Safety and Adverse Events Profiles of Intravenous Gammaglobulin Products Used for Immunomodulation:A Single-Center ExperienceAshley A.Vo,*Vinh Cam,*Mieko Toyoda,†Dechu P.Puliyanda,*Marina Lukovsky,*Suphamai Bunnapradist,*Alice Peng,*Kai Yang,‡and Stanley C.Jordan*†*Comprehensive Transplant Center,†Transplant Immunology Laboratory,and‡Department of Medical Genetics, Cedars-Sinai Medical Center,David Geffen School of Medicine at University of California Los Angeles,Los Angeles, CaliforniaIntravenous Ig(IVIg)products are used in various medical conditions.Differences in excipients account for most adverse events(AE).Reports of complications including acute myocardial infarction(AMI)and acute renal failure(ARF)have emerged.Herein is described one institution’s experience with IVIg-related complications.This study is a retrospective analysis of infusion-related AE that are associated with various IVIg products.Infusion-related AE were monitored during and after the administration of three IVIg products:Gamimune-N10%(n؍76),Polygam(n؍105),and Carimune(n؍98).AE segregated to specific IVIg products.No patients who received Gamimune-N experienced AMI or ARF.Five(4.7%)patients (P<0.01)in the Polygam group experienced AMI.Eight(8.2%)patients(P<0.0001)in the Carimune group developed ARF. IVIg was safe to give on hemodialysis.IVIg products differ in osmolality,pH,and sugar and sodium content;this results in specific AE.Polygam resulted in no ARF but an increase in AMI.Carimune products at9%concentration resulted in an increase in ARF.Gamimune-N10%and other IVIg products were frequently associated with headaches.Administration of IVIg to patients who are on hemodialysis seems to be safe and effective.Clin J Am Soc Nephrol1:844–852,2006.doi:10.2215/CJN.01701105I ntravenous Ig(IVIg)products initially were developed fortreatment of immune deficiency disorders.The immuno-modulatory effects of IVIg rapidly led to a broader usage of IVIg in autoimmune and inflammatory disorders,usually at much higher doses(1).More recently,IVIg has been used in kidney transplantation for decreasing panel reactive antibodies in highly sensitized patients(2)and for the treatment of anti-body-mediated rejection(AMR)(3–5).Although many consider that all IVIg products are similar,it now is clear that they differ greatly in regard to excipient compounds and related adverse effects(6).Proper product selection for each patient is critical because the adverse effect profiles of each formulation differ on the basis of the excipient.Certain patients,such as those with diabetes or those who are at risk for renal failure and/or heart disease,may not tolerate particular IVIg formulations.Product features that affect tolerability include volume load,infusion rates,osmolality,pH,and sodium or sugar content.Specific adverse effects seem to correlate with product excipient(su-crose/sodium)and osmolality.Therefore,there is a need to define better the relationship among various IVIg preparations, patient risk factors,and specific adverse effects.Twenty-nine cases of thrombotic complications with the use of IVIg have been reported and include acute myocardial in-farction(AMI),cerebral infarction,pulmonary embolism(PE), deep venous thrombosis(DVT),hepatic veno-occlusive disease, and spinal cord ischemia(7–12).No correlation yet has been made between particular IVIg products and thrombotic com-plications.Many papers suggest that the thrombosis was in-cited specifically from the gammaglobulin incipient,contami-nants such as activated factor XI,or a high rate of drug infusion (13,14).There have been attempts to delineate the mechanism of IVIg-induced thrombosis(7,15–18),but no clear cause has been established.Another known complication of IVIg is acute renal failure (ARF)(19).Previous