THE UNIVERSITY OF NEW MEXICOHEALTH SCIENCES CENTER

COLLEGE OF PHARMACYALBUQUERQUE, NEW MEXICO

Correspondence Continuing Education Courses For Nuclear Pharmacists and Nuclear

Medicine Professionals

VOLUME X, NUMBER 1

Radiopharmaceuticals and Dialysis

By

James A. Ponto, MS, RPh, BCNPUniversity of Iowa Hospitals and Clinics, and College of Pharmacy

Iowa City, IA

The University of New Mexico Health Sciences Center College of Pharmacy is accredited by the AmericanCouncil on Pharmaceutical Education as a provider of continuing pharmaceutical education. Program No.039-000-02-005-H04. 2.5 Contact Hours or .25 CEUs

Radiopharmaceuticals and Dialysis By:

James A. Ponto

Coordinating Editor and Director of Pharmacy Continuing EducationWilliam B. Hladik III, MS, RPh

College of PharmacyUniversity of New Mexico Health Sciences Center

Managing EditorJulliana Newman, ELS

Wellman Publishing, Inc.Albuquerque, New Mexico

Editorial BoardGeorge H. Hinkle, MS, RPh, BCNP

William B. Hladik III, MS, RPhJeffrey P. Norenberg, MS, PharmD, BCNP, FASHP

Neil A. Petry, RPh, MS, BCNP, FAPhALaura L. Boles Ponto, PhD, RPh

Timothy M. Quinton, PharmD, MS, RPh, BCNP

Guest ReviewerAmy Barton Pai, PharmD

Assistant ProfessorUniversity of New Mexico Health Sciences Center

College of Pharmacy2502 Marble NE

Albuquerque, NM 87131

While the advice and information in this publication are believed to be true and accurate at press time, the author(s), editors, or

the publisher cannot accept any legal responsibility for any errors or omissions that may be made. The publisher makes no war-

ranty, express or implied, with respect to the material contained herein.

Copyright 2002

University of New Mexico Health Sciences Center

Pharmacy Continuing Education

Albuquerque, New Mexico

RADIOPHARMACEUTICALS AND DIALYSIS

STATEMENT OF OBJECTIVES

The purpose of this lesson is to increase the reader’s knowledge and understanding of the

effects of dialysis on radiopharmaceutical biodistribution and of purposeful uses of

radiopharmaceuticals in patients undergoing dialysis.

Upon completion of this lesson, the reader should be able to:

1. describe the basic process of dialysis, both hemodialysis and peritoneal dialysis.

2. describe reported alterations in radiopharmaceutical biodistribution associated with dialysis

or complications thereof.

3. describe reported uses of radiopharmaceuticals to purposefully evaluate

complications of dialysis.

4. discuss radiopharmaceutical therapy in dialysis patients, in terms of both patient

management and radiation safety.

5. describe reported uses of radiopharmaceuticals to evaluate certain functional aspects

of dialysis equipment.

COURSE OUTLINE

I. INTRODUCTION

II. DESCRIPTION OF DIALYSIS

III. ALTERATIONS IN RADIO-PHARMACEUTICAL BIODIS-TRIBUTION

IV. USE OF RADIOPHARMACEU-TICALS TO EVALUATE COM-PLICATIONS OF DIALYSIS

V. RADIOPHARMACEUTICALTHERAPY IN DIALYSISPATIENTS

VI. USE OF RADIOPHARMACEU-TICALS TO EVALUATE DIA-LYZER FUNCTION

VII. REFERENCES

VIII. QUESTIONS

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RADIOPHARMACEUTICALS ANDDIALYSIS

By:James A. Ponto, MS, RPh, BCNP

University of Iowa Hospitals and Clinics,and College of Pharmacy

Iowa City, IA

INTRODUCTIONNuclear pharmacists and other nuclear

medicine staff are occasionally confrontedwith situations involving nuclear medicineprocedures in dialysis patients. For example,questions may arise regarding dialysis-relat-ed alterations in radiopharmaceutical biodis-tribution, either prospectively or in retro-spective trouble-shooting of atypical images.On the other hand, suggestions can beoffered regarding nuclear medicine proce-dures that may be valuable in the evaluationof certain complications of dialysis. Also,consultation can be provided in cases involv-ing the desire to treat a dialysis patient witha therapeutic radiopharmaceutical.

Unfortunately, there exists a paucity ofreadily available information regarding

radiopharmaceuticals and dialysis. Suchinformation is rarely mentioned in standardtextbooks and radiopharmaceutical refer-ences--for example, a classic review articleon alterations in radiopharmaceutical biodis-tribution includes only two paragraphs onthe subject,1 and a similar chapter in a promi-nent book includes only three paragraphs.2

Information scattered throughout the pri-mary literature consists almost entirely ofanecdotal descriptions, abstracts, and isolat-ed case reports; only a few small studiesinvolving the evaluation of certain complica-tions have been published. Therefore, toaddress this information gap to the extentpossible, the purpose of this lesson is to sum-marize and review available information onthe various topics involved with radiophar-maceuticals and dialysis.

DESCRIPTION OF DIALYSISThe term dialysis derives from the Greek

dia (meaning through or across) and lyein(meaning dissolve or loosen). Hence, dialy-sis can be defined as the separation of sub-stances in solution by means of their unequaldiffusion through semipermeable mem-branes. In the healthcare setting, dialysis isa general term used to describe some type of

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Figure 1. Simplified schematic diagram of a hemodialyzer. Small solutes ( · ) diffuse through pores in the dialysis membrane dependent on a concentrationgradient (arrows). Fluid and larger molecules (•)pass through membrane pores dependent on apressure gradient (block arrows).

renal replacement therapy in patients withinsufficient renal function or renal failure.Although dialysis can be used as an acutetherapy (e.g., in patients with acute renalfailure), it is most commonly used as achronic therapy (e.g., in patients with end-stage renal disease). Although the goal ofdialysis is to remove metabolic waste prod-ucts from the blood, many drugs are alsosubject to removal by dialysis.

HemodialysisThe conventional approach is hemodial-

ysis--withdrawing blood from an artery orvein, passing it through a dialyzer, and infus-ing it back into a vein. Within the dialyzer, asemi-permeable membrane separates theblood compartment from the dialysate com-partment. During transit through the dialyz-er, certain molecules in the blood can passthrough the membrane and be eliminated inthe dialysate solution (see Figure 1).Movement of small solute molecules acrossthe membrane is primarily by the process ofdiffusion, with net movement from an areaof high concentration (i.e., the blood) to anarea of low concentration (i.e., the dialysate).Diffusion is dependent on a concentrationgradient, so blood and dialysate generally

flow in opposite directions to better maintainconcentration gradients and thereby maxi-mize diffusive transfer.

Fluid removal occurs primarily by theprocess of convection, i.e., movement alonga pressure gradient. Some solutes and largermolecules are removed by being draggedalong with the solvent (see Figure 1). Thisprocess does not require a concentration gra-dient. However, convective transport isdependent on a pressure gradient, so thedialysate compartment is typically main-tained at a lower atmospheric pressure rela-tive to the blood compartment. The term"ultrafiltration" is often used in associationwith high-permeability membranes thatmaximize convective transport.

Dialyzers have evolved over the years toincrease the available surface area of themembranes. Twin-coil and parallel-platedesigns have now been superceded by hol-low fiber technology. In current designs,blood flows through the hollow fibers, inbundles of thousands, while dialysate circu-lates around them. This allows for a largesurface area and high transfer rates, whilekeeping the physical dimensions to a reason-able size.

Dialysis membranes may be manufac-

Type Material Flux Biocompatibilitycellulose cuprammonium [Cupraphane] low lowsubstituted cellulose cellulose acetate low intermediate

cellulose diacetate high intermediatecellulose triacetate high intermediate

cellulosynthetic cellulose with tertiary amino low highsubstitutions [Hemophan]

synthetic polyacrylonitrile (PAN) high highPAN-methyallyl sulfonate high highpolyamide high highpolycarbonate low highpolymethylmethacrylate high or low high(PMMA)polysulfone (PS) high or low high

Table 1. Characteristics of Common Dialysis Membranes (adapted from references 4 and 5)

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tured from many different materials.Traditional, or conventional, membranes arebased on cellulose. For the commonly usedCuprophane membrane, the cellulose isregenerated using a cupric ammoniumprocess. Because unsubstituted cellulose hasa large number of free hydroxyl groups thatcan activate the complement system as bloodflows along its surface, substituted celluloseand synthetically-modified cellulose prod-ucts have been developed which are morebiocompatible. Non-cellulose syntheticmembranes have also been developed whichhave high-flux capabilities and are biocom-patible. Table 1 summarizes characteristicsof several common dialysis membranes.

The term "high efficiency" refers to dia-lyzers that are capable of high urea clear-ance. Traditional cellulosic membranes,which have only a modest urea clearance,can be made into high-efficiency dialyzersby increasing the surface area.

The term "high flux" refers to dialyzerswhose membranes possess large pore sizesand thus have high ultrafiltration characteris-tics. The high-permeability membranes usedin this type of dialyzer allow greater convec-tive clearance of larger molecules. Althoughcellulosic membranes can be manufacturedwith large pore sizes, most high-flux dialyz-ers rely on synthetic membranes (see Table 1).

Many factors influence the dialyzabilityof molecules.3-5 First are the physiochemicalcharacteristics of the substance. Molecularweight is a very important factor; generally,any substance with a molecular weight of <1000 daltons will diffuse much more easilythan those with molecular weights > 1000daltons. Larger molecules, up to about10,000 daltons, are not readily removed bydiffusion, but may undergo convectiveremoval in high-flux dialyzers. Also impor-tant is the solubility of the substance;because the dialysate is aqueous, highlywater soluble substances will be removed toa greater extent than will be lipid-solublesubstances.

A second group of factors is the biologi-cal handling of the substance. Generally,

dialysis is potentially useful for those sub-stances normally excreted by the kidney butis ineffective for substances excreted by non-renal routes (e.g., hepatobiliary). In order tobe available for diffusion across the dialysismembrane, substances must be free in plas-ma; conversely, substances that are highlyprotein bound are not readily dialyzed. Also,because diffusion is dependent on a concen-tration gradient, substances that have a smallvolume of distribution (i.e., are more con-centrated in the blood) are better dialyzedthan are substances that have a large volumeof distribution (i.e., are distributed through-out tissues).

