Renal transplantation in patients with Fabry disease

Anderson-Fabry disease (AFd) is a rare X-linked disorder characterized by deficiency of alpha-galactosidase A that leads to systemic accumulation of neutral glycosphingolipids, predominantly globotriaosylceramide (Gb3), in body fluids and visceral tissues, including the kidney. End-stage renal failure is a common manifestation in hemizygous males that often occurs by the third to fourth decade of life. Usually transplanted patients exhibit improvement in clinical symptoms of the disease, probably related to the production of alpha-galactosidase A from the grafted kidney, but mainly related to the increase in Gb3 clearance by the functioning kidney, and increased survival of red cells due to the correction of the uremic status with an evident decrease in the production of Gb3 depending from hemolysis. Several Fabry patients with successful kidney graft survived for 10-15 years and died for cardiovascular complications related to the metabolic disease. The loss of grafted kidney is due to rejection, thrombosis or sepsis. An important issue considering renal transplantation in AFd is the recurrence of the disease in the kidney graft; however, no evidence regarding this possibility has occurred up to now. We report herein the ultrastructural study of the urinary sediment of a 35-year-old male Fabry patient with a severe clinical form of the disease with progression to ESRF at age 29, and submitted to renal transplantation at 33 years. Ultrastructural findings of the urinary sediment documented several cells, probably tubular epithelial cells, with typical accumulation of myelinic bodies resulting from intracellular storage of neutral glycosphingolipids. This morphological evidence arises the problem of the possible recurrence of AFd in the kidney graft in patients with severe phenotype of the metabolic disease.     

Multifocal bilateral renal cell carcinoma and retinal angiomas in a patient with de novo von Hippel-Lindau disease: identification of a new germline mutation

Von Hippel-Lindau (VHL) disease is a rare autosomal dominant disorder characterized by multifocal and bilateral renal cell carcinoma and cysts, retinal angiomas, hemangioblastoma of the central nervous system, pheochromocytoma, epididymis cystoadenoma, pancreatic cysts and/or islet cell tumors. However, phenotypic manifestations and clinical outcome are wide ranging including inter and intra-familial patterns. The VHL gene has been localized on chromosome 3 p 25-26 and more than 250 germline mutations have been described. The sensitivity of analytic techniques of VHL gene is close to 100%. It is well known that about 25% of VHL patients present de novo mutations, and first cases function as possible founders of new VHL kindreds. Herein, we report the clinical case of a 45-year-old Caucasian female patient affected by bilateral polycystic kidney disease with two renal carcinomas in both kidneys without lynphoadenopathies. She underwent ophthalmologic surgery at 19