Case Report | Relato de Caso

Focal and Segmental Glomerulosclerosis and Membranous Nephropathy overlapping in a patient with Nephrotic Syndrome: a case report* Glomeruloesclerose Segmentar e Focal e Nefropatia Membranosa sobrepostas em paciente com Síndrome Nefrótica: relato de caso

Authors Abstract Resumo 1 Crislaine Aparecida da Silva Introduction: Some cases of membra- Introdução: Alguns casos de nefropatia Fabiano Bichuette Custódio1 nous nephropathy (MGN) present focal membranosa (NM) apresentam glomeru- Maria Luíza Gonçalves dos Reis segmental glomerulosclerosis (FSGS) ty- loesclerose segmentar e focal (GESF) tipi- 1 Monteiro pically associated with disease progres- camente associada a progressão da doença. 2 Stanley de Almeida Araújo sion. However, we report a case of a Contudo, relatamos o caso de uma paciente 1 Liliane Silvano Araújo patient who seemed to have MGN and que parece ter NM e GESF, ambas primárias. 1 Rosana Rosa Miranda Côrrea FSGS, both primary. Case presentation: A Apresentação do caso: Uma jovem branca 1 Marlene Antônia dos Reis 17-year-old female, Caucasian, presenting de 17 anos de idade com edema de membros Juliana Reis Machado1 lower extremity edema associated with inferiores associado a episódios de urina episodes of foamy urine and high blood espumosa e hipertensão apresentou-se com 1 Universidade Federal do pressure, had physical and laboratorial achados físicos e laboratoriais sugestivos de Triângulo Mineiro, Instituto de exams indicating nephrotic syndrome. síndrome nefrótica. Foi realizada biópsia Ciências Biológicas e Naturais, Uberaba, MG, Brasil. A renal biopsy was performed and focal renal. GESF foi observada por microscopia 2 Universidade Federal de Minas and segmental glomerulosclerosis were de luz em alguns glomérulos que apresen- Gerais, Hospital das Clínicas, Belo observed under light microscopy in some tavam lesões de ponta, enquanto em outros Horizonte, MG, Brasil. glomeruli presented as tip lesion, and in o achado era acompanhado por hipertrofia others it was accompanied by podocyte podocitária e descolamento de podócitos no hypertrophy and podocyte detachment espaço urinário, compatíveis com podoci- in urinary space, compatible with po- topatia GESF. Além disso, as alças capila- docytopathy FSGS. Besides, there were res estavam espessadas com irregularidades thickened capillary loops with basement na membrana basal devido a “espículas” membrane irregularities due to “spikes” compatíveis com NM estágio II. Imunofluo- compatible with MGN stage II. Immuno- rescência revelou depósitos finamente granu- fluorescence showed finely granular IgG, lares de IgG, IgG4 e PLA2R nas alças capila- IgG4, and PLA2R deposits in capillary res. Microscopia eletrônica exibiu depósitos loops and, in electron microscopy, sube- subepiteliais e apagamento de pedicelos. pithelial deposits and foot process efface- Tais achados morfológicos são compatíveis ment. These morphological findings are com GESF e NM estágio II. Conclusões: No compatible with FSGS and MGN stage II. presente caso, as características clínicas e Conclusions: In the present case, clinical morfológicas revelaram uma possível sobre- and morphological characteristics showed posição de GESF primária e NM, uma vez a possible overlap of primary FSGS and que a glomeruloesclerose segmentar e focal MGN as focal and segmental glomerulos- não parece estar relacionada com a pro- clerosis does not seem to be related with gressão da NM, mas com a podocitopatia MGN progression but with the podocyto- GESF. Submitted on: 11/19/2018. pathy FSGS. Approved on: 12/07/2018. Keywords: Glomerulosclerosis, Focal Seg- Palavras-chave: Glomerulosclerose Segmen- mental; Glomerulonephritis, Membranous; tar e Focal; Glomerulonefrite Membranosa; Correspondence to: Juliana Reis Machado Nephrotic Syndrome. Síndrome Nefrótica. E-mail: [email protected]

DOI: 10.1590/2175-8239-JBN-2018-0239

*The study was performed in the General Pathology and Nephropathology Service of Federal University of Triangulo Mineiro.

