Clinical and Pathological Findings in Women with Fabry Disease

Introduction. Fabry disease is a rare metabolic disorder caused by the genetic deficiency of the lysosomal hydrolase alpha-galactosidase A, located on chromosome X. Females with the defective gene are more than carriers and can develop a wide range of symptoms. Nevertheless, disease symptoms generally occur later and are less severe in women than in men. The enzyme deficiency manifests as a glycosphingolipidosis with progressive accumulation of glycosphingolipids and deposit of inclusion bodies in lysosomes giving a myelinlike appearance. Patients and Methods. Records of renal biopsies performed on adults from 1st January 2008 to 31st August 2011, were retrospectively examined at the Renal Pathology Laboratory. We retrieved biopsies diagnosed with Fabry disease and reviewed clinical and laboratory data and pathology findings. Results. Four female patients with a mean age of 49.3±4.5 (44-55) years were identified. The mean proteinuria was 0.75±0.3 g/24h (0.4-1.2) and estimated glomerular filtration rate (CKD EPI equation) was 71±15.7 ml/min/1.73m2 (48-83). Three patients experienced extra-renal organ involvement (cerebrovascular, cardiac, dermatologic, ophthalmologic and thyroid) with distinct severity degrees. Leukocyte α-GAL A activity was below normal range in the four cases but plasma and urinary enzymatic activity was normal. Light microscopy showed predominant vacuolisation of the podocyte cytoplasm and darkly staining granular inclusions on paraffin and plastic-embedded semi-thin sections. Electron microscopy showed in three patients the characteristic myelin-like inclusions in the podocyte cytoplasm and also focal podocyte foot process effacement. In one case the inclusions were also present in parietal glomerular cells, endothelial cells of peritubular capillary and arterioles. Conclusion. Clinical signs and symptoms are varied and can be severe among heterozygous females with Fabry disease. Intracellular accumulation of glycosphingolipids is a characteristic histologic finding of Fabry nephropathy. Since this disease is a potentially treatable condition, its early identification is imperative. We should consider it in the differential diagnosis of any patient presenting with proteinuria and/or chronic kidney disease, especially if there is a family history of kidney disease.

Neuroendocrine Tumours of the Female Genital Tract: a Case-Based Imaging Review with Pathological Correlation

BACKGROUND: Both primary and secondary gynaecological neuroendocrine (NE) tumours are uncommon, and the literature is scarce concerning their imaging features. METHODS: This article reviews the epidemiological, clinical and imaging features with pathological correlation of gynaecological NE tumours. RESULTS: The clinical features of gynaecological NE tumours are non-specific and depend on the organ of origin and on the extension and aggressiveness of the disease. The imaging approach to these tumours is similar to that for other histological types and the Revised International Federation of Gynecology and Obstetrics (FIGO) Staging System also applies to NE tumours. Neuroendocrine tumours were recently divided into two groups: poorly differentiated neuroendocrine carcinomas (NECs) and well-differentiated neuroendocrine tumours (NETs). NECs include small cell carcinoma and large cell neuroendocrine carcinoma, while NETs account for typical and atypical carcinoids. Cervical small cell carcinoma and ovarian carcinoid are the most common gynaecological NE tumours. The former typically behaves aggressively; the latter usually behaves in a benign fashion and tends to be confined to the organ. CONCLUSION: While dealing with ovarian carcinoids, extra-ovarian extension, bilaterality and multinodularity raise the suspicion of metastatic disease. NE tumours of the endometrium and other gynaecological locations are very rare. TEACHING POINTS: • Primary or secondary neurondocrine (NE) tumours of the female genital tract are rare. • Cervical small cell carcinoma and ovarian carcinoids are the most common gynaecological NE tumours. • Cervical small cell carcinomas usually behave aggressively. • Ovarian carcinoids tend to behave in a benign fashion. • The imaging approach to gynaecological NE tumours and other histological types is similar.

A Prospective Assessment of Renal Transplantation Versus Haemodialysis: Which Therapeutic Modality Is Good Value for Society?

Background: Economic evaluations help health authorities facing budget constraints. This study compares the health-related quality of life (HRQOL) and costs in patient subgroups on haemodialysis (HD) and renal transplantation (KT). Methods: In a prospective study with follow-up of 1-3 years, we performed a costutility analysis of KT vs. HD, adopting a lifetime horizon. A societal perspective was taken. Costs for organ procurement, KT eligibility, transplant surgery and follow-up of living donors were included. Key clinical events were recorded. HRQOL was assessed using the EuroQol instrument. Results: The HRQOL remained stable on HD patients. After KT, mean utility score improved at 3 months while mean EQ-VAS scores showed a sustained improvement. Mean annual cost for HD was 32,567.57€. Mean annual costs for KT in the year-1 and in subsequent years were, 60,210.09€ and 12,956.77€ respectively. Cost for initial hospitalization averaged 18,740.74€. HLA-mismatches increased costs by 75% for initial hospitalization (p < 0.001) and 41% in the year-1 (p < 0.05), and duplicate the risk of readmission in the year-1 (p < 0.05). The incremental costutility ratio was 5,534.46€/QALY, increasing 35% when costs for organ procurement were added. KT costs were 41,541.63€ more but provided additional 7.51 QALY. Conclusions: The KT is cost-effective compared with HD. Public funding should reflect the value created by the intervention and adapt to the organ demand.