A third group of factors is the functional-ity of the dialysis membrane. Numerousmembranes are available, each with uniquecharacteristics including pore size, ultrafil-tration coefficient, surface area, and materialcomposition. Pore size dictates the molecu-lar weight of substances that can passthrough the membrane; membranes with alarger pore size allow better dialysis of larg-er molecules. The ultrafiltration coefficientis the amount of ultrafiltrate that can be pro-duced at a given transmembrane pressure;membranes with a higher ultrafiltrate coeffi-cient have the potential to remove more sub-stance through the process of convection.Surface area determines the opportunity forsubstance exposure to the membrane; thegreater the surface area, the greater thepotential for diffusion across it and hence thegreater efficiency. Membranes are createdfrom different types of materials based oncellulosic and synthetic polymers (see Table1). Because different membranes have dif-ferent water- and solute-removing character-istics, making broad generalizations aboutmembranes is difficult. Detailed specifica-tions of commonly used dialyzers are avail-able in standard texts.4,5

The final factor is the operation of thedialyzer. Dialysate and blood flow throughthe unit in opposite directions. The faster theblood flow, the more rapidly the substance isexposed to the dialysis membrane. Once thesubstance passes through the membrane, itaccumulates in the dialysate and thereby

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decreases the concentration gradient.Removal of the accumulated substance fromthe dialyzer is necessary to maintain an ade-quate concentration gradient for further dial-ysis. Hence, increasing the dialysate flowrate will increase the rate of removal andthus will better maintain a high concentra-tion gradient and maximize the dialytic effi-ciency. For larger molecules removed byconvection, increasing the transmembranepressure (i.e., increasing the pressure differ-ential between the blood and the dialysate)will increase clearance by ultrafiltration.

Given the large diversity in dialysismembranes and dialyzer operation, cautionshould be used in applying drug removaldata from one hemodialysis technique toanother.

Peritoneal DialysisA reasonable option for many patients

needing chronic dialysis is peritoneal dialy-sis. In contrast to hemodialysis which usesartificial membranes in vitro, peritoneal dial-ysis uses an in vivo biological membrane –the peritoneal membrane. Simply, dialysatefluid is periodically placed into the peri-toneal cavity where it accumulates sub-stances that transfer into it by passingthrough the peritoneal membrane.Peritoneal dialysis involves a combination ofdiffusive and convective transport for soluteremoval. Diffusion occurs along a concen-tration gradient, similar to that occurring inhemodialysis. Convection with fluidremoval occurs because of an osmotic pres-sure gradient, which is created by usinghyper-osmotic dextrose dialysate, analogousto the hydrostatic pressure gradient inhemodialysis.

Peritoneal dialysis is inherently an inter-mittent batch process. Dialysate is instilledinto the peritoneal cavity, dwells there forsome period of time during which solute andfluid transfer occurs, and then is drained.Initially after instillation of the dialysate intothe peritoneal cavity, high concentration andpressure gradients allow maximal diffusionand convection. However, as these gradientsdiminish over time, the rates of diffusion and

ultrafiltration correspondingly diminish.Therefore the dialysate must be periodicallychanged, which may be performed either anintermittent basis or continuously.

Intermittent peritoneal dialysis (IPD)generally consists of dialysate changes 3-4times per week for 10-14 hours per session.Because of its low efficiency and inconven-ience, IPD is now rarely used. Nocturnalintermittent peritoneal dialysis (NIPD), amore effective and convenient variant ofIPD, typically consists of 8-10 hours of ther-apy every night, and involves the use of acycler device to perform 4-5 dialysatechanges per nightly session. Continuousambulatory peritoneal dialysis (CAPD), asthe name implies, is performed continuously24 hours per day, seven days a week. CAPDtypically involves 4-5 dialysate changes eachday. Because a cylcer machine is not need-ed, this method is preferred by many activepatients. A hybrid of NIPD and CAPD iscontinuous cycling peritoneal dialysis(CCPD). CCPD consists of 4-6 cycler-con-trolled dialysate changes during the nightand then allows a dialysate batch to dwell inthe peritoneal cavity throughout the day.This method provides good performancewith less interruption of the patient’s day-time schedule.

Advantages of peritoneal dialysis overhemodialysis include eliminating the chanceof acquiring blood-borne viral infectionsfrom other patients (e.g., from re-use of con-taminated dialysis equipment), eliminationof the need to have an arterial-venous access,elimination of the need to spend many hoursper week at a dialysis center, and lower cost.6

Peritoneal dialysis patients are allowed toambulate freely and carry out normal activi-ties in between fluid exchanges, which caneasily be performed by the patients them-selves at home.

In peritoneal dialysis, substances areremoved by diffusion and by convection.Many of the physicochemical (e.g., molecu-lar weight) and biological characteristics(e.g., normal route of excretion, proteinbinding, volume of distribution) that influ-ence the hemodialyzability of substances, as

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described above, similarly influence peri-toneal dialyzability. Additional factors influ-encing peritoneal dialysis include theexchange volume, the frequency ofexchanges, and the presence of peritonitis.3-5

Larger exchange volumes will providegreater initial concentration gradients andallow more total accumulation of waste sub-stances before equilibrium is reached. Eachexchange of dialysate provides a renewedconcentration gradient, so more frequentexchanges result in greater substanceremoval. The presence of peritonitis (i.e.,inflammation of the peritoneal membrane)may provide increased "pore size" and allowgreater accumulation of substances withlarger molecular weights.

Given the large diversity in peritonealdialysis methods and protocols, cautionshould be used in applying drug removaldata from one peritoneal dialysis techniqueto another.

ALTERATIONS IN RADIOPHARMA-CEUTICAL BIODISTRIBUTION

Many radiopharmaceuticals are eliminat-ed, in significant fraction, by the kidneys. Inrenal failure, abrogation of this eliminationpathway results in altered biodistributionsuch as prolonged blood pool activity andpossible enhanced clearance through hepato-biliary tract. In addition, the biodistributionof some radiopharmaceuticals may bealtered by the development of conditionssecondary to renal failure. In some cases,dialysis performed shortly after radiophar-maceutical administration may effectivelysubstitute for kidney elimination and thusallow the imaging procedure to proceed rel-atively unaffected.

Bone AgentsApproximately half of the injected dose

of Tc-99m bone agents is normally excretedin the urine in the first several hours afteradministration. In patients with renal insuf-ficiency, decreased clearance of the radio-pharmaceutical results in prolonged bloodpool activity and higher than normal soft-tis-sue activity. However, increased blood lev-

els in these patients do not lead to higheruptake of the radiopharmaceutical in thebone. Hence, in patients with renal failure(and without metabolic bone disease), bone-to-soft tissue ratios are substantially lowerthan normal. In these patients, hemodialysisperformed from 15 minutes to 5 hours afterinjection of the radiopharmaceutical can suc-cessfully decrease blood pool and soft tissueactivity to nearly normal levels.7,8

Diffuse abdominal uptake of Tc-99mbone agent was reported in a patient under-going CAPD.9 Tc-99m medronate (MDP) isable to diffuse through semi-permeablemembranes, so localization in the peritonealcavity occurred as a result of diffusion fromthe blood into the dialysate solution along aconcentration gradient.

The selective adsorption of Tc-99mdiphosphonates to newly mineralizing bonesuggests that overall skeletal uptake will berelated to the general metabolic state of theskeleton, as influenced by parathyroid hor-mone (PTH), vitamin D, calcium, and phos-phorous availability. For conditions associ-ated with increased bone turnover, and thusincreased bone formation, increased uptakeand whole-body retention of Tc-99m diphos-phonates will result. Hence, bone scintigra-phy in dialysis patients with metabolic bonedisease (e.g., osteitis fibrosa) typicallyexhibit generalized increased uptake in theskeleton.8 This increased bone metabolism,and corresponding increased radiopharma-ceutical uptake, in renal failure is largelyrelated to secondary hyperparathyroidism.

Dialysis patients frequently have elevat-ed blood levels of calcium and phosphorous.When the Ca x PO4 solubility product isexceeded, extra-osseous precipitation canoccur. This is referred to as calcinosis ormetastatic calcification. Similar to uptake onbone, Tc-99m diphosphonates can localize atthese sites. The threshold for this phenome-non in dialysis patients is a Ca x PO4 prod-uct of about 60, where the concentration ofeach substance is in units of mg/dl.10

Solubility is also affected by regional pH, socalcification tends to occur initially in tissuesthat are relatively alkaline, namely lungs

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(because of expiration of carbon dioxide),gastric mucosa (because of secretion ofhydrochloric acid), kidneys (because ofexcretion of hydrogen ion), and left ventricle(because of low carbon dioxide content).10

Increased uptake on skeletal scintigraphydue to calcification is most often seen inlungs, but may also be observed in stomach,heart, kidneys, and joints.8,10-19 Calcificationscan occur in other soft tissues, includingmajor blood vessels, and can be similarlyobserved with bone scintigraphy.13,20

Calcifications of coronary arteries and car-diac valves, while common in patients withend-stage renal disease, are rarely visualizedwith bone scintigraphy due to their smallsize, but may be detected with electron beamcomputed tomograpy.21,22 Uptake of Tc-99mbone agent in a calcified dialysis access grafthas also been reported.23 A word of cautionhowever: stomach uptake is not alwaysrelated to gastric calcification. In one report,visualization of stomach (with or withoutthyroid visualization) in several hemodialy-sis patients was related to uptake of freepertechnetate liberated from radiochemicalinteraction of Tc-99m bone agents withdialysate solution constituents (i.e., calciumand magnesium) in a closed-circuithemodialysis device that used recirculatingdialysate.24

Another condition associated withhemodialysis is amyloidosis (i.e, a conditionassociated with deposition of ß2 microglob-ulin in joint spaces). Increased uptake of Tc-99m bone agents has been observed in amy-loid deposits, especially in periarticularareas.8,25

High blood levels of aluminum are occa-sionally encountered in dialysis patients sec-ondary to use of aluminum hydroxide as aphosphate binding agent. Hyperaluminemiacan cause aluminum-related bone disease,which manifests as a generalized decrease inskeletal uptake on bone scintigraphy. Thisdecreased uptake may be related to alu-minum directly suppressing the parathyroidglands’ secretion of parathyroid hormoneand/or directly inhibiting bone mineraliza-tion.8

The radiation dose received by patientswith impaired renal function is expected tobe somewhat higher because of prolongedretention in blood pool and soft tissuesand/or increased skeletal uptake due to meta-bolic bone disease. Under these conditions,the effective dose equivalent is slightlyincreased from 4.4 mSv/550 MBq (440mrem/14.86 mCi) to 4.5 mSv/550MBq (450mrem/14.86 mCi).8

Brain AgentsUnusual brain images in two patients on

chronic hemodialysis have been reported.26

In each patient, prominent and dilatedappearance of cranial sinuses on the 3-4 hourdelayed images suggests excessive bloodpool activity. In one patient, this alteredbiodistribution was possibly caused byhemodialysis-related elevated blood levelsof tin that resulted in in vivo radiolabeling ofred blood cells with Tc-99m sodium pertech-netate. In the other patient, the authors spec-ulate that chemical alteration of Tc-99m pen-tetate (DTPA) or mechanical damage to thered cells may have played a role.

