Case report: lipid inclusion in glomerular endothelial and mesangial cells in a patient after contrast medium injection

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Su et l. BMC Nephrology (2018) 19:53 https://doi.org/10.

1 Su et l. BMC Nephrology (2018) 19:53 CASE REPORT Cse report: lipid inclusion in glomerulr endothelil nd mesngil cells in ptient fter contrst medium injection Hu Su, Chen Ye, Qin Wen, Hong-Yn Zhu, Li-Xi Yi nd Chun Zhng * Open Access Astrct Bckground: It is well-recognized tht injection of iodinted rdiogrphic contrst medi (CM) sometimes cuses cute renl injury vi multiple mechnisms, such s vsoconstriction, toxicity on glomerulr endothelium nd tuulr epithelium nd so forth. Cse presenttion: A 51-yer-old mn developed cute renl injury with proteinuri fter CM dministrtion. To our surprise, in his renl iopsy smple the myelin figure like structure ws oserved in glomerulr endothelium nd mesngil cells y trnsmission electron microscopy. However the ptient didn t hs ny clinic clues of Fry disese nd other lysosoml storge disorders. Moreover in vitro cultured glomerulr endothelil nd mesngil cells we found CM triggers lipid ggregtion long with the incresed CD36 nd decresed ABCA1 undnce. Thus this ptient ws dministrted sttin to correct the errnt lipid trfficking, 2 months lter t his next visit we found his renl function prtilly recovered with reduced proteinuri. Conclusions: Besides the well-known underlying mechnisms, CM my cuse renl impirment y triggering the dysregulted trnsporttion of lipid. Furthermore sttin is suggested to e very promising medicine to decrese side effects of CM. Keywords: Cse report, Contrst medi, Lipidosis, Endothelil cells, Mesngil cells, CD36, ABCA1 Bckground Contrst medi (CM) dministrtion my initite cute renl injury nd the underlying mechnisms including prolonged reduction of renl lood flow, endothelil dysfunction, dysregultion of tuulr trnsport, etc. [1]. Prophylctic intrvenous hydrtion to void ischemic insult nd ntioxidnt therpy re elieved to e the mjor preventive strtegies for contrst-induced nephropthy (CIN). In this pper, we report CIN cse morphologiclly presented with lipid inclusion in glomerulr resident cells, especilly in endothelil nd mesngil cells. Cse presenttion A-51-yer-old mn ws referred to urology for drenl mss nd potentilly relted secondry * Correspondence: drzhngchun@126.com Deprtment of Nephrology, Union Hospitl, Tongji Medicl College, Huzhong University of Science nd Technology, Wuhn , Chin hypertension. Except for five yers of uncontrolled hypertension with hypoklemi he hs no other history of mediction nd diseses including renl disese, dietes or other systemic disorders. His sl serum cretinine (scr) ws 1.9 mg/dl with microluminuri, ut no hemturi nd cylinduri were detected t dmission. Aprt from the increse lood pressure there ws no significnt physicl normlity ws identified. And his renl disorder ws deem to e ssocited with enign nephrosclerosis cused y uncontrolled hypertension. To mke etter evlution for the drenl mss efore surgery he ws sujected to enhnced drenl CT scn with intrvenous injection of iomeprol ( nonionic, monomeric iodinted contrst medium). Ahed of CM injection preventive therpies (intrvenous hydrtion with reduced glutthione) were given to minimize the side effects of CM. The opertion went extremely well nd his lood pressure ws well controlled fter tht; however his scr ws incresed to 3.3 mg/dl with 2+ dysmorphic The Author(s) Open Access This rticle is distriuted under the terms of the Cretive Commons Attriution 4.0 Interntionl License ( which permits unrestricted use, distriution, nd reproduction in ny medium, provided you give pproprite credit to the originl uthor(s) nd the source, provide link to the Cretive Commons license, nd indicte if chnges were mde. The Cretive Commons Pulic Domin Dediction wiver ( pplies to the dt mde ville in this rticle, unless otherwise stted.

