MANUSCRIPT COVER LETTER

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MANUSCRIPT COVER LETTER

  1. 1. 0 MANUSCRIPTCOVER LETTER We are requestingconsiderationof thispaperforpublicationinthe LSMBNewsletter. Thispaperhas notbeen publishedpreviouslyandisnotcurrentlybeingconsideredbyanother journal. We acknowledgeanypotential conflictof interest.The final versionof the manuscripthasbeenreadandapprovedbyall of the authors. Dr. Sherri D. OnyiegoandDr. AlanLebatohave beendesignatedasthe correspondingauthorand theirmailing addressesare: Dr. AlanLebato LSUHSC FamilyMedicine ResidencyProgramatLake CharlesMemorial Hospital 1525 Oak Park Blvd Lake Charles,LA 70601 (337) 494-2023 (Office) (337)434-6750 (Fax) And Dr. Sherri D. OnyiegoMD,PhD 2221 HadleySt Houston,TX 77003 (832)273-0858 (Cellular) sherridstring@yahoo.com Signaturesof all the authors: Dr. Sherri D. Onyiego Dr. AlanL. LeBato Dr. Luan D. Truong
  2. 2. 1 Acute Renal Failure as the Initial Presentation of Multiple Myeloma Sherri D. Onyiego, M.D, Ph.D.,……………………….., Luan D. Truong, M.D., …..Alan L. Lebato, M.D. From the Department of Family Medicine, LSUHSC-New Orleans Family Medicine Residency at Lake Charles Memorial Hospital, Lake Charles, LA; And the Department of Pathology, The Methodist Hospital, Houston, TX Please addresscorrespondence to: AlanLebato,MD From: Departmentof FamilyMedicine,LSUHSC-New OrleansFamilyMedicineResidencyatLake Charles Memorial Hospital,Lake Charles,LA.1525 Oak ParkBlvd,Lake Charles,LA 70601 Phone:(337) 494-2023 Fax:(337) 494-6750 And Sherri D. Onyiego,MD,PhD 2221 HadleySt Houston,TX 77003 Email:sherridstring@yahoo.com
  3. 3. 2 ABSTRACT Multiple myelomaaccountsfor1% of all malignanciesandslightlymore than10% of all hematological malignancies.Multiple myelomaischaracterizedbythe proliferationof asingle clone of plasmacellsproducing a monoclonal immunoglobulin.Thisproliferationoccursinthe bone marrow,resultinginextensive bony destructionandotherclinical featuresincludinganemia,elevatedserumcalciumlevelsandrenal insufficiency. Thisarticle illustratesacase presentationof apatientwhoinitiallypresentedwithrenal insuffiencyandeventual severe tubulointerstitialinjurylikelyrelatedtomyelomacasts.Acute renal failure due tomyelomacast nephropathyisoftenthe initial presentationof multiplemyeloma,inwhichcase the diagnosismaybe first suggestedbythe renal biopsyfindingsandissubsequentlyconfirmed.Thissequence isillustratedinthe current patient. INTRODUCTARY CASE PRESENTATION A 58-year oldCaucasianmanwas admittedtothe hospital fromthe LSU FamilyMedicine Clinicof Lake Charles Memorial Hospital forthe complaintof nausea,weakness,anddizziness.The patientreportedasyncopal episode while doingyardworkonthe dayprior to admission.He feltthatitwassecondarytothe heatand later tooka coldshowerandrestedforthe restof the day.Since the patient’sweaknesspersisted,he wasbroughtto the FamilyMedicine clinicforfurtherevaluation. Significantpastmedical historyincludedanemergencyroomvisitapproximatelyone monthpreviouslyfora hypertensive crisis.The patient’santihypertensiveregimenwaschangedinthe EmergencyRoom fromlisinopril 20mg dailytolisinopril40mgdaily,withsubsequentstabilizationof hisbloodpressure.Hiscurrentmedications includedlisinopril,hydrochlorothiazide,allopurinol,andatorvastatin. On admission, laboratorystudiesshowedaserumcreatinine of 4.0mg/dL (normal range 0.5-1.6mg/dL), hemoglobinwas8.8g/dL(normal range 13.0-17.0 gm/dL),and hematocritwas27% (normal range 37.2-51.9%). A CT scan of the brainon admissioninthe evaluationof hissyncope wasnormal. One year previouslythe patient’sbaseline creatinine was1.6mg/dl likelyreflectingunderlyinghypertension. The admittingdiagnoseswere acute renal insufficiency,likelysecondary tomedicationsandanemiasecondary to hypertension-inducedchronicrenal insufficiency.Afterrehydration,the patient’sBUN and creatinine improvedto29 mg/dL(normal range 5-26mg/dL) and 2.32 mg/dL(normal range 0.5-1.6mg/dL) respectively;but the hemoglobinremained8.8g/dL(normal range 13.0-17.0 gm/dL) withnormal indices.The patienthadno
