Skip to main content

Effectiveness of immunosuppressive therapy for nephrotic syndrome in a patient with late-onset Fabry disease: a case report and literature review



Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations of the GLA gene, followed by deficiency in α-galactosidase A (α-gal) activity. Nephrotic syndrome, as the renal phenotype of FD, is unusual. Here, we report the rare case of a patient with FD with nephrotic syndrome whose proteinuria disappeared by immunotherapy.

Case presentation

A 67-year-old Japanese man was admitted to our hospital because of emesis, abdominal pain, and facial edema due to nephrotic syndrome. The patient was diagnosed with focal segmental glomerulosclerosis (FSGS) by renal biopsy before being diagnosed with FD, and immunotherapy was initiated. After treatment, the kidney biopsy results showed typical glycosphingolipid accumulation in the podocytes of this patient. The white blood cell α-gal activity was very low, and genetic analysis revealed a GLA gene variant (M296I), which is known as a late-onset genetic mutation of FD. Immunotherapy (steroids and cyclosporine A) dramatically improved the massive proteinuria. Currently, he has been undergoing enzyme replacement therapy, and his proteinuria has further decreased. There is the possibility that other nephrotic syndromes, such as minimal change nephrotic syndrome or FSGS, may co-exist in this patient.


We experienced the rare case of a FD patient whose nephrotic syndrome disappeared by immunotherapy. These findings suggest that immunosuppressive treatment may be considered if nephrotic syndrome develops, even in patients with FD.

Peer Review reports


Fabry disease (FD) is a rare X-linked lysosomal storage disorder that is caused by a deficiency of α-galactosidase A (α-gal) activity, which leads to the accumulation of globotriaosylceramide (GB-3) in cells. The accumulation of GB-3 in various organs, such as the kidneys and heart, as well as the nervous system, has been speculated to be the mechanism involved in tissue damage [1, 2]. The major conditions associated with this disease are life-threatening complications, such as heart failure, renal failure, and cerebrovascular diseases at a young age. FD is classified into three main categories, i.e., classical variants, late-onset variants, and heterozygous variants, based on the presence or absence of characteristic symptoms, age of onset, sex, and gene mutation. The impairment of podocytes caused by GB-3 accumulation leads to the development of microalbuminuria and proteinuria as the first signs of renal functional impairment in FD [1]. However, a few FD patients with nephrotic range proteinuria have been reported, and massive proteinuria is unusual in this disease. Here, we report the rare case of a patient with late-onset FD with nephrotic syndrome, who achieved complete remission after immunosuppressive therapy, with a literature review.