2 Su et l. BMC Nephrology (2018) 19:53 Pge 2 of 5 hemturi nd 2+ proteinuri three dys lter fter iomeprol injection. Therefore he remined hospitlized for the elevted scr level; unfortuntely the scr filed to drop to his sl level despite three weeks comprehensive tretment (reduced glutthione plus prostglndin E1 dministrtion). And the hemturi nd proteinuri still persisted. Then, he ws trnsferred to nephrology. And he ws dignosed s cute kidney injury (AKI) superimposed on chronic kidney disese (CKD). A series of serologic nd rdiologic workup ws ordered. Except for the elevted scr other serologic results were unremrkle including serum potssium. Emission Computed Tomogrphy indicted glomerulr filtrtion rte ws decresed. To get etter understnding of the nture of the renl injury the kidney iopsy ws performed. On immunofluroscence microscopy no dignostic stining of immunogloulin nd complement were detected in glomeruli, tuulointerstitium nd vessels. Under light microscopy there ws only mild to moderte ischemic ltertion of glomeruli without prolifertive lesions which is elieved to e ssocited with the history of uncontrolled hypertension. Moreover focl mild cute tuulr injury ws identified presenting s the loss of rush order nd isometric vcuoliztion of tuulr epithelil cells. No corse vcuole degenertion, the feture of hypoklemic nephrosis, ws seen in tuulr epithelium (dt not shown). Interestingly, with the id of trnsmission electron microscopy we found scttered distriuted myelin figure like structure, presenting s lmost-empty vcuoles circled with electron-dense memrne, in endothelium, mesngil cells nd less frequently in podocyte (Fig. 1). Comining the clinic fetures nd pthologic findings we elieved tht in this cse the CKD ws due to moderte nephrosclerosis which could e explined y longstnding secondry hypertension. OntheotherhndtheAKImyreltetomildcute tuulr injury nd scttered distriuted myelin figure like structure ws oserved in glomerulr cells. Wht mde us confused ws the underlying etiology for the formtion of myelin figure structure. As we known, zer odies nd myelin-like figures re ordinrily seen in Fry disese nd vrious lysosoml storge disorders nd usully infer lipid ccumultion in cell odies or sucellulr orgnelles. However, our ptient didn t hve ny other systemic symptoms or fmily history of tht genetic diseses. More importntly, his renl impirment just ggrvted fter CM dministrtion. Thus we were curious to study whether CM will led to the lipidosis in glomerulr endothelil nd mesngil cells. To test tht, we exposed the cultured glomerulr endothelil nd mesngil cells to the CM, iomeprol, to evlute whether this tretment will cuse the lipid ccumultion s we oserved in vivo (Additionl file 1). In c Fig. 1 Myelin figure like structures re oserved in glomeruli under trnsmission electron microscopy. -c Low mgnifiction shows lipid inclusion in endothelium (rrows), mesngil cell (rrowheds) nd podocyte (sterisks). (Originl mgnifiction, 2500) d Higher mgnifiction shows lmost-empty vcuoles circled with electrondense memrne in endothelium (rrow) (Originl mgnifiction, 5000) e Higher mgnifiction shows myelin figure like structure with empty vcuoles in mesngil cell (rrowheds). (Originl mgnifiction, 5000) detil, cells were treted with iomeprol or cultured in regulr medium for 1 h. After tht they were stined with Oil Red O or Sudn Blck to detect the deposition of neutrl lipids nd phospholipids. Interestingly, our dt reveled tht iomeprol exposure promotes the lipid ccumultion in the cytoplsm of endothelil nd mesngil cells oviously (Figs. 2, 3). Next we explored the underlying mechnisms of ove normlities. It is well-estlished tht CD36 is n essentil trnsporter mediting lipid uptke, wheres ATP-inding cssette trnsporter A1 (ABCA1) ccelertes the dischrge of lipid from cytosol [2, 3]. Our immunofluorescence stining showed tht with the tretment of iomeprol CD36 is upregulted ccompnying with diminished ABCA1 intensity in oth glomerulr endothelil nd mesngil cells (Figs. 2, 3) nd which is the potentil underlying mechnism ccounting for the lipid ggregtion during CM exposure. d e

Oil Red nd Sudn Blck stining presents lipid inclusion in endothelium in Ctrl nd CM groups. Immunofluorescence stining indictes CD36 nd ABCA1 protein expression in Ctrl nd CM groups.

