Scoring system for renal pathology in Fabry disease: report of the International Study Group of Fabry Nephropathy (ISGFN).

BACKGROUND: In Fabry nephropathy, alpha-galactosidase deficiency leads to accumulation of glycosphingolipids in all kidney cell types, proteinuria and progressive loss of kidney function. METHODS: An international working group of nephrologists from 11 Fabry centres identified adult Fabry patients, and pathologists scored histologic changes on renal biopsies. A standardized scoring system was developed with a modified Delphi technique assessing 59 Fabry nephropathy cases. Each case was scored independently of clinical information by at least three pathologists with an average final score reported. RESULTS: We assessed 35 males (mean age 36.4 years) and 24 females (43.9 years) who mostly had clinically mild Fabry nephropathy. The average serum creatinine was 1.3 mg/dl (114.9 micromol/l); estimated glomerular filtration rate was 81.7 ml/min/1.73 m(2) and urine protein to creatinine ratio was 1.08 g/g (122.0 mg/mmol). Males had greater podocyte vacuolization on light microscopy (mean score) and glycosphingolipid inclusions on semi-thin sections than females. Males also had significantly more proximal tubule, peritubular capillary and vascular intimal inclusions. Arteriolar hyalinosis was similar, but females had significantly more arterial hyalinosis. Chronic kidney disease stage correlated with arterial and glomerular sclerosis scores. Significant changes, including segmental and global sclerosis, and interstitial fibrosis were seen even in patients with stage 1-2 chronic kidney disease with minimal proteinuria. CONCLUSIONS: The development of a standardized scoring system of both disease-specific lesions, i.e. lipid deposition related, and general lesions of progression, i.e. fibrosis and sclerosis, showed a spectrum of histologic appearances even in early clinical stage of Fabry nephropathy. These findings support the role of kidney biopsy in the baseline evaluation of Fabry nephropathy, even with mild clinical disease. The scoring system will be useful for longitudinal assessment of prognosis and responses to therapy for Fabry nephropathy.

Splenomegaly, hypersplenism and peripheral blood cytopaenias in patients with classical Anderson-Fabry disease.

A 39-year-old male with classical Anderson-Fabry disease (AFD) and long-standing idiopathic splenomegaly, who had been on haemodialysis since the age of 24, was splenectomised for symptomatic pancytopaenia. Spleen enlargement was first noted at clinical presentation, at age 16, but despite thorough investigation its cause remained unclear. Anaemia, leukopaenia and thrombocytopaenia were first observed a few years thereafter, but well before the start of dialytic treatment. On gross pathological examination the spleen weighed 700 g and had a fibrocongestive appearance. Histologically, it showed expansion of the red pulp and decreased white pulp. Some histiocytes and many of the endothelial cells lining the sinusoids had vacuolated cytoplasm with argyrophilic material within, suggesting their involvement in the storage pathology of AFD. In a retrospective review of our cohort of patients with classical AFD (n = 10), complete blood counts showing anaemia, leukopaenia or thrombocytopaenia were found in five, two and four patients, respectively, including a 6-year-old boy, whose spleen was also enlarged. Data from AFD international registries show that peripheral blood cytopaenias, particularly anaemia, are prevalent among these patients. Sinusoidal endothelial involvement resulting in compromise of splenic blood flow may be the cause of congestive splenomegaly and hypersplenism in classical AFD.

Kidney biopsy findings in heterozygous Fabry disease females with early nephropathy.

Fabry disease is an X-linked glycosphingolipidosis caused by deficiency of alpha-galactosidase. Progressive chronic kidney disease (CKD) is a major cause of morbidity and mortality in males. Although 40% of heterozygous females may develop renal involvement, pathologic data on Fabry nephropathy in heterozygotes are scarce. We reviewed the kidney biopsies of four affected females who had normal to slightly sub-normal renal function, two of them with overt proteinuria. Chronic non-specific degenerative lesions and glycosphingolipid accumulation per cell type were semi-quantitatively assessed by light and electron microscopy. Cellular distribution of glycosphingolipid deposits was best assessed on semithin sections. Podocyte effacement was seen only in proteinuric patients. Combined analysis of our data with those of two earlier series showed that glomerular sclerosis and tubulointerstitial fibrosis are predictors of proteinuria and CKD stage. There was no histopathological evidence supporting a major role of vascular damage in the early pathogenesis of Fabry nephropathy in females.

