Renal Adventures in Imaging
Transcript of Renal Adventures in Imaging
-
8/9/2019 Renal Adventures in Imaging
1/32
ADVENTURES IN RENALIMAGING
JOEL M. TOPF, M.D.
Clinical Nephrologist248.470.8163
N O O N
C O N F E R E N C EYou gotta eat lunch any ways, might as well learn how reduce the
number of patients you kill
2 2 2 0 1 M o r o s s R o a d , D e t r o i t t e l e p h o n e : 3 1 3 . 8 8 6 . 8 7 8 7
f a x : 3 1 3 . 8 8 6 . 4 1 0 3 w w w . p b f l u i d s . c o m
-
8/9/2019 Renal Adventures in Imaging
2/32
Introduction
The pattern of modern medical care:
The patient gets sick and presents with a set of symptoms.
Chest pain, shortness of breath
The physician determines a differential of possible diagnosis
Cardiac failure, cardiac ischemia, PE, pneumonia
The physician orders and performs a slate of diagnostic studies
Stress test, CT angio, Chest x-ray, troponins, D-dimers, cultures
After establishing a diagnosis drugs are administered and procedures performed
to cure or alleviate symptoms
antibiotics, thrombolytics, angiogram
A common calculation in determining the treatment is to weigh the risks inherent inthe therapy and compare them to the risks of the disease itself. The more severe the
disease the more toxicity we are wiling to accept in the therapy. Contemporary hospi-
talized patients are so ill that physicians routinely order therapies with huge degrees
of risk and associated morbidity: bypass surgery, chemotherapy, liver transplantation,
radiation therapy; there is nearly no limit to the amount of risk we will take to battle disease.
I believe that physicians have become so used to exposing patients to risk in thetreatment phase that they do not adjust the assessment of risk-benefit when exposing
patients to the risks inherent in diagnostic tests.
The benefit that patients receive from undergoing a diagnostic tests are more difficult
to pin-down than the benefit from treatment. What benefit does a patient gain from
accurately diagnosing a self-limited, spontaneously resolving condition like post-
strep GN? What benefit does a patient gain from accurately diagnosing a fatal and
untreatable condition like metastatic pancreatic cancer? Obviously patients have little
to gain from these procedures when they are successful. So, we should accept
very little risk in the diagnostic work-up of these conditions.
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 2
-
8/9/2019 Renal Adventures in Imaging
3/32
When determining acceptable risk to patients in the diagnostic phase, you need to
have less tolerance for risk than in the treatment phase.
There are three different diagnostic situations where renal issues figure prominently:
1. The risk of contrast nephropathy with iodinated contrast agents
2. The risk of nephrogenic systemic sclerosis with gadolinium containing
paramagnetics for MRI/MRA
3. The risk of acute renal failure with sodium phosphate for bowel prep prior
to colonoscopy.
Acute phosphate nephropathy! 4Sodium phosphorous and nephrocalcinosis! 4Epidemiology! 6Conclusion! 10Key teaching points! 11
Gadolinium and Nephrogenic Fibrosing Dermopathy! 12Nephrogenic Fibrosing Dermopathy! 13Gadolinium! 13Epidemiology! 15Treatment! 16Conclusion! 17Key teaching points! 18
Strategies to Avoid Contrast Nephropathy: Case report! 19Definition of contrast nephropathy! 20Epidemiology! 20Consequences of contrast nephropathy! 22Preventing contrast nephropathy ! 24
The Contrast Agents! 24Hydration Strategies! 25Acetylcysteine! 29
Key Teaching points! 31
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 3
-
8/9/2019 Renal Adventures in Imaging
4/32
Acute phosphate nephropathyCC: Im still on dialysis
A 61 y.o. Caucasian female presented to my office after being told that she needed temporary
dialysis for acute renal failure. After 6 weeks of peritoneal dialysis there are no signs that her
kidneys are healing. Four months prior, she had started feeling tired and losing weight. Her
primary care doctor did some tests and told her that she had renal failure and sent her to a
nephrologist. This nephrologist performed a kidney biopsy (See below) and told her that she
had acute tubular necrosis, with calcium deposits in her kidneys, but that the glomeruli looked
great and he expected full recovery.
Past Medical History
No history of hypertension, diabetes or heart disease. No history of primary hyperparathyroid-
ism or renal tubular acidosis. Patient has a recto-vaginal fistula from Crohns disease that was
surgically repaired 4 months ago.
Patients who receive phosphate containing cathartics occasionally develop severe
acute renal failure. As the biopsy shows, unlike most renal disease the glomeruli are
spared with calcified debris in the tubules.
H & E Stain: Strange intratubular
deposits
Van Kossa Stain: Deposits are
calcium deposits
Hanging out on peritoneal dialysis
waiting for my kidneys to get
better.