Case presentation

A 67-year-old Japanese man was admitted to Munakata Suikokai General Hospital, Fukuoka, Japan, in December 2016 for angina and was subsequently diagnosed with atypical angina. He was treated with a Ca blocker (benidipine hydrochloride) and nitric acid without percutaneous coronary angiography. The urinary protein level before admission to the hospital was (±) by dipstick test, and the serum albumin level was 3.7 g/dL. His leg edema was rapidly worsening before admission to the hospital. In April 2017, he presented to the Kurume University Hospital, Fukuoka, Japan, because of emesis, abdominal pain, and facial edema due to hypoalbuminemia. The patient’s leg edema rapidly appeared 1 week before admission, suggesting the rapid onset of nephrotic syndrome. Typical FD findings, such as angiokeratoma, acroparesthesia, hypohidrosis, and corneal opacities, were absent. His mother had died from uterine body cancer at 50 years of age. Typical renal and heart disease or symptoms of FD in his brothers and maternal family members were not detected in family history. On examination, his blood pressure, pulse rate, height, and weight were 103/63 mmHg, 62 bpm (regular sinus rhythm), 167 cm, and 63 kg, respectively. Table 1 shows the patient’s laboratory data. His serum creatinine and blood urea nitrogen levels were 1.10 and 27.4 mg/dL, respectively. Urinalysis demonstrated 3+ protein as well as oval fat bodies, wide and fat casts, and mulberry cells. His urinary protein and albumin levels were 11.13 g/gCr and 1.63 g/dL, respectively. He was then diagnosed with nephrotic syndrome. After hospitalization, his creatinine level continued to increase to a peak of 2.7 mg/dL, and his urine output decreased. Because of the rapid progression of nephrotic syndrome and renal dysfunction, oral prednisolone was immediately initiated at a dose of 1 mg/kg/day. In addition, cyclosporine A (CyA) was prescribed at a dose of 100 mg/day as an additional immunosuppressive therapy. The massive proteinuria dramatically improved, and his serum creatinine and albumin levels returned to baseline (0.6 mg/dL and 4 g/dL, respectively). Percutaneous renal biopsy was performed 4 days after admission. Fifteen glomeruli were evaluated using light microscopy, and segmental sclerosis (Fig. 1a), vacuolization, and foamy changes in podocytes were observed (Fig. 1b and c). These foamy changes were also observed in the tubular epithelial cells, although to a much lesser extent than in the podocytes. These foamy cells were also found in the urine, which are known as mulberry bodies (Fig. 1d). No vascular involvement was observed. Immunohistochemistry showed no specific deposition of immunoglobulin or complement factors (data not shown). Electron microscopy revealed abundant lamellar bodies in the podocyte cytoplasm with widespread foot process fusion (Fig. 1e). These findings were compatible with renal FD. White blood cell (WBC) α-gal activity was 1 nmol/h/mg protein (normal range, 20–80 nmol/h/mg protein), and the plasma lyso-GB-3 level was 7.4 nmol/L (normal range, 0.14–0.75 nmol/L). We performed gene analysis, and the M296I mutation was detected, which is well known as a late-onset variant of FD [3]. Over the next 12 months, prednisolone and CyA were slowly tapered, and enzyme replacement therapy (ERT) (agalsidase-β, 1 mg/kg, 57 mg every 2 weeks) was initiated intravenously. His proteinuria became undetectable, and he showed sustained nephrotic syndrome remission (0.15 g/gCr) (Fig. 2). There were no adverse events related to immunotherapy or ERT during the follow-up period.

Table 1 Laboratory characteristics of the patient
Fig. 1

Representative images of the renal pathology in the patient. a Fifteen glomeruli were collected, and one showed segmental sclerosis visible on hematoxylin and eosin staining (magnification × 400, scale bar indicates 100 μm). b Masson trichrome staining showed vacuolization in podocytes (magnification × 400, scale bar indicates 100 μm). c Toluidine blue staining revealed inclusion bodies in podocytes (magnification × 400, scale bar indicates 50 μm). d Mulberry corpuscles were also found in the urine sediment. e Lamellar bodies in podocytes were observed by electron microscopy

Fig. 2

Clinical course of the patient. Before enzyme replacement therapy, a decrease in the urinary protein level was observed, and the serum albumin level was normalized with immunosuppressive therapy. uPCR = urinary protein/creatinine ratio; sAlb = serum albumin