Fruit and vegetable consumption and gastric cancer by location and histological type: case-control and meta-analysis.

The available information favours a greater impact of environmental exposures on intestinal type gastric cancer, and risk factors for the cardia and distal stomach cancers also appear to be different. We aimed to estimate the association between fruit and vegetable intake and gastric cancer, by location and histological type. We performed a population-based case-control study and a meta-analysis of studies addressing this issue. Incident cases (n=305) were identified in two large teaching hospitals (Porto, Portugal), and controls were randomly sampled among city dwellers (n=1129). Published studies were searched through PubMed, and effects were combined with random effects meta-analysis. In our case-control study, the odds ratio (OR) for the comparison of the highest vs. lowest tertile of fruit consumption was 0.47 [95% confidence interval (CI): 0.21-1.05] for cardia, 0.53 (95% CI: 0.35-0.80) for non-cardia cancer, 0.36 (95% CI: 0.20-0.62) for intestinal, and 1.00 (95% CI: 0.53-1.90) for the diffuse histological type. For vegetables, the corresponding OR was 0.59 (95% CI: 0.26-1.35), 0.85 (95% CI: 0.58-1.26), 0.95 (95% CI: 0.57-1.57), and 0.60 (95% CI: 0.32-1.14). In meta-analysis, considering fruit consumption (highest vs. lowest category), the combined OR was 0.58 (95% CI: 0.38-0.89) for cardia, 0.61 (95% CI: 0.44-0.84) for non-cardia, 0.49 (95% CI: 0.33-0.72) for intestinal type, and 0.82 (95% CI: 0.57-1.20) for diffuse type. Vegetables also decreased the risk of cardia (OR=0.63, 95% CI: 0.50-0.79), non-cardia (OR=0.75, 95% CI: 0.59-0.95), intestinal (OR=0.61, 95% CI: 0.44-0.86), and diffuse type (OR=0.67, 95% CI: 0.44-1.01). Fruit or vegetable intake was associated with a decreased risk of gastric cancer regardless of the anatomical location and the histological type, although dietary intake had a more clear-cut protective effect on intestinal type cancers.

Systemic polyarteritis nodosa associated with acute Epstein-Barr virus infection.

Polyarteritis nodosa (PAN) is a rare cause of systemic vasculitis in children, affecting medium and small-sized arteries. We report on a patient who presented with prolonged fever, shock, acute renal failure with nephrotic range proteinuria, hypertension, and sudden deterioration of consciousness. Cranial tomography revealed a left extensive hemorrhagic lesion. Renal biopsy revealed a large fibrinoid necrosis lesion consistent with PAN. Epstein-Barr virus (EBV) infection was confirmed by real-time polymerase chain reaction (RT-PCR) detection of EBV DNA. The patient was successfully treated with oral prednisolone and intravenous pulse of cyclophosphamide. To our knowledge, this is the first reported case of c-PAN related to active EBV infection.

Renal diseases: a 27-year renal biopsy study.

BACKGROUND: Data from registries of renal biopsy (RB), currently an important source for diagnosing renal disease, are available for a number of countries, but different patterns seem to exist in different countries. METHODS: We reviewed the records of all patients who underwent an RB at our institution over a 27-year period (January 1, 1977, to December 31, 2003), in northern Portugal, a European region with a predominantly Caucasian population. We aimed at identifying patterns of glomerular disease frequency, as well as the corresponding changes over time. The patients were grouped for analysis in 9-year intervals: period A (1977 through 1985), period B (1986 through 1994) and period C (1995 through 2003). RESULTS: Nephrotic syndrome was the most common clinical presentation for RB (42.0%), followed by urinary abnormalities (28.5%), acute renal failure (9.7%), chronic renal failure (9.3%) and nephritic syndrome (9.3%). Primary glomerulonephritis (GN) was the most common type of kidney disease in the present study, representing 50.4% of all renal pathology, followed by secondary GN (29.4%) and vascular and tubulointerstitial diseases (14.0%). The relative frequency of secondary GN and vascular and tubulointerstitial diseases increased significantly over time, and so did IgA nephropathy, the most common type of primary glomerular disease in the present study (31.2%). Focal and segmental glomerulosclerosis represented 6.9% of primary glomerular disease, and its frequency did not increase in the time period under study. Regarding secondary glomerular diseases, apparent changes were noted in the incidence of a number of diseases, including vasculitis, thin glomerular basement membrane disease and Henoch-Schönlein pur-pura. A somewhat similar situation was noted with vascular and tubulointerstitial diseases. CONCLUSIONS: We conclude that, as occurs in other European and Asiatic populations, and unlike the findings in the American continent, IgA nephropathy is the most frequent glomerular disease in our population.