Localization of Tc-99m pertechnetate inthe choroid plexus has been observed innumerous hemodialysis patients, in spite ofpre-medication with potassium perchlorateor iodide.27 Persistent localization in the sali-vary and thyroid glands of these samepatients suggest that some alteration in anionhandling occurs in renal failure. The factthat visualization of choroid plexus was notseen when Tc-99m DTPA was used furthersupports the hypothesis of altered anion han-dling in renal failure patients.

Myocardial Perfusion AgentsThe mainstay myocardial perfusion

agents, Tl-201 thallous chloride (Tl-201),Tc-99m sestamibi, and Tc-99m tetrofosmin,are also used in the evaluation of parathyroidglands. Increased uptake of these agents inparathyroid glands is seen in dialysis patientswho have developed secondary hyper-parathyroidism. The purposeful use of thisprocedure to detect and evaluate this compli-cation is discussed later in this lesson.

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Visualization of bone structure with Tc-99m sestamibi was observed in one patienton hemodialysis.28 The cause of this abnor-mal uptake was not related to increased boneturnover or to marrow hyperplasia, as indi-cated by normal bone and marrow scinti-grams. Perhaps delayed clearance due torenal failure played a role in this case.

Tl-201 has also been reported to accu-mulate in articular and periarticular sites ofactive amyloidosis.25 This localization maybe related to a local inflammatory process.

Renal AgentsIn many centers, imaging with Tc-99m

renal agents is performed early after renaltransplantation to monitor function and pro-vide information about post-operative com-plications. In patients undergoing renaltransplantation directly from CAPD mainte-nance, loculated collections of residualdialysate solution may remain in theabdomen for up to a week. These fluid col-lections may produce photon-deficientlesions on Tc-99m DTPA renal transplantscintigrams performed soon after transplan-tation.29 Such photon-deficient areas couldbe misinterpreted as hematoma, urinoma,lymphocele, etc. In these situations, an ultra-sound procedure should be performed forclarification.

Gallium-67 CitrateEarly after injection, gallium-67 citrate

(Ga-67) undergoes significant bowel and uri-nary elimination. However, because Ga-67is highly protein-bound to plasma transfer-rin, dialysis may be much less effective inreducing plasma levels of Ga-67 than it is inreducing plasma levels of radiopharmaceuti-cals that are not highly bound to plasma pro-teins.

In a study of 3 patients, Levine et al.30

determined that peritoneal dialysis removed2-5% of administered Ga-67 in the first 24hours. This compares to normal urinaryexcretion of 12-26% in the first 24 hours.The concentration of Ga-67 in the dialysatewas proportional to that in the plasma, with aplasma:dialysate ratio of approximately

50:1. Although peritoneal dialysis was onlymodestly effective for removing Ga-67,imaging at 24 hours revealed normal biodis-tribution. The authors concluded that peri-toneal dialysis is not a contraindication toradiogallium scintigraphy.

A case report involving another CAPDpatient found similar results.31 FollowingGa-67 injection, two successive 12-hourperiods of peritoneal dialysis removed only0.57% and 0.66% of the administered activi-ty, respectively. Plasma clearance of Ga-67was determined to be 0.7 ml/min. Althoughperitoneal dialysis removed a negligiblefraction of Ga-67, images obtained up to 144hours after injection showed normal biodis-tribution with the exception of mild diffuselung accumulation and some uptake at thesite of the dialysis catheter.

Studies of the effect of hemodialysis onGa-67 removal also found similar results.32

In eight patients undergoing hemodialysiswith a standard membrane, 0.5%-8% of theinjected Ga-67 was removed. In one patientundergoing ultrafiltration, Ga-67 removalwas 0.5%. Images of all patients at 24 hoursshowed good quality with no alterationsattributable to dialysis. Moreover, the timeof injection prior to dialysis, ranging from 10minutes to 4 hours, had no effect on the qual-ity of the images.

Diffuse pulmonary uptake of Ga-67 hasbeen noted in some dialysis patients.16 In theabsence of other causative factors (e.g., pul-monary inflammation, infection, malignan-cy, or pulmonary-toxic medications), thisuptake appears to be related to uremic pul-monary calcification (calcinosis), similar tothat observed with Tc-99m bone agents.

Another case report of altered Ga-67biodistribution in a hemodialysis patientinvolved the additional factors of aluminumtoxicity and desferoxamine treatment.33 Theimage of this patient obtained at 48 hoursshowed diffuse whole body activity withminimal localization in any organ. Themechanism for this altered biodistribution isnot confirmed, but it is known that high lev-els of aluminum can displace gallium fromtransferrin binding sites and that desferox-

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Radiopharmaceutical Alteration Mechanism

Tc-99m bone agents � soft tissue activity � renal clearance

diffuse abdominal uptake diffusion into CAPD dialysate solution

� bone uptake � bone metabolism due to secondary hyperparathyroidism

� uptake in lungs, stomach, calcinosiskidneys, heart, and joints

� uptake in joints amyloidosis

� bone uptake aluminum-related bone disease

Tc-99m pertechnetate � blood pool activity radiolabeled red cells due to � blood levels of Sn

� uptake in choriod plexus, altered anion handling by tissuesthyroid, and salivary glands

Tc-99m DTPA � blood pool activity � renal clearance; mechanicaldamage to red blood cells (?)

"cold spots" in abdomen collections of CAPD dialysate fluid

Tc-99m sestamibi � uptake in parathyroid nodules parathyroid hyperplasia

� uptake in bone � renal clearance

Tc-99m tetrofosmin � uptake in parathyroid nodules parathyroid hyperplasia

Tl-201 � uptake in parathyroid nodules parathyroid hyperplasia

� uptake in joints amyloidosis

Ga-67 citrate � blood pool activity � renal clearance

� uptake in lungs calcinosis

diffuse whole body activity binding to desferoxamine

� uptake in joints amyloidosis

I-131 sodium iodide � blood pool activity � renal clearance

� thyroid uptake prolonged plasma concentrations provide increased availability of I-131 for thyroid uptake

I-131 MIBG � soft tissue activity � renal clearance

� adrenal uptake prolonged plasma concentrations provide increased availability ofI-131 MIBG for adrenal uptake

In-111 or Tc-99m � lung uptake leukocyte aggregation related to leukocytes activation of the complement

cascade by the dialysis membrane

Table 2. Reported Alterations in Radiopharmaceutical Biodistribution Caused byChronic Renal Failure/Dialysis.(see text for further descriptions and reference citations)

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amine avidly binds gallium.Ga-67 has also been reported to accumu-

late in articular and periarticular sites ofactive amyloidosis.25 This localization maybe related to a local inflammatory process.

RadioiodineIt is difficult to determine thyroid func-

tion in patients with severe renal diseasebecause the usual radioactive iodine tech-niques depend on normal excretion of iodide.Low renal clearance of iodine results in ele-vated and prolonged plasma concentrationswhich promotes increased radioactive iodineuptake in the thyroid, at least until saturationof the trapping mechanism occurs. Hence, athyroid radioactive iodine uptake value inthe normal range may not rule out hypothy-roidism.34

The ability of hemodialysis to removeradioiodine was studied in seven patients.34

Dialysis performed one hour after oraladministration of I-131 sodium iodide wascapable of removing approximately 82% ofradioactivity present in the blood.

In a more detailed study involving 13patients, hemodialysis was performed 2-6days following administration of I-131 sodi-um iodide.35 The amount of "available"iodine (i.e., iodine not already taken up intothe thyroid gland) removed by dialysisranged from 3% to 77%, with a mean of45%. The percent removed was directlyrelated to the plasma concentration ofradioiodine, i.e., it correlated with the con-centration gradient between plasma anddialysate. During the dialysis procedure, theclearance of radioiodide was 154 ± 18mL/min, which is approximately six-foldgreater that the renal clearance in controlsubjects of 26.2 ± 7.4 mL/min.

I-131 MIBGI-131 iobenguane (MIBG) is primarily

excreted unchanged through the kidneys.Hence, impaired renal function would beexpected to alter its biodistribution andkinetics. This hypothesis was confirmed inone anephric patient on hemodialysis.36

Imaging of this patient showed higher back-

ground activity and more prominent adrenaluptake compared to patients with normalrenal function. This probably resulted fromsustained, high blood activity that forcedmore of the agent to the tissues. Dialysisproved to be ineffective, with negligible oronly slight decrement of blood activity fol-lowing two hemodialysis sessions. The dis-tribution of radioactivity between plasmaand red cells demonstrated an unusually highplasma concentration in the anephric patient(89% vs. 15% in controls). As a result ofaltered kinetics and clearance in renal fail-ure, the radiation dose to blood in thisanephric patient was approximately 30 timesgreater than in patients with normal renalfunction.

In-111 LeukocytesHemodialysis can lead to complement

activation with subsequent leukocyte aggre-gation in the pulmonary capillaries.Increased localization of In-111 leukocytesmay be observed in the lungs of dialysispatients, and should not necessarily be inter-preted as infection.37

Summary of Reported AlterationsAlterations in the biodistribution of

radiopharmaceuticals may be caused by avariety of factors associated with chronicrenal failure or dialysis, including decreasedrenal excretion, electrolyte abnormalities,hormonal modulation, and inflammatoryprocesses. Reported alterations are summa-rized in Table 2.

USE OF RADIOPHARMACEUTICALSTO EVALUATE COMPLICATIONS OFCHRONIC RENAL FAILURE ANDDIALYSIS

Several metabolic conditions are associ-ated with chronic renal failure and dialysis,including disorders of the skeleton, joints,and parathyroid glands. Non-metaboliccomplications, such as peritoneal leaks dur-ing peritoneal dialysis, can also occur.Although these complications are frequentlydiagnosed and monitored by physical assess-

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ment and lab testing, nuclear medicine imag-ing can play an important role in manypatients.

Metabolic Bone DiseasesRenal osteodystrophy describes the spec-

trum of disorders of mineral and skeletalmetabolism associated with chronic renalfailure. The mechanisms involved in thedevelopment of osteodystrophy are complexand include numerous factors which interactto variable degrees to result in variable man-ifestation of disease.

