Nephrotic Syndrome Due to Metformin
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118 Olgu Sunumu/Case Report Turk Neph Dial Transpl 2016; 25 (1): 118-120 Nephrotic Syndrome Due to Metformin Metformine Bağlı Nefrotik Sendrom Garip Şahin 1 Yusuf KaraKaŞ 2 Fatih TaŞTeKin 2 Mustafa Fuat açıKalın 3 1 Eskişehir Osmangazi University Faculty of Medicine, Department of Nephrology, Eskişehir, Turkey 2 Eskişehir Osmangazi University Faculty of Medicine, Department of Internal Diseases, Eskişehir, Turkey 3 Eskişehir Osmangazi University Faculty of Medicine, Department of Pathology, Eskişehir, Turkey doi: 10.5262/tndt.2016.1001.16 Correspondence Address: Garip Şahin Eskişehir Osmangazi Üniversitesi Tıp Fakültesi, Nefroloji Bilim Dalı, Eskişehir, Turkey Phone : +90 222 239 29 79 E-mail : [email protected] absTracT Heavy proteinuria and nephrotic syndrome may occur in association with a wide variety of primary and systemic diseases and also with drugs. Major drugs that can induce nephrotic syndrome and glomerular damage are gold, penicillamine, bucillamine and non-steroidal anti-inflammatory drugs. In nephrotic syndrome due to these drugs, the major type of renal disease is membranous glomerulonephritis and the nephropathy resolves completely when the drug is withdrawn. Here we report a patient who developed nephrotic syndrome after the initiation of metformin. Laboratory parameters improved rapidly after the discontinuation of the drug. Our case is important as it is the first case with nephrotic syndrome due to metformin in the literature. Key words: Proteinuria, Nephrotic syndrome, Metformin, Drug nephropathy ÖZ Ağır proteinüri ve nefrotik sendrom primer, sekonder hastalıklar ya da ilaçların değişik oranlarda katkıları ile birlikte oluşabilir. Altın, penisilamin, busilamin ve steroid olmayan yangı giderici ilaçlar nefrotik sendrom ve glomerüler hasarı oluşturan önemli ilaçlardır. Bu ilaçlardan dolayı oluşan nefrotik sendromda renal hastalığın önemli tipi membranöz glomerülonefrittir ve ilaç kesildiği zaman nefropati tamamı ile gerileyebilir. Biz metformin başlandıktan sonra nefrotik sendrom gelişen olguyu rapor ediyoruz. Laboratuvar parametreleri ilaç kesildikten sonra hızlı birşekilde iyileşmişti. Bizim olgumuz literatürde metformine bağlı nefrotik sendrom olan ilk olgu olmasından dolayı öneme sahiptir. anahTar sözcüKler: Proteinüri, Nefrotik sendrom, Metformin, İlaç nefropatisi Received : 08.09.2014 Accepted : 09.11.2014 ınTroducTıon Heavy proteinuria and the nephrotic syndrome may occur in association with a wide variety of primary and systemic diseases. In adults, approximately 30 percent have a systemic disease such as diabetes mellitus, amyloidosis, or systemic lupus erythematosus; the remaining cases are usually due to primary renal disorders such as minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy (1, 2) Nephrotic syndrome can be induced by drugs. Major drugs that induce drug- related nephrotoxicity are antibiotics, NSAID, radiocontrast media, anticancer drug and antirheumatic drugs. Drug- induced nephropathy can cause various forms of renal diseases. The nephropathy consists of acute tubular necrosis, acute tubulointerstitial nephritis, pre-renal type renal failure, obstructive renal failure, chronic tubulointerstitial nephritis and glomerular damage (3, 4). Major drugs that induce nephrotic syndrome and glomerular damage are gold, penicillamine, bucillamine and NSAID. In the nephrotic syndrome due to these drugs, the major type of renal disease is membranous glomerulonephritis and the nephropathy resolves completely when the drug is withdrawn; renal function does not deteriorate, and corticosteroids are unnecessary (3-5).
Transcript of 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 :[email protected]
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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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).