Disruption of Urate Transport in Familial Renal Glucosuria and Report on SGLT2 Expression in Normal and Pathological Kidney

Familial renal glucosuria (FRG) is a rare co -dominantly inherited benign phenotype characterized by the presence of glucose in the urine. It is caused by mutations in the SLC5A2 gene that encodes SGLT2, a Na+ -glucose co -transporter. The purpose of our current work was twofold: to characterize the molecular and phenotype findings of an FRG cohort and, in addition, to detail the SGLT2 expression in the adult human kidney. The phenotype of FRG pedigrees was evaluated using direct sequencing for the identification of sequence variations in the SLC5A2 gene. The expression of SGLT2 in the adult human kidney was studied by immunofluorescence on kidney biopsy specimens. In the absence of renal biopsies from FRG individuals, and in order to evaluate the potential disruption of SGLT2 expression in a glucosuric nephropathy, we have selected cases of nucleoside analogues induced proximal tubular toxicity. We identified six novel SLC5A2 mutations in six FRG pedigrees and described the occurrence of hyperuricosuria associated with hypouricaemia in the two probands with the most severe phenotypes. Histopathological studies proved that SGLT2 is localized to the brush -border of the proximal tubular epithelia cell and that this normal pattern was found to be disrupted in cases of nucleoside analogues induced tubulopathy. We present six novel SLC5A2 mutations, further contributing to the allelic heterogeneity in FRG, and identified hyperuricosuria and hypouricaemia as part of the FRG phenotype. SGLT2 is localized to the brush -border of the proximal tubule in the adult human normal kidney, and aberrant expression of the co -transporter may underlie the glucosuria seen with the use of nucleoside analogues.

American Society of Anesthesiologists Score: Still Useful After 60 Years? Results of the EuSOS Study

OBJECTIVE: The European Surgical Outcomes Study described mortality following in-patient surgery. Several factors were identified that were able to predict poor outcomes in a multivariate analysis. These included age, procedure urgency, severity and type and the American Association of Anaesthesia score. This study describes in greater detail the relationship between the American Association of Anaesthesia score and postoperative mortality. METHODS: Patients in this 7-day cohort study were enrolled in April 2011. Consecutive patients aged 16 years and older undergoing inpatient non-cardiac surgery with a recorded American Association of Anaesthesia score in 498 hospitals across 28 European nations were included and followed up for a maximum of 60 days. The primary endpoint was in-hospital mortality. Decision tree analysis with the CHAID (SPSS) system was used to delineate nodes associated with mortality. RESULTS: The study enrolled 46,539 patients. Due to missing values, 873 patients were excluded, resulting in the analysis of 45,666 patients. Increasing American Association of Anaesthesia scores were associated with increased admission rates to intensive care and higher mortality rates. Despite a progressive relationship with mortality, discrimination was poor, with an area under the ROC curve of 0.658 (95% CI 0.642 - 0.6775). Using regression trees (CHAID), we identified four discrete American Association of Anaesthesia nodes associated with mortality, with American Association of Anaesthesia 1 and American Association of Anaesthesia 2 compressed into the same node. CONCLUSION: The American Association of Anaesthesia score can be used to determine higher risk groups of surgical patients, but clinicians cannot use the score to discriminate between grades 1 and 2. Overall, the discriminatory power of the model was less than acceptable for widespread use.

Recommendations for Vaccination in Adult Patients with Systemic Inflammatory Rheumatic Diseases from the Portuguese Society of Rheumatology

Serious infections are a major cause of morbidity and mortality in systemic inflammatory rheumatic disease (SIRD) patients. Although vaccination may prevent numerous infections, vaccination uptake rates are low in this group of patients. OBJECTIVES: To develop evidence-based recommendations for vaccination in SIRD patients. METHODS: We searched MEDLINE (until 31 October 2014) and EMBASE (until 14 December 2014) databases, as well as the ACR and EULAR congress abstracts (2011-2014). Patients with any systemic inflammatory rheumatic disease were included and all vaccines were considered. Any safety and efficacy outcomes were admitted. Search results were submitted to title and abstract selection, followed by detailed review of suitable studies. Data were subsequently pooled according to the type of vaccine and the SIRD considered. Results were presented and discussed by a multidisciplinary panel and systematic literature review (SLR)-derived recommendations were voted according to the Delphi method. The level of agreement among rheumatologists was assessed using an online survey. RESULTS: Eight general and seven vaccine-specific recommendations were formulated. Briefly, immunization status should routinely be assessed in all SIRD patients. The National Vaccination Program should be followed and some additional vaccines are recommended. To maximize the efficacy of vaccination, vaccines should preferably be administered 4 weeks before starting immunosuppression or, if possible when disease activity is controlled. Non-live vaccines are safe in SIRD, including immunosuppressed patients. The safety of live attenuated vaccines in immunosuppressed patients deserves further ascertainment, but might be considered in particular situations. DISCUSSION: The present recommendations combine scientific evidence with the multidisciplinary expertise of our taskforce panel and attained desirable agreement among Portuguese rheumatologists. Vaccination recommendations need to be updated on a regular basis, as more scientific data regarding vaccination efficacy and safety, emergent infectious threats, new vaccines as well as new immunomodulatory therapies become available.