Diffuse thin glomerular basement membrane in association with Fabry disease in a Chinese female patient

Three kidneys, two diseases, one antibody? pregnancy or infection were ruled out [5]. In the literature, two different autoantibodies have been described, suggesting different pathogenesis: the factor H C-terminal surfacebinding region would be the target of aHUS autoantibodies, while ‘miniautoantibodies’ targeting the factor H N-terminal regulatory domain would be involved in MPGN [6]. The first would promote endothelial cell damage by affecting surface regulatory functions of factor H. The second scenario has been described in only one patient [3] in which IgG lambda-chain dimers would affect factor H regulatory function in the fluid phase. Our case, however, suggests that the same autoantibody will disturb factor H activity and according to the environment will result in either MPGN or aHUS. This case underlines the need for complete exploration of complement pathway, especially in relation to the major regulator protein factor H when confronted with cases of both MPGN and aHUS. In our case, plasma exchanges finally allowed us to suppress anti-factor H antibody though this was performed too late to save the second transplant. However, in theory, plasma exchanges and rituximab therapy [7] or even the use of eculizimab (humanized monoclonal anti-C5 antibody) [8], before and during the second transplantation, might have blocked the development of aHUS on the second renal graft. Finally, this case supports the hypothesis that MPGN and aHUS are closely linked by common pathogenic mechanisms, with a central role for the dysregulation of the complement alternative pathway [6]. 3813 Acknowledgements. Many thanks to Stuart Fraser for English corrections. Conflict of interest statement. None declared. References 1. Dragon-Durey M, Loirat C, Cloarec S et al. Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol 2005; 16: 555–563 2. Dragon-Durey M, Sethi SK, Bagga A et al. Clinical features of antifactor H autoantibody-associated hemolytic uremic syndrome. J Am Soc Nephrol 2010; 21: 2180–2187 3. Meri S, Koistinen V, Miettinen A et al. Activation of the alternative pathway of complement by monoclonal lambda light chains in membranoproliferative glomerulonephritis. J Exp Med 1992; 175: 939–950 4. Boyer O, Noël L, Balzamo E et al. Complement factor H deficiency and posttransplantation glomerulonephritis with isolated C3 deposits. Am J Kidney Dis 2008; 51: 671–677 5. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med 2009; 361: 1676–1687 6. Skerka C, Licht C, Mengel M et al. Autoimmune forms of thrombotic microangiopathy and membranoproliferative glomerulonephritis: indications for a disease spectrum and common pathogenic principles. Mol Immunol 2009; 46: 2801–2807 7. Kwon T, Dragon-Durey M, Macher M et al. Successful pre-transplant management of a patient with anti-factor H autoantibodies-associated haemolytic uraemic syndrome. Nephrol Dial Transplant 2008; 23: 2088–2090 8. de Jorge EG, Macor P, Paixão-Cavalcante D et al. The development of atypical hemolytic uremic syndrome depends on complement C5. J Am Soc Nephrol 2011; 22: 137–145 Received for publication: 9.5.11; Accepted in revised form: 27.6.11 Nephrol Dial Transplant (2011) 26: 3813–3816 doi: 10.1093/ndt/gfr455 Advance Access publication 22 August 2011 Diffuse thin glomerular basement membrane in association with Fabry disease in a Chinese female patient Zhi-yong Cai1,2,3, You-kang Zhang1,2,3, Su-xia Wang1,2,3, Qiu-yuan Fang1,2,3 and Yu-qing Chen1,2,3 1 Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China, 2Institute of Nephrology, Peking University, Beijing, China and 3Key Laboratory of Renal Diseases, Ministry of Health of China, Beijing, China Correspondence and offprint requests to: Su-xia Wang; E-mail: Abstract We report a 41-year-old Chinese female with Fabry disease and diffuse thinning of the glomerular basement membrane (GBM). The patient presented with peripheral edema, mild proteinuria, microscopic hematuria, normal renal function, hypertension and tinnitus. Family screening showed that her daughter had microscopic hematuria, tinnitus and neuropathic pain. Renal biopsy of the proband showed focal segmental glomerulosclerosis with cytoplasmic vacuolization of the glomerular visceral epithelial cells by light microscopy. Laminated myelin inclusions in some of the glomerular podocytes, parietal epithelia, distal tubular epithelial cells and vascular endothelial cells along with diffuse thinning of the GBM (mean thickness of GBM: 216 6 31 nm) were identified by electron microscopy. Genetic analysis detected a de novo novel GLA mutation, 1208 ins 21 bp, while a new variant of COL4A3 SNP M1209I was carried by mother and daughter as well as the proband’s father (I-1) and one sister (II-4). The coexistence of thinned GBM should be considered in patients with Fabry disease-manifested familial hematuria. Keywords: COL4A3; Fabry disease; GLA; thin basement membrane nephropathy; mutation Ó The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: 3814 Fabry disease (Anderson–Fabry disease, FD, OMIM 301500) is an X-linked inherited disorder caused by mutations of GLA gene, which encodes the a-galactosidase A (a-Gal A). The disease results in intracellular accumulation of enzyme substances, mainly globotriaosylceramide (Gb3) in the lysosomes of a variety of organs [1]. The kidneys are one of the main target organs. Fabry nephropathy manifests as proteinuria and progressive renal dysfunction [2, 3]. The homozygous males usually present the classical phenotype of FD and develop end-stage renal disease in the third to fifth decades of life, while heterozygous females show variable clinical features [4]. Diffuse thinning of the glomerular basement membrane (GBM) is a characteristic of thin basement membrane nephropathy (TBMN), which usually presents with persistent hematuria and normal renal function. About 40% of TBMN cases have been associated with heterozygous mutations of COL4A3 and COL4A4 [5–7]. Here, we firstly report a case of FD coexisting with TBMN in a Chinese female. Case report A 41-year-old female was referred in 2006 for evaluation of proteinuria, intermittent swelling of the ankles and hypertension. She suffered from chronic pain in childhood, hypohidrosis, tinnitus, vertigo and fatigue. There was no history of diabetes or macroscopic hematuria. Her blood pressure was 160/100 mmHg, pulse rate 78 beats per min and temperature 36.7°C. A few reddish angiokeratomas on the abdomen were detected. Urinalysis showed a proteinuria of 0.75 g/24 h, RBC 4–6 per HP. The serum creatinine and serum albumin were 0.92 mg/dL (81 lmol/L) and 3.9 g/dL, respectively. According to the Chinese formula, her eGFR was 71.83 mL/min (eGFR (mL/min/1.73 m2) ¼ 175 * (Scr, mg/dL)
1.234 * (age, year)
0.179 * (0.79 female)). Other measurements including serum c (...truncated)