3 Su et l. BMC Nephrology (2018) 19:53 Pge 3 of 5 Fig. 2 Lipid is ccumulted in iomeprol treted glomerulr endothelil cells. Rt glomerulr endothelil cells were cultured in DMEM/F12 supplemented with 10% FBS nd then treted without (Ctrl) or with iomeprol (CM, 50 μl/ml) for 1 h. Oil Red nd Sudn Blck stining presents lipid inclusion in endothelium in Ctrl nd CM groups. Immunofluorescence stining indictes CD36 nd ABCA1 protein expression in Ctrl nd CM groups. (Originl mgnifiction, 400) Fig. 3 Lipid is deposited in glomerulr mesngil cells under iomeprol stimultion. Rt glomerulr mesngil cells were cultured in Minimum Essentil Medium supplemented with 10% FBS nd then treted without (Ctrl) or with iomeprol (CM, 50 μl/ml) for 1 h. Oil Red nd Sudn Blck stining shows lipid ccumultion in mesngil cells from Ctrl nd CM groups. Immunofluorescence stining presents CD36 nd ABCA1 protein expression in Ctrl nd CM groups. (Originl mgnifiction, 400) Bsed on the morphologic ltertions from iopsy smple nd the experimentl dt from in vitro cultured cells, the ptient ws prescried orl sttins (fluvsttin, 20 mg, qn) nd ntioxidnt (Atomolm, 0.4, tid). Two months lter, his next visit, we found the hemturi ws resolved, nd the proteinuri decresed to 1+ with improved renl function (scr ws 2.4 mg/dl). (The whole timeline of this cse is shown in Fig. 4). Discussion nd Conclusions Here we report the renl iopsy findings from n cute kidney injury cse fter CM injection. Conspicuously, scttered memrne-ound lmost-empty vcuoles were oserved in glomerulr resident cells, primrily in endothelil nd mesngil cells, under electron microscopy. However, this ptient didn t hve ny typicl clinicl fetures of lysosoml storge diseses or other hereditry disese frequently cusing renl lipidosis. Also this ptient didn t tke ny medicine ffecting the ctivity of lysosoml enzymes, such s miodrone nd chloroquine, which hs een reported to led to lipid ccumultion in kidney [4]. Concerning the deteriortion of renl function nd the presence of hemturi nd proteinuri were occurred just fter the CM dministrtion, we speculted glomerulr lipidosis my e relted to the CM in this cse. CIN is generlly descried s n cute worsening of renl function with n solute increse in scr y 0.3 mg/dl from seline or reltive increse in scr levels y 50% from seline within 72 h [5]. Multiple mechnisms re involved in cute kidney injury during intrvsculr injection of CM. Of note, CM possesses cytotoxic property on vsculr nd

4 Su et l. BMC Nephrology (2018) 19:53 Pge 4 of 5 Fig. 4 The timeline of this cse report glomerulr endothelium, s well s tuulr epithelium. A few contriuting fctors hve een suggested for these toxicities, such s the elevted formtion of rective oxygen species nd oxidtive stress, reduced prostglndins, nitric oxide nd denosine production, intrcellulr C 2+ overlod nd so on [6, 7]. Besides its functionl impirment, y scnning electron microscopy C. Gospos lso oserved the morphologic chnge of endothelium, such s, cell shrinkge, nucler protrusion nd formtion of microvilli on the cell memrne [8]. Interestingly, here we oserved lipid ccumultion in glomerulr resident cells, prominently in endothelil nd mesngil cells fter injection of CM. Furthermore, CM induces lipidosis in cultured glomerulr endothelium nd mesngil cell long with the incresed CD36 nd decresed ABCA1 expression. CD36, lso nmed ftty cid trnslocse, is plsm memrne trnsporter mediting long chin ftty cid uptke. While ABCA1, known s the cholesterol efflux regultory protein, is