reports seem to suggest that sucrose-based products are commonly associated with ARF(19–22). Here,we report on the adverse effect profiles of three prod-ucts that were used at Cedars-Sinai Medical Center between 1997and2004.This study represents a nonrandomized,retro-spective study of patients who received those IVIg products during that period.Specific product use was based on phar-macy purchasing practices.Furthermore,no protocols for pre-medication before IVIg infusion to reduce adverse effects have been established.Here,we discuss procedures that were devel-oped at our center to attempt to decrease adverse events(AE) that are related to IVIg infusion.Received November10,2005.Accepted March12,2006.Published online ahead of print.Publication date available at .Address correspondence to:Dr.Ashley A.Vo,Center for Kidney Diseases&Transplantation,Cedars-Sinai Medical Center,8635W.3rd Street,Suite590W,Los Angeles,CA90048.Phone:310-423-2967;Fax:310-423-6369;E-mail:ashley.vo@Copyright©2006by the American Society of Nephrology ISSN:1555-9041/104-0844Materials and MethodsPatients and AEAfter approval was obtained from the Institutional Review Board, 279patients who received IVIg at Cedars-Sinai Medical Center between 1997and2004were identified for retrospective analysis.Seventy-six patients received Gamimune-N10%(Bayer Biologicals,West Haven, CT;October1997to June2000);105patients received Polygam(Baxter Inc.,Los Angeles,CA;April2000to February2002),and98patients received Carimune(ZLB Biologicals,Berne,Switzerland;March2002to September2004).A retrospective analysis of significant AE that were associated with various IVIg products was performed.Premedication protocols and product selection paradigms were developed from the data and applied to minimize serious AE.Postimplementation moni-toring of AE then was recorded.Any documentation of AMI,ARF,hypotension,or death within72h of administration was considered related to IVIg infusion.In addition, reports of other common adverse effects of headaches,flushing,pruri-tus,or rash were noted.To determine whether there was causality,we calculated an Adverse Drug Reaction score on the basis of10questions that were developed by Naranjo et al.(23)by two independent review-ers.A score of9of13or higher was considered highly probable, whereas5to8was moderate and1to4was unlikely.Once an AE was identified and found to be specific to a particular IVIg formulation with probable causality,product selection paradigms and premedication protocols were developed and applied to minimize AE.After these changes were made in2002,postimplementation mon-itoring for AE was reported.Three primary areas of risk for IVIg infusions were identified.These were cardiovascular disease,renal disease,and propensity for hyper-coagulation.Risk factors for AMI were based on National Cholesterol Education Program(NCEP)III guidelines(24)and included age(Ͼ50 for men,Ͼ60for women),history of AMI,hypertension,hypercholes-terolemia,diabetes,obesity,or previous evidence of peripheral vascu-lar disease(e.g.,stroke,atherosclerotic aortoiliac disease).Risk factors for ARF included(1)a history of diabetes,(2)history of cardiovascular disease and congestive heart failure,(3)history of elevated serum creatinine(Ͼ2.0mg/dl),and(4)advanced age(Ͼ70yr).Statistical AnalysesStatistical analysis was performed using the2test.AE in each IVIg group were analyzed and compared.Differences were considered sig-nificant at the0.05level.ResultsProduct Composition and Relations to AEGamimune-N10%,Carimune,and Polygam were the three IVIg products that were used at Cedars-Sinai Medical Center during the study period.Product selection was based on phar-macy purchasing practices.Table1identifies the most common IVIg products that were commercially available in