Osteitis fibrosa, the most common bonedisorder in end-stage renal disease, involvesincreased bone turnover (resorption and for-mation) and is associated with variabledegrees of marrow fibrosis. As functionalrenal mass is lost, the renal conversion ofVitamin D to its active metabolites decreas-es, which leads to reduced intestinal absorp-tion of calcium, which leads to hypocal-cemia. Failing kidneys also inadequatelyexcrete phosphate, thus leading to hyper-phosphatemia which further aggravateshypocalcemia. Hypocalcemia is the mostpowerful stimulus for secretion of parathy-roid hormone, which attempts to normalizecalcium and phosphate concentrations byincreasing tubular reabsorption of calciumand excretion of phosphate. Laboratorystudies suggest that elevated serum phospho-rous can also stimulate parathyroid hormonesynthesis and release, independent of serumcalcium concentrations.38 Parathyroid hor-mone stimulates bone resorption and forma-tion, and prolonged elevation of parathyroidhormone levels leads to a variable degree ofmarrow fibrosis and subperiosteal neo-osto-sis (new bone formation).8

Osteomalacia is characterized by a delayin matrix mineralization, resulting in theaccumulation of osteoid tissue. Commonlyco-existing with osteitis fibrosa, osteomala-cia is also associated with deficiency ofVitamin D active metabolites. Another fac-tor associated with osteomalacia is high con-centrations of aluminum, mainly due to alu-minum-contaminated dialysis solutions8 andthe use of aluminum hydroxide as a phos-

phate binder.Adynamic bone disease is also related to

aluminum overload, which interferes withosteoblast function. Hence, this leads to for-mation of defective bone, which is more sus-ceptible to fracture.8

Common features of bone scintigraphyin the evaluation of metabolic bone disease,especially in patients with secondary hyper-parathyroidism, include diffuse increasedactivity in the axial skeleton, long bones,sternum, skull, jaw, and wrists, beading ofthe costochrondral junctions, and faint orabsent kidney uptake.8,20,39-41 If bone diseaseis aluminum-related or is purely osteoma-lacitic, however, bone scintigraphy showsdecreased skeletal uptake and high soft tis-sue activity.8,41 Skeletal fractures related toosteomalacia or adynamic bone disease arereadily detected by bone scans as focallesions.8

A simple method to evaluate diffuseincreased skeletal activity in patients withmetabolic bone disease is with target-to-non-target (i.e., bone-to-soft tissue) ratios ondelayed images.39,42-44 For example, one studyreported mean 4-hour bone-to-soft tissueratios of 4.05 ± 0.69 and 6.29 ± 1.6 in normalcontrols and in patients with renal osteodys-trophy, respectively.44 Additionally, elevatedbone-to-soft tissue ratios may favorablydecrease in response to medical (e.g., oralcalcium and Vitamin D) or surgical (e.g.,parathyroidectomy) treatment.41-42 In somecases, however, the magnitude of diffuseincreased skeletal uptake in metabolic bonedisease may be difficult to discern, especial-ly in patients with mild disease or whoexhibit less substantial changes during serialmonitoring. Simple bone-to-soft tissueratios are of limited utility in these situationsbecause of the variability in soft tissue con-centrations. Hence, semi-quantitative tech-niques for evaluating skeletal uptake havebeen developed.7,40,45-47 The semi-quantitativeanalyses may also be helpful in evaluatingresponse to oral calcium and Vitamin D ther-apy.46 A quantitative method has also beendescribed which relies on determination of24-hour whole body retention of Tc-99m

11

diphosphonate.44

CalcinosisCrystal deposition in soft tissues can

occur in patients with renal bone disease.Elevations in the Ca X P product, predomi-nately due to increased phosporous concen-tration, is a common cause of extra-osseouscalcifications in patients on chronichemodialysis; at autopsy, pulmonary calcifi-cations were observed in 60-75% of adultpatients, renal calcifications in 53-92%, gas-tric calcifications in 53-60%, and cardiaccalcifications in 53-58%.8 Depending onsize and chemical composition, these calcifi-cations are readily detected on bone scintig-raphy (see Figure 2). In dialysis patientswith hyperphosphatemia and hypermagne-semia, formation of amorphous Ca/Mg/Pcomplexes may result in calcifications in vis-ceral organs. However, poor localization ofTc-99m diphosphonates in crystals high inMg and pyrophosphate content leads to afairly low overall sensitivity of bone scintig-raphy for visceral calcinosis.8

Deposition in joints of hydroxyapatite,alone or in combination with calciumpyrophosphate dihydrate crystals, can cause

significant articular disease, especially inshoulders, hips, knees, and wrists.8,11

Elevations in the Ca X P product in patientson peritoneal dialysis or hemodialysis maybe related to the development of articularcalcifications.11 Increased joint uptake of Tc-99m bone agents is non-specific, however,so correlation with other tests is necessaryfor a specific diagnosis.

Pulmonary calcification in hemodialysispatients is associated with impaired lung dif-fusion capacity. In one rare case, diffuse cal-cification of alveolar capillary walls led toacute respiratory failure and death of ahemodialysis patient.19 Tc-99m diphospho-nate imaging for detection of pulmonary cal-cinosis may by useful in the evaluation ofhemodialysis patients who have unexplaineddyspnea.12,19

Cardiac calcification in hemodialysispatients poses a serious risk for life-threaten-ing thromboembolic complications. Tc-99mdiphosphonate imaging for detection of car-diac calcinosis may be useful in the evalua-tion of hemodialysis patients who have car-diac complications, and in the monitoring oftreatment modifications in these patients.18

Figure 2. Calcinosis.Chest and abdomen images from a Tc-99m medronate bone scan demonstrate localization inlungs and stomach wall due to calcification in these organs.

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AmyloidosisDeposition of amyloid in various areas of

the body may result in a number of differentclinical syndromes such as carpal tunnel syn-drome, cystic bone lesions, and arthritis invarious joints. Amyloid (specifically ß2-microglobulin amyloid) deposits appear tobe related to duration of dialysis, and are sel-dom seen with hemodialysis therapy of lessthan 5 years.8 The development of amyloi-dosis rises to about 50% after 15 years andessentially 100% after 20 years of dialysis.The optimal treatment of amyloidosis isrenal transplantation.48 Unfortunately, mostpatients with amyloidosis are not suitablecandidates for transplantation. For thesepatients, palliative treatment may includeanalgesics, corticosteroids, or surgery.48

Switching from conventional cellulose mem-branes to high-flux biocompatible mem-branes may also provide subjective improve-ment.48

Amyloid preferentially deposits in colla-gen-rich osteo-articular tissue. Accordingly,bone scintigraphy frequently demonstratesincreased uptake in articular and/or periartic-ular areas, such as wrists, hips, knees, andankles.8,25,49,50 Although bone imaging cannotmake a definite diagnosis of amyloidosis, itis particularly useful as a diagnostic adjunct,especially in those patients unable or unwill-ing to undergo biopsy.50 Moreover, boneimaging is useful in determining appropriatesite(s) for biopsy.25 However, bone imagingis not able to differentiate active from inac-tive amyloidosis, and hence is not useful formonitoring response to therapy.25

In a study of 8 patients demonstratingincreased periarticular uptake on bonescintigraphy associated with dialysis-relatedamyloidosis, Tl-201 and Ga-67 citrate imag-ing showed analogous increased periarticularuptake in 6 of these patients.25 Repeat imag-ing performed after 3 months of therapyshowed marked reductions in periarticularuptake of Ga-67 citrate and nearly completeresolution of Tl-201 uptake. Hence, Tl-201and Ga-67 citrate appear to be able to differ-entiate active from inactive amyloidosis, andthus may be useful for monitoring response

to therapy.Theoretically, radiolabeled amyloid

should be able to provide improved sensitiv-ity and specificity for detecting abnormalamyloid deposition. Successful visualiza-tion of amyloid deposits in wrists, shoulders,hips, and knee joints of hemodialysispatients has been reported using I-131 ß2-microglobulin.49 One limitation of thisagent, however, is that it cannot be used inindividuals with any intact renal functionsince ß2-microglobulin is promptly excreted;hence, it cannot be used to monitor amyloi-dosis after renal transplantation. A similaragent, I-123 radiolabeled serum amyloidprotein (SAP), has also shown extremelypromising results in visualizing amyloiddeposits, especially in wrists, knees, andspleen.51 Localization in affected shouldersand hips has been more difficult, however,because of blood pool background, tissueattenuation, and anatomical constraints. I-123 SAP has also demonstrated utility inmonitoring regression of amyloid deposits inlong-term dialysis patients following renaltransplantation.51 [Note: neither I-131 ß2-microglobulin nor I-123 SAP is commercial-ly available in the United States.]

Secondary HyperparathyroidismParathyroid hormone secretion is stimu-

lated in patients receiving dialysis inresponse to hypocalcemia and hyperphos-phatemia. Secondary hyperparathyroidismcan be satisfactorily treated or prevented inmost dialysis patients, but in a few patients itescapes medical control. Progressive, severehyperparathyroidism probably occursbecause of a shift in parathyroid tissuegrowth pattern, switching from polyclonal tomonoclonal or oligoclonal proliferation.52 Inadvanced stages, this tumor-like clonalgrowth results in a change from diffuse tonodular tissue hyperplasia. Treatment inthese situations is surgical.

Although parathyroid scintigraphy is ofproven utility in the pre-operative localiza-tion of parathyroid glands or adenomas inprimary hyperparathyroidism, its usefulnessin managing secondary hyperparathyroidism

13

pre-operatively is still controversial. Thesensitivity for identifying hyperplasticglands is only about 50-70%.52-54 However,for those hyperplastic glands that are identi-fied, the specificity is nearly 100%.52 Also,parathyroid scintigraphy may be very helpfulin detecting ectopic parathyroid glands.52,53,55

Parathyroid scintigraphy is superior to mag-netic resonance imaging and to ultrasonogra-phy in the localization of hyperplasticparathyroid glands and ectopic parathyroidglands in hemodialysis patients with second-ary hyperparathyroidism.53

In the continued management of patientswith persistent or recurrent hyperparathy-roidism post-parathyroidectomy, parathyroidscintigraphy is the method of choice to local-ize parathyroid glands missed by surgery.55

Parathyroid scintigraphy has traditional-ly been performed using Tl-201 with thyroid(i.e., I-123 or Tc-99m pertechnetate) subtrac-tion.56 Nowadays, most centers use Tc-99msestamibi for parathyroid scintigraphy.Imaging is usually performed very soon afterinjection, which shows uptake in both thy-roid and hyperplastic parathyroid glands,and again after 90-120 minutes to assess dif-

ferential washout.52,53,55 Hyperplasticparathyroid glands generally exhibit a muchslower rate of washout than does thyroid tis-sue, so these foci tend to stand out ondelayed images (see Figure 3). In somepatients, the anatomic location of theseglands may be better delineated usingSPECT (see Figure 4). It is postulated thataddition of I-123 subtraction may furtherimprove sensitivity.52 Tc-99m tetrofosminmay also be used for early localization ofhyperplastic parathyroid glands,54 but doesnot provide washout information like Tc-99m sestamibi does.