mjor regultor for the efflux of cellulr cholesterol nd phospholipid. Bsed on this, our findings suggest tht CM induces errnt CD36 nd ABCA1 expression nd which ccounts for glomerulr lipidosis. Lipid overlod triggers oxidtion rection, mitochondril dysfunction, nd other undesirle moleculr processes which eventully results in cell nd tissue dmge [9]. Sttin therpy showed clinicl enefit in terms of preventing CIN. In met-nlysis Ukigwe A [10] reported tht ptients with type 2 dietes, chronic kidney disese, congestive hert filure who receiving > 140 ml of CM will enefit from sttins therpy. Consistently, severl other met-nlysis indicted tht short-term, pre-procedurl, potent sttin (torvsttin, rosuvsttin) therpy mrkedly minimized CIN risk, however the potentil mechnism remins uncertin [11 13]. A few studies suggested tht renoprotective effects of sttin might e ssocited with reduction of poptosis, oxidtive stress nd nti-inflmmtory ctions [14, 15]. Currently we provide evidence tht CM induces glomerulr lipid ggregtion long with the errnt CD36 nd ABCA1 expression. Given the fct tht sttin could depress CD36 nd stimulte ABCA1 expression [16, 17], erly dministrtion of sttin might e n idel mesurement for CIN prevention y correcting the errnt lipid trfficking. Although wedonotgetthedirectevidencetoprovecmttriutes to myelin figure formtion in vivo, our finding still dvnces the understnding of the mechnisms of CIN nd renoprotective effects of sttin. In the ner future we will perform exmintions to firmly confirm the link etween CM nd glomerulr lipid ccumultion.

5 Su et l. BMC Nephrology (2018) 19:53 Pge 5 of 5 Additionl file Additionl file 1: Mterils nd Methods. (DOCX 13 k) Arevitions ABCA1: ATP-inding cssette trnsporter A1; AKI: Acute Kidney Injury; CIN: Contrst Induced Nephropthy; CKD: Chronic Kidney Disese; CM: Contrst Medium; scr: Serum Cretinine Acknowledgements We thnks Dr. Fn Yi from Shndong University to give us the cell line of rt glomerulr endothelium s gift. Funding This work ws supported y grnts from the Ntionl Nturl Science Foundtion of Chin (No , No , nd No ). And this funding ody supports the design of this study nd collection, nlysis, nd interprettion of dt s well s the writing nd puliction of this mnuscript. Avilility of dt nd mterils All dt generted during this study re included in this pulished rticle nd its supplementry informtion files. Authors contriutions HS, HZ nd LY re responsile for the dignostic nd technicl processes of the renl iopsy. HS, CY nd QW prticipted in the orgniztion nd implementtion of the in vitro studies. CZ contriuted to ptient mngement nd contriuted to mnuscript. HS nd CZ designed the study nd edited nd reviewed the mnuscript. HS nd CZ wrote the first nd lst drfts of the mnuscript. All uthors red nd pproved the finl version of the mnuscript. Ethics pprovl nd consent to prticipte Informed consent ws otined from ech ptient for renl iopsy nd this study ws in complince with the Declrtion of Helsinki nd ws pproved y the locl ethicl committees. Otherwise, no dditionl ethicl pprovl ws required for this cse report. 7. Sendeski MM. Pthophysiology of renl tissue dmge y iodinted contrst medi. Clin Exp Phrmcol Physiol. 2011;38: Gospos C, Freudenerg N, Stuesnd J, Mthis K, Ppchrlmpos X. The effect of contrst medi on the ortic endothelium of rts. Rdiology. 1983; 147: Jnikiewicz J, Hnzelk K, Kozinski K, Kolczynsk K, Dorzyn A. Islet β-cell filure in type 2 dietes within the network of toxic lipids. Biochem Biophys Res Commun. 