SODIUM PHOSPHOROUS AND NEPHROCALCINOSISColonoscopy for cancer screening is increasing in the United States. In 2002 over 14
million colonoscopies were performed for cancer screening. Two prep agents are used
in almost all of these procedures: polyethylene glycol (PEG, Golytely) and oral so-
dium phosphate solution (OSPS, Fleet EZ-Prep). Sodium phosphate produces the
superior prep with better patient tolerance according to most analysis. An inadequite
prep increases the likelihood of aborting the procedure or missing a neoplasm.
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 4
-
8/9/2019 Renal Adventures in Imaging
5/32
While generally safe, OSPS has some theoretical disadvantages compared to PEG.
OSPS causes fluid shifts, allows phosphorous absorption, and has numerous contra-
indications for use in various populations.
In June 2004 Markowitz et al described 5 patients who developed serious renal com-
plications from the OSPS and ushered in a new era of caution regarding colonic prep.(Markowitz GS, Nasr SH, Klein P, Anderson H, Et al. Hum Pathol 35: 675-684; 2004.)
1 2 3 4 5
demo-
graphics
69 whitemale
82 AfricanAmericanmale
55 hispanicfemale
64 AfricanAmericanfemale
76 whitefemale
PMH
HTN, Pros-tate Ca1 HyperparaRad. proctitis
HTNCOPDcolon perf.
HTNDMCAD/MI
HTNDMobesity
HTNspastic colon
Meds
ARB ARBHCTZglitazone,
ASA
ACEiHCTZglitazone
ASA
ARBASA
Cr (GFR)before Na-Phos
1.2 mg/dl (64mL/min)2 weeksbefore
0.9 (104 mL/min)1 day before
0.6 (110 mL/min)3.5 monthsbefore
0.9 (81 mL/min)4 monthsbefore
0.9 (65 mL/min)1 yearbefore
Crafter Na-Phos
6.71 month after
5.21 week after
4.52 weeks after
2.38 weeks later
63 days after
Cr at Bi-opsy
6.37 weeks
4.94 weeks
4.016 weeks
3.028 weeks
8.01 week
Final Cr 8.5 (7 mL/min)6 weeks afterthe bx
4.3 (17 mL/min)3 monthsafter bx
3.5 (14 mL/min)5 weeks afterbx
3.3 (18 mL/min)3 weeks afterbx
3.7 (15 mL/min)3 wks afterbx
All the patients were biopsied and had normal glomeruli (except patient 4 who hadconcurrent nodular diabetic glomerulopathy) but significant acute and chronic
changes to the tubules. There were prominent tubule lesions of calcium phosphate.
Patients also had variable amounts of interstitial inflammation.
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 5
-
8/9/2019 Renal Adventures in Imaging
6/32
OSPS have been used as a cathartic since the 1893. In the early 90s their use as a
bowel prep agent was recognized. Prior to Markowitz, Fleets was thought of as a be-
nign agent as recognized in its other-the-counter status. The company quotes a rate of
serious adverse events of 1 per 1.4
million doses. Most adverse events
are related to inappropriate dosesor use in inappropriate patients.
Despite this enviable safety record
there were some warning signals
that there maybe problems with
OSPS.
Transient hyperphosphatemia isubiquitous and, previously, had
been thought to be without clinical
significance. It is likely that in pa-
tients with volume depletion and
decreased nephron mass (i.e.
chronic kidney disease) the in-
creased phosphorous load com-
bined with increased water reabsorption in the proximal tubules causes a pathologi-
cally elevated intratubular phosphorous concentration. This results in a spontaneousprecipitation of calcium phosphate and permanently damages the tubule and causes
loss of the nephron.
EPIDEMIOLOGY
Considerable caution should be ad-vised before OsmoPrep Tablets are used
in patients with the following illnesses:
severe renal insufficiency (creatinine
clearance less than 30 mL/minute),
congestive heart failure, ascites, unsta-
ble angina, gastric retention, ileus,
acute bowel obstruction, pseudo-
obstruction of the bowel, severe chronic
constipation, bowel perforation, acute
colitis, toxic megacolon, gastric bypass
or stapling surgery, or hypomotility
syndrome.
0
2
4
6
8
Vanner, 1990 Cohen, 1994
SerumPhos(mg/dL)
pre-OSPS
2 hr after 2nd dose
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 6
http://www.rxlist.com/script/main/art.asp?articlekey=3896http://www.rxlist.com/script/main/art.asp?articlekey=3896http://www.rxlist.com/script/main/art.asp?articlekey=2362http://www.rxlist.com/script/main/art.asp?articlekey=2362 -
8/9/2019 Renal Adventures in Imaging
7/32
Markowitzs paper
resulted in a wave of
case reports and
small case series
showing similar find-
ings. Markowitzhimself published a
definitive article with
21 cases. (Markowitz
GS et al. J Am Soc
Nephrol 2005; 16:3389.) The proposed risk factors of
decreased renal function, ACEi/ARB and diuretics were all verified. Case
reports and case-control studies are incapable of estimating the incidence of this prob-lem. There have been numerous studies that tried to retrospectively determine if this
was a common but unrecognized cause of renal failure or was rare.