HypothyroidismMany patients on chronic hemodialysis

develop symptoms of hypothyroidism.34 Thecause of this is poorly understood, and isprobably multi-factorial. The thyroid glanditself appears to maintain its functionality, asdemonstrated by normal pertechnetate scansand normal increased I-131 uptake inresponse to TSH stimulation.34 Thus otherfactors, affecting thyroid function eitherdirectly or indirectly, appear to be responsi-ble. Available evidence suggests that thepredominant mechanism may be directeffects by uremic toxins on the pituitarygland resulting in decreased release of TSH.Other potential mechanisms include directeffects by uremic toxins on the thyroidgland, interference of thyroid function bymalnutrition, and elevation of inorganiciodide levels in plasma.34,57

Unfortunately, determination of thyroidradioactive iodine uptake in these patients isof little value in establishing the degree ofhypothyroidism. For example, an abnormal-ly low rate of thyroid uptake may be coun-terbalanced by the elevated and prolongedplasma concentration of radioiodine whichmay produce a final radioactive iodineuptake in the normal range.34

The decreased clearance of iodine, espe-cially in combination with a high dietaryintake of iodine, can result in a marked ele-vation in serum iodine levels in hemodialysisor CAPD patients.58 Another cause of ele-vated serum iodine levels in dialysis patients

Figure 3. Parathyroid Hyperplasia.Planar image at 90 minutes shows greaterretention of Tc-99m sestamibi in a hyperplasticparathyroid gland than in thyroid tissue.

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may be absorption of iodine from topical orintraperitoneal povidone-iodine antiseptics,especially in CAPD patients.59 In rare cases,this iodine excess can induce hypothy-roidism. Such patients exhibit elevated TSHlevels, enlarged thyroid glands, preservedradioactive iodine uptake values, and posi-tive perchlorate discharge tests, all indicatingan organification defect in the thyroid due tothe Wolff-Chaikoff effect (i.e., iodine-induced inhibition of organification).58

Correction of organification failure andrestoration of euthyroidism may be achievedwith a restricted iodine diet and avoidance ofpovidone-iodine products.

Peritoneal LeaksPeritoneal dialysis can induce leakage

from the peritoneum into other cavities andspaces. The mechanism is not entirely clear,but may be related to pressure-enhancedtransit of fluid through lymphatic channels,pressure-enhanced flow through microscopicor macroscopic defects in membranes, orpressure-induced opening of hernias.60-62 Inaddition to the dialysate fluid itself, the

hypertonicity of the dialysate may draw localfluid into the cavity, thus adding to the vol-ume and pressure. Chronic inflammationmay also play a role in the leakage.Treatment of CAPD-induced leakage fromthe peritoneum is generally limited to eithermodification of CAPD therapy (e.g., smallerdialysate volume, intermittent therapy withrest periods in between, or switch tohemodialysis) or surgical interventions,6,62-67

although intra-cavitary administration ofsclerosing agents has been used successfullyin some cases.62,68,69

Peritoneal leaks often develop in CAPDpatients who have pre-existing structuraldefects. Prospective peritoneal scintigraphyprior to initiating CAPD is of limited prog-nostic value, however, because many pre-existing asymptomatic structural defects donot develop into symptomatic peritonealleaks, and many peritoneal leaks develop denovo in the absence of identifiable pre-exist-ing defects.70

Hydrothorax refers to the accumulationof fluid in the pleural cavity. In some cases,it may result in serious problems such as

Figure 4. Parathyroid Hyperplasia.SPECT imaging shows uptake of Tc-99m sestamibi in a hyperplastic parathyroid gland on acoronal slice (72). This slice is relatively deep in the body, demonstrating that the hyperplasticparathyroid gland is posterior to the thyroid gland which is seen in a more anterior slice (82).

15

dyspnea or respiratory distress. Dialysis-related hydrothorax may be unilateral orbilateral, but most commonly occurs on theright side.62,66 It occurs more commonly infemales than in males.66 Hydrothorax maydevelop at almost any time during CAPDtherapy, from one day to 8 years,62 with about40% occurring within the first 2 weeks.66

The overall incidence of hydrothorax inCAPD patients is in the range of about 1.6%to 10%.62

The diagnosis of CAPD-relatedhydrothorax can usually be established withstandard tests such as chest x-ray and pleu-rocentesis that demonstrates high glucose,low protein, and low lactate dehydrogenasecontent.68 However, differential diagnosis issometimes difficult, especially in the pres-ence of other conditions such as congestiveheart failure, hypoalbuminemia, malignantpleural effusion, or diabetes. In these situa-tions, imaging of Tc-99m macroaggregatedalbumin (MAA) or Tc-99m colloid injected

into the peritoneal cavity can be valuable fordetection of peritoneal-pleural communica-tion60,62,66-74 (see Figure 5).

Hernias are a relatively common compli-cation of CAPD. The sustained elevation ofintra-abdominal pressure during CAPD pre-disposes these patients to developing struc-tural defects in the peritoneum and abdomi-nal wall. The incidence of hernias in thispopulation is in the range of about 5-24%.Identification and surgical correction of her-nias are important because of their potentialfor life-threatening complications such asstrangulation or incarceration. Hernias ofvarious types (i.e., inguinal, umbilical/peri-umbilical, and ventral) can be readily detect-ed following administration of Tc-99mDTPA or Tc-99m sulfur colloid into the peri-toneal contents.6,64,67,70,75,76

Scrotal edema can develop in some menfollowing initiation of CAPD. This is appar-ently caused by opening of an inguinal her-nia due to increased intra-abdominal pres-sure and flow of dialysis fluid from the peri-toneal cavity through a patent processusvaginalis into the scrotum. The processusvaginalis is a downward fingerlike projec-tion of the peritoneal cavity that developsduring the second trimester of fetal life. Itextends through the inguinal ring to allowthe hormonally-stimulated descent of thetestes into scrotum. Normally, almost all ofthis channel closes and a fibrous band retainsthe testicle at the distal end. However, in upto 15-37% of males, the processus vaginalisfails to obliterate and complete or partialpatency persists.77 Peritoneal-scrotal commu-nication can be readily visualized followingadministration of Tc-99m MAA, Tc-99mDTPA, or Tc-99m sulfur colloid into theperitoneal contents.60,63,64,67,70,75-82

Pericatheter leaks of dialysis fluid at thesite where the dialysis catheter passesthrough the abdominal wall can cause soft-tissue edema of the abdominal wall, flanks,buttocks, and external genitalia. These leakscan be readily visualized following adminis-tration of Tc-99m colloid into the peritonealcontents.6,60,65,67,70,75 Corrective action for peri-catheter leaks generally consists of either

Figure 5. Peritoneal-PleuralCommunication.Following injection into the peritoneal cavity,Tc-99m sulfur colloid is observed in the rightpleural cavity, indicating the existence of aperitoneal-pleural communication.

16

revision of catheter placement or insertion ofa new catheter.

Several technical factors have been citedas important aspects in performing peri-toneal scintigraphy in order to provide opti-mal diagnosis of peritoneal leaks.6,64,67,75,82

Obviously, correct camera positioning overthe area of suspected leakage and clinicalcorrelation at the time of imaging is a pre-requisite for a diagnostically accurate proce-dure. A non-absorbable radiopharmaceuticalis preferred in order to prevent transferacross the normal, intact peritoneal mem-brane. The radiopharmaceutical should bemixed with or administered into the usualvolume of dialysate solution used by thepatient (e.g., typically 2 L), because lesservolumes may not increase intra-abdominalpressure sufficiently to demonstrate somedialysis-related leaks. Imaging soon afterinstillation is important to confirm uniformdistribution within the peritoneal space, butdelayed imaging is also important becausesome leaks may not become apparent forseveral hours. In some cases, leaks may beenhanced by patient activities, such as posi-tional changes vis-à-vis gravity (e.g., stand-ing vs. supine), movement (e.g., twisting,rolling, ambulation), or increased intra-abdominal pressure (e.g., Valsalva’s maneu-ver). Lastly, some small leaks may only bedemonstrated following drainage of theradiopharmaceutical/dialysate to removebackground intraperitoneal activity. Tc-99msulfur colloid is the radiopharmaceutical ofchoice because it is non-absorbable andshows little retention in the peritoneal spacefollowing drainage. Tc-99m MAA, whilealso non-absorbable, may be inferior fordetection of certain leaks because it is lesslikely to flow through very small structuraldefects and it demonstrates substantial reten-tion in the peritoneal cavity followingdrainage.60,75

Catheter-Related InfectionsInfection of vascular access sites is a signifi-cant complication in patients on hemodialy-sis. Bacteremia frequently follows vascularaccess infection, which occasionally can lead

to localized infection elsewhere in the body.83

Risk factors for vascular access infectioninclude excessive catheter manipulation,length of catheter placement, number of dial-ysis sessions, and diabetes. Staphlococcusaureus is the most common cause of vascu-lar access infections in dialysis patients.

In rare cases, vascular access infectionscan lead to osteomyelitis. Clavicle, thoracicspine, ribs, tibia, and toes are usual sites ofinfection. Sternal osteomyelitis is rare. In-111 leukocyte imaging, with or without Tc-99m diphosphonate bone imaging, or Ga-67imaging may be useful in establishing adiagnosis of osteomyelitis.84 These imagingprocedures can also be useful in monitoringresponse to antibiotic therapy.84

AbscessMinimal kidney function/urinary output

in dialysis patients is associated with thedevelopment of urinary tract infections,especially in patients with polycystic kidneydisease. In spite of antibiotic treatment,many of these infections go on to result inperinephric abscesses. Such perinephricabscesses can be readily identified with Ga-67 citrate scintigraphy.85

PneumonitisPulmonary edema in the absence of fluid

overload or cardiac failure is a recognizedcomplication of chronic renal failure. Onecontributing factor may be reduced plasmaosmotic pressure, especially in patients withhypoalbuminemia resulting from malnutri-tion, proteinuria, or peritoneal losses whileon CAPD. Another contributing factor maybe increased permeability of the alveolarmembrane resulting from endothelial dam-age caused by complement activation, neu-trophil sequestration, or superoxide releaseassociated with interactions with hemodialy-sis membranes. Limited information hasbeen published, however, on the possiblechanges in pulmonary clearance of inhaledTc-99m DTPA aerosol in dialysis patients.86

This information is important becausesome dialysis patients concurrently haveAIDS, and thus are at risk of developing

17

Pneumocystis carinii pneumonia (PCP). Thepulmonary clearance of inhaled Tc-99mDTPA aerosol in patients without renal dis-ease has been shown to be markedlyincreased in patients with PCP. A recentstudy investigated the pulmonary clearanceof inhaled Tc-99m DTPA aerosol in dialysispatients.86 The results showed that Tc-99mDTPA clearance in both hemodialysispatients and CAPD patients, when controlledfor smoking, were not significantly differentfrom normal subjects. Therefore, pulmonaryclearance of Tc-99m DTPA can be useful inthe evaluation of suspected PCP in AIDSpatients who are also on dialysis.

Another study evaluated alveolar perme-ability and lung ventilation in hemodialysispatients using Tc-99m DTPA aerosol.87 Thepulmonary clearance rate was slightly butsignificantly faster in hemodialysis patientsthan in normal control subjects. Visualassessment of the radioaerosol inhalationimages revealed that nearly two-thirds of thehemodialysis patients showed ventilationabnormalities consisting of excess accumu-lation in the central portions of the lungsand/or hypoventilation of the basilar regions.The significance of these findings areunknown, but Tc-99m DTPA aerosol inhala-tion lung scans may be useful in the evalua-tion of lung ventilation and alveolar perme-ability in hemodialysis patients.

