Detection and Localization of Proteinuria by Dynamic Contrast-Enhanced Magnetic Resonance Imaging Using MS325
Yantian Zhang*,
Peter L. Choyke*,
Huiyan Lu,
Hideko Takahashi,
Roslyn B. Mannon,
Xiaojie Zhang,
Hani Marcos*,
King C.P. Li* and
Jeffrey B. Kopp
* Department of Radiology, Warren Grant Magnuson Clinical Center and Transplanation Branch, and Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
Address correspondence to: Dr. Jeffrey Kopp, 10 Center Drive, MSC 1268, National Institutes of Health, Bethesda, MD 20892. Phone: 301-594-3403; Fax: 301-402-0014; E-mail: jbkopp{at}nih.gov
Received for publication November 19, 2004.
Accepted for publication March 11, 2005.
After renal transplantation, persistent glomerular disease affectingthe native kidneys typically causes albuminuria, at least fora period of time, making it difficult to determine in a noninvasivefashion whether proteinuria originates in the native kidneysor the renal allograft. To address this problem, dynamic contrast-enhancedmagnetic resonance imaging (MRI) using gadolinium (Gd)-basedalbumin-bound blood pool contrast agent (MS325) to localizeproteinuria was investigated. Glomerular proteinuria was inducedin Sprague-Dawley rats by intravenous injection of puromycinaminonucleoside (PAN), whereas control rats received physiologicsaline vehicle. Both groups of animals underwent a 40-min dynamiccontrast-enhanced MRI using radio frequency spoiled gradientecho imaging sequence after injection of Gd-labeled MS325. Contrastuptake and clearance curves for cortex and medulla were determinedfrom acquired MR images. Compared with controls, proteinuricrats exhibited significantly lower elimination rate constants.The use of gadopentetate dimeglumine (Gd-DTPA) as a contrastagent showed smaller and less specific differences between proteinuricand control groups. In rats with one proteinuric kidney (PAN-treated)and one normal kidney (transplanted from a normal rat), MRIusing MS325 was able to differentiate between the two kidneys.The results suggest that MRI with an albumin-bound blood poolcontrast agent may be a useful noninvasive way to localize proteinuria.If this technique can be successfully applied in human patients,it may allow for the localization of proteinuria after kidneytransplant and thereby provide a noninvasive way to detect diseaseaffecting the renal allograft.
The glomerular filtration barrier, composed of the endothelialcells, glomerular basement membrane, and visceral epithelialcells (podocytes), retards the passage of macromolecules fromthe plasma into the urinary space (1). Size exclusion is a functionof molecular radius and molecular charge. The passage of albumin,with a mass of approximately 67 kD and net anionic charge, iseffectively retarded by the glomerular filtration barrier. Nevertheless,because of the large amount of albumin present in the plasma,1 to 2 g of albumin are filtered by the human kidney each day.The proximal renal tubule reabsorbs nearly all this filteredalbumin, so that daily normal human urine excretion is <30mg. Proximal tubular epithelial cells take up albumin from thelumen, mediated by the apical surface receptors megalin andcubulin (2). When the glomerular filtration barrier is compromisedbecause of glomerular disease, plasma albumin passes readilyinto the proximal tubule and overwhelms the reabsorptive functionof the tubule. Consequently, glomerular disease is associatedwith greatly increased quantities of urine albumin.
When ESRD develops, urine production typically continues fora period of months to years, and the urine often contains significantamounts of protein, including albumin. When patients undergorenal allograft transplantation, the urine at first representsthe combination of urine production by the native and allograftkidneys. Thus, the presence of proteinuria in renal transplantpatients in many cases is an unreliable marker for allograftdysfunction, although a large increase in proteinuria comparedwith the value obtained before transplantation strongly suggestsallograft disease.
A particular clinical problem is recurrent FSGS. IdiopathicFSGS accounts for 2% of ESRD incident cases in the US and isthe leading cause of incident ESRD cases among primary glomerulardiseases (3). In approximately 30% of FSGS patients who undergorenal transplantation, FSGS recurs in the transplanted kidney(4). The mechanism is not well understood, but there is evidencethat a circulating protein acts on the glomerulus as a permeabilityfactor (5). Recurrent FSGS typically manifests within the first6 mo after transplantation, and many patients lose allograftfunction because of progressive glomerular scarring. The recurrenceof FSGS after renal transplant can be detected by an increasein proteinuria and is confirmed on renal biopsy. Therapy withplasma exchange may be effective if instituted early (6–8);therefore, regular screening is desirable to detect recurrentFSGS. Unfortunately, many FSGS patients who undergo renal transplantationhave high levels of proteinuria originating from their nativekidneys; therefore, urine protein measurements are unreliablein detecting the source of proteinuria. A noninvasive methodto detect whether urinary protein, in particular albumin, originatesin the native kidney or in allograft kidney would be of considerablebenefit in managing these patients.