  4. 4. 3 furthercomplaintsof nauseaanddizziness.Hisbloodpressureremainedstable.Uponadmission,the patient’s home medications,lisinopril andallopurinol,were discontinuedonadmission,andamlodipine 2.5mgdailywas startedfor bloodpressure control. Afterhospital discharge,a24 hour collectionof urine forproteinexcretionandcreatinineclearance was obtained,the studyshoweda24-hoururine volume of 3050 ml (normal range 800-1800mL), 24-hour urine proteinexcretionof 3904 mg/24hr (normal range 0-150 mg/24hr), urine creatinine2.1gm/24hr(normal range 0.7-2.0 gm/24hr),and a creatinine clearanceof 51 cc/min/1.73M2 (normal range 72-141 cc/min/1.73M2). Of note,a 24 hour urine collectiontakenapproximatelyone yearpreviouslyduringthe workupof hisrenal insufficiencydid notreveal anyevidence of proteinuria. Two weekslater,the patientreturnedwithcomplaintsof fatigue,butthe patientdidnothave anynauseaor anorexia,andhisurinaryoutputwasnormal.However,laboratorystudiesshowedworseningrenal insufficiency, witha creatinine of 7.37 mg/dL (normal range 5-26mg/dL),and hemoglobinof 7.8g/dL(normal range 13.0-17.0 gm/dL).He was admittedwithadiagnosisof acute renal failure due torapidlyprogressive glomerulonephritisor drug-inducedacute tubulointerstitial nephritis.Afteranephrologyconsultationwasobtained,anultrasound showedthe sizesof the rightandleftkidneystobe 11.1cm and 12.5cm respectively.Urine analysisrevealed3 redbloodcellsand7 white bloodcells/high-powerfield. Hemodialysisandepoetinalfaforhisanemiawere startedtogetheraftera transfusionof 2 unitsof packedredbloodcells. A renal biopsywasperformedandshowedseveretubulointerstitial injurypossiblyrelatedtomyelomacast nephropathy.(Seebelow) A bone marrowbiopsyshowedactive normocellularhematopoieticmarrow andtrilineagematuration.Serum proteinelectrophoresis(S-PEP) revealedamonoclonal patternwithabnormalityof albumin3.11g/dL (normal range 3.40-5.10 g/dL),and normal rangesof α1, α2, β, andγ respectively.However,urine protein electrophoresis(U-PEP) revealedanatypical bandormonoclonal spike thatwasdetectedinthe kapparegion, and quantitative BenceJonesproteinina24 hour urine collectionrevealedkappalightchainsof 150mg/dL (normal range <1.9mg/dL).This wasinterpretedasaMonoclonal gammopathywithtrace IgG and IgA in the urine.There wasnoevidence of IgMin the urine.Beta-2microglobulinwaselevatedat5.3 mg/L(range 0.5- 1.5mg/L). Immunofixationstudiesrevealedthe detectionof IFEparaprotein. Rheumatoidfactorand complementlevelswere negative andwithinnormal limitsrespectively.Thisdatadidnotsupportany
  5. 5. 4 autoimmune involvement.LDHanduric acidwere alsoobtainedwhichwere withinnormal limits. Throughoutthe restof hishospitalizationthe patient’sbloodpressureremainedstable,andnosignificant clinical findingswere notedaside fromedemasecondarytosteroids,whichwere switchedtoalow dose oral taperupon discharge. The patientwassubsequentlyreferredtothe MD AndersonHospital inHouston,TX,where abone scan revealedasingle lyticlesioninthe leftclavicle.Stemcell transplantationhasbeenrecommendedfortreatment of thispatient'smultiple myeloma. RENAL BIOPSY FINDINGS Lightmicroscopy:The