Most use a similar methodology of combing a database of colonoscopies and looking
for patients who incidentally had pre- and post-procedure creatinines.
The Bronx VA
Singal et. al. reviewed 311 patients who underwent colonoscopy at the Peters Veter-
ans Hospital in the Bronx New York who incidentally had a creatinine in the 12
months preceding the procedure and the 12 months after the procedure. They found a
tiny difference in the change in the average serum creatinine (0.09 mg/dL lower with
PEG, p=0.005) and a large difference in the number of patients with a 25% increase in
serum creatinine. However, none of the patients had severe irreversible renal failure.
In the three patientswhose creatinines
rose over 2, all re-
turned to pre-
colonoscopy levels
within 6 months. No
cases of irreversible
severe renal failure in150+ administrations
of OSPS.
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 7
CONTRAINDICATIONS TO NA PHOS
SOLUTIONS FOR COLONOSCOPY PREP
Renal failure
Hyperparathyroidism
Congestive heart failure
Liver failure
Intestinal obstruction
0%
5%
10%
15%
20%
8%
20%
25%increaseinCr
p
-
8/9/2019 Renal Adventures in Imaging
8/32
Henry Ford Hospital
Researchers at Henry Ford Hospital looked at colonoscopies done from 1999-2005.
They excluded pre-existing renal disease, patients without at least one creatinine
within 12 months prior and 6 months after the procedure. This lead to a study popu-
lation of 2,352 patients. OSPS was used in 2,083 and PEG in 269. Eighty-eight of these
patients dropped their GFR below 60 cc/min in the 6 months after the colonoscopy
without an obvious explanation following chart review. There was no association be-
tween using OSPS and developing renal failure (RR 1.14 95% CI: 0.55-2.39). They did find
some general risk factors for developing renal insufficiency after a colonoscopy. See
table.
FACTOR RR 95% CI
Age > 65 3.23 2.08-5.03
African American Race 1.70 1.02-2.83
Baseline GFR 60-90 mL/min 5.60 3.18-9.86
Hypertension 2.99 1.73-5.19
ACEi 1.90 1.23-2.95
ARB 2.69 1.43-5.05
Thiazide diuretics 2.26 1.47-3.45
Russmann S, Lamerato L, Marfatia A, Motsko SP. Am J Gastroenterol 2007; 102: 2655-
2663.
University of Pennsylvania Health System
Bruneli performed a case control study of 141 cases of incident ARF following endo-
scopy (25% or 0.5 mg/dL increase in creatinine) and found no association with OSPS.
(Brunelli SM, Lewis JD, Gupta M, et al. J Am Soc Nephrol 18: 3199-3205, 2007)
Archives of Internal Medicine
Case control study of 286 patients with normal kidney function who underwent out-
patient colonoscopy with OSPS compared to 125 age and sex matched controls. Un-
fortunately since nearly everyone who underwent colonoscopy at this institution
used OSPS the investigators had to use control patients who did not get colonosco-
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 8
-
8/9/2019 Renal Adventures in Imaging
9/32
pies. The control group does allow one to look at the affect of the prep without being
confused by natural age-related loss of renal function.
70
72
74
76
78
80
Baseline 6 mo 12 mo
GFR(mL/min) =0.20
=0.002
-
8/9/2019 Renal Adventures in Imaging
10/32
CONCLUSION
In December 2008, the FDA required a boxed warning for OSPS regarding phosphate
nephropathy and identified the following risk groups:
Individuals who appear to have an increased risk of acute phosphate neph-
ropathy following the use of OSPs include persons: who are over age 55;who are hypovolemic or have decreased intravascular volume; who have
baseline kidney disease, bowel obstruction, or activecolitis; and
who are using medications that affect renal perfusion or function (such as
diuretics, angiotensin converting enzymeinhibitors, angiotensin
receptor blockers, and possibly nonsteroidal anti-inflammatorydrugs).
OSPS can have devastating renal complications. Unfortunately we have no idea who
is at risk of developing those complications. The risk profile we develop from case
series (ACEi, diuretics, elderly) looks almost exactly like a population that regularly
receives OSPS without any complications.
Though the risk factors have not been conclusively determined it seems prudent to
avoid using OSPS in patients with any degree of renal insufficiency (even with a
normal creatinine) and to stop ACEi, ARB and diuretics prior to the prep.
The most important next step would be to perform high quality prospective studies
to help determine the true incidence and risk factors for this devastating but rare
complication.