Alveolar permeability before and duringhemodialysis was studied in a small group ofpatients using pulmonary clearance of Tc-99m DTPA aerosol.88 Tc-99m DTPA aerosolclearance was significantly faster in non-smoking, chronic renal failure patients thanin control subjects, indicating excessivealveolar permeability in the renal failurepatients prior to hemodialysis. Following 4-5 hours of hemodialysis, however, Tc-99mDTPA aerosol clearance significantlyslowed, indicating partial normalization ofalveolar permeability. The mechanism forthis improvement in alveolar permeabilityassociated with hemodialysis is not known.

Tc-99m DTPA aerosol clearance wasalso used by another group to study alveolarpermeability in hemodialysis patients.89

Using one particular hemodialysis mem-brane and dialysate solution, pulmonaryclearance of Tc-99m DTPA aerosol did notsignificantly change before and after dialy-sis. This lack of effect, in contrast to thatreported above, may have been related to useof one particular dialysis membrane anddialysate solution which was more biocom-patible.

Pulmonary EmbolismApproximately 50% of patients receiving

hemodialysis have an arteriovenous polyte-traethylene (PTFE) graft for vascular access.The rate of graft occlusion is these patients isabout 25-45% per year. Thus clottedhemodialysis access grafts are a majorsource of morbidity and hospitalization ofthis group. Traditionally, surgery was thestandard treatment for clotted access grafts.Recently, however, percutaneous thromboly-sis has become widely accepted. This proce-dure is performed by administering a lyticagent (e.g., urokinase [historically] oralteplase) or a pulsed spray of heparinizedsaline, followed by angioplasty of thestenosed vein.90-92

A potential complication of these throm-bolysis procedures is the production of pul-monary emboli. Perfusion imaging usingTc-99m MAA, with or without ventilationimaging (e.g., Xe-133), can readily detectsignificant pulmonary emboli in thesepatients.90-92

DementiaSome dialysis patients develop progres-

sive mental deterioration, including dimin-ished alertness, attention, and concentration;disturbances in memory, conceptualization,and speech; and dementia. Potential causesthat have been suggested include inadequatedialysis (i.e., the presence of uremic toxins),recurrent hypotension or hypoglycemia,recurrent osmotic injury, electrolyte distur-bances (e.g., hypercalcemia), depletion ofwater-soluble vitamins and metabolites,accumulation of heavy metals and alu-minum, and accumulation of plasticizers.93

Use of aluminum-free dialysate and reducing

18

other sources of aluminum has markedlyreduced, but not eliminated, impairments incognitive function.94

Traditional brain scans using Tc-99mpertechnetate in hemodialysis patients havebeen normal.93 On the other hand, nuclearcisternography studies in these patients havedemonstrated marked deviations in cere-brospinal fluid (CSF) flow and slow rates ofclearance from the CSF.93 Altered anion han-dling by the choroid plexus in hemodialysispatients, as demonstrated with Tc-99mpertechnetate imaging, may also be involvedas it relates to secretion of CSF.27 It remainsunclear, however, whether these defects inCSF dynamics is the cause or an accompani-ment of dialysis dementia.

SPECT brain imaging using Tc-99mexametazime (HMPAO) has demonstratedan abnormal distribution of cerebral perfu-sion in chronic hemodialysis patients.94

Although hemisphere-to-cerebellar uptakeratios were normal, there was significant rel-ative hypoperfusion in the frontal cortex andthalmus, while perfusion of the occipital cor-tex was well preserved. This perfusion pat-tern is distinctly different from that seen inpatients with Alzheimer’s disease. Becauseregional perfusion abnormalities did not cor-relate with cognitive test scores, however,the potential role of SPECT brain scans indialysis patients remains unclear.95

PET studies using O-15 water and O-15O2 have been performed in hemodialysispatients to investigate the possible correla-tion of anemia with cerebral blood flow andoxygen metabolism.88 Cerebral blood flowand oxygen extraction efficiency were high-er in anemic hemodialysis patients comparedto control subjects, apparently as an attemptto compensate for the decreased oxygendelivery in anemic hypoxia. Followingtreatment of anemia with recombinanthuman erythropoietin, cerebral blood flowand oxygen extraction efficiency decreasedtoward normal values as a direct function ofhematocrit. Cerebral oxygen metabolism,however, was abnormally low in the anemicstate and showed no improvement followingtreatment of anemia. Therefore it appears

that suppressed brain metabolism inhemodialysis patients is not related to ane-mia per se, but is probably due to vascularinjuries or other chemical metabolic abnor-malities related to chronic uremia.

Albumin CatabolismHypoalbuminemia often occurs in

patients with chronic renal failure, possiblybecause of restricted protein diets. This con-dition is generally corrected with mainte-nance hemodialysis. If desired in selectedpatients, albumin catabolism can be deter-mined using radioiodinated human serumalbumin.96

Gastric Emptying Many patients receiving peritoneal dialy-

sis, and a few receiving hemodialysis, exhib-it symptoms of anorexia, nausea, and vomit-ing which, in addition to presentingincreased stress for the patient, may alsocontribute to malnutrition. These symptomsmay be related, at least in part, to decreasedrates of gastric emptying. Using Tc-99mlabeled food (e.g., scrambled egg meal), gas-tric emptying rates can be easily determinedin these patients.97-99

Gastric emptying of solids has beenreported to be prolonged in about one-half ofCAPD patients.97 Several of these patientsalso exhibited delayed gastric emptying ofliquids, as demonstrated using In-111 DTPA.These delayed gastric emptying results wereunrelated to the presence of diabetes melli-tus. The cause of delayed gastric emptyingin these patients is unknown, but may berelated to autonomic dysfunction or a directeffect of uremic toxins on gastric smoothmuscle.

Another potential cause of delayed gas-tric emptying in CAPD patients is increasedintra-abdominal pressure. A recent study inperitoneal dialysis patients indicates thatgastric emptying is normal when no dialysisfluid is in the abdomen (drained) but is sig-nificantly slower when 2 L of dialysis fluid isin the abdomen.99 Furthermore, this effecttended to be more pronounced in patientswith smaller body surface area. In patients

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Complication Radiopharmaceutical Characteristic Feature(s)metabolic bone disease Tc-99m bone agents � skeletal uptake, associated with secondary � kidney uptakehyperparathyroidismmetabolic bone disease, Tc-99m bone agents � skeletal uptake, aluminum-related � soft tissue activitycalcinosis Tc-99m bone agents � uptake at sites of calcification

(e.g., lungs, stomach, heart, kidney, joints)

amyloidosis Tc-99m bone agents, � uptake in jointsTl-201, Ga-67 citrate,I-131 ß2-microglobulin,I-123 serum amyloid protein(SAP)

secondary Tl-201, � uptake in parathyroid hyperparathyroidism Tc-99m sestamibi, hyperplasia

Tc-99m tetrofosminhypothyroidism I-131 sodium iodide not useful because � rate of

thyroid uptake may be counter-balanced by � plasma concentrations which may result in a normaluptake value

peritoneal leaks in Tc-99m sulfur colloid, flow into communicatingCAPD patients Tc-99m MAA, structures (e.g., pleural cavity,

Tc-99m DTPA hernias, scrotum, catheter tunnel)(administered intoperitoneal cavity)

infection/abscess In-111 leukocytes, � uptake at site of infectionGa-67 citrate

pneumonitis/pulmonary Tc-99m DTPA aerosol � rate of pulmonary clearance edema due to � capillary permeabilitypulmonary embolism Tc-99m MAA � uptake in affected lung regionsecondary to thrombolysis of clotted access graftdementia I-131 radioiodinated serum altered CSF flow and � clearance

albumin (intrathecal) from CSF; unclear whether this is a cause or an effect

Tc-99m HMPAO � uptake in frontal cortex and thalmus; however, these abnormalities do not correlate with cognitive test scores

O-15 oxygen � cerebral oxygen metabolism

Table 3. Reported Use of Radiopharmaceuticals to Evaluate Complications of ChronicRenal Failure/Dialysis.(see text for further descriptions and reference citations)

20

who demonstrate slowed gastric emptying,use of smaller dialysis fluid volumes and/ornocturnal intermittent peritoneal dialysisshould be considered.

Solid phase gastric emptying studies areuseful not only in the evaluation of dialysis-related gastroparesis, but also in assessingresponse to therapy.98 Improvements in gas-tric emptying in response to prokinetic drugtherapy (e.g., metoclopramide or erythromy-cin) can be extremely useful to guide thera-py. Successful treatment of gastroparesis inthese patients has resulted in significantimprovements in serum albumin levels, atleast in patients with moderately severehypoalbuminemia.

Pericardial EffusionPericardial effusion has been reported as

an infrequent complication in hemodialysispatients.100 Excessive fluid accumulation inthe pericardial sac may occur in patients withuremic pericarditis associated with inflam-mation and fibrin formation. Such effusioncan be readily visualized following intra-venous injection of Tc-99m human serumalbumin (HSA).100 [Note: because humanserum albumin kits are no longer commer-cially available in the Unites States, thisradiopharmaceutical would have to be

extemporaneously compounded.]

Cardiac NeuropathySome patients with chronic renal failure

develop cardiac complications such asmyocardial hypertrophy or decreased leftventricular contractility. Using I-123 ioben-guane (MIBG) imaging, a group ofhemodialysis patients exhibited more hetero-geneous myocardial distribution and signifi-cantly faster cardiac clearance of I-123MIBG compared with control subjects.101

Plasma levels of dopamine and norepineph-rine were also higher in hemodialysispatients than in controls. These data suggestthat chronic renal failure patients onhemodialysis develop cardiac sympatheticoveractivity. In addition, abnormal clear-ance of I-123 MIBG from the lungs in thesepatients implies concurrent pulmonary sym-pathetic dysfunction and/or endothelial dys-funtion. The impact of this information onpatient management remains to be deter-mined. [Note: I-123 MIBG is not commer-cially available in the United States.]

Summary of Reported Uses to EvaluateComplications

Routine nuclear medicine procedures canplay an important role in evaluating compli-

Table 3 Continued.

Complication Radiopharmaceutical Characteristic Feature(s)hypoalbuminemia I-131 radioiodinated serum � plasma half-life, � urine associated with excessive albumin excretionalbumin catabolismdelayed gastric emptying Tc-99m sulfur colloid in � rate of gastric emptying due to

cooked egg, autonomic dysfunction or effects Tc-99m DTPA of uremic toxins

delayed gastric emptying Tc-99m sulfur colloid in � rate of gastric emptying due to in CAPD patients cooked egg increased intra-abdominal pressure

related to dialysis fluid in peritoneal cavity

pericardial effusion Tc-99m HSA accumulation in pericardial saccardiac neuropathy I-123 MIBG heterogenous cardiac uptake,

� clearance from the heart,� clearance from the lungs

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cations of chronic renal failure or dialysis,including metabolic disorders in organs suchas the skeleton, joints, and parathyroidglands and non-metabolic problems such aperitoneal leaks. Reported uses of radio-pharmaceuticals to evaluate complicationsare summarized in Table 3.