113 FSGS and membranous overlap

Introduction There were 23 glomeruli for analysis by LM. All glo- meruli had thickened capillary loops due to epimem- Membranous nephropathy (MGN) is caused by branous deposits (Figure 1A). There were also base- the deposition of subepithelial immunocomplexes, ment membrane irregularities forming “spikes” in a accounts for about 20% of primary glomerulopathies global and diffuse pattern in glomeruli (Figure 1B). in adults and predominantly affects men between 40- Besides, 10 glomeruli had increased mesangial matrix 50 years old1. Patients present , edema, with collapse of capillary loops in less than half of hypoalbuminemia and hyperlipidemia, and the pri- each , characterizing segmental sclerosis; mary form (75%) is due to in situ immunoglobulin some had podocyte hypertrophy and podocyte deta- deposits against phospholipase A2 receptor (PLA2R) chment in urinary space, with a glomerulus showing a podocyte antigen. In stage I of the disease, glomeruli tip lesion (Figure 1C). Interstitial fibrosis and tubu- are normal in light microscopy (LM) and diagnosis lar atrophy were mild. Vascular compartment was is possible only through immunofluorescence which unremarkable. showed IgG subepeithelial deposits (IF) and trans- IF showed marked granular global and diffu- mission electron microscopy (TEM), which evidence se staining for IgG, IgG4, and PLA2R, in glomeruli IgG subepithelial deposits. Stage II presents glomeru- (Fig.1D), as well as Kappa and Lambda light chains. lar basement membrane (GBM) projections between C3 had mild granular segmental positivity in glome- deposits, named “spikes”, better visualized by silver ruli and segmental positivity in Bowman’s capsule. stain. As the disease progresses, deposits are incorpo- IgA, IgM, C1q and fibrinogen were negative. rated in GBM, which results in a pinhole aspect (stage TEM showed electron-dense amorphous subepi- III) and are posteriorly reabsorbed, creating a thicker thelial deposits, with some deposits separated from GBM (stage IV)2. each other by basement membrane spikes (Figure The coexistence of MGN with other renal disea- 1E), areas of immune complex reabsorption and foot ses was already reported3-6 including MGN and FSGS process effacement (Fig.1F). There was no mesangial, 7, 8, with FSGS cellular9 and collapsing variants10,11. subendothelial, or other glomerular deposits. Therefore, we report the case of a patient with mor- After the diagnosis was confirmed, treatment with phological characteristics of two primary glomerular angiotensin-converting enzyme inhibitor (ACEI) was diseases, MGN and FSGS. started and the patient presented spontaneous remis- sion for 1 year. After this period, there was an in- Case presentation crease in proteinuria (5712 mg/24h) and cyclosporine A 17 year-old female, Caucasian, investigating treatment was started. Due to lack of response for 3 proteinuria, presented lower extremity edema asso- months, treatment with cyclophosphamide alternated ciated with episodes of foamy urine and high blood with prednisone was started, with improvement of pressure. The patient reported no use of medications, proteinuria. no arthralgia, arthritis, or skin lesions, and no family history of nephropathy. Laboratorial exams at admis- Discussion sion showed serum creatinine: 0.8 mg/dL; urea: 22 This is a case report of a patient with nephrotic mg/dL; glycemia: 82 mg/dL; total cholesterol: 460 syndrome (NS), which renal biopsy showed mor- mg/dL; LDL cholesterol: 340 mg/dL; triglycerides: phological pattern of two different diseases. GBM 243 mg/dL; and serum albumin: 2.59 g/dL. Her pro- irregularities by LM, IgG, and PLA2R deposits by IF, teinuria was 4370 mg/24h and urinalysis had 300 and subepithelial electron-dense deposits by TEM are mg/dL of proteins, 10,000 leucocytes and 22,000 characteristic of membranous nephropathy stage II2. erythrocytes. Rheumatoid factor was 13 UL/mL and In addition, LM findings of focal and segmental glo- plasma complement particles C3 and C4 were nor- merulosclerosis, podocyte hypertrophy and tip lesion, mal. Dosages of FAN, anti-DNA, and serology for and TEM findings of foot process effacement charac- HIV, HCV, HBV, and VDRL were negative. After terize the podocytopathy FSGS12. There was no evi- exams, she started using 40 mg/day furosemide and dence of secondary diseases. 20 mg/day Simvastatin. MGN and FSGS are important causes of NS in The patient underwent renal biopsy without any adults, MGN being responsible for 20% of cases and intercurrence, and LM, IF, and TEM were performed. FSGS for 40% of cases. MGN pathogenesis involves