the United States during the study period and their constituent makeup. Gamimune-N-10%excipient(Glycine)had the least amount of sodium chloride,had no sucrose,and is isosmolar(274 mOsm/L at10%).Carimune is a lyophilized powder that can be reconstituted in sterile water or normal saline.It contains 1.67g sucrose/g IVIg and at12%in saline has an osmolality of 1074mOsm/L and when reconstituted in sterile water has an osmolality of768mOsm/L.Polygam10%also is lyophilized and can be reconstituted in sterile water or normal saline.If reconstituted in NS,Polygam10%has an osmolality of1250 mOsm/L.In fact,at10%,the osmolality is identical to a2% saline infusion.The indications for use of IVIg in the279patients were hypogammaglobulinemia,idiopathic thrombocytic purpura, treatment of acute AMR,polyneuropathy,hematologic malig-nancy,and desensitization of highly HLA-sensitized patients who were awaiting solid-organ transplantation.Ages of recip-ients were4mo to92yr,and there was equal gender distribu-tion among groups.Approximately half of the patients in each group had risk factors for heart disease.Dosages received were between0.5and2g/kg(Table2).All IVIg products were infused at rates recommended by the manufacturer.For Gamimune-N10%the start infusion rate was0.01to0.02ml/kgTable1.Product characteristicsPreparation/ Concentrations Available Manufacturer Osmolality Sucrose Content(g/g protein)Sodium Content(mEq/L at5%concentration)Gamimune-N10% N/5%,10%Bayer309mOsm/kg solvent(water)for5%solution;274mOsm/kgsolvent(water)for10%solution0TraceGammagard/5%,10%Hyland Division ofBaxter Healthcare 636mOsm/kg solvent(water)for5%solution;1250mOsm/kgsolvent(water)for10%solution0147Polygam/5%,10%Hyland Division ofBaxter Healthcare 590mOsm/kg solvent(water)for5%solution;1179mOsm/kgsolvent(water)for10%solution0147Carimune3%,6%, 9%,12%ZLB CentralLaboratory3%,192mOsm/kg;6%,384mOsm/kg;9%,576mOsm/kg;12%,768mOsm/kg solvent(water)1.67 1.3Clin J Am Soc Nephrol1:844–852,2006Safety and Adverse Events of IVIg for Immunomodulation845per min for30min.If no adverse reactions occurred,then the rate was increased gradually to a maximum of0.08ml/kg per min.For Carimune,the start infusion rate was30ml/h for30 min,then60ml/h for30min,and was increased as tolerated by 30ml/h every15min to a maximum rate of120ml/h.For Polygam,the start infusion rate was0.5ml/kg per h and was increased slowly to a maximum rate of4ml/kg per h if well tolerated in patients with thrombotic risk factors such as coro-nary artery disease,hypertension and cerebrovascular disease, and diabetes.Significant AE(AMI and ARF)were noted only in the Po-lygam(PϽ0.01)and Carimune(PϽ0.0001)groups,respec-tively.Headache was the only notable adverse effect of Gamimune-N10%infusion(52%)but also occurred in other products.In our experience,headaches were self-limited and did not require additional investigation(computed tomogra-phy or magnetic resonance imaging)and usually respond to acetaminophen.Patient demographics are shown in Table2. The distribution of AE and significant AE is shown in Table3. IVIg and AMIFive cases of AMI were noted in patients who received IVIg. The ages ranged from34to72yr(Table4).All five patients had risk factors for cardiac disease.The number of IVIg treatments that were received before the event ranged from one to eight. Each patient developed symptoms during or shortly(3to5h) after IVIg infusion,which included shortness of breath and chest pain.The diagnosis of AMI was confirmed by electrocar-diogram and/or troponin elevations.In four cases,AMI pro-longed hospitalization.In the fifth case,the diagnosis of AMI resulted in the hospitalization after the patient received IVIg as an outpatient infusion.All patients recovered without signifi-cant long-term effects.Because AMI occurred