Discussion and conclusion

Patients with FD usually show less proteinuria, at approximately 1 g/day or less, despite the accumulation of GB-3 in podocytes. Although 7.3% of male FD patients have been reported to have nephrotic-range proteinuria [4], only a few male cases of FD with nephrotic syndrome have been reported to date (Table 2). Zarate et al. reported the case of a patient with a nonsense FD mutation (W226X) with nephrotic syndrome developing secondary to minimal change disease [11]. Oral prednisolone at a dose of 2 mg/kg/day divided into two doses significantly improved his proteinuria to 100 mg/dL [11]. This team concluded that other causes of renal pathology must be considered because patients may respond to immunotherapy. Indeed, several glomerular diseases can coexist with FD, including IgA nephropathy, membranous GN, lupus nephritis, and crescentic GN, including ANCA-positive renal disease [6, 13,14,15]. Further, it should be noted that the rarity of proteinuria > 1 g/day in Fabry nephropathy in women should strongly suggest the presence of an alternate diagnosis. In our case, treatment with prednisolone led to remission of the heavy proteinuria. Renal pathology showed focal segmental glomerulosclerosis (FSGS), which could suggest the coexistence with FD. However, since prednisolone rapidly reduced the massive proteinuria regardless of the low selectivity index, minimal change nephrotic syndrome might not be excluded. Although we did not perform whole-exome sequencing analysis, it would be interesting to test for genes related to FSGS, although the strike rate is expected to be low in steroid-sensitive nephrotic syndrome in adults. The other mechanisms by which immunosuppressive drugs improve nephrotic syndrome in patients with FD are likely related to the inhibition of FD-associated inflammation and immune responses caused by GB-3. FD has been reported to lead a proinflammatory profile in cells, including podocytes, and immune abnormalities could be related to proteinuria and renal dysfunction in patients with FD. Indeed, increased levels of proinflammatory cytokines and oxidative stress have been reported in patients with FD, who were treated with ERT [16]. Francesco et al. reported that the proinflammatory state involves two key subsets of innate immunity and provided direct evidence of GB-3 playing a proinflammatory role, likely mediated by Toll-like receptor-4 [17]. Furthermore, compared with healthy controls, induced pluripotent stem cells from peripheral blood cell-derived endothelial cells in FD showed considerably increased reactive oxygen species (ROS) production [18]. In addition, the excess accumulation of GB-3 suppressed superoxide dismutase 2 expression and increased ROS production, finally causing vascular endothelial dysfunction in human umbilical vein endothelial cells [18]. Because prednisolone improves puromycin aminonucleoside-induced podocyte damage through the inhibition of mitochondrial dysfunction and ROS generation [19], the FD-associated massive proteinuria in our case may be improved by steroid therapy through inhibiting the dysregulation of ROS generation induced by GB-3. Moreover, the beneficial effect of calcineurin inhibitors on proteinuria is not dependent on the inhibition of nuclear factor activation in T cells but rather results from stabilization of the actin cytoskeleton in kidney podocytes [20]. Therefore, the mechanism of proteinuria normalization with a calcineurin inhibitor in this patient might be explained at least in part by stabilization of the actin cytoskeleton in podocytes. Further clinical and basic research is necessary to clarify this issue.

Table 2 Clinical and laboratory data of 10 cases with nephrotic syndrome in Fabry disease patients

Although repeat renal biopsy is not available, biopsy findings on EM before and after immunosuppressive therapy and ERT would be of interest. All EM specimens showed foot process effacement, suggesting podocyte injury in this patient. It has been reported that podocyte foot process effacement is an early sign of FD without proteinuria or a decreased GFR [21]. It is speculated that foot process effacement might be recovered and lamellar bodies in podocytes might be reduced by the immunosuppressive therapy in association with the reduced proteinuria in this case.

In this case, we detected mulberry bodies in the urine. Recently, mulberry bodies and cells have become useful noninvasive diagnostic markers in patients with late-onset FD, even in those with normoalbuminuria and/or normal renal function [22]. The source of mulberry bodies is believed to be podocytes and/or distal tubular epithelial cells. Since many podocytes detach from the glomerular basement membrane in late-stage FD, mulberry bodies can easily be detected in the early stage of FD, as in this case.

This is the rare case of a patient with FD and nephrotic syndrome. Before FD was diagnosed, the patient’s urinary protein level had dramatically increased to the nephrotic range but was normalized with immunosuppressive therapy. Nephrotic syndrome is unusual in patients with FD, and few cases have been reported [5,6,7,8,9,10,11,12] (Table 2). One patient was diagnosed with FD before renal biopsy [11], whereas the others were diagnosed with FD after renal biopsy. All patients exhibited the accumulation of glycosphingolipids in the glomerular epithelial cells on renal biopsy with or without typical findings of other nephropathy. Five patients including our case received steroid therapy and 4 patients achieved complete recovery from nephrotic syndrome [7, 9, 11]. A good response to steroid therapy is atypical in FD patients with heavy proteinuria. Three nephrotic patients including our case developed renal dysfunction, which was completely improved by the immunosuppressive therapy [9, 11]. Therefore, if nephrotic-range proteinuria continues and develops, the coexistence of other nephropathies should be considered. In this regard, immunotherapy might be recommended in addition to ERT in nephrotic syndrome patients diagnosed with FD on renal biopsy.

Availability of data and materials

The data that support the findings of this case report are available from KF (corresponding author).



Cyclosporine A


Enzyme replacement therapy


Fabry disease


Focal segmental glomerulosclerosis



GLA gene:

α-galactosidase A gene


Reactive oxygen species


White blood cell

α-gal activity:

α-galactosidase A activity


  1. 1.