tissue sectionsshowed12 glomeruli,three of whichwere globallyscleroticbutthe others displayednosignificantchanges.The bloodvesselsshowedmildintimal fibrosis,consistentwithhypertensive changes.The most remarkable changeswere severechronictubulointerstitialinjurycharacterizedbytubular atrophy,interstitialfibrosis,andinterstitial inflammatorycellinfiltrates(Figure 1A).Several tubulescontained casts featurescharacteristicforthe typesof renal tubularcastsseeninmultiple myeloma.i.e.large,fragmented, negative bythe periodicacid-Schiffstain,andassociatedwithmultinucleatedgiantcellsorneutrophils(Figure 1B and 1C). The tissue portionsubmittedforimmunofluoresecentstudiesforimmunoglobulinandcomplementcomponents showedonlymedullarytissue,withoutglomeruli.Tubularcastswere notseenandthere wasno stainingfor tubularbasementmembrane. Electronmicroscopicstudyshowednosignificantglomerularchanges.Specifically,featuresof lightorheavy chaindepositionoramyloidosiswere notseen.The final diagnosiswassevere tubulointerstitial injuryprobably relatedtomyelomacasts. DISCUSSION The renal biopsyshowedtubulointerstitial injury,whichcanbe correlatedwiththe apparentlyacute renal failure inthispatient.The renal biopsyfindingsalsohelpestablishmultiple myelomaasthe cause of the acute renal
  6. 6. 5 failure. The type of tubularcastsseeninthisbiopsyhave characteristicfeatures,i.e.large,fragmented,negative inPAS stain,andassociatedwithmultinucleatedgiantcells,whichare almostpathognomonicformultiple myeloma. The monoclonal immunoglobulinfragment,includinglightorheavychains,inmultiple myelomacandepositin kidneytissue,anddependingmostlyonitsphysicochemical characteristics,caninduce myelomacast nephropathy,lightchainorheavychaindepositiondisease,lightorheavychainamyloidosis,orcrystal nephropathy,amongwhichmyelomacastnephropathyisprobablythe mostfrequent.Thesediseasesare usually mutuallyexclusive inanindividual patient,butmayco-exist,withthe mostfrequentcombinationbeing myelomacastnephropathyandlightchaindepositiondisease. Patientswithmultiplemyelomaoftendeveloprenal failureduringthe disease course.Its causesmaybe multifactorial,including,hydroelectrolyticabnormalities,superinfection,radiocontrastnephrotoxicity, medications,andmyelomacastnephropathy.Amongthese causes,myelomacastnephropathyisprobablythe mostfrequent.Furthermore,acute renal failure due tomyelomacastnephropathyisoftenthe initial presentationof multiplemyeloma,inwhichcase the diagnosismaybe firstsuggestedbythe renal biopsy findingsandissubsequentlyconfirmed.Thissequence isillustratedinthe currentpatient. Heavyproteinuriaisusuallythe manifestationof significantglomerularinjury.Sincemyelomacastnephropathy ischaracterizedbymarkedtubulointerstitial injury,withoutsignificantglomerular involvement,proteinis usuallyabsentormild.Onthe otherhand,thispatienthadnephroticrange proteinuria,whichcannotbe readily accountedforby myelomacastnephropathy.Asmentionedabove,myelomacastnephropathycanrarelybe associatedwith lightchaindepositiondisease,whichtendstoinvolve glomeruli andthusisassociatedwith heavyproteinuria.We therefore carefullyevaluate thispossible associationinthe currentrenal biopsy. Unfortunately,glomeruli are notavailable inthe portion submittedforimmunofluorescentstudy,whichisthe mostsensitive diagnostictestforlightchaindepositiondisease.Electronmicroscopyoftenshowstypical featuresof lightchaindepositiondisease,yetitcanbe negative inthe earlyphasesof the disease,thusa negative electronmicroscopicfinding,asinthe currentcase,cannot completelyeliminate the possibilityof light chaindepositiondisease.
