A Novel Missense GLA Mutation (p.G35V) Detected in Hemodialysis Screening Leads to Severe Systemic Manifestations of Fabry Disease in Men and Women.

BACKGROUND/AIMS: Fabry disease (FD), an X-linked lysosomal storage disorder, leads to accumulation of globotriaosylceramide. Screening in dialysis patients may identify genetic variants of unknown clinical significance. We aimed to characterize the pathogenicity of a novel GLA gene mutation identified during hemodialysis screening and the histologic findings of early Fabry nephropathy. METHODS: One out of 108 male hemodialysis patients screened for FD presented low α-galactosidase A activity. A novel missense mutation (p.G35V) in the GLA gene was detected. Family screening identified 11 additional cases (8 women). Clinical investigation was conducted in 10 patients (index case and 9 relatives). Pathogenicity of the new mutation was investigated by clinical and laboratory tests, cardiac and cranial magnetic resonance imaging, and kidney biopsy. RESULTS: Cardiac manifestations were detected in most patient from both genders, such as left ventricular hypertrophy and short PR interval. White matter lesion was present in 3 women. Pulvinar lesion of the thalamus and ischemic stroke were detected in male patients. Abnormal glomerular filtration rate (GFR) and/or albuminuria were present in 5 patients (3 women). Renal biopsies (n = 7) revealed globotriaosylceramide deposits in different cell types and foot processes effacement in all patients, including women with normal albuminuria. Despite a normal GFR, tubulointerstitial fibrosis ranging from 5 to 20% was present in young women and men with normal or high albuminuria, respectively. CONCLUSION: The novel missense mutation p.G35V leads to severe systemic manifestations of FD in men and women. Kidney histological changes, including tubulointerstitial fibrosis, may predate albuminuria and GFR changes in adult women. Novel non-invasive markers are required for early detection of Fabry nephropathy.

An overview on frequency of renal biopsy diagnosis in Brazil: clinical and pathological patterns based on 9,617 native kidney biopsies.

BACKGROUND: Studies about the prevalence of renal and particularly glomerular diseases in Brazil are still scarce. METHODS: We evaluated retrospectively the reports of 9,617 renal biopsies, analyzed by the same pathologist, from January 1993 to December 2007. RESULTS: The 9,617 renal biopsies performed in subjects of all ages in native kidneys. 4,619 were primary glomerulopathies (GN), the most frequent was focal segmental glomerulosclerosis (FSGS, 24.6%), followed by membranous nephropathy (MN, 20.7%), IgA nephropathy (IgAN, 20.1%), minimal change disease (MCD, 15.5%), mesangioproliferative non IgAN (nonIgAN, 5.2%), diffuse proliferative GN (DPGN, 4.7%) and membranoproliferative GN (MPGN, 4.2%). Lupus nephritis was responsible for most cases which etiology was determined, i.e., 950 out of 2,046 cases (45.5%), followed by post infectious GN (18.9%), diabetic nephropathy (8.5%), benign and malignant nephroangiosclerosis (7.3%), haemolytic-uraemic syndrome and thrombotic thrombocytopenic purpura (HUS/TTP), amyloidosis (4.8%) and vasculitis (4.7%). There was a predominance of secondary GN in the North, mostly due to lupus nephritis (LN); FSGS was very common in Northeast (27.7%), Central (26.9%) and Southeast regions (24.1%); IgAN was most frequent in South (22.8%) and MN in North (29.6%); the total prevalence of MPGN was low, and its regional distribution has not changed along the years. CONCLUSION: FSGS was the most frequent primary glomerular disease, followed closely by MN and IgAN. The predominance of FSGS is in accordance with recent studies all over the world that revealed its frequency is increasing. Lupus nephritis predominated among secondary GN in most regions, a finding observed in other studies.

Early presence of calcium oxalate deposition in kidney graft biopsies is associated with poor long-term graft survival.

Accumulated oxalate will be excreted after renal transplantation, creating an increased risk of tubular precipitation, especially in the presence of allograft dysfunction. We evaluated calcium oxalate (CaOx) deposition in renal allograft biopsies with early dysfunction, its association with acute tubular necrosis (ATN) and graft survival. We studied 97 renal transplant patients, submitted to a graft biopsy within 3 months post-transplant, and reanalyzed them after 10 years. We analyzed renal tissue under polarized light and quantified CaOx deposits. CaOx deposits were detected in 52.6% of the patients; 26.8% were of mild and 25.8% of moderate intensity. The deposits were more frequent in biopsies performed within 3 weeks post-transplant (82.4 vs. 63.0%, p < 0.05) and in allografts with more severe renal dysfunction (creatinine 5.6 mg/dL vs. 3.4 mg/dL, p < 0.001). ATN incidence was also higher in patients with CaOx deposits (47% vs. 24%, p < 0.001). Twelve-year graft survival was strikingly worse in patients with CaOx deposits compared to those free of deposits (49.7 vs. 74.1%, p = 0.013). Our study shows a high incidence of CaOx deposits in kidney allografts with early dysfunction, implying an additional risk for acute tubular injury, with a negative impact on graft survival.