only with Po-lygam,these were reported to the manufacturer and the Food and Drug Administration MedWatch.This resulted in a“Dear Doctor Letter”regarding the risk for thrombotic events that were associated with Polygam(25).Polygam’s excipient is a sodium chloride solution with an approximate osmolality of1250mOsm/L at10%.Analysis using the Naranjo algorithm yielded a moderate probability of causality.The risk for development of thrombotic events with Polygam also was statistically significantly different when com-pared with the other IVIg products(PϽ0.01).We hypothesized that the salt-based high-viscosity vehicle of this product likely was responsible for initiation of the thrombotic event seenTable2.DemographicsCarimune (nϭ98)Gamimune-N(nϭ76)Polygam(nϭ105)Gender(%)male484151female525949Indications(%)desensitization776637autoimmune212655immune deficiency288Age range2to84yr15to75yr4mo to92yr Cardiovascular risk factors a(%)565040Dose(g/kg;averageϮSD) 1.1Ϯ0.47 2.0 1.25Ϯ0.63a Coronary heart disease and coronary heart disease risk equivalents as defined by National Cholesterol Education Program (NCEP)III.Table3.AE and SAE aCarimune (nϭ98)Gamimune-N(nϭ76)Polygam(nϭ105)%AE or SAE nϭ8(SAE)N/A nϭ5(SAE) Gender3male/5female N/A2male/3female Age range(yr)39to7915to7534to77 Type of AE/SAEthrombotic005(4.7%);PϽ0.01 ARF8(8.2%);PϽ0.00100other(headache)49(50%)39(52%)52(50%)Doses2g/kgϭ7patients1g/kgϭ1patient 2g/kg2g/kgϭ4patients1g/kgϭ1patienta AE,adverse events;ARF,acute renal failure;SAE,significant adverse events.846Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol1:844–852,2006T a b l e 4.M y o c a r d i a l i n f a r c t i o n i n p a t i e n t s w h o r e c e i v e d P o l y g a m aP a t i e n t A g e /G e n d e rC o m o r b i d i t i e sI n d i c a t i o n f o r I V I g T o t a l N o .o f I V I g D o s e s D o s e o f I V I gR a t e o f I V I g I n f u s i o n b T i m e C o r r e l a t i o n b e t w e e n I V I g I n f u s i o n a n d O n s e t o f S y m p t o m s54/m a l e A I D S ,n o n -H o d g k i n ’sl y m p h o m a ,a o r t i c s t e n o s i sI T P2(i n p a t i e n t )D a y 1ϭ70g (1g /k g ;1400m l o f 5%)D a y 2ϭ70g (700m l o f10%)o v e r 12h ,1.7m l /k g p e r h o v e r 6h ,1.7m l /k g p e r h D a y 2:5h i n t o I V I g i n f u s i o nd e v e l o p e d S O B ,n o N /V ,C P .E C G c h a n g e s ,e l e v a t e dt r o p o n i n s ,t r a n s f e r r e d t oI C U .D i s c h a r g e h o m e 10dl a t e r49/f e m a l e P a u c i i m m u n eg l o m e r u l o n e p h r i t i s ,E S R D ,S /p k i d n e y t r a n s p l a n t ,h y p e r c h o l e s t e r o l e m i aS /p k i d n e y t r a n s p l a n t w i t hi n c r e a s i n g S C r 1(i n p a t i e n t )140g (2g /k g ;1400m l o f 10%)o v e r 5h ,3.9m l /k g p e r h A t t h e e n d o f i n f u s i o n ,p a t i e n t d e v e l o p e d C Pr a d i a t i n g t o l e f t a r m ,N /V ,S O B .S T e l e v a t i o n s ,e l e v a t e d t r o p o n i n .T r a n s f e r r e d t o I C U .D i s c h a r g e d h o m e 6d l a t e r34/f e m a l e S L E ,E S R D S /p k i d n e yt r a n s p l a n tT o r e d u c e P R A8(e v e r y m o n t h i n t h e o u t p a t i e n t p r o c e d u r e c e n t e r )100g (2g /k g ;1000m l o f 10%)o v e r 6h ,3.4m l /k g p e r h 5h a f t e r s t a r t o f i n f u s i o n ,d e v e l o p e d C P ,r a d i a t i n g t ot h e j a w ,S O B .E l e v a t e dt r o p o n i n s .D i s c h a r g e dh o m e 4d l a t e r77/f e m a l e C A D ,C H F ,M V R ,p a c e m a k e rp l a c e m e n t 1m o a g o ,d i a be t e s ,h y p e r t e n s i o nI T P 2.5(i n p a t i e n t )D a y 1ϭ66g (1g /k g ;660m l o f 10%)D a y 2ϭ63g (1g /k g ;630m l o f 10%)D a y 3ϭ31g (0.5g /k g ;310m l o f 10%)o v e r 6h ,1.7m l /k g p e r ho v e r 6h ,0.8m l /k g p e r hD a y 2:3h a f t e r s t a r t o fi n f u s i