Braz. J. Nephrol. (J. Bras. Nefrol.) 2020;42(1):113-117 114 FSGS and membranous overlap

Figure 1. Histological sections of renal biopsy with morphological diagnosis of membranous (MGN) concurrent with focal segmental glomerulosclerosis (FSGS). Light microscopy shows (A) thickening of capillary loops due to epimembranous deposits (HE). (B) Segmental sclerosis tip lesion, podocyte hypertrophy, and podocyte detachment in urinary space (HE). (C) Irregularities in glomerular basement membrane forming “spikes” (PAMS). Immunofluorescence for (D) IgG, (E) IgG4, and (F) PLA2R in a marked positive, finely granular, subepithelial, global and diffuse pattern. Electron microscopy showing a capillary loop with electron-dense subepithelial deposits with “spikes” formation in GBM (G) and foot process effacement with areas with deposits reabsorption (F).

115 Braz. J. Nephrol. (J. Bras. Nefrol.) 2020;42(1):113-117 FSGS and membranous overlap the formation of immunocomplexes in subepithelial A case of a young female with a similar age to our region and it is considered an autoimmune disease patient, in whom segmental sclerosis accompanied by limited to the as the immunocomplex forma- podocyte hypertrophy, finely granular IgG deposition tion is due to immunoglobulin binding to podocytary and foot process pedicels effacement was observed, antigen PLA2R in situ, which leads to activation of suggested the concomitance of the two entities9. complement system, causing podocytary injury and Our patient presented a primary MGN-compatible consequently NS and renal failure13. FSGS is a po- antibody marking profile, since PLA2R and IgG4 docytopathy in which glomerular injury is caused by deposition were found in the biopsy. It has recently intrinsic and/or extrinsic changes in podocytes, which been observed that patients with MGN combined wi- leads to foot process effacement and sclerosis12. th FSGS present clinical and autoantibodies profiles MGN has a widely variable clinical course, as compatible with primary MGN. Approximately 80% there may be patients with spontaneous remission of of MGN-FSGS patients presented circulating PLA2R, proteinuria, persistent proteinuria, and progression similar to those with MGN alone. In patients with to renal failure1. Glomerulosclerosis is a common fin- FSGS alone, PLA2R screening was negative. Likewise, ding of MGN and these patients usually have a higher 75% of the patients with combined lesions and 79% blood pressure, longer duration of proteinuria, persis- of the MGN patients had positive PLA2R glomerular tent hematuria, and higher creatinine levels compared expression. In addition, patients presenting MGN wi- to patients without this finding. Besides, marked in- th or without sclerosis had glomerular deposition of terstitial fibrosis and tubular atrophy and the presen- IgG4 in contrast to patients with only FSGS18. ce of atherosclerosis are observed, indicating a poorer Regarding clinical evolution, after one year, our prognosis for these patients, which probably repre- patient entered spontaneous remission. Then, the sents an evolution of MGN to chronicity. Most of disease progressed to baseline proteinuria of 2.655 these cases have MGN in more advanced stages, such mg/24h, until the present moment. It has been repor- as III and IV, since glomerulosclerosis could be due to ted that the presence of sclerosis in MGN is related injuries in podocytes as a result of disease progression to worse prognosis19. After a 3-year follow-up, 64 itself, generating active and degenerative changes in patients with combined lesions presented worse evo- these cells, leading to adhesion to parietal epithelium lution than patients with only MGN, and this was and development of sclerosis14, 15. not related to more advanced stages of MGN20. This Although glomerulosclerosis in MGN may be re- shows that the occurrence of the two overlapping di- lated to the natural progression of the disease, scle- seases may predict the clinical course of patients with rosis in this case is probably not related to epithelial MGN regardless of staging. damage caused by progression of disease to advanced In view of our findings and literature descriptions, stages, but most likely represents a morphologic cha- we conclude that FSGS and MGN can be superimpo- racteristic of the primary glomerular disease FSGS. sed, but the mechanism of concomitance is not kno- Therefore, this patients most probably have primary wn. An initial glomerular injury can predispose the FSGS and primary MGN as two overlapping diseases, onset of an immunocomplex-mediated disease due to as segmental sclerosis focally as tip lesion, glomeruli injury to the glomerular filtration barrier13. Thus, da- with podocyte hypertrophy, and detached podocytes mage to podocytes in FSGS can lead to subepithelial in urinary space, strongly suggest segmental sclero- immunocomplex formation by exposure of local anti- sis due to podocytopathies16. In contrast, segmental gens, as observed in a patient in whom, after 7 years sclerosis due to scars generally present as sclerosis of diagnosis of FSGS, had MGN in a second biopsy8, with hypocellular areas and adhesion to Bowman’s indicating primary lesion of FSGS may have led to capsule. the development of MGN. In addition, MGN’s inju- This fact corroborates the literature that shows ries may lead to the emergence of FSGS, as subepi- about 78% of the patients with FSGS with MGN pre- thelial deposits may hinder the adhesion of podocytes sent segmental sclerosis with hypertrophic podocytes to GBM through α3β1 integrin, leading to podocyte in addition to hypertension, hematuria, and higher loss. Denuded areas of GBM favor the adhesion of proteinuria when compared to patients with MGN these regions to parietal epithelium with synechiae without sclerosis17.