MS325 was developed as gadolinium (Gd)-binding blood pool agentfor magnetic resonance (MR) angiography. This agent binds stronglybut reversibly to human serum albumin in vitro, with an associationconstant (KA1) of 11 mmol (9). As many as 30 MS325 moleculescan bind to one albumin molecule at high chelate concentrations.MS325 has a small volume of distribution because of the highprotein binding and the low cellular uptake. In primates andrabbits, the elimination half-life is relatively long (2 to3 h), whereas in rats it is shorter (25 min) (10). Comparedwith primates and rabbits, rats exhibit lower protein bindingof MS325, particularly during the first 5 min after administration,and the agent has a two-fold higher volume of distribution inrats than in humans.
After intravenous administration, equilibrium is reached betweenfree MS325, which is a low-molecular-weight compound, and MS325bound to albumin. This equilibrium has three advantages froma clinical perspective (9). First, albumin binding serves toprolong plasma half-life in vivo by preventing renal excretionof the Gd–MS325 complex, which has a molecular weightof 957 Da and would otherwise be readily filtered at the glomerulus.Second, Gd complexes with high molecular weight or that exhibitplasma protein binding demonstrate higher T1 relaxivities, resultingin higher signal intensity compared with gadopentetate dimeglumine(Gd-DTPA) (11). Third, the reversibility of the interactionbetween Gd–MS325 and albumin assures the rapid clearanceof Gd from the body, whereas the chelation of Gd ensures thatthis toxic compound is not taken up by tissues (12). MS325 hasbeen used for angiography in rabbits (13), rats (14), and mice(15,16). Recently, clinical studies have demonstrated its usefulnessand safety in human subjects (17,18).
In this study, we have evaluated dynamic contrast enhanced magneticresonance imaging (DCE-MRI) using MS325 for noninvasive detectionof glomerular proteinuria in a rat model. We hypothesized thatcontrol rats would exhibit prompt excretion of filtered MS-325,because the only unbound MS325 can pass the glomerulus and enterthe renal tubule. We hypothesized that MS325 would accumulatein proteinuric kidneys as a consequence of its binding to albuminand consequent uptake by tubular epithelial cells.
Puromycin Aminonucleoside Animal Model
We used a standard rat model of nephrosis induced by puromcyinaminonucleoside (PAN) (19). PAN is toxic to the glomerular podocyte,a key component of the glomerular filtration barrier (19). Inthis model, a single injection of PAN reproducibly induces proteinuria,with a peak at 7 to 10 d after administration
Male Sprague-Dawley rats (Harlan, Indianapolis, IN) weighing200 to 300 g received a single tail vein injection of PAN (Sigma,St. Louis, MO) at a dose of 75 mg/kg, diluted in physiologicsaline. Control rats received intravenous injection of an identicalvolume of physiologic saline. In preliminary studies, the peakof proteinuria was found to occur 7 d after PAN injection. Therefore,at day 7, urine was collected for 24 h using metabolic cagesand urine protein was measured using pyrogallol red method performedon a Beckman-Coulter LX20 (Beckman, Fullerton, CA). A totalof 30 rats were scanned by DCE-MRI. Two animals died becauseof technical complications before imaging was complete, andthese animals were excluded from further analysis.
Rats were imaged 7 to 10 d after induction of proteinuria. Beforeimaging, rats were anesthetized by inhalation of 2 to 3% isofluraneand an intravenous catheter was placed in the femoral artery.Respiratory rate was measured using a pneumatic probe and bodytemperature was measured using a rectal temperature probe. Temperatureand respiratory rate were monitored and recorded using a BiopacMP150 system (Biopac Systems, Santa Barbara, CA). The levelof anesthesia was adjusted to maintain a respiratory rate of60 to 80 breaths per minute. Body temperature was maintainednear 37°C using a water blanket connected to a circulatingwarm water system. After imaging, animals were euthanized byinjection of potassium chloride via the implanted femoral arterialcatheter. Animal care was performed using protocols approvedby the National Institute of Diabetes and Digestive and KidneyDiseases Animal Care and Use Committee and was in accordancewith National Institutes of Health (NIH) guidelines for animalcare.
