invasive or open surgical approach. Since this is a double blind study, 
the patients’ treatment assignments can be viewed in the CRDB only by the hospital 
pharmacists who are dispensing the study drugs. 
 
After eligibility is established and immediately after consent is obtained, patients will be 
registered in the Protocol Participant Registration (PPR) system and randomized using the 
Clinical Research Database (CRDB), by calling the MSKCC PPR Office at 646-735-8000 
between the hours of 8:30 am and 5:30 pm, Monday - Friday. 
 
16.0 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study who will provide 15% of data 
management support. The responsibilities of the RSA include project compliance, data 
collection, abstraction and entry, data reporting, regulatory monitoring, problem resolution 
and prioritization, and coordination of the protocol study team activities. The data collected 
for this study will be entered into a secure departmental database. A minimal data set will be 
added to CRDB. 
 
16.1 
Quality Assurance 
 
Monthly registration reports will be generated to monitor patient accrual and 
completeness of registration data. Routine data quality reports will be generated to assess 
missing data and inconsistencies. Accrual rates, and extent and accuracy of evaluations 
will be monitored throughout the study period. Potential problems will be brought to the 
attention of the study team for discussion and action. 
 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and 
Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm. 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 

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clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk, and degree of monitoring required. Each type of protocol (e.g. NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc) will be addressed and 
the monitoring procedures will be established at the time of protocol activation. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Benefits and risks: The experimental intervention (mannitol) is preferentially omitted by 
certain oncological surgeons and is inconsistent in daily clinical practice at MSKCC. A 
previous study has suggested there is no benefit and there are theoretical arguments that it 
may do harm. Therefore we do not believe that the therapeutic aspects of this trial pose any 
risks different from those faced for patients undergoing a partial nephrectomy off-study. 
 
Toxicities/side effects: Adverse outcomes have not been associated with the doses of 
mannitol being used in the protocol. 
 
Alternatives/options for treatment: The alternative to participation in the trial would be to 
undergo a partial nephrectomy according to the surgeon’s standard practice rather than be 
randomized. No other aspect of patient care would differ. 
 
Financial costs/burdens: The subjects will not be compensated for their participation and 
there are no costs involved in participation. 
 
Privacy and confidentiality: Every effort will be made to keep the study records private. No 
identifiers will be used in any reports or publications resulting from the study, however, the 
data will be used in the interests of ongoing research. 
 
Voluntary nature of the study: Participation is entirely voluntary. All aspects of patient’s 
care and monitoring will be unaffected by whether the patient chooses to consent for the 
study. 
 
17.1 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2 
Serious Adverse Event (SAE) Reporting 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at  sae@mskcc.org. The report should contain the following 
information: 
 
Fields populated from CRDB: 

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• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number 
written at the top of the report. If appropriate, the report will be forwarded to the FDA by the 
SAE staff through the IND Office. 
 
17.2.1 
 
This protocol is not an Industry or Cooperative group protocol. 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 

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Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
19.0 
REFERENCES 
 