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 10
-
8/9/2019 Renal Adventures in Imaging
11/32
KEY TEACHING POINTS
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 11
-
8/9/2019 Renal Adventures in Imaging
12/32
Gadolinium and
Nephrogenic Fibrosing DermopathyChief Complaint: My legs are made of wood.
38 year old dialysis patient complains
of lower extremity edema. The patient
is poorly compliant with fluid restric-
tions and regularly comes in for di-
alysis with 5 to 6 kg of weight gain
since last dialysis. Additionally the
patient has resistant hypertensionwith systolic blood pressures running
from 180 to 200.
Past medical history
Diabetic nephropathy resulting in
ESRD, OSA with non-compliance
with CPAP, obesity and recent fever
associated with neck pain. The patient
had an MRI with gadolinium to rule
out a paraspinal abscess.
Physical exam
Remarkable for a pleasant, obese man.
His blood pressure is 180/79 with
lower extremities that have wood-like
skin changes, erythema, and indurated
plaque-like lesions.
Patient course:
The patient is aggressively ultra-filtered with additional treatments and prolonged nocturnal
dialysis. Unfortunately no improvement in the lower extremity edema or wood-like skin oc-
curs. He develops increased erythema resistant to IV antibiotics to treat a presumed cellulitis.Vascular surgery and infectious diseases suspect inadequate lower extremity circulation. An-
giography shows adequate perfusion and no venous insufficiency.
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 12
-
8/9/2019 Renal Adventures in Imaging
13/32
A skin biopsy is ultimately performed and shows:
The dermis demonstrates haphazardly arranged collagen bundles and a strikingly increased
number of spindled and plump fibroblast-like cells. There is a distinct absence of inflammatory
cells. The diagnosis is Nephrogenic Fibrosing Dermopathy.
NEPHROGENIC FIBROSING DERMOPATHY
Nephrogenic fibrosing dermopathy (NFD) is now more often referred by the more gen-
eral term nephrogenic systemic fibrosis (NSF) due to pathologic going beyond the skin.
In 2000, Cowper et al. published a case series of 14 hemodialysis patients who had
thickened, hardened skin, features suggestive ofscleromyxedema, however, none of the patients had
monoclonal gammopathy. In a later paper the same
group characterized the histology and suggested that
this was a new disease entity that had not previously
been recognized. (Lancet 2000;356: 1000-1)
NFD is an acquired condition that usually occurs in
patients on dialysis. The condition is characterized by
swelling of the distal extremities (legs and arms)
which then moves proximally (trunk), sparing the
face. Skin changes begin with swelling and progresses
to induration and stiffening joints. Pruritis is a vari-
able complaint. The speed of progression varies from case to case.
GADOLINIUM
Numerous agents and factors were suspected of causing NSF including ACEi, epo-
etin, clotting abnormalities, antiphospholipid antibodies, and acidosis. In January
2006, a case series of 5 patients with NFD was reported in which every patient had
received gadodiamide 2-4 weeks before the initial skin changes. They noted that all
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 13
-
8/9/2019 Renal Adventures in Imaging
14/32
the patients were acidotic and that 4 control patients that were on dialysis and ex-
posed to gadodiamide but were not acidotic did not develop NFD. The average dose
of contrast was 35 mL. (Grobner T. Nephro Dial Transplant 2006; 21: 1104-1108.)
This was substantiated by a second report of 13 hemodialysis patients who received
gadodiamide 2-75 days (mean 25 days) prior to development of skin changes. Theaverage dose was 38 mL. However; this group did not find any association with aci-
dosis. (Marckmann P, Skov L, Rossen K, et al. J Am Soc Nephrol 2006; 17: 2359-2362.)
Further corroborating the link between gadolinium and NFD were two reports that
demonstrated gadolinium deposition in the affected areas of the skin biopsies. (Boyd
A, Zic JA, Abraham JL. J Am Acad Dermotol 2007; 56: 27-30.)
Gadolinium contrast agents for MRI/MRA are rapidly cleared with a half
life of 1.3 hours in healthy volunteers.
In chronic kidney disease the half-life
can be extended from 30 to 120 hours.
Dialysis effectively clears gadolinium.
See graph. (study of 70 dialysis pa-
tients, each dialysis session was 4hours long. Okada S, Katagiri K, Et al.
Acta Radiol 2001; 42: 339-341.)
With the current hypothesis that gado-
linium is the cause of NSF the FDA
recommends avoiding gadolinium in
any patient with a GFR < 30 mL/min,any degree of acute renal failure, and
particularly with patients in hepatore-
nal syndrome. The FDA also recom-
mends that if at-risk patients are exposed to gadolinium that they receive prompt
and repeated (up to 4) dialysis sessions.