    Breunig F, Weidemann F, Beer M, Eggert A, Krane V, Spindler M, Sandstede J, Strotmann J, Wanner C. Fabry disease: diagnosis and treatment. Kidney Int Suppl. 2003;84:S181–5.

    Article  Google Scholar 

  2. 2.

    Møller AT, Jensen TS. Neurological manifestations in Fabry’s disease. Nat Clin Pract Neurol. 2007;3(2):95–106.

    Article  Google Scholar 

  3. 3.

    Nakao S, Takenaka T, Maeda M, Kodama C, Tanaka A, Tahara M, Yoshida A, Kuriyama M, Hayashibe H, Sakuraba H. An atypical variant of Fabry’s disease in men with left ventricular hypertrophy. N Engl J Med. 1995;333(5):288–93.

    CAS  Article  Google Scholar 

  4. 4.

    Ortiz A, Oliveira JP, Waldek S, Warnock DG, Cianciaruso B, Wanner C, Registry F. Nephropathy in males and females with Fabry disease: cross-sectional description of patients before treatment with enzyme replacement therapy. Nephrol Dial Transplant. 2008;23(5):1600–7.

    CAS  Article  Google Scholar 

  5. 5.

    Reyes Marín FA, Gómez Navarro B, Tamayo y Orozco J, Larriva Sahd J, Hernández Pando R, Velázquez Forero F, Peña JC. Nephropathy in a case of Fabry’s disease. Rev Investig Clin. 1991;43(4):373–6.

    Google Scholar 

  6. 6.

    Majima K, Ishizaki T, Inoue T, Hori Y, Egami J, Oohara A, Nishida H, Miyake Y, Matsumoto S, Kinoshita E. A case of Fabry’s disease associated with lupus nephritis. Nihon Jinzo Gakkai Shi. 1992;34(11):1189–94.

    CAS  PubMed  Google Scholar 

  7. 7.

    Thamboo TP, Sivaraman P, Chan NH. Pathologic quiz case: an unsuspected cause of nephrotic syndrome. Heterozygous Fabry disease. Arch Pathol Lab Med. 2004;128(5):593–4.

    PubMed  Google Scholar 

  8. 8.

    Inagaki S, Migita M, Hayakawa M, Fujita A, Yoshida J, Ishizaki M, Kotani M, Sakuraba H, Shimada T, Murakami M, et al. An asymptomatic heterozygous female with fabry disease: implications for enzyme replacement therapy. J Nippon Med Sch. 2005;72(6):387–90.

    Article  Google Scholar 

  9. 9.

    Chinen S, Tana T, Kohagura K, Yamazato M, Iseki K, Takishita S. Two unusual cases of Anderson-Fabry disease in a Japanese family. Clin Nephrol. 2005;63(5):390–3.

    CAS  Article  Google Scholar 

  10. 10.

    Fischer EG, Moore MJ, Lager DJ. Fabry disease: a morphologic study of 11 cases. Mod Pathol. 2006;19(10):1295–301.

    Article  Google Scholar 

  11. 11.

    Zarate YA, Patterson L, Yin H, Hopkin RJ. A case of minimal change disease in a Fabry patient. Pediatr Nephrol. 2010;25(3):553–6.

    Article  Google Scholar 

  12. 12.

    Trimarchi H, Karl A, Raña MS, Forrester M, Pomeranz V, Lombi F, Iotti A. Initially nondiagnosed Fabry’s disease when electron microscopy is lacking: the continuing story of focal and segmental glomerulosclerosis. Case Rep Nephrol Urol. 2013;3(1):51–7.

    CAS  Article  Google Scholar 

  13. 13.

    Maixnerová D, Tesař V, Ryšavá R, Reiterová J, Poupětová H, Dvořáková L, Goláň L, Neprašová M, Kidorová J, Merta M, et al. The coincidence of IgA nephropathy and Fabry disease. BMC Nephrol. 2013;14:6.

    Article  Google Scholar 

  14. 14.

    Liu Y, Xie H, Lin H, Chen S, Wang W, Zhao G, Zhang X. Coexistence of Fabry disease and membranous nephropathy. Iran J Kidney Dis. 2016;10(1):48–50.