Rat Renal Transplant Model
Renal transplantation was performed as described previously(20) using a modification of the technique of Fabre et al. (21).Kidneys from Lewis rats (Charles River, Cambridge, MA) weretransplanted into Lewis recipients that had been treated withPAN 4 d previously. The donor kidney, ureter, and bladder wereharvested en bloc, including the renal artery with a 3-mm aorticcuff and the renal vein with a 3-mm vena caval cuff. These vascularcuffs were anastomosed to the recipient abdominal aorta andvena cava, respectively, using 10.0 nylon monofilament suture.Total ischemic time averaged 10 to 15 min. Donor and recipientbladders were attached dome-to-dome. The right native kidneywas removed at the time of transplantation. The left nativekidney was left in place. Comparison was between the right normaltransplanted kidney and the left native proteinuric kidney.Surgical mortality in recipients was 25%. Surviving rats underwentMR imaging with Gd–albumin 3 d after surgery, which was7 d after PAN administration.
MR Renal Functional Imaging and Analysis
MR images of rat kidneys were acquired on a wide-bore 4.7-TBruker Biospec MR scanner (Bruker, Billerica, MA) at the NIHMouse Imaging Facility. A number of gradient echo scout imageswere acquired first for placement of target slices over kidneys.During dynamic contrast-enhanced imaging, four two-dimensionalimage slices encompassing both kidneys were repeatedly acquiredover 40 min with a spoiled gradient echo imaging sequence. Imagingparameters were: matrix size 256 x 128 pixels, field of view8 cm, slice thickness 2 mm, echo time 2.5 ms, repetition time75 ms, tip angle 45°, bandwidth 88 KHz, number of excitations2, and repetition number 120. The total scan time was 40 min.Bolus injection of the contrast was made 1 min after startingof DCE-MRI image acquisition, followed by the bolus injectionof the saline flush.
MS325 (Epix Medical, Cambridge, MA) was administered to 20 ratsat a dose of 0.05 mmol/kg, a dose similar to that used in clinicalstudies. Magnevist (Gd-DTPA; Berlex, Richmond, CA) was administeredto an additional 10 rats at a dose of 0.05 mmol/kg. Both agentswere injected via femoral artery catheter, followed immediatelyby a bolus of 1 ml physiologic saline.
Early MR contrast-enhanced images with good cortical medullaimage contrast were processed using MEDx software (Sensor Systems,Sterling, VA) to select regions of interest (ROI). ROI overthe cortex and medulla were defined with an interactive segmentationtool provided with the software. Time–signal curves forthe entire series were generated from the defined ROIs.
For each time–signal curve generated, the peak signalfollowing the rapid contrast uptake was identified. The signalcurve subsequent to this time point depicts the contrast clearancethrough the kidney. These clearance curves were then fit toa single exponential component decay model Y(t) = A x exp(–t/D),in which Y is the signal amplitude in arbitrary units, t istime in minutes, and A is a scaling factor in arbitrary units.Decay constants D were estimated from the fitting procedures,
Statistical Analyses
Data are presented as mean ± SEM. Statistical tests includedMann–Whitney test for nonparametric data and linear regression.Statistical significance was taken at P < 0.05.
In the test group (n = 9), urine protein reached 487 ±164 mg/d 7 d after PAN injection. In comparison, daily urineprotein was 31 ± 12 mg/d in the control group (n = 10,P < 0.01) 7 d after injection of physiologic saline of thesame volume. Thus, PAN produced the expected severe proteinuria,consistent with glomerular injury.
Contrast enhancement within cortex and medulla reached a peakapproximately 1 to 2 min after administration of MS325. Thepeak contrast enhancement was similar between control rats andproteinuric rats in cortex (18,065 ± 1026 versus 18,445± 756 expressed as arbitrary units) and medulla (19,898± 1023 and 19,292 ± 860). These similarities suggestthat peak uptake reflects primarily blood flow, which is likelysimilar between the two experimental groups. In normal rats,image intensity in cortex and medulla showed subsequent exponentialdecay caused by renal clearance of MS325 (cortical decay curveshown in Figure 1A). By contrast, nephrotic rats exhibited aflattened decay curve in cortex and medulla and a significantlyprolonged excretion time, indicating reduced clearance throughthe kidney (cortical decay curve shown in Figure 1B). Amongproteinuric rats, there was no correlation between proteinuriaand MS325 decay constant (R = 0.02).
