Nephrotic Syndrome Due to Metformin

118

Olgu Sunumu/Case Report

Turk Neph Dial Transpl 2016; 25 (1): 118-120

Nephrotic Syndrome Due to Metformin

Metformine Bağlı Nefrotik Sendrom

Garip Şahin1

Yusuf KaraKaŞ2

Fatih TaŞTeKin2

Mustafa Fuat açıKalın3

1 EskişehirOsmangaziUniversityFacultyofMedicine,DepartmentofNephrology,

Eskişehir,Turkey2 EskişehirOsmangaziUniversityFaculty

ofMedicine,DepartmentofInternalDiseases,Eskişehir,Turkey

3 EskişehirOsmangaziUniversityFacultyofMedicine,DepartmentofPathology,

Eskişehir,Turkey

doi: 10.5262/tndt.2016.1001.16

Correspondence Address:Garip ŞahinEskişehirOsmangaziÜniversitesiTıpFakültesi,NefrolojiBilimDalı,Eskişehir,TurkeyPhone :+902222392979E-mail :gsahin@ogu.edu.tr

absTracT

Heavyproteinuriaandnephroticsyndromemayoccurinassociationwithawidevarietyofprimaryandsystemicdiseasesandalsowithdrugs.Majordrugsthatcaninducenephroticsyndromeandglomerulardamagearegold,penicillamine,bucillamineandnon-steroidalanti-inflammatorydrugs.Innephroticsyndromeduetothesedrugs,themajortypeofrenaldiseaseismembranousglomerulonephritisandthenephropathyresolvescompletelywhenthedrugiswithdrawn.Herewereportapatientwhodevelopednephroticsyndromeaftertheinitiationofmetformin.Laboratoryparametersimprovedrapidlyafterthediscontinuationofthedrug.Ourcaseisimportantasitisthefirstcasewithnephroticsyndromeduetometforminintheliterature.

Key words:Proteinuria,Nephroticsyndrome,Metformin,Drugnephropathy

Öz

Ağır proteinüri ve nefrotik sendrom primer, sekonder hastalıklar ya da ilaçların değişik oranlardakatkılarıilebirlikteoluşabilir.Altın,penisilamin,busilaminvesteroidolmayanyangıgidericiilaçlarnefrotiksendromveglomerülerhasarıoluşturanönemliilaçlardır.Builaçlardandolayıoluşannefrotiksendromdarenalhastalığınönemlitipimembranözglomerülonefrittirveilaçkesildiğizamannefropatitamamı ile gerileyebilir. Biz metformin başlandıktan sonra nefrotik sendrom gelişen olguyu raporediyoruz.Laboratuvarparametreleriilaçkesildiktensonrahızlıbirşekildeiyileşmişti.Bizimolgumuzliteratürdemetforminebağlınefrotiksendromolanilkolguolmasındandolayıönemesahiptir.

anahTar sözcüKler:Proteinüri,Nefrotiksendrom,Metformin,İlaçnefropatisi

Received :08.09.2014Accepted :09.11.2014

ınTroducTıon

Heavy proteinuria and the nephroticsyndrome may occur in association witha wide variety of primary and systemicdiseases.Inadults,approximately30percenthave a systemic disease such as diabetesmellitus, amyloidosis, or systemic lupuserythematosus; the remaining cases areusuallyduetoprimaryrenaldisorderssuchasminimalchangedisease,focalsegmentalglomerulosclerosis, and membranousnephropathy(1,2)

Nephrotic syndrome can be inducedby drugs. Major drugs that induce drug-related nephrotoxicity are antibiotics,NSAID, radiocontrast media, anticancerdrug and antirheumatic drugs. Drug-

induced nephropathy can cause variousforms of renal diseases. The nephropathyconsists of acute tubular necrosis, acutetubulointerstitial nephritis, pre-renal typerenal failure, obstructive renal failure,chronic tubulointerstitial nephritis andglomerulardamage(3,4).

Major drugs that induce nephroticsyndromeandglomerulardamagearegold,penicillamine, bucillamine and NSAID.In the nephrotic syndrome due to thesedrugs, the major type of renal disease ismembranous glomerulonephritis and thenephropathy resolves completely whenthe drug iswithdrawn; renal function doesnot deteriorate, and corticosteroids areunnecessary(3-5).

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Türk nefroloji diyaliz ve Transplantasyon dergisiTurkish Nephrology, Dialysis and Transplantation Journal Şahin G et al: Nephrotic Syndrome Due to Metformin

Turk Neph Dial Transpl 2016; 25 (1): 118-120

Our case is important as it is the first case with seriousproteinuriaduetometforminintheliterature.

Here,wereportacasewithnephroticrangeproteinuriathatdevelopedduringtreatmentwithmetformin.

case reporT

A 49 year-old woman patient presented with a 2-3 weekhistoryoffatigueandprogressive-diffuseperipheraloedemaandwas hospitalized in 11November 2012.Her previous historywas unremarkable; however, she had used metformin 2*500mgrinthelastmonth.

On physical examination, blood pressure was 130/80mmHgandpulse72permin.Symmetrical3+pretibialoedemawasfound.Hereyeexaminationdidnotshowhypertensiveordiabeticretinopathy.

Before the use ofmetformin, blood count, clotting, serumelectrolytes ,renal functions, lipid profile and liver functionvalueswereallnormal.Themicroscopicexaminationofurinewasnormal.