o n d e v e l o p e ds u b s t e r n a l c h e s t p a i n ,d i a p h o re s i s ,n o S O B ,N /V .E C G c h a n g e s ,e l e v a t e dt r o p o n i n s .D a y 3:N oc o m p l i c a t i o n s .U nde r w e n ts c h e d u l e d M V R n e x t d a y69/m a l e B r o n c h i e c t a s i s ,r e c u r r e n tr e s p i r a t o r y i n f e c t i o n s ,H /od e c r e a s e d I g G l e v e l s w i t hn o r m a l a n t i g e n r e s p o n s eT o m a i n t a i n a n t i b a c t e r i a l /v i r a l a n t i b o d y t i t e r s t op r e v e n t r e c u r r e n ti n f e c t i o n s1(i n p a t i e n t )70g (1g /k g ;700m l o f 10%)o v e r 6h ,1.7m l /k g p e r h E l e v a t e d t r o p o n i n ,u n d e r w e n t e m e r g e n ts t e n t i n gaC AD ,c o r o n a r y a r t e r y d i s e a s e ;C H F ,c o n g e s t i v e h e a r t f a i l u r e ;C P ,c h e s t p a i n ;E C G ,e l e c t r o c a r d i o g r a m ;H /o ,h i s t o r y o f ;I C U ,i n t e n s i v e c a r e u n i t ;I T P ,i d i o p a t h i c t h r o m b o c y t o p e n i c p u r p u r a ;I V I g ,i n t r a v e n o u s I g ;M V R ,m i t r a l v a l v e r e p a i r ;N /V ,n a u s e a a n d v o m i t i n g ;P R A ,p a n e l r e a c t i v e a n t i b o d i e s ;S C r ,s e r u m c r e a t i n i n e ;S L E ,s y s t e m i c l u p u s e r y t h e m a t o s u s ;S O B ,s h o r t n e s s o f b r e a t h .b P o l y g a m S /D 5%s o l u t i o n s h o u l d b e i n f u s e d a t a n i n i t i a l r a t e o f 0.5m l /k g p e r h .I f t h i s r a t e c a u s e s t h e p a t i e n t n o d i s t r e s s ,t h e n t h e r a t e m a y b e i n c r e a s e d g r a d u a l l y u p t o 4m l /k g p e r h .T h e 10%s o l u t i o n c a n b e s t a r t e d a t 0.5m l /k g p e r h u p t o a m a x i m u m o f 8m l /k g p e r h .Clin J Am Soc Nephrol 1:844–852,2006Safety and Adverse Events of IVIg for Immunomodulation847(AMI).Therefore,steps were taken to change the standard default IVIg formulation to one of a non–sodium-based lower osmolality solution(530mOsm/L;Carimune9%)or309 mOsm/L(Gamimune-N10%).In addition,premedication with aspirin as well as an option to hydrate patients was suggested. Because these changes were implemented and after approxi-mately250IVIg doses,no further cases of AMI have been reported.IVIg and ARFAfter the change from routine use of Polygam to that of either Carimune or Gamimune-N10%,eight cases of ARF were seen. ARF occurred only in patients who received the sucrose-con-taining IVIg(Carimune;PϽ0.0001;see Tables2and3).A Naranjo algorithm analysis also yielded a moderate probability of causality(score6).All eight patients had identifiable risk factors for ARF.Five of the eight patients had a history of chronic kidney disease or had received a kidney transplant,and the other three had diabetes,congestive heart failure,or recent IV contrast dye administration.Six of eight patients had signif-icant renal dysfunction with doubling of serum creatinine after IVIg administration,with six requiring hemodialysis.However, recovery of renal function occurred in all patients within2mo.A renal allograft biopsy was done in one patient who had marked delayed graft function and received IVIg before kidney transplantation for a positive cross-match.Results were notable for acute tubular necrosis and marked vacuolization of proxi-mal tubular cells that were attributed to IVIg/sucrose.Table5 shows the characteristics of patients who developed ARF after sucrose-containing IVIg infusions.Figure1shows an electron micrograph demonstrating vacuolization in renal tubules in a patient with osmotic nephropathy after sucrose-containing IVIg infusion.After noting the relationship between ARF and previous kidney dysfunction in patients who received Carimune,all patients who receive IVIg now are required to have a preinfu-sion