RADIOPHARMACEUTICAL THERA-PY IN DIALYSIS PATIENTS

Compared to diagnostic procedures,radiopharmaceutical therapies represent avery small, but expanding, fraction ofnuclear medicine practice. Needless to say,the need to perform radiopharmaceuticaltherapy in a patient receiving dialysis is rare.However, the situation may arise, and mayelicit concerns such as modification of treat-ment dose, increased radiation doses to nor-mal tissues, and increased radiation exposureto medical staff and family members. Asmight be expected, published information onthe subject is limited, and is primarily in theform of case reports.

I -131An early report described I-131 ablation

therapy in a dialysis patient following sub-total thyroidectomy.102 Preliminary investi-gations using a tracer dose of I-131 showedthat, in this patient, thyroid uptake increasedfrom 6% at 24 hours to 10% at 48 hours, andthat hemodialysis was able to removeapproximately 90% of radioiodide in plas-ma. Calculations indicated that waiting toperform dialysis until 48 hours after radioio-dine administration would result in a cumu-lated activity (i.e., mCi-hours) of about 4times that for patients with normal renalfunction. Accordingly, the patient was treat-ed with only one-fourth of the customarydosage of I-131.

The second report of I-131 ablation ther-apy in a hemodialysis patient revealed some-what different findings.103 Following sub-total thyroidectomy for thyroid papillary car-cinoma, the patient was treated with a rela-tively low dose, 50 mCi, of I-131 based onthe case report described above. Residualand progressive disease, indicated by persist-

ent focal uptake of diagnostic I-131 and per-sistently elevated thyroglobulin levels, wassubsequently treated with 120 mCi I-131,and again with 150 mCi 1-131, but withoutsuccess. Review of these failed treatmentssuggested that inadequate radiation dose wasdelivered because of rapid plasma clearanceof I-131 by dialysis. Consequently, a tracerdose of I-131 was administered to the patientand its clearance from blood by the dialysisunit was monitored (each dialysis removedabout 72% of the I-131 in the blood). Basedon new dosimetry calculations incorporatingthese clearance data, the patient was treatedwith a high dose, 250 mCi, of I-131 withhemodialysis performed at 48 hour intervalsafter I-131 administration. Finally, partialsuccess was achieved for ablating thepatient’s residual and metastatic thyroidtumor.

These same authors also described someof the radiation safety aspects of I-131 treat-ment in the hemodialysis patient.103 Afterremoving disposable parts and flushing themachine, contamination of the dialysisequipment was minimal and was thereforeused again the next day for other patients.As might be expected, moderate contamina-tion was detected on the patient’s pillow caseand inside the toilet. The only significantcontamination occurred during one dialysissession when the dialysis waste fluid wasdirected into an improperly drained sink.

The management of I-131 therapy forthyroid cancer in another dialysis patient wasdetailed in a recent report.104 Diagnosticimaging and blood sampling following atracer dose of I-131 showed that hemodialy-sis performed 67 hours after administrationremoved 67% of whole body activity (80%of blood pool activity), and that a secondhemodialysis performed at 115 hoursremoved 59% of remaining whole bodyactivity (65% of remaining blood pool activ-ity). Calculations determined that 100 mCicould be administered to this patient, whichwould deliver approximately 16,000 rads toresidual thyroid tissue and functioningmetastases and approximately 68 rads to thewhole body. The patient was treated with

22

100 mCi I-131 and dialysis was performed41 hours and again at 89 hours. Surveymeter measurements before and after thefirst dialysis showed a whole body reductionin radioactivity of 76%.

These authors also described radiationsafety aspects involved in this particulartreatment.104 The patient’s hospital room wasprepared according to the institution’s cus-tomary procedures for radioactivity contam-ination control. To avoid spills, the drainhose from the dialysis unit was connected tothe toilet for drainage of effluent dialysiswaste. A 10-cm thick mobile lead shield waspositioned to provide radiation protection todialysis operators, and direct patient contactwas limited to a maximum of two hours foreach nurse. Film badges worn bydialysis/nursing personnel demonstrated nosignificant exposures (i.e., all badges regis-tered below 10 mrem). Thyroid surveys ofnuclear medicine, dialysis, and healthphysics personnel indicated no detectable I-131 uptake. Radioactive contamination ofthe dialysis machine was insignificant,allowing the equipment to be safely usedafter routine flushing maintenance.Contamination of the patient’s room wassimilar to that typically seen for otherpatients treated with I-131.

Another group also reported on iodinedialysance and radiation safety concerns in acase involving I-131 treatment in a patienton hemodialysis.105 The dialytic efficiencyfor radioiodide removal from the body wasfound to be dependent on time (or really onthe amount of radioiodine remaining in thebody), with about 60-70% removal soonafter administration but dropping to 10% orless at later times. Exposure rates and con-tamination levels from the dialysis machinewere minimal following flushing, thusallowing the machine to be safely reused forother patients.

I-131 treatment of thyroid cancer in twodialysis patients is the subject of anotherreport.106 Iodine kinetics in thyroid, salivarygland, and blood were variable, suggestingthe necessity for individualized measure-ments and dosimetry determinations. In one

patient, hemodialysis performed 3 days afterI-131 administration showed reductions inwhole body activity of 60% and in bloodactivity of 78%.107 There was no significantcontamination of dialysis equipment. Theauthors suggest that dialysis could be per-formed earlier to decrease the absorbed doseto extra-thyroidal tissues.

I-131 treatment in 3 dialysis patients, onewith Graves’ Disease and two with thyroidcancer, was recently described.108 Removalof radioiodide from the body by hemofiltra-tion was about 50% in the thyroid cancerpatients and about 20% in the Graves’Disease patient. Whole body effective half-lives were prolonged 2- to 3-fold in the thy-roid cancer patients compared to patientswith normal renal function, and at least 4-fold in the Graves’ Disease patient. Lowerfractional removal by dialysis and prolongedbody retention in Grave’s Disease is due tothe much higher thyroidal uptake of I-131.

Graves’ Disease was successfully treatedin another patient on hemodialysis.109

Treatment with 12.5 mCi of I-131 resulted infrank hypothyroidism by 3 months, whichwas effectively treated with thyroid hormonereplacement therapy. No problems wereencountered during the treatment, and therewas no detectable radioactive contaminationof the hemodialysis tubing.

Peritoneal dialysis, rather than hemodial-ysis, may be performed in some patientsOne group described I-131 ablation therapyin two CAPD patients following thyroidec-tomies for thyroid cancer.110,111 Preliminaryinvestigations using tracer doses of I-131 orI-123 showed slightly elevated thyroid rem-nant uptakes of 2.9% and 3.5% in these twopatients (compared to an average of 0.14% in6 patients with normal renal function) andmarkedly prolonged blood elimination half-lives of 81.1 hours and 52.8 hours (comparedto an average of 10.2 hours in 8 patients withnormal renal function), respectively. The 24-hour dialytic removal of radioiodide was22.6% and 25.0% of the administered dosein the two CAPD patients (compared to anaverage 24-hour urinary excretion of 72.4%in 8 patients with normal renal function).

23

Because mean total body residence timeswere nearly 5-fold greater in CAPD patientsthan in patients with normal renal function,absorbed doses per mCi to red marrow andtotal body would be 4- to 5-fold greater inCAPD patients. Accordingly, only 26.6 mCiand 29.9 mCi of I-131 were administered tothese two CAPD patients (compared to acustomary dosage of 150 mCi in patientswith normal renal function). After 7-8 yearsof follow-up, neither patient had clinicalrecurrence of thyroid cancer.

In summary, dialysis patients can be suc-cessfully treated with I-131 for hyperthy-roidism or thyroid cancer. Because dialysisis less efficient at removing I-131, comparedto normal renal function, blood and totalbody retention are prolonged in dialysispatients. Biological half-lives vary substan-tially between individuals and are furtherinfluenced by procedure-related factors suchas type of dialysis (hemodialysis vs. peri-toneal) and timing of dialysis. Therefore,preliminary investigations using a tracerdose of radioiodide should be performed indialysis patients to determine individualkinetics and provide data for individualizeddosimetry calculations. Radiation protectionof dialysis and nursing personnel can beachieved with mobile shielding, time limita-tions for direct patient contact, and properdisposal of dialysis effluents. With properhandling and flushing, contamination ofdialysis equipment can be held to acceptablelevels.

Sm-153A recent report described bone pain pal-

liation with Sm-153 lexidronam (EDTMP)in a dialysis patient.112 Because 6-hour uri-nary excretion of Sm-153 EDTMP is nor-mally about 35% of the injected dose, bloodand whole body retention of Sm-153EDTMP was expected to be prolonged inthis patient. Therefore, the administereddose was reduced from the standard 1mCi/kg to 0.75 mCi/kg. Hemodialysis wasperformed 44 hours post-administration.Counting of blood and dialysate samplesindicated that the dialysate concentration of

Sm-153 was about 22% of the blood concen-tration. Disposable portions of the dialysisequipment showed slight contamination andwere stored for decay.

USE OF RADIOPHARMACEUTICALSTO EVALUATE DIALYZER FUNC-TION

The unique properties of radiopharma-ceuticals allow them to be used for otherinvestigative purposes. Of relevance hereare a few reports of using radiopharmaceuti-cals to study various aspects of dialyzerfunction.

Tc-99m DTPA has been investigated asto its utility for measuring the effectivenessof dialysis.113 Clearances of both creatinineand Tc-99m DTPA were determined in eightpatients undergoing hemodialysis therapyand in six patients undergoing peritonealdialysis. In hemodialysis patients, Tc-99mDTPA clearance was significantly correlatedwith creatinine clearance but averaged only38% of creatinine clearance. Althoughdialysance of Tc-99m DTPA increased lin-early with increased rates of blood flow, thisincrease was markedly blunted compared tothat observed with creatinine. The modesteffect of blood flow rate on Tc-99m DTPAclearance is because the dialysance of largermolecules is primarily related to the mem-brane permeability and surface area, and isless dependent on blood flow. In the peri-toneal dialysis patients, Tc-99m DTPA clear-ance was significantly correlated with creati-nine clearance and averaged 65% of creati-nine clearance. Higher clearance of Tc-99mDTPA, relative to creatinine, in peritonealdialysis is due to the higher permeability ofthe peritoneum to larger molecules relativeto that of standard hemodialysis membranes.Tc-99m DTPA is thus a good marker forstudying the permeability of hemodialysisand peritoneal membranes for middle-sizedmolecules. Moreover, Tc-99m DTPA can beused to assess the efficacy of new dialyzersor dialysis protocol variables.