[Solitary fibrous tumor -- report of two cases]. / Tumor solitário fibroso -- a propósito de dois casos clínicos.

Solitary Fibrous Tumor is a rare neoplasm derived from mesenchymal cell. To achieve a diagnosis and to differentiate from others neoplasm immunohistochemical analysis is needed. The majority of these tumours are benign, and complete surgical resection remains the mainstay of therapy for both the benign and malignant variants. However, there are cases of local and distant recurrences, so patients should have a close follow-up and it is far incorrect to look at this lesion as definitely benign. The authors review clinical presentation, radiological features, histological findings, and treatment options for this tumor and report two clinical cases discussing the differences between them.

Immunohistochemical diagnosis of Fabry nephropathy and localisation of globotriaosylceramide deposits in paraffin-embedded kidney tissue sections.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder of glycosphingolipids, mostly globotriaosylceramide (Gb3). Proteinuric chronic kidney disease develops frequently, and recognition of Fabry nephropathy on a kidney biopsy may be the first clue to the underlying diagnosis. Since the accumulated glycosphingolipids are largely extracted by the paraffin-embedding procedure, the most characteristic feature of Fabry nephropathy on routine light microscopy (LM) is nonspecific cell vacuolization. To test whether residual Gb3 in kidney tissue might be exploited for the specific diagnosis of Fabry nephropathy, paraffin-embedded kidney biopsies of nine FD patients (one boy, four men, four women) and of a female carrier of a mild genetic mutation, with no evidence of Fabry nephropathy, were immunostained with an anti-Gb3 antibody. The adult biopsies were additionally co-stained with a lysosomal marker (anti-lysosomal-associated membrane protein 2 (anti-LAMP2) antibody). The distribution of Gb3 deposits was scored per cell type and compared to the histological scorings of glycosphingolipid inclusions on semi-thin sections. FD patients had residual Gb3 in all types of glomerular, tubular, interstitial and vascular kidney cells. The highest expression of LAMP2 was seen in tubular cells, but there were no meaningful associations between LAMP2 expression and prevalence of Gb3 deposits on different kidney cell types. The histological scorings of glycosphingolipid inclusions were relatively higher than the corresponding immunohistochemical scorings of Gb3 deposits. In the mildly affected female, Gb3 expression was limited to tubular cells, a pattern similar to controls. Gb3 immunostaining allows the specific diagnosis of Fabry nephropathy even in kidney biopsies routinely processed for LM.

Embryonal rhabdomyosarcoma of the caruncle in a 4 year-old boy: case report.

Rhabdomyosarcoma is a rare tumor, with an annual incidence of 4.3 cases per million children. Even thought, it is the most common soft tissue sarcoma in childhood, with a mean age of 6 to 8 years at diagnosis. A 4 year-old boy presented with a history of a fast growing (1-month) nodular lesion in the caruncle of his left eye. Slit lamp examination showed a vascularized solid nodular lesion in the semilunar fold. The lesion was surgically removed obtaining infiltrated edges with tumoral cells. A second surgery was performed with free tumour edges. The diagnosis of embryonal rhabdomyosarcoma, botryoid type, of intermediate differentiation was made. The treatment for botryoid rhabdomyosarcoma is basically surgical with the combined use of adjuvant polychemotherapy. In adolescent or adult patients (not in infants where growth bone disturbances can occur) external beam radiotherapy can be combined with chemotherapy. Rhabdomyosarcomas of the conjunctiva without orbital extension are rarely reported. We presented a case of a child with a rare tumor which we had a high suspicion of malignancy and early diagnosis and treatment and child is free of systemic disease 6 and half years later. Our research group believes that the key in these tumors is the high index of suspicion and early treatment.