  7. 7. 6 FIGURELEGEND A: There istubularatrophy,thickenedtubularbasementmembrane,interstitial fibrosis,andmildinterstitial inflammation.Tubularcasts,whichare large,fragmented,andPASstain-negative (Arrows),are alsoseen.The glomeruli are unremarkable (PASstainx 200). B: The tubularcastsare associatedwithmonoandmultinucleated macrophages(Arrows) (H&E,x 400). C: Some othertubularcastsare associatedwithneutrophils(Arrows) (H&E, x400). CONCLUSIONS Multiple myelomaaccountsfor1% of all malignanciesandslightlymore than10% of all hematological malignancies.Annual incidence of the diseaserangesfrom4 to5 per 100,000. Multiple myelomaoccursinall races andgeographiclocations.The incidence inAfricanAmericansistwice thatof Caucasiansandit isslightly more frequentinmenthanwomen. Multiple myelomais characterizedbythe proliferationof asingle clone of plasmacellsproducingamonoclonal immunoglobulin.Thisproliferationoccursinthe bone marrow and resultsinextensive bonydestructionwith osteolyticlesions,osteopenia,pathologicfracturesandpain.Otherclinical featuresmayinclude anemia, elevatedserumcalciumlevelsandrenal insufficiency. Bone pain,particularlyinthe chestandback, isthe mostcommonpresentingcomplaint.The bone painismore commonwithmovementandusuallydoes notawakenthe patientfromsleepexceptwithmovement.Bone pain occurs inroughly60% of patients.Weaknessandfatigue mayalsobe notedinupto 32% of patientsandisfeltto be associatedwithanemia.Weightlossmayoccurinup to 24% of patients. Feverisuncommon(<1%) unless associatedwithco-existinginfection.Conventionalradiographswill reveal alesionin80% of patientsat the time of diagnosis.Focal,lyticlesionswill be foundin60% of these patientswithosteoporosis,pathologicfractures,or compressionfracturesbeingpresentin20%of the patients.Hypercalcemiaispresentin20% of patients. The literature supportsthe factthat renal insufficiencyrangingfrommildtosevere casescanbe foundinas manyas 50% of patientswithmultiplemyeloma.Thisrenal impairmentusuallypresentsasproteinuriaandrenal insufficiency.The pathogenesiscanoftenbe multifactorial.Lightchainimmunoglobulin,inparticular,can directlycause kidneydestructionbycausingproximal tubulardamage andmyelomacastnephropathy.(2 ) Dehydration,nephrotoxicdrugs(ex,NSAIDs,andcertainantibiotics),infection,hyperuricemia,and
  8. 8. 7 hypercalcemiaare otherfactorsthatmay contribute torenal insufficiencyinmyelomapatients,andshould consequently be managedinthe contextof the clinical presentation.The riskforthe developmentandseverity of renal failure hasbeenassociatedwiththe level of lightchainexcretion.( 1,3 ) Whencomparingpatientswith multiple myeloma withoutrenal failure versusmultiple myelomapatientswhopresentwithrenal failure/insufficiencyorcast nephropathy,the patientswithconcomitantrenal insufficiencyare more likelyto have concomitanthypercalcemia,severe anemia,andadvancedmyeloma,inparticularlightchainmyeloma.( 1 ) Thispatientwasunusual inthat he had no bone pain,anormal bone marrow,and normal serumcalciumlevels on initial workup.Radiographicstudiesfoundonlyasingle lyticlesioninhisclavicle,andthatwas afterthe diagnosiswasmade byelectrophoresisandonlyafteritwassuspectedbyrenal biopsy. Early andaggressive treatmentandmanagementof the renal insufficiencyandmyelomaare critical for improvingsurvival.One of the mainstaysof treatmentistodecrease the level of lightchainproductionby chemotherapeuticagentsalone orincombinationwithstemcell transplantation,bothof whichhave been offeredtothe patientpresentedinthiscase. ACKNOWLEDGEMENTS The authors are grateful forthe consultationandadvice: Dr.LuanTruong, Dr. Michael Broussard,andDr. Tony Leung. REFERENCES 1. KorbetS.M.,Schwartz M.M. Multiple Myeloma.JAmSoc Nephrol 17: 2533-2545, 2006 2. SamsonD. et al.DiagnosisandManagementof Multiple Myeloma.Guideline.BritishJournal of Haematology.2001, 115, 522-540 3. KnudsenLM, etal.Renal functioninnewlydiagnosedmultiple myeloma:A demographicstudyof 1353 patients.The NordicMyelomaStudyGroup.Eur J Haematol 65: 175-181, 2000.

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