Tc-99m DTPA has also been used to

24

measure the effects of changes in dialysisparameters within a single hemodialysis ses-sion.114 In a comparison of two differenttypes of dialyzer units, no significant differ-ence in clearance was seen. Similar to theresults of the study reported in the previousparagraph, alterations in blood flow to thedialyzer resulted in small, but not statistical-ly significant, changes in Tc-99m DTPAclearance. However, alterations in dialysateflow did result in significant changes in Tc-99m DTPA clearance.

Devices with large surface areas, such asdialyzers, have the potential to consume cir-culating platelets by platelet-thrombus for-mation, embolization, and platelet disinte-gration. Platelets radiolabeled with In-111 orTc-99m have been used to quantitate thethrombogenicity of hemodialyzers.115

Transient leukopenia following initiationof hemodialysis is a common phenomenon.Animal studies have suggested that leuko-cytes are sequestered in the lungs rather thanin the dialyzer. In order to study this effectin humans, imaging of autologous leuko-cytes labeled with Tc-99m HMPAO was per-formed following initiation of hemodialysisusing three different dialysis membranes.116

In comparison to normal Tc-99m leukocyteaccumulation in lungs without hemodialysis,a marked spike in lung sequestration of Tc-99m leukocytes occurred 10-20 minutesafter the start of hemodialysis. This abnor-mal spike in pulmonary sequestration ofleukocytes is likely related to activation ofcomplement cascade by the dialysis mem-brane. The magnitude of this spike in pul-monary sequestration of leukocytes isstrongly dependant on the type of dialysismembrane used, ranging from marked toundetectable for different membrane types.

Related to leukocyte sequestration inlungs during hemodialysis, release ofinflammatory mediators is thought to causemicrocirculatory inflammation in the lungs.Changes in the alveolar-arterial oxygen gra-dient due to this leukocyte trapping andincreased alveolar permeability may beresponsible, at least in part, for hypoxemiaseen in many hemodialysis patients.89 Tc-

99m DTPA aerosol clearance is a useful toolfor assessing alveolar inflammation. In arecent study utilizing one particular type ofdialysis membrane and dialysate solution,there was no significant change in Tc-99mDTPA aerosol clearance before and afterhemodialysis, indicating no measurableeffect of hemodialysis on alveolar inflamma-tion.89 Thus, determination of Tc-99m DTPAclearance may be useful for assessing bio-compatibility of various dialysis membranesand dialysate solutions.

Amyloidosis will invariably develop inanuric hemodialysis patients because dialy-sis cannot effectively remove ß2-microglob-ulin from the plasma. Nonetheless, somedialysis membranes and/or techniques, espe-cially those utilizing highly permeable mem-branes, are better than others at clearing thisprotein and thus delaying the onset of clini-cal symptoms.4 I-131 ß2-microglobulin hasbeen used to evaluate the effectiveness ofvarious dialysis membranes and techniquesfor removal of ß2-microglobulin from thebody.117 Differences in the binding of ß2-microglobulin to various dialysis membraneshas also been studied using I-131 ß2-microglobulin.117

In the laboratory, Tc-99m MAA has beenused as a nondiffusible marker molecule toinvestigate the ultrafiltration and pressureprofiles in dialyzers with different hydraulicpermeabilities.118 Because this agent is toolarge to cross dialysis membranes, changesin its concentration occur in response tochanges in blood water content. Imaging ofthe dialyzer unit during different experimen-tal conditions showed changes in radioactiveconcentration along the length of the unitwhich provided information on water fluxesinvolving filtration and backfiltration.

CONCLUSIONDialysis, either hemodialysis or peri-

toneal dialysis, is a common therapy inpatients with chronic renal failure. A varietyof factors associated with chronic renal fail-ure or dialysis can alter the biodistribution ofmany radiopharmaceuticals. On the other

25

hand, a variety of radiopharmaceuticals canbe used in the evaluation of many metabolicand non-metabolic complications of chronicrenal failure/dialysis, as well as in the evalu-ation of certain aspects of dialyzer function.Also, several dialysis-related factors mayrequire modification or individualization of

radiopharmaceutical therapy regimens.Hopefully the information reviewed and

summarized in this lesson will assist thereader in his/her professional consultationswith other healthcare staff and therebyenhance the care of patients undergoing dialysis.

26

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QUESTIONS

1. Dialysis refers to the separation of sub-stances by:a. Differential retention in a

chromatographic column.b. Specific binding to membrane-

bound receptors.c. Concentration-gradient dependent

diffusion through a semi-permeable membrane.

d. Variable adsorption to an ion-exchange resin.

2. Dialysis, in a healthcare setting, gener-ally refers to supplementation orreplacement of _______ function.a. Gastrointestinalb. Hepatic metabolismc. Hepatobiliaryd. Renal

3. Which of the following characteristicspositively influences the ability of aparticular molecule to be dialyzed?a. Highly protein-boundb. Highly soluble in waterc. Large molecular weightd. Large volume of distribution

4. Based on physiochemical characteris-tics and biological handling, which ofthe following would be expected to bemost efficiently removed from theblood by hemodialysis?a. Tc-99m gluceptateb. Tc-99m mebrofeninc. Tc-99m red blood cellsd. In-111 capromab pendetide

5. In CAPD, movement of substancesacross the peritoneal membrane is by:a. Active transport.b. Convection along an osmotic

pressure gradient.c. Diffusion along a concentration

gradient.d. Both (b) and (c).

6. Which of the following is NOT a com-mon site of metastatic calcification indialysis patients?a. Heartb. Liverc. Lungsd. Stomach

7. Which of the following best describesthe ability to remove Ga-67 citratefrom plasma?a. Normal kidneys > hemodialysis >

CAPDb. Hemodialysis > normal kidneys >

CAPDc. CAPD > hemodialysis > normal

kidneysd. All three methods are equally

effective

8. For which of the following ishemodialysis LEAST effective forremoval from the blood?a. Ga-67 citrateb. Tc-99m bone agentsc. I-131 MIBGd. I-131 sodium iodide

9. In hemodialysis patients, In-111 leuko-cytes tend to exhibit increased localiza-tion in:a. Liver.b. Lungs.c. Marrow.d. Spleen.

10. Skeletal scintigraphy generally demon-strates elevated bone-to-soft tissueratios in dialysis patients with:a. Aluminum-related bone disease.b. Osteitis fibrosa accompanied by

secondary hyperparathyroidism.c. Hypothyroidism.d. Osteomalacia.

35

11. Articular uptake of Tc-99m diphospho-nates may be seen with each of the fol-lowing, EXCEPT:a. Amyloidosis.b. Elevated Ca X P product.c. Hydroxyapatite calcinosis.d. Hypermagnesiemia.

12. Increased uptake in areas affected byamyloidosis has been reported with allof the following, EXCEPT:a. Ga-67 citrate.b. I-131 ß2 microglobulin.c. Tc-99m DTPAd. Tl-201 thallous chloride.

13. Parathyroid scintigraphy in dialysispatients may be useful in detectingeach of the following, EXCEPT:a. Diffuse hypofunction of the

parathyroid glands.b. Ectopic parathyroid tissue.c. Nodular hyperplasia of

parathyroid tissue.d. Residual parathyroid tissue

missed by surgery.

14. Which of the following is NOT a con-tributing factor for developing leakageof dialysate from the peritoneal cavityin patients undergoing CAPD?a. Chronic inflammation of

peritoneal membranesb. Presence of pre-existing

structural defects in the peritonealmembrane

c. Unnaturally high pressure in the peritoneal cavity

d. Use of hypotonic dialysis solutions

15. Peritoneal scintigraphy in CAPDpatients can be used to detect each ofthe following, EXCEPT:a. Hydrothorax.b. Inguinal hernia.c. Pericardial effusion.d. Pericatheter leaks.

16. Technical factors recommended in per-forming peritoneal scintigraphy inCAPD patients include all of the fol-lowing, EXPEPT:a. Administration of radiopharma-

ceutical with or into the patient’s regular dialysis volume.

b. Imaging at multiple times (e.g., soon after administration, afterseveral hours delay, after dialysaterainage).

c. Maintaining the patient motionlessin a supine position.

d. Use of a non-absorbable radio-pharmaceutical.

17. Alveolar permeability in dialysispatients can evaluated using:a. Tc-99m DTPA aerosol.b. Tc-99m MAA.c. Tc-99m sulfur colloid.d. Xe-133 gas.

18. A potential complication of throm-bolytic treatment of a clottedhemodialysis access graft is:a. Cardiac neuropathy.b. Dementia.c. Pericatheter leak.d. Pulmonary embolism.

19. Potential factors involved in delayedgastric emptying in some peritonealdialysis patients include each of thefollowing, EXCEPT:a. Autonomic dysfunction related to

uremic toxins.b. Direct effect of uremic toxins on

gastric smooth muscle.c. Large volumes of dialysis fluid in

the abdomen.d. Prophylactic treatment with

erythromycin.

36

20. Hemodialysis performed soon afteradministration of I-131 sodium iodidefor thyroid cancer treatment will gener-ally remove about ____ of plasmaactivity.a. 10%-30%b. 30%-50%c. 50%-70%d. 70%-90%

21. Peritoneal dialysis performed for 24hours after administration of I-131sodium iodide for thyroid cancer treat-ment will generally remove about ___of body activity.a. 10%-30%b. 30%-50%c. 50%-70%d. 70%-90%

22. Which of the following is recommend-ed when treating a dialysis patient withI-131 sodium iodide?a. Preliminary determination of

radioiodide kinetics and individualized dosimetry calculations

b. Treatment with the customary dosage of I-131

c. Treatment with 1/4 - 1/2 of the customary dosage of I-131 because prolonged blood pool activity produces increased thyroid uptake

d. Treatment with 2 – 3 times the customary dosage of I-131 because dialysis produces exceptionally rapid blood pool clearance

23. All of the following are recommendedwhen treating a hemodialysis patientwith I-131, EXCEPT:a. Limit time of direct patient

contact.b. Place mobile shielding between

the patient and staff personnel.c. Properly dispose of dialysis

effluent.d. Store dialysis machine for

10 half-lives before flushing.

24. Which of the following would be mostuseful for assessing the efficacy of newdialyzers or dialysis protocol vari-ables?a. Tc-99m DTPAb. Tc-99m MAAc. Tc-99m sodium pertechnetated. Tc-99m sulfur colloid

25. Using various radiopharmaceuticals,functional differences in dialysis mem-branes have been evaluated with regardto each of the following, EXCEPT:a. Causing hypoalbuminemia.b. Inducing pulmonary seques-

tration of leukocytes.c. Removing ß2-microglobulin

from the body.d. Thrombogenicity.

37