There has been an interest (especially from the manufacturers at the number of cases
fractionated by the specific gadolinium compound used. The Dallas VA uses Pro-
Hance and in a retrospective analysis of 198 exposures in hemodialysis patients they
found no cases of NFD. (Clin J Am Soc Nephrol 3: 747-751, 2008). In an animal study,
only rats exposed to gadodiamide developed NFD like symptoms. (Eur Radiol. 2008;
18: 2164-73.)
0
25
50
75
100
Infusion 1 2 3 4
0.0
78.2
95.6 98.7 99.5
Fractionofgadoliniumcleared
Hemodialysis Treatment
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 14
-
8/9/2019 Renal Adventures in Imaging
15/32
GENERIC
NAME
BRAND
NAME
DISSOCIATION
HALF-LIFE
NSF CASES: FDA
MEDWATCH
Gadobenate-
dimeglumineMultiHance N/A 10
Gadodiamide Omniscan 30 seconds 283
Gadopentate
dimeglumineMagnevist 10 minutes 125
Gadoteridol ProHance 3 hours 9
Gadoverse-
tamide Optimark N/A 20
EPIDEMIOLOGY
80% of reported cases have been in patients on dialysis and no patients have been
reported with CKD stages 1-3.
Two recent analysis have focused on patients with advanced CKD, not yet on dialysis.
Chrysochou looked at 2,278 Gd-MRI scans in patients not on dialysis and retrospec-
tively looked for evidence of subsequent
NFD over a ten year period in England.
(Clin J Am Soc Nephrol 5: 484-489, 2010)
They found no cases of NFD. One con-
cern is that 65% of the scans used Multi-
hance, a Gd compound with an appar-ently lower rate of NFD and only 2%
0
250
500
750
1,000
CKD1
CKD2
CKD3
CKD4
CKD5
Number of scans by CKD stage
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 15
Multihance
Magnevist
OmniscanDotarem
Gadovist
Vasovist
-
8/9/2019 Renal Adventures in Imaging
16/32
used gadodiamide, a frequent offender.
A few studies have attempted to look at the rate of NFD when following exposure to
gadolinium. Collidge and colleagues found an attack rate of 3.1% when they looked
at a cohort of dialysis patients who underwent MRI with gadolinium. They also
found a tight relationship of gadolinium exposure and increasing diagnosis of NFD.(Collidge TA,Thomson PC, et al. Radiology 2007: 245; 168.)
Deo and Cowper looked at NSF in and around Bridgeport, Connecticut. They found a
2.4% attack rate per MRI. (Deo A, Fogel M, Cowper SE. Clin J Am Soc Nephrol 2: 264
267, 2007.)
TREATMENT
Unfortunately there are no proven therapies for NSF. Some attempted therapies in-
clude: oral and topical steroids, cytoxin, extracorporeal photopheresis (ECP), tacro-
limus, IV IG, plasmapheresis, alpha interferon.
In one series from Stanford 5 patients underwent ECP. ECP is an immune modulating
treatment.
1. The patient ingests or is infused with a light-activatable drug, called psoralen.
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 16
-
8/9/2019 Renal Adventures in Imaging
17/32
2. Blood is temporarily removed from the patients. White blood cells are separated
out and then mixed outside the body with the patient's plasma, saline, heparin,
and 8-methoxyposoralen.
3. The preparation is then passed through a device where it is exposed to ultraviolet
light.
4. The treated mixture and untreated blood is combined and returned to the patient.
The procedure takes approximately 4 hours.
In the Stanford series 3 of the 5 patients reported marked improvement in self-
ambulation with the therapy (after 45 treatments, 6 and 20 weeks) A mean of 20
treatments were required to see an affect. Objective improvement in joint mobilitywas modest in the three responders and 2 patients had no improvement. The 60%
response rate is greater than the 20% improvement rate found in most series. (Rich-
mond H, Zwerner J, et al. Arch Dermatol.2007;143:1025-1030.)CONCLUSION
NSF is a new disease entity that occurs in dialysis patients. It was first recognized in
2000. NSF is characterized by thickened skin that causes joint contractures. It cancause fibrosis of the heart, diaphragm and skeletal muscle. It has been associated with
the use of gadolinium contrast used in MRI/MRA. There is no evidence that dialysis
reduces the risk of NSF after gadolinium exposure but since dialysis effectively re-
moves gadolium it is recommended that patients get dialysis immediatley after any
gadolinium exposure. J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 17
-
8/9/2019 Renal Adventures in Imaging
18/32
KEY TEACHING POINTS
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 18
-
8/9/2019 Renal Adventures in Imaging
19/32
Strategies to Avoid Contrast Nephropathy:
Case report
Chief Complaint: chest pain
70 year old African American presents to the ER with typi-
cal chest pain.
Past medical history:
Hypertension, hyperlipidemia diabetes and chronic kidney
disease with a baseline Cr of 2.5 mg/dL.
Patient course:
He is admitted to the CCU for unstable angina and rules out
for an MI with serial negative enzymes. Has undergoes
stress test for risk stratification and this shows reversible
ischemia with intact ejection fraction.
He goes for a cardiac catheterization following NAC and generous hydration with isotonicbicarbonate fluid. During the cath, a high grade lesion in the LAD is stented with a sirolimus
stent. Total dose of low osmolar, non-ionic dye is 220 cc.
On the second day after the catheterization his creatinine rises to 4.5 mg/dL. He remains non-
oliguric. The primary team consults neph-
rology. The next day the creatinine is 4.3
and nephrology clears the patient for dis-
charge with follow-up.
At the follow-up visit in one week the
creatine is 3.2 and 2 weeks after the cathe-
terization the creatinine is back baseline.
Summary
A patient at high risk for contrast
nephropathy gets exposed to contrast for a solid indication, gets sate of the art pro-
phylaxis, but develops contrast nephropathy anyways. Fortunately the patient gets
better without requiring dialysis.
0
1
2
3
4
5
Admit
Cath
PCD1
PCD2
PCD3
D/C
PCD7
P
CD14
SerumCrmg/dL
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 19
-
8/9/2019 Renal Adventures in Imaging
20/32
DEFINITION OF CONTRASTNEPHROPATHY
Radio contrast nephropathy (RCN)
is one of the leading causes of hospi-
tal acquired acute renal failure (12-
14% of ARF). It follows administra-tion of iodinated contrast for vascu-
lar visualization in CT scans, angi-
ography and venography. In pa-
tients who develop contrast nephro-
pathy the creatinine begins rising
immediately after exposure to the
contrast and typically peaks on the fourth day. The creatinine usually takes more thana week to return to pre-hydration levels.
RCN typically causes non-oliguric acute renal failure.
While over two thirds of patients (68%) will manifest some increase in creatinine, only
increases in creatinine of 0.5 mg/dL or 25% are considered clinically significant and
labelled as contrast nephropathy.
The 0.5 mg/dL comes from a questionnaire sent to attending physicians which asked:
What is the smallest change in creatinine that would cause you to delay a follow-up pro-
cedure or discharge?
Eighty percent of the 84 respondents responded an increase of 0.5 mg/dL or lower.
The 25% increase in creatininecomes from empiric data on 1
year mortality data based on
change in creatinine following
contrast.
EPIDEMIOLOGY
The incidence is generally about1-5% in unselected patients but
can rise to a much higher level in
high risk patients. The numerous
risk factors have been identified
0%
10%
20%
30%
40%
0-10%
11-25%
26-50%
>50%
1yearmortality
rise in creatinine
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 20
-
8/9/2019 Renal Adventures in Imaging
21/32
in the proliferation of studies on RCN
but two risk factors have been significant
in every study of sufficient power:
chronic kidney disease and diabetes.
(Rihal CS et al. Circulation 2002; 105:
2259-2264.)
0%
10%
20%
30%
40%
0-1.1
1.2-1.9
2.0-2.9
3.0
Mayo Clinic cardiac cath data
Frequencyof
RCN
Pre-Catheterization Cr
DM No DM
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 21
-
8/9/2019 Renal Adventures in Imaging
22/32
CONSEQUENCES OF CONTRAST NEPHROPATHY
Retrospective studies have looked at
the consequences of these modest
increases in creatinine and com-pared them to patients who did not
develop contrast nephropathy. Levy
found nearly a 5-fold increase in
death among patients with contrast
nephropathy regtardless if they
needed dialysis. (Levy EM, Horwitz
RI, Et al. JAMA 1996;275(19):1489-1494.)
The Mayo clinic has a registry of all the
cardiac catheterizations done at that insti-
tution. (Rihal CS, Et al. Circulation 2002;
105: 2259-2264.) They tracked their pa-
tients for five years following the expo-
sure and looked at mortality based on thedevelopment of contrast nephropathy.
The data is striking:
0%
15%
30%
45%
60%
75%
NoCN
CN
CN,noHD
CNandHD
62%
31%34%
7%
Levy, Horwitz, Et. al.
HospitalMortality
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 22
0%
10%
20%
30%
40%
50%
6 mo 12 mo 60 mo
15%
4%2%
45%
12%10%
Mayo Clinic Cath Registry
Mortality
Contrast Nephropathy No Contrast Nephropathy
-
8/9/2019 Renal Adventures in Imaging
23/32
The retrospective data is weak and few successful trials have been done with
intension-to-treat analysis. The few that have been done however have supported the
contention that contrast nephropathy itself is harmful and not just a marker of sus-
ceptible patients.
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 23
0%
2%
4%
6%
8%
10%
MAC
E
30-D
ayMort.
Fractionofpatients
0%
6%
12%
18%
24%
30%
Hospit
almo
rt.
12mon
thmo
rt.
Mueller C, Et al. Arch Intern Med
2002; 162: 329-336
Marenzi G, Marana I, Lauri G, et al. N
En Med 2003; 349: 1333-40.
Saline CVVH0.9% 0.45%
contrast
-
8/9/2019 Renal Adventures in Imaging
24/32
PREVENTING CONTRAST NEPHROPATHY
The Contrast Agents
While the dose of contrast is an important risk factor for RCN, the nature of the con-
trast agent itself is also a risk factor.
The first generation iodinatedcontrast agents were high os-
molar. These agents were tested
in a large trial of over 1000 pa-
tients and found to have a low
risk of contrast nephropathy,
approximately 2%. In the mid
90s low osmolar agentsemerged with two advantages:
better quality imaging and pur-
ported lower incidence of RCN.
Randomized trials of unselected
patients showed no advantage
to low osmolar agents (RCN
2.8% with high osmolar vs.
2.7% with low osmolar agents,
P=0.85, Harris KG, et al Radiol-
ogy 1991; 179:849-852.), how-
ever there was a trend to im-
proved safety in patients at
higher inherent risk. Follow-up studies restricted to high risk patients confirmed this
trend. These low osmolar agents were only low osmolar compared to the first genera-
tion agents. Low osmolar agents were still hypertonic to plasma with an osmolarity of
600-915 mOsm/kg H2O.
There is one contrast agent which is isosmolar to blood, iodixanol. In a pair of well
done randomized controlled trials (one in CT scans and the other in cardiac caths)
iodixanol has been shown to be safer than iohexol in regards to RCN. (Chalmers N,
Jackson RW. Br J Radiol 1999; 72: 701-3. Aspelin P, Aubry P, Fransson SG, et al. N EngJ Med 2003; 348: 491-9.)
Blood
Iodixanol
Ioxaglate
Iomeprol
loversoliopromide
iohexol
iopamidol
iopentol
iobitridol
diatrizoate
iothalamate 2,130
2,000
915
810
796
780
770702
620
600
290
290
Osmolality
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 24
-
8/9/2019 Renal Adventures in Imaging
25/32
Two subsequent studies (ICON by Mehran and CARE by Solomon) have challenged
this conclusion while the RECOVER trial by Jo support the use of isosmolar agents.
Hydration Strategies
Half normal saline
The traditional standard of care for preventing RCN is hydration with half normalsaline one mL per Kg for 12 hours before and 12 hours after exposure. The interesting
thing is this has never been tested in a RCT except as the control group in a negative
trial.
The Solomon trial (Solomon R, et al. N Engl J Med 1994; 331: 1416-20) looked at fu-
rosemide vs. manitol vs. placebo. All three groups received hydration with half nor-
mal saline.
The control group did less
bad than either of the ex-
perimental groups, thus
crowning half normal sa-
line as the champion and
standard of care.
Iodixanol Iohexol
0%
10%
20%
30%
Cr rise >0.5 Cr rise >1.0
15%
25%
3%
Aspelin data on Cardiac Cath
FrequencyofCN
Isotonic saline
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 25
-
8/9/2019 Renal Adventures in Imaging
26/32
The best study on hydration is a German study by Christian Mueller who hypothe-
sized that If half normal saline was good, then full normal normal saline should be
twice as good. He randomized 1,620 patients undergoing coronary angioplasty to
either 0.9% Saline for 24-hours or 0.45% saline for 24-hours. The patient population
was relatively low risk: 20% CKD, 16% diabetes, 65% hypertension, 16% EF< 45%.
Despite the low risk profile there was less than half as much CN with the normal sa-
line (p=0.04). This advantage was extended in three prospectively determined sub-
groups: women, patients with diabetes and patients receiving high volumes of con-
trast (>250 mL). There was no advantage among patients with CKD (Cr > 1.3) P=0.36.
Isotonic bicarbonate
0%
2%
4%
6%
Wom
en
Diabe
tes
>250mL
CKD
Freq.ofRCN
0.9% Saline
0.45% Saline
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 26
-
8/9/2019 Renal Adventures in Imaging
27/32
With isotonic saline crowned as superior to hypotonic fluids the question progressed
to whether chloride was the ideal anion to associate with sodium. In 2004 Merten, et
al published a randomized control trial of isotonic bicarbonate versus isotonic saline.
(Merten, Et al. JAMA 2004; 291: 2328-2334.) The study looked at 120 high risk popula-
tion: average creatinine 1.8, 48% diabetics and 95% cardiac catheterizations.
They found a 14% rate of CN with NaCl and 2% with Na Bicarbonate.
This study was criticized because the data safety monitoring board stopped the study
early and probably shouldnt have.