    PubMed  Google Scholar 

  15. 15.

    Hanaoka H, Hashiguchi A, Konishi K, Ishii T, Kuwana M. A rare association between Fabry’s disease and granulomatosis with polyangiitis: a potential pathogenic link. BMC Nephrol. 2014;15:157.

    Article  Google Scholar 

  16. 16.

    Biancini GB, Vanzin CS, Rodrigues DB, Deon M, Ribas GS, Barschak AG, Manfredini V, Netto CB, Jardim LB, Giugliani R, et al. Globotriaosylceramide is correlated with oxidative stress and inflammation in Fabry patients treated with enzyme replacement therapy. Biochim Biophys Acta. 2012;1822(2):226–32.

    CAS  Article  Google Scholar 

  17. 17.

    De Francesco PN, Mucci JM, Ceci R, Fossati CA, Rozenfeld PA. Fabry disease peripheral blood immune cells release inflammatory cytokines: role of globotriaosylceramide. Mol Genet Metab. 2013;109(1):93–9.

    Article  Google Scholar 

  18. 18.

    Tseng WL, Chou SJ, Chiang HC, Wang ML, Chien CS, Chen KH, Leu HB, Wang CY, Chang YL, Liu YY, et al. Imbalanced production of reactive oxygen species and mitochondrial antioxidant SOD2 in Fabry disease-specific human induced pluripotent stem cell-differentiated vascular endothelial cells. Cell Transplant. 2017;26(3):513–27.

    Article  Google Scholar 

  19. 19.

    Yu L, Liu Y, Wu Y, Liu Q, Feng J, Gu X, Xiong Y, Fan Q, Ye J. Smad3/Nox4-mediated mitochondrial dysfunction plays a crucial role in puromycin aminonucleoside-induced podocyte damage. Cell Signal. 2014;26(12):2979–91.

    CAS  Article  Google Scholar 

  20. 20.

    Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med. 2008;14(9):931–8.

    CAS  Article  Google Scholar 

  21. 21.

    Tøndel C, Kanai T, Larsen KK, Ito S, Politei JM, Warnock DG, Svarstad E. Foot process effacement is an early marker of nephropathy in young classic Fabry patients without albuminuria. Nephron. 2015;129(1):16–21.

    Article  Google Scholar 

  22. 22.

    Shimohata H, Maruyama H, Miyamoto Y, Takayasu M, Hirayama K, Kobayashi M. Urinary mulberry cells and mulberry bodies are useful tool to detect late-onset Fabry disease. CEN Case Rep. 2017;6(2):148–51.

    Article  Google Scholar 

Download references


We would like to thank Miss Shinkai for her excellent staining of the renal specimens.


There was no funding support for this case report.

Author information




All authors have read and approved the manuscript in its current state. HF, RY and YN treated the patient. SN provided his knowledge and ideas about Fabry disease. YK, NN, and AN diagnosed Fabry disease from the renal biopsy specimen. TTogawa, TTsukimura, and HS measured GAL activity and analyzed gene mutations. KF performed work related to the manuscript.

Corresponding author

Correspondence to Kei Fukami.

Ethics declarations

Ethics approval and consent to participate

This research was approved by the Ethical Committee of Kurume University, Fukuoka, Japan (protocol identification number: 2018018). All procedures performed in this study involving this participant were in accordance with the ethical standards of the institutional and national research committee at which the study was conducted and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent for publication

Written informed consent was obtained from the patient for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor of this journal.

Competing interests

KF has received personal fees from Sumitomo Dainippon Pharma Co., Ltd., outside of the submitted work. HS has received personal fees and research funding from Sumitomo Dainippon Pharma Co., Ltd., and Sanofi Japan Co. TT1 corresponding to Tadayasu Togawa has received grants from Sanofi Japan Co., outside of the submitted work.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Fujisawa, H., Nakayama, Y., Nakao, S. et al. Effectiveness of immunosuppressive therapy for nephrotic syndrome in a patient with late-onset Fabry disease: a case report and literature review. BMC Nephrol 20, 469 (2019).

Download citation


  • Fabry disease
  • Late-onset variant
  • Nephrotic syndrome
  • Immunotherapy
  • Enzyme replacement therapy