2015;460: Ukigwe A, Krmchry P, Mhmood M, Pthk R, Aryl MR, Jlot L, Donto AA. Met-nlysis on efficcy of sttins for prevention of contrstinduced cute kidney injury in ptients undergoing coronry ngiogrphy. Am J Crdiol. 2014;114: Sheht M, Hmz M. Impct of high loding dose of torvsttin in dietic ptients with renl dysfunction undergoing elective percutneous coronry intervention: rndomized controlled tril. Crdiovsc Ther. 2015;33: Hn Y, Zhu G, Hn L, Hou F, Hung W, Liu H, Gn J, Jing T, Li X, Wng W, Ding S, Ji S, Shen W, Wng D, Sun L, Qiu J, Wng X, Li Y, Deng J, Li J, Xu K, Xu B, Mehrn R, Huo Y. Short-term rosuvsttin therpy for prevention of contrst-induced cute kidney injury in ptients with dietes nd chronic kidney disese. J Am Coll Crdiol. 2014;63: Mrenzi G, Cosentino N, Wer JP, Tedesco CC, Vegli F, Brtorelli AL. A met-nlysis of rndomized controlled trils on sttins for the prevention of contrst-induced cute kidney injury in ptients with nd without cute coronry syndromes. Int J Crdiol. 2015;183: Su J, Zou W, Ci W, Chen X, Wng F, Li S, M W, Co Y. Atorvsttin meliortes contrst medium-induced renl tuulr cell poptosis in dietic rts vi suppression of rho-kinse pthwy. Eur J Phrmcol. 2014;723: Wu K, Lei W, Tin J, Li H. Atorvsttin tretment ttenutes renl injury in n experimentl model of ischemi-reperfusion in rts. BMC Nephrol. 2014;15: Mndosi E, Fllrino M, Gtti A, Crnovle A, Rossetti M, Lococo E, Buchetti B, Filetti S, Lenti L, Morno S. Atorvsttin downregultes monocyte CD36 expression, nucler NF kppb nd TNF lph levels in type 2 dietes. J Atheroscler Throm. 2010;30(17): Shimizu T, Miur S, Tnigw H, Kuwno T, Zhng B, Uehr Y, Sku K. Rosuvsttin ctivtes ATP-inding cssette trnsporter A1-dependent efflux ex vivo nd promotes reverse cholesterol trnsport in mcrophge cells in mice fed high-ft diet. Arterioscler Throm Vsc Biol. 2014;34: Consent for puliction Written informed consent ws otined from the ptient for puliction of this cse report nd ny ccompnying imges. A copy of the written consent is ville for review y the editor of this journl. Competing interests The uthors declre tht they hve no competing interests. Pulisher s Note Springer Nture remins neutrl with regrd to jurisdictionl clims in pulished mps nd institutionl ffilitions. Received: 7 Octoer 2016 Accepted: 20 Ferury 2018 References 1. Mehrn R, Nikolsky E. Contrst-induced nephropthy: definition, epidemiology, nd ptients t risk. Kidney Int Suppl. 2006;100:S Prk YM. CD36, scvenger receptor implicted in therosclerosis. Exp Mol Med. 2014;46:e Bielicki JK. ABCA1 gonist peptides for the tretment of disese. Curr Opin Lipidol. 2016;27: Brcmonte ER, Kowlewsk J, Strr J, Gitomer J, Alpers CE. Itrogenic Phospholipidosis mimicking Fry disese. Am J Kidney Dis. 2006;48: Lkhl K, Ehrmnn S, Chri A, Lissy JP, Régnier B, Wolff M, Pjot O. Acute kidney injury network definition of contrst-induced nephropthy in the criticlly ill: incidence nd outcome. J Crit Cre. 2011;26: Heymn SN, Rosen S, Rosenerger C. Renl prenchyml hypoxi, hypoxi dpttion, nd the pthogenesis of rdiocontrst nephropthy. Clin J Am Soc Nephrol. 2008;3: Sumit your next mnuscript to BioMed Centrl nd we will help you t every step: We ccept pre-sumission inquiries Our selector tool helps you to find the most relevnt journl We provide round the clock customer support Convenient online sumission Thorough peer review Inclusion in PuMed nd ll mjor indexing services Mximum visiility for your reserch Sumit your mnuscript t

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