Kidney histologic alterations in α-Galactosidase-deficient mice.

Fabry disease is a rare X-linked disorder caused by mutations in the α-galactosidase gene (GLA), the resultant deficiency of lysosomal α-galactosidase enzyme activity leading to systemic accumulation of globotriaosylceramide and other glycosphingolipids. GLA knockout mice ("Fabry mice") were generated as an animal model for Fabry disease but, as they do not manifest progressive chronic kidney disease (CKD), their relevance as a model for human Fabry nephropathy is uncertain. We evaluated the histological alterations in the kidneys of Fabry mice at different ages, as contrasted to those observed in wild-type mice. Furthermore, we compared the renal histological alterations of Fabry mice to the kidney pathology reported in patients with Fabry disease at comparable age ranges and across different CKD stages, using a scoring system that has been developed for Fabry nephropathy. Fabry mice are phenotypically different from wild-type mice, displaying progressive age-related accumulation of glycosphingolipids in all types of renal cells. There were no statistically significant differences between Fabry mice and Fabry patients in the prevalence of glycosphingolipid storage per renal cell type with the exceptions of mesangial (higher in humans) and proximal tubular cells (higher in mice). However, Fabry mice lack the nonspecific histological glomerulosclerotic and interstitial fibrotic renal lesions that best correlate with progressive CKD in Fabry patients, and do not develop large podocyte inclusions. We postulate that the elucidation of the mechanisms underlying these species differences, may contribute important clues to a better understanding of the pathogenesis of Fabry nephropathy.

Embryonal rhabdomyosarcoma of the caruncle in a 4 year-old boy: case report / Rabdomiossarcoma embrionário da carúncula em um menino de 4 anos: relato de caso

Rhabdomyosarcoma is a rare tumor, with an annual incidence of 4.3 cases per million children. Even thought, it is the most common soft tissue sarcoma in childhood, with a mean age of 6 to 8 years at diagnosis. A 4 year-old boy presented with a history of a fast growing (1-month) nodular lesion in the caruncle of his left eye. Slit lamp examination showed a vascularized solid nodular lesion in the semilunar fold. The lesion was surgically removed obtaining infiltrated edges with tumoral cells. A second surgery was performed with free tumour edges. The diagnosis of embryonal rhabdomyosarcoma, botryoid type, of intermediate differentiation was made. The treatment for botryoid rhabdomyosarcoma is basically surgical with the combined use of adjuvant polychemotherapy. In adolescent or adult patients (not in infants where growth bone disturbances can occur) external beam radiotherapy can be combined with chemotherapy. Rhabdomyosarcomas of the conjunctiva without orbital extension are rarely reported. We presented a case of a child with a rare tumor which we had a high suspicion of malignancy and early diagnosis and treatment and child is free of systemic disease 6 and half years later. Our research group believes that the key in these tumors is the high index of suspicion and early treatment.

Rabdomiossarcoma é um tumor raro, com uma incidência anual de 4,3 casos por milhão de crianças. É o sarcoma de partes moles mais comum na infância, com uma idade média de 6 a 8 anos no momento do diagnóstico. Um menino de 4 anos apresentou-se com uma história de um crescimento rápido (1 mês) lesão nodular em carúncula de seu olho esquerdo. O exame biomicroscópico mostrou uma lesão vascularizada sólida nodular na prega semilunar. A lesão foi removida cirurgicamente com obtenção de bordas infiltradas com células tumorais, segunda cirurgia foi feita com bordas tumorais livres. O diagnóstico de rabdomiossarcoma embrionário, tipo botrióide, de diferenciação intermediária foi feita. O tratamento para a rabdomiossarcoma botrióide é basicamente cirúrgico com o uso combinado de poliquimioterapia adjuvante. Em pacientes adolescentes e adultos (e não em lactentes onde os distúrbios do crescimento ósseo pode ocorrer) radioterapia externa pode ser combinada com a quimioterapia. Rabdomiossarcomas da conjuntiva sem extensão orbital são raramente relatadas. Apresentamos um caso de uma criança com um tumor raro que tivemos uma alta suspeita de malignidade e diagnóstico precoce e tratamento e criança é livre de doença sistêmica 6 anos e meio depois. Nosso grupo de pesquisa acredita que a chave para esses tumores é o alto índice de suspeita e tratamento precoce.

