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

0 Key Laboratory of Renal Diseases, Ministry of Health of China , Beijing, China 1 Institute of Nephrology, Peking University , Beijing, China 2 Renal Division, Department of Medicine, Peking University First Hospital , Beijing, China 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]. - Acknowledgements. Many thanks to Stuart Fraser for English corrections. Conflict of interest statement. None declared. Received for publication: 9.5.11; Accepted in revised form: 27.6.11 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 probands father (I-1) and one sister (II-4). The coexistence of thinned GBM should be considered in patients with Fabry disease-manifested familial hematuria. Fabry disease (AndersonFabry 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 [57]. 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 46 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) 175 * (Scr, mg/dL) 1.234 * (age, year) 0.179 * (0.79 female)). Other measurements including serum complements, ANA, ANCA and hepatitis serology of HBV and HCV, were normal or negative. Shortening of the PR intervals and hypertrophy of the left ventricular wall were detected by Holter ECG and echocardiogram. Renal ultrasound identified a cyst with a diameter of 12 mm on the upper right kidney. Audiometric test showed a high-frequency loss at 8 kHz of the right ear. The examination of ophthalmology was normal. Her 20-year-old daughter (III-1) had neuropathic pain, hypohidrosis, tinnitus, vertigo, transient ischemic attack as well as hematuria. One of her sisters (II-4) had isolated hematuria without proteinuria, hypertension, renal insufficiency or any sign of FD. Renal biopsy of the proband revealed that 4/35 glomeruli had global sclerosis on light microscopy, 3 showed segmental sclerosis with adhesion to the capsule and the remaining showed mild mesangial expansion with cytoplasmic vacuolization of the visceral epithelial cells. Focal atrophy of tubules with mild interstitial infiltrates was observed. There was moderate arteriolar sclerosis. Collagen Type IV a3 and a5 chains were normally positive while no immune deposits were detected by immunofluorescence (IF). Electron microscopy (EM) showed laminated myelin inclusions in some of the podocytes, parietal epithelia, endothelial cells, distal tubular epithelial cells and interstitial vascular endothelial cells. Diffuse thinning of the GBM with a thickness of 216 31 nm was identified (Figure 1) without splitting or lamellation. (The normal range of GBM thickness in a Chinese female is 335 39 nm in our laboratory). Enzyme activity of a-Gal A was determined in isolated blood leukocytes using a fluorometric assay [8]. Leukocyte levels of a-Gal A, respectively, were 33 and 75 U in the proband and her daughter (III-1); both were lower than the normal level (50 normal controls established the normal range was 100500 U). Other members of her family had normal a-Gal A levels. Genetic analysis of GLA and COL4A3, COL4A4, COL4A5 genes revealed novel variants of 1208 ins 21 bp in Exon 7 of GLA (Supplementary Figures 1, 2) and M1209I with the methionine substitution of isoleucine in Exon 42 of COL4A3 (Supplementary Figure 3), respectively, which were not reported previously. Their presentation in 50 nonhematuric healthy individuals, defined 1208 ins 21 bp of GLA as a mutation, while M1209I of COL4A3 was detected in 2% of a healthy population, as a polymorphism (Table 1). Family screening for a GLA mutation and COL4A3 polymorphism is shown in Figure 2. The proband (II-2) and her daughter (III-1) carried the novel GLA mutation 1208 ins 21 bp and COL4A3 SNP M1209I; the probands father (I-1) and one sister (II-4) carried COL4A3 SNP M1209I. (...truncated)