baseline serum creatinine and screening for risk factors for renal disease.Subsequently,avoidance of sucrose-based prod-ucts in patients who are at risk by specifically selecting non–sucrose-containing isosmolar products has resulted in no addi-tional cases of ARF.IVIg Infusions in ESRD Patients on Hemodialysis Administering IVIg is challenging in patients who are unable to tolerate high volumes or solute loads,such as those with congestive heart failure and ESRD.This is particularly impor-tant for prekidney transplant recipients,who usually are dial-ysis dependent and prone to volume overload.Like any other blood product,we infused IVIg(Gamimune-N10%)during hemodialysis and compared this with placebo(albumin0.1%) as part of the NIH IG02study(26).More than300infusions of IVIg were given to50patients and compared with an equiva-lent number of placebo infusions to52patients.Analysis showed that IVIg was well tolerated with a low incidence of volume overload,pruritus,and rash.The number of minor (7.7%in IVIg versus7.5%in albumin)and significant(0.3%IVIg versus2.8%albumin)AE were comparable to or less than that of placebo.DiscussionThe use of IVIg products for the treatment of autoimmune and inflammatory disorders has increased dramatically in the past decade.In addition,recent data suggest that IVIg products are useful in the treatment of highly HLA-sensitized patients who are awaiting transplantation and for the management of viral infections and AMR(26–28).The use of higher doses, concentrations,and rapid rates of infusion of IVIg products has resulted in higher rates of infusion-related complications that, at first,were not anticipated and were poorly understood.It now is very clear that IVIg products vary considerably in their composition and that these differences have clinical im-plications(29).All contain IgG molecules(90to99%)but differ considerably in excipient.IVIg products differ in osmolality, pH,and sugar and sodium content,and this is postulated to result in product-specific adverse effects(6).The use of Po-lygam,which contains high concentrations of sodium at10%, was associated with five cases of AMI.MI is a known compli-cation of IVIg infusion(10,14).Our findings suggest that this may be due to the excipient(sodium chloride)and not incipient as evidenced by the lack of events with sucrose-based and isosmolar products.In addition,these events did not occur when Polygam was administered to patients who were on hemodialysis,suggesting that reductions in sodium content and/or heparinization was protective.Furthermore,it seems that viscosity of the diluent may be a factor that increases the risk for thrombosis as Polygam10%had a much higher osmo-lality than Carimune9%or Gamimune-N10%.Previous re-ports have shown that IVIg increases blood viscosity(30),and it is possible that it contributes to the thrombogenic nature of sodium-based IVIg formulations.Other possible explanations for the prothrombotic effects of IVIg suggest that there might be an effect on platelet aggregation.However,Vassilev et al.(31) showed that IVIg actually contains antibodies that are inhibi-tory to inducers of platelet aggregation.Data from Abe et al.(32)also support an antithrombotic effect of IVIg in Kawasaki disease.The antiplatelet agent aspirin may decrease the risk for myo-cardial events during IVIg infusion.Whether Ig causes in-creased platelet aggregation in vivo is unknown but seems unlikely on the basis of published data.This is consistent with previous experiments in which IVIg did not cause an increase in platelet ADP release and actually can reduce aggregation that is seen with other agents(7,11).However,unless there is a contraindication,we would recommend that patients who are at higher risk for thrombosis or MI receive