Braz. J. Nephrol. (J. Bras. Nefrol.) 2020;42(1):113-117 116 FSGS and membranous overlap

formation, capillary obliteration, and later sclerosis, 5. Balafa O, Kalaitzidis R, Liapis G, Xiromeriti S, Zarzoulas F, 15 Baltatzis G, et al. Crescentic glomerulonephritis and mem- developing segmental glomerulosclerosis . branous nephropathy: a rare coexistence. Int Urol Nephrol Some cases of MGN present focal segmental glo- 2015;47:1373-7. merulosclerosis typically associated with disease pro- 6. Liu Y, Xie H, Lin H, Chen S, Wang W, Zhao G, et al. Coexis- tence of Fabry Disease and Membranous Nephropathy. Iran J gression. However, we report a case of a patient who Kidney Dis 2016;10:48-50. seemed to have FSGS and MGN, both primary, as 7. Amenta PS, Swartz C, Katz SM. Concurrent focal segmental glomerulosclerosis and membranous nephropathy. Clin Ne- morphological characteristics of biopsy and clinical phrol 1989;32:173-7. evolution strongly suggested the concomitance of the 8. Warwick GL, McLay A, Boulton-Jones JM. Membranous ne- phropathy developing in a patient with previously diagnosed two primary glomerular diseases. Nevertheless, the focal glomerulosclerosis. Am J Kidney Dis 1991;18:520-2. mechanisms of injury in these cases are still uncertain. 9. Kambham N, Markowitz GS, Slater LM, D’Agati VD. An 18-year-old female with acute onset of nephrotic syndrome. Therefore, more studies are needed to elucidate the Am J Kidney Dis 2000;36:441-6. overlap of these primary glomerulopathies. 10. Al-Shamari A, Yeung K, Levin A, Taylor P, Magil A. Collap- sing glomerulopathy coexisting with membranous glomerulo- in native kidney biopsies: a report of 3 HIV-negative Acknowledgements patients. Am J Kidney Dis 2003;42:591-5. 11. Larsen CP, Beggs ML, Walker PD, Saeed M, Ambruzs JM, The authors appreciate the financial sup- Messias NC. Histopathologic effect of APOL1 risk alleles in port of Conselho Nacional de Desenvolvimento PLA2R-associated membranous glomerulopathy. Am J Kidney Dis 2014;64:161-3. Científico e Tecnológico (CNPq), Coordenação 12. Sethi S, Zand L, Nasr SH, Glassock RJ, Fervenza FC. Focal de Aperfeiçoamento de Pessoal de Nível Superior and segmental glomerulosclerosis: clinical and kidney biopsy (CAPES), Fundação de Amparo a Pesquisa do Estado correlations. Clin Kidney J 2014;7:531-7. 