1. 
Sprenkle, P. C., Power, N., Ghoneim, T. et al.: Comparison of open and minimally invasive 
partial nephrectomy for renal tumors 4-7 centimeters. Eur Urol, 61: 593, 2012 
2. 
Srinivas, V., Herr, H. W., Hajdu, E. O.: Partial nephrectomy for a renal oncocytoma 
associated with tuberous sclerosis. J Urol, 133: 263, 1985 
3. 
Shilliday, I., Allison, M. E.: Diuretics in acute renal failure. Ren Fail, 16: 3, 1994 
4. 
Novick, A. C.: Renal hypothermia: in vivo and ex vivo. Urol Clin North Am, 10: 637, 1983 
5. 
Gelman, S.: Does mannitol save the kidney? Anesth Analg, 82: 899, 1996 
6. 
Zager, R. A., Mahan, J., Merola, A. J.: Effects of mannitol on the postischemic kidney. 
Biochemical, functional, and morphologic assessments. Lab Invest, 53: 433, 1985 
7. 
Johnston, P. A., Bernard, D. B., Perrin, N. S. et al.: Prostaglandins mediate the vasodilatory 
effect of mannitol in the hypoperfused rat kidney. J Clin Invest, 68: 127, 1981 
8. 
Kurnik, B. R., Weisberg, L. S., Cuttler, I. M. et al.: Effects of atrial natriuretic peptide versus 
mannitol on renal blood flow during radiocontrast infusion in chronic renal failure. J Lab Clin 
Med, 116: 27, 1990 
9. 
Flores, J., DiBona, D. R., Beck, C. H. et al.: The role of cell swelling in ischemic renal 
damage and the protective effect of hypertonic solute. J Clin Invest, 51: 118, 1972 
10. 
Brezis, M., Rosen, S., Silva, P. et al.: Renal ischemia: a new perspective. Kidney Int, 26: 
375, 1984 
11. 
Lang, F.: Osmotic diuresis. Ren Physiol, 10: 160, 1987 
12. 
Morris, C. R., Alexander, E. A., Bruns, F. J. et al.: Restoration and maintenance of 
glomerular filtration by mannitol during hypoperfusion of the kidney. J Clin Invest, 51: 1555, 
1972 
13. 
Schrier, R. W., Arnold, P. E., Gordon, J. A. et al.: Protection of mitochondrial function by 
mannitol in ischemic acute renal failure. Am J Physiol, 247: F365, 1984 
14. 
Brezis, M., Rosen, S., Silva, P. et al.: Transport activity modifies thick ascending limb 
damage in the isolated perfused kidney. Kidney Int, 25: 65, 1984 
15. 
Hersey, P., Poullis, M.: Does the administration of mannitol prevent renal failure in open 
abdominal aortic aneurysm surgery? Interact Cardiovasc Thorac Surg, 7: 906, 2008 
16. 
Wijnen, M. H., Vader, H. L., Van Den Wall Bake, A. W. et al.: Can renal dysfunction after 
infra-renal aortic aneurysm repair be modified by multi-antioxidant supplementation? J 
Cardiovasc Surg (Torino), 43: 483, 2002 
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Paul, M. D., Mazer, C. D., Byrick, R. J. et al.: Influence of mannitol and dopamine on renal 
function during elective infrarenal aortic clamping in man. Am J Nephrol, 6: 427, 1986 
18. 
Nicholson, M. L., Baker, D. M., Hopkinson, B. R. et al.: Randomized controlled trial of the 
effect of mannitol on renal reperfusion injury during aortic aneurysm surgery. Br J Surg, 83: 
1230, 1996 
19. 
Anto, H. R., Chou, S. Y., Porush, J. G. et al.: Infusion intravenous pyelography and renal 
function. Effect of hypertonic mannitol in patients with chronic renal insufficiency. Arch Intern 
Med, 141: 1652, 1981 
20. 
Weisberg, L. S., Kurnik, P. B., Kurnik, B. R.: Risk of radiocontrast nephropathy in patients 
with and without diabetes mellitus. Kidney Int, 45: 259, 1994 

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21. 
Solomon, R., Werner, C., Mann, D. et al.: Effects of saline, mannitol, and furosemide to 
prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med, 
331: 1416, 1994 
22. 
Majumdar, S. R., Kjellstrand, C. M., Tymchak, W. J. et al.: Forced euvolemic diuresis with 
mannitol and furosemide for prevention of contrast-induced nephropathy in patients with 
CKD undergoing coronary angiography: a randomized controlled trial. Am J Kidney Dis, 54: 
602, 2009 
23. 
Zacharias, M., Conlon, N. P., Herbison, G. P. et al.: Interventions for protecting renal function 
in the perioperative period. Cochrane Database Syst Rev: CD003590, 2008 
24. 
Kelly, A. M., Dwamena, B., Cronin, P. et al.: Meta-analysis: effectiveness of drugs for 
preventing contrast-induced nephropathy. Ann Intern Med, 148: 284, 2008 
25. 
Green, R. D., Boyer, D., Halasz, N. A. et al.: Pharmacological protection of rabbit kidneys 
from normothermic ischemia. Transplantation, 28: 131, 1979 
26. 
Collins, G. M., Green, R. D., Boyer, D. et al.: Protection of kidneys from warm ischemic 
injury. Dosage and timing of mannitol administration. Transplantation, 29: 83, 1980 
27. 
Weimar, W., Geerlings, W., Bijnen, A. B. et al.: A controlled study on the effect of mannitol on 
immediate renal function after cadaver donor kidney transplantation. Transplantation, 35: 99, 
1983 
28. 
Miller, R. D.: Miller's Anesthesia 6th edition. Philadelphia: Elsevier, Churchill, 2005 
29. 
American Society of Hospital Pharmacists.: Drug information fulltext DIF. Bethesda, MD: 
American Society of Hospital Pharmacists : SilverPlatter International 
30. 
Better, O. S., Rubinstein, I., Winaver, J. M. et al.: Mannitol therapy revisited (1940-1997). 
Kidney Int, 52: 886, 1997 
31. 
Dindo, D., Demartines, N., Clavien, P. A.: Classification of surgical complications: a new 
proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg, 240: 
205, 2004 
 
 
 
20.0 
APPENDICES 
 
No appendices.