aspirin and hydra-tion(250ml of0.9normal saline over30min)before IVIg infusion.There are no data to support any particular premed-ication regimen.However,our experience supports the pre-IVIg infusion use of Benadryl25to50mg orally or intrave-nously,Tylenol650mg orally,or aspirin325mg orally and Solu-Medrol40mg intravenously30min before the infusion to reduce infusion-related adverse effects.Selection of products with lower osmolality or reduction in osmolality of sodium-848Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol1:844–852,2006T a b l e 5.I V I g a n d r e n a l f a i l u r e aP a t i e n t A g e /G e n d e rC o m o r b i d i t i e sI n d i c a t i o n f o r I V I gT o t a l N o .o f I V I g D o s e s D o s e o f I V I g R a t e o f I V I g I n f u s i o n T i m e C o r r e l a t i o n b e t w e e n I V I g I n f u s i o n a n d O n s e t o f S y m p t o m s40/f e m a l e S /p l i v i n g -u n r e l a t e d k i d n e y t r a n s p l a n tw i t h r e n a l i n s u f f i c i e n c y (b a s e l i n ec r e a t i n i n e 1.9)S /p k i d n e y t r a n s p l a n t ϫ1m o w i t hp o s i t i v e c r o s s -m a t c h 2140g o v e r 8h ,2.5m l /k g p e r h D a y 2:F o l l o w -u p a t r e n a l t r a n s p l a n tc l i n i c r e v e a l ed t h a t c re a t i n i n e w a se l e v a t e df r o m b a s e l i n e o f 1.9t o 2.3.P a t i e n t u n d e r w e n t b i o p s y ,w h i c hs h o w e d e a r l y c a l c i n e u r i n t o x i c i t y .R e n a l f u n c t i o n r e c o v e r e d a f t e r 4d .72/m a l e S /p c a d a v e r i c k i d n e y t r a n s p l a n t w i t hr e n a l d y s f u n c t i o n (b a s e l i n e c r e a t i n i n e3.4).P e r i p h e r a l v a s c u l a r d i s e a s eI T P 170g o v e r 6h ,1.2m l /k g p e r h D a y 2:C r e a t i n i n e i n c r e a s e d f r o mb a s e l i n e o f 3.4t o 7.2.P a t i e n t r e q u i r e dh e m o d i a l y s i s .R e n a l f u n c t i o n s l o w l yr e c o v e r e d t o b e t t e r t h a n b a s e l i n e a f t e r5w k ,a n d p a t i e n t w a s t a k e n o f fd i a l y s i s .54/f e m a l e C o n g e s t i v e h e a r t f a i l u r e w i t h r e n a li n s u f f i c i e n c y ,r e c e n t c o n t r a s t d y ea d m i n i s t r a t i o n ,g o u tP o s i t i v e Q u i c k S c r e e n P R A a n d c r o s s -m a t c h b e f o r e h e a r t t r a n s p l a n t 270g o v e r 8h ,1.2m l /k g p e r h D a y 2:C r e a t i n i n e i n c r e a s e d a f t e r s e c o n dd o se of I V Ig f r o m 1.3t o 1.9w i t ha n u r i a .P a t i e n t r e q u i r e d h e m o d i a l y s i sa n d h i g h -d o s e d i u r e t i c .P a t i e n tr e q u i r e d d i a l y s i s f o r 1w k b u tr e c o v e r e d c o m p l e t e l y .79/m a l e D i a b e t e s w i t h C K D ,b a s e l i n e c r e a t i n i n e1.5t o2.2.H e a r t f a i l u r e ,g o u t ,a n dn e p h r o l i t h i a s i s .A t r i a l f i b r i l l a t i o nI T P 170g 1.2m l /k g p e r h D a y 2:C r e a t i n i n e i n c r e a s e d f r o m 1.3t o7.0.P a t i e n t b e c a m e o v e r t l y u r e m i c a n dr e q u i r e d d i a l y s i s f o r 7d .R e n a lf u n c t i o n r e c o v e r e d a n d c r e a t i n i n e w a sb ac k t o b a s e l i n e b y 10d a f te r I V I gi n f u s i o n .70/f e m a l e S /p c a d a v e r i c k i d n e y t r a n s p l a n tP o s i t i v e c r o s s -m a t c h b e f o r e k i d n e yt r a n s p l a n t .G i v e n r i g h t b e f o r et r a n s p l a n t170g o v e r 4h ,2.5m l /k g p e r h D a y 1:D e l a y e d g r a f t f u n c t i o ni m m e d i a t e l y a f t e r k i d n e y t r a n s p l a n t .P a t i e n t r e q u i r e d h e m o d i a l y s i s f o r 1w k b u t r e c o v e r e d c o m p l e t e l y .B i o p s ys h o w e d p r o x i m a l t u b u l a r c e 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