Onemonthafterstartingmetformin,bloodchemistryrevealedhypoproteinemiawithtotalproteinof4.5g/dl(normal6.0-8.5)and albumin of 2.0 g/dl (normal 3.5-5), and hyperlipidemiawith total cholesterol of 454 mg/dl (normal 112-200 ). LDLcholesterol was 207 mg/dl (normal 0-100), triglyceride levelwas 1320mg/dl.A 24-h urine collection identified 7.45 g ofprotein. Other hematological and biochemical parameterswere within normal limits. The microscopic examination ofurinewasnormal.Hepatitismarkersandantinuclearantibodywere negative Complement levels were also normal. Serumimmunoglobulinandserumproteinelectrophoresiswerenormal.Renalultrasonographicevaluationwasnormal.

A total of 18 glomeruli were seen in the renal biopsyspecimen. Two of them were globally sclerotic. One of twoglomeruli showed mild increase in mesangial matrix andmesangial hypercellularity.Other glomeruli, tubular, vascular,interstitium were normal. Immunofluorescence study did notshowimmunedeposits(Figure1).

The diagnosis was nephrotic syndrome due to metforminusagewiththesefindings.

A month after metformin was discontinued, her renalfunctionimprovedwith80%reductionofproteinuriato1.59g/day.Thealbumin,whichhaddecreasedtoamaximumof1.8-2g/dlincreasedto3.4mg/dlatthistimeandlipidswerenormal.

At2monthsafterdiagnosis,proteinuriaof7.45g/dayhadreducedto1.1g/daySerumalbuminincreasedto3.6mg/dlandtheLDLcholesterolleveldecreasedto74mg/dl.

Monthly controls were continued during this period. Theserum albumin levels were normal and proteinuria level wasabout<300mg/day.

dıscussıon

Drug-induced kidney disease is an important cause ofacute renal failure and chronic kidney disease. Drug-inducednephropathycanshowvariousformsofrenaldiseasesbyvariousmechanisms.Somemechanismsaredecreasedrenalperfusion,vascularordirecttubularinjury,allergicinterstitialinflammation,andglomerularbasementmembraneinjury(3).Inthispaperwereport a casewith nephrotic range proteinuria that developedduringtreatmentwithmetformin.Themajortypeofrenaldiseasein the nephrotic syndrome due to these drugs ismembranousglomerulonephritis (4).Drugs that inducenephrotic syndromeandglomerulardamagearegold,penicillamine,bucillamineand,NSAIDS,certainCOX-2inhibitors,mercury,captopril,lithiumformaldehyde,trimethadione,probenecid2-Mercaptopropionylglycine, procainamide, hydralazine, isoniazid, methyldopa,chlorpromazine, quinidine, propylthiouracil, anti-TNF drugsand anti cancer drugs (5). In these cases, the nephropathymay resolve completely after withdrawal of the drug andimmunosuppressant drugs, glucocorticoids, hemodialysis arerequiredforthetreatmentofrenalfailureinmostofthecases.

Wepresentedacaseofnephroticsyndromethatdevelopedduringusingmetforminfortype2diabetesmellitus.Metforminis an oral biguanide used in the management of non insulindependent diabetes mellitus. It is one of the most widelyprescribedoralantidiabeticdrugsintype2diabetes.Itreducesblood glucose levels by improving peripheral sensitivity toinsulin, and reducing gastrointestinal glucose absorption andhepatic glucose production (6). Metformin has potentiallybeneficialeffectsonserumlipidlevelsandfibrinolyticactivity.Metforminreducescardiovascularmorbidityandmortality(7).Metforminalsohasintracellularantioxidantproperties,preventsglucose-inducedoxidativestressinpodocytesandpreventsthedevelopmentofglomerularinjuryasacomplicationofdiabetesmellitus (8). Metformin also provides protection againstgentamycin-induced renal injury by preventingmitochondrialpermeability disorders and decreasing the production ofhighlyreactiveoxygenspecies(9).Metformin isconsideredasafe and effective drug and is usedwidely but has some sideeffectsinadditiontotheabovementionedbeneficialeffects.Themost serious complicationassociatedwithmetformin is lacticacidosis.OthersideeffectsaregastrointestinaldisturbancesandvitaminB12deficiency(10).Inourliteraturereview,wecouldnotfindanyothercasesofnephroticsyndromethatdevelopedafter metformin usage. To the best of our knowledge, this isthe first case that developed nephrotic syndrome after usingmetformin. In our case, the proteinuria started after initiationofmetforminandthepatient’srenalfunctionimprovedwithoutspecific treatmentaftermetforminwasdiscontinued.Nootheretiological factorswere found and these strongly suggest thatthenephroticsyndromeoccurredduetometforminusage.

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Türk nefroloji diyaliz ve Transplantasyon dergisiTurkish Nephrology, Dialysis and Transplantation Journal Şahin G et al: Nephrotic Syndrome Due to Metformin

Turk Neph Dial Transpl 2016; 25 (1): 118-120

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10.HowlettHC,BaileyCJ:Arisk-benefitassessmentofmetforminintype2diabetesmellitus.DrugSafety1999;20:489-503

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Figure 1: The glomerulus at the lower right shows a mild increase in mesangial matrix and cellularity. Other glomeruli, tubules and interstitium are unremarkable (H&E x100).