13. Debiec H, Ronco P. Immunopathogenesis of membranous ne- de Minas Gerais (FAPEMIG), and Fundação de phropathy: an update. Semin Immunopathol 2014;36:381-97. Ensino e Pesquisa de Uberaba (FUNEPU). 14. Van Damme B, Tardanico R, Vanrenterghem Y, Desmet V. Adhesions, focal sclerosis, protein crescents, and capsular le- The authors thank the Universidade Federal do sions in membranous nephropathy. J Pathol 1990;161(1):47- Triângulo Mineiro, the discipline of general patholo- 56. 15. Dumoulin A, Hill GS, Montseny JJ, Meyrier A. Clinical and gy and the employees of the nephropatology service: morphological prognostic factors in membranous nephropa- Alberto Borba, Edson Santos, João Noberto, Laura thy: significance of focal segmental glomerulosclerosis. Am J Kidney Dis 2003;41:38-48. Penna, Lívia Alves and Vandair Gonçalves. 16. D’Agati VD, Fogo AB, Bruijn JA, Jennette JC. Pathologic clas- sification of focal segmental glomerulosclerosis: a working pro- References posal. Am J Kidney Dis 2004;43:368-82. 17. Wakai S, Magil AB. Focal glomerulosclerosis in idiopathic 1. Lai WL, Yeh TH, Chen PM, Chan CK, Chiang WC, Chen YM, membranous glomerulonephritis. Kidney Int 1992;41:428-34. et al. Membranous nephropathy: a review on the pathogenesis, 18. Gu QH, Cui Z, Huang J, Zhang YM, Qu Z, Wang F, et al. diagnosis, and treatment. J Formos Med Assoc 2015;114:102- Patients With Combined Membranous Nephropathy and Focal 11. Segmental Glomerulosclerosis Have Comparable Clinical and 2. Fogo AB, Lusco MA, Najafian B, Alpers CE. AJKD Atlas of Autoantibody Profiles With Primary Membranous Nephropa- Renal Pathology: Membranous Nephropathy. Am J Kidney Dis thy: A Retrospective Observational Study. Medicine (Baltimo- 2015;66:e15-7. re) 2016;95:e3786. 3. Ma XZ, Zhang H, Wang SX, Zou WZ, Wang HY. [Two cases 19. Gupta R, Sharma A, Mahanta PJ, Jacob TG, Agarwal SK, report and literature review of IgA nephropathy combined with Roy TS, et al. Focal segmental glomerulosclerosis in idiopathic primary membranous nephropathy]. Zhonghua Nei Ke Za Zhi membranous glomerulonephritis: a clinico-pathological and 2006;45:472-4. [Article in Chinese]. stereological study. Nephrol Dial Transplant 2010;25:444-9. 4. Kobayashi Y, Fujii K, Hiki Y, Chen XM. Coexistence of IgA 20. Lee HS, Koh HI. Nature of progressive glomerulosclerosis in nephropathy and membranous nephropathy. Acta Pathol Jpn human membranous nephropathy. Clin Nephrol 1993;39:7-16. 1985;35:1293-9.

117 Braz. J. Nephrol. (J. Bras. Nefrol.) 2020;42(1):113-117