Figure 1. Contrast uptake and clearance curve in a renal cortical region of interest (ROI) after administration of MS325. (A) In a normal rat, the peak enhancement is seen within 2 min of contrast injection and is followed by rapid decay of signal enhancement over 40 min. (B) In a proteinuric rat, contrast enhancement also peaks within 2 min but then displays a remarkably flat signal decay curve, indicating impaired clearance of contrast agent from the cortex.
A sample time–signal curve fitted to a single exponentialdecay model of contrast clearance is illustrated in Figure 2A.For this analysis, we selected cortical and medullary ROI thatshowed homogenous enhancement and lacked blood vessels. Afteradministration of Gd-DTPA, the decay constants were not significantlydifferent between proteinuric rats and control rats in cortex(290 + 63 versus 172 ± 17) and medulla (721 ±342 versus 293 ± 85) (Figure 2B), although there wasa trend toward larger decay constants in proteinuric animals.After administration of MS325, proteinuric rats had larger decayconstants than did control rats in both the cortex (451 ±169 versus 120 ± 12; P < 0.01) and the medulla (407± 112 versus 206 ± 75; P < 0.001) (Figure 2C).
Figure 2. Exponential fit of the contrast clearance curve and contrast clearance time constants with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). (A) After administration of MS325 to a normal rat, the time–signal curve of cortical contrast enhancement was fitted to a single parameter exponential model. This model provides a numerical decay constant that is inversely proportional to the clearance rates. This procedure was followed for cortical and medullary ROI for all rats in the study. (B) With gadopentetate dimeglumine (Gd-DTPA) as the contrast agent, cortical and medullary signals were similar between the two groups. (C) Using the contrast agent MS325, increased signal was detected in both renal cortex and medulla of proteinuric rats compared with control rats.
Figure 3 shows a temporal series of an image slice in the first3 min after the start of DCE-MRI. Images were acquired at therate of three per minute. Contrast (MS325) was injected 1 minafter start of imaging. Image intensity changes in the kidneysdepicted the initial rapid contrast in the renal arteries beforecontrast filtration and clearance.
Figure 3. Temporal series of an image slice in the first 3 min after start of DCE-MRI. Images were acquired at the rate of three per minute. MS325 was injected 1 min after the start of imaging. Image intensity changes in the kidneys indicated initial rapid contrast inflow through the renal arteries, accompanied by diffuse cortical enhancement, and followed by medullary enhancement which came to predominate in the later images.
Figure 4 shows comparable image slices of the kidneys of controlrats during the late vascular phase approximately 1 to 2 minafter administration of MS325 (Figure 4A) or Gd-DTPA (Figure 4B).These images demonstrate vascular enhancement, with visualizationof the descending aorta, renal arteries, and renal segmentalarteries. In addition, at this late phase there is contrastenhancement of both cortex and medulla, with a lesser degreeof enhancement of outer medulla; these images likely reflectthe filtration of the contrast agent through the glomerulusand into the renal tubule.
Figure 4. Contrast-enhanced rat kidney images with MS325 and Gd-DTPA. Images were acquired near the peak of contrast enhancement, approximately 1 to 2 min after administration of MS325 (A) or Gd-DTPA (B). These images are comparable, although vascular images are superior with MS325, consistent with blood pool labeling.
In the renal transplant experiment, a PAN-treated rat that hadreceived a normal kidney had 51 mg/d proteinuria 7 d after PANadministration and 3 d after surgery. By contrast, a saline-treatedrat that had received a normal kidney had 6 mg/d proteinuria7 d after saline administration and 3 d after surgery. As shownin Figure 5A, the PAN-treated rat with a proteinuric kidneyon the left and the normal (transplanted) kidney on the righthad strikingly different MR images. As shown in Figure 5B, thedecay curves are markedly flattened in both cortex and medullafor the proteinuric left kidney compared with the normal (transplanted)kidney on the right. The saline-treated rat with the normalkidney transplant exhibited comparable decay curves in cortexand medulla in both kidneys (data not shown).
Figure 5. Renal transplantation study using MS325. A rat received PAN and 4 d later underwent renal transplantation, with the right kidney removed and replaced by a kidney from a normal donor rat. (A) The normal (transplanted) kidney is on the right and the proteinuric (native) kidney is on the left. (B) The time constants show a marked slowing of contrast clearance through the left proteinuric kidney, both cortex and medulla, compared with the normal right kidney. Injections were made at 160 s.