Antioxidant vitamins and risk of gastric cancer: a case-control study in Portugal.

We quantified the effect of antioxidant vitamins in gastric cancer risk, taking into account Helicobacter pylori seropositivity and overall fruit and vegetable intake. Incident cases were identified in two large hospitals in Porto, Portugal, and controls were randomly sampled among city dwellers. Food intake was assessed with a previously validated semiquantitative food-frequency questionnaire. A commercially available chromatographic immunoassay was used for the detection of immunoglobulin G antibodies. Complete questionnaire information and serum samples were available for 233 cases and 311 controls. Compared with subjects in the lowest tertile of dietary intake, the odds ratios (ORs) for those in the highest were 0.85 (95% confidence interval, CI = 0.45-1.60) for vitamin C, 1.04 (95% CI = 0.60-1.80) for vitamin E, and 1.33 (95% CI = 0.77-2.30) for provitamin A carotenoids after further adjusting for fruit and vegetable consumption. Fruit and vegetables remained an independent protective factor (OR = 0.45; 95% CI = 0.23-0.89) after further adjustment for the intake of antioxidant vitamins. H. pylori status had no significant interaction with dietary items. Factors other than H. pylori infection and intake of vitamin C and provitamin A carotenoids seem to account for the inverse association between fruit and vegetable consumption and gastric cancer.

[Lung-kidney syndrome]. / Sindrome pulmão-rim.

The lung-kidney syndrome is characterized by the coexistence of glomerulonephritis and pulmonary hemorrhage. However these manifestations can define different pathologies. The association of diffuse pulmonary hemorrhage, glomerulonephritis and circulating anti-glomerular basement membrane antibodies define Goodpasture syndrome. We report a case of Goodpasture syndrome with review of the literature.

Renal dopamine and salt sensitivity of blood pressure in IgA nephropathy.

BACKGROUND: Patients with chronic glomerulonephritis exhibit salt-sensitive (SS) hypertension. In the early stage, however, the exact characteristics are still unclear. A decrease in renal dopamine production under basal conditions or after a sodium load has been reported in a subset of patients with SS primary hypertension. AIMS: The present study examined 17 untreated IgA-N patients with near-normal renal function, to determine whether salt sensitivity appears before hypertension and whether this sensitivity is related to renal dopamine production. METHODS: Daily urinary excretion of dopamine, the amine precursor--L-DOPA, and metabolites was monitored in conditions of basal sodium ingestion, followed by three consecutive 5-day periods of 100, 20 and 350 mmol/day sodium intake. The sodium sensitivity index (SSI) was evaluated in each patient. In addition, the patients were considered SS when showing an increase > or =5 mm Hg in 24-hour mean BP when they changed from a 20- to a 350-mmol/day sodium diet. RESULTS: Urinary dopamine output was lower in SS than in salt-resistant patients throughout the study (p < 0.001). This was accompanied by lower creatinine clearance values and higher urinary protein excretion in SS IgA-N patients. A strong negative relationship was observed in these 17 IgA-N patients between the SSI and the daily urinary excretion of dopamine in conditions of both 20 mmol/day sodium intake (r2 = 0.592; p = 0.0003) and 350 mmol/day sodium diet (r2 = 0.352; p = 0.01). However, urinary dopamine output varied appropriately throughout the study in SS patients, in agreement with changes in sodium intake. CONCLUSION: We conclude that in IgA-N patients, a rightward shift in the 'pressure natriuresis' can appear before hypertension and is related with a reduced renal production of dopamine. It is suggested that decreased renal dopamine synthesis in SS IgA-N patients results from acquired tubulointerstitial injury. In contrast to what has been found in SS primary hypertension, renal dopamine may behave appropriately in SS IgA-N patients, as a compensatory hormone.