The RENO trial randomized patients going for emergency PCI. (Recio-Mayoral A,
Chaparro M, Prado B, et al. J Am Coll Cardiol 2007; 49: 1283-8) Sodium bicarbonate
plus NAC versus isotonic salinie. Unfortunately this study had three variables which
varied between the control and experimental groups making it impossible to tease
out the relative contributions of the individual factors
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 27
-
8/9/2019 Renal Adventures in Imaging
28/32
The study demonstrated a powerful treatment effect:
Masuda, Ozcan and Briguori all performed
additional trials of various sizes (n=59, 264,
326) that also supported the use of isotonic
bicarbonate.
Masuda M, Yamada T, Mine T, et al.
Am J Cardiol 2007; 100: 781-6.
Ozcan EE, Guneri S, Akdeniz A, et al. Am Heart J 2007; 154: 539-44.
Briguori C, Airoldi F, D-Andrea D, et al. Circulation. 2007; 115: 1211-7.
In 2008, Maioli and Brar published two larger trials (n=502, 353) of isotonic bicarbon-
ate that showed no benefit.
Maioli M, Toso A, Leoncini M, Et al. J Am Coll Cardiol, 2008; 52:599-604
Brar SS, Yuh-Jer Shen A, Jorgensen MB, Et al. JAMA, 2008; 300:1038-1046
Further confusing the issue were two meta-analysis published in 2009 with conflict-
ing conclusions. Navaneethan published a meta-analysis in AJKD of 12 trials repre-
senting 1,854 patients but did not include Maiolis data. He concluded:
Hydration with sodium bicarbonate decreases the incidence of contrast-
induced nephropathy in comparison to hydration with normal saline with-out a significant difference in need for renal replacement therapy and in-
hospital mortality.
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 28
0
8
16
24
32
Crrise>0.5
Crrise25%
Crrise50%
AnuricARF
RENO Trial
IncidenceofRCN(%)
Experimental ControlCONTROL EXPERIMENTAL
0.9% Saline Isotonic bicarbonate
1 mL/kg for
12 hours after
exposure
5mL/kg bolus over 1
hour then 1.5 mL/kg
for 12 hours
600 mg of
NAC q12h x2
following
exposure
2400 mg of IV NAC
with the initial bolus
-
8/9/2019 Renal Adventures in Imaging
29/32
Zoungas in the Annals of Internal Medicine analyzed 23 trials of 3,563 patients and
concluded:
The effectiveness of sodium bicarbonate treatment to prevent CIN in high-
risk patients remains uncertain. Earlier reports probably overestimated the
magnitude of any benefit, whereas larger, more recent trials have had neu-tral results.
Navaneethan SD, Singh S, Appasamy S, Et al. Am J Kidney Dis. 2009 53: 617-
27.
Zoungas S, Ninomiya T, Huxley R, Et al. Ann Intern Med. 2009; 151: 631-8.
Acetylcysteine
In 2000 Mark Tepel published a small study on contrast nephropathy in the New Eng-
land Journal of Medicine. It was a small under powered study that had business be-
ing significant, except it was. He randomized 41 patients to acetylcysteine and 43 to
placebo. All patients underwent a contrasted CT scan and 10 developed contrast
nephropathy, 1 from the acetylcysteine group and 9 from the placebo group. Over-
night this changed our approach to contrast nephropathy.
N-acetylcysteine was previously used to restore glutathione levels in Tylenol toxicity
and to break up mucous when given by nebulizer. It is cheap and safe. In rats the
LD50 is 7,888 mg/kg.
Despite the immediate
and widespread adop-
tion of acetylcysteine
there was a deep level of
skepticism in the neph-
rology community.
Within a year and a half
the journals were awash
in acetylcysteine studies
and shortly after that, aslew of meta-analysis
filled the land.
Despite variations in
technique the general
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 29
-
8/9/2019 Renal Adventures in Imaging
30/32
consensus of the meta-analysis was that acetylcysteine worked. It appeared to reduce
the incidence of contrast nephropathy by roughly 60%. The problem was it didnt
seem to prevent any patient oriented outcome. Acetylcysteine prevents the creatinine
from rising more than 25% or 0.5 mg/dL but it has not been able to prevent dialysis,
major adverse cardiovas-
cular events or death.
This maybe because ace-
tylcysteine alters creati-
nine handling in the
proximal tubule. Acetyl-
cysteine, actually accel-
erates the excretion ofcreatinine resulting in
decreased serum creati-
nine.
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 30
-
8/9/2019 Renal Adventures in Imaging
31/32
KEY TEACHING POINTS
J o e l M. To pf , M.D.! N o o n C o n f e r e n c eA d v e n t u r e s i n R e n a l I m a g i n g! 31
-
8/9/2019 Renal Adventures in Imaging
32/32
Joel M. Topf, MDNephrology248.470.8163
http://pbfluids.com/