This study demonstrates that MR imaging of kidney using MS325,a chelate that binds reversibly to albumin, provides a distinctivesignal in proteinuric rats compared with controls. Specifically,MR signal decay constants were higher in proteinuric rats, consistentwith a markedly slower rate of MS325 renal clearance in proteinuricrats. We interpret this result to mean that the abnormal filtrationof the albumin-bound contrast agent at the glomerulus leadsto tubular accumulation, which is detectable as a delayed excretion.
MS325 binds reversibly to albumin, which makes it an excellentblood pool imaging agent. MS325 exists in equilibrium betweenalbumin-bound (high-molecular-weight) and unbound (low-molecular-weight)fractions. Albumin binding is lower in rats compared with humans,which in rodents gives MS325 properties of both a macromolecularcontrast agent and a low-molecular-weight contrast agent, suchas Gd-DTPA. Thus, a component of the injected dose was filteredfreely by the glomerulus in both proteinuric rats and controlrats. The overall renal enhancement represents the combinedsignal from the MS325 within the intrarenal vascular pool, filteredalbumin-bound MS325, and filtered unbound MS325. After administrationof MS325, the decay constant of elimination was increased bythree-fold in cortex and medulla in proteinuric animals comparedwith controls. In normal animals, MS325 is present in the bloodpool and is filtered as unbound MS325; thus, clearance fromthe kidney is relatively rapid. By contrast, MS325 clearancefrom the kidney is reduced in proteinuric rats, presumably becauseMS32 bound to albumin has entered the renal tubule because ofabnormal glomerular permeability. This albumin-bound MS325 remainswithin the kidney for a period of time, transiently locatedwithin the tubular lumen or taken up by the proximal tubularepithelial cells and present within the cell until degradationoccurs. Thus, decreased renal clearance of MS325 can be usedto identify and localize proteinuria. In human subjects, withincreased MS325 binding to albumin compared with rats, the renalsignal differences between normal and proteinuric states shouldbe even more striking.
Gd-DTPA, a low-molecular-weight contrast agent, showed lesspronounced differences in clearance between the control andproteinuric states. The decay constants for Gd-DTPA clearancein the cortex and medulla showed differences in proteinuricrats compared with control rats, but these differences did notreach statistical significance. Thus, Gd-DTPA was not as usefulas MS325 in differentiating normal and proteinuric kidneys.
Our findings confirmed known characteristics of MS325 as a bloodpool imaging agent. MS325 gave excellent enhancement of therat renal vasculature, as expected for a blood pool agent. Ourdata are consistent with the kidney as the primary route ofexcretion for MS325, as is known from biodistribution studies.Finally, MS325 and Gd-DTPA achieved similar peak enhancementlevels at equivalent doses.
There are limitations to this study. The images likely representa composite of MS325–albumin located within the renalvascular blood pool, the tubular lumen, and the renal interstitium.However, we were unable to confirm the exact distribution ofthe agent in each of these compartments. Future studies willfocus on distribution of MS325 within these compartments. Approachesunder consideration include ultrahigh resolution, high-field-strengthMRI microscopy on tissue slices, or the administration of radio-labeled(or biotinylated) MS325, with analysis of tissue slices by microscopy.
In conclusion, MR imaging with MS325 may be a useful noninvasivemethod to localize proteinuria. This approach may be clinicallyrelevant in patients with FSGS who manifest proteinuria aftertransplantation who also still have native kidney function.In these patients, proteinuria may be an early sign of recurrentFSGS affecting the allograft, whereas in others proteinuriamay simply reflect pre-existing disease in the native kidneys.In patients with this diagnostic dilemma, MS325 imaging mayoffer a rapid, sensitive, and noninvasive method of localizingthe source of glomerular proteinuria. We plan studies to addressthe usefulness of this approach in human subjects.
Acknowledgments
The authors wish to acknowledge the contributions of ChristineKing and Tracy MacGowan in measuring urine protein, Dr. MartyLizak and Alan Olson for animal imaging, and Daryl Despres foranesthesia and animal surgery. MS325 was provided via a CooperativeResearch and Development agreement between Epix Medical andthe NIH. The authors appreciate the advice and encouragementof Dr. Randall Lauffer of Epix Medical in completing these studies.The authors thank Dr. Chagriya Kitiyikara for a critical readingof the manuscript.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Received for publication November 19, 2004.
Accepted for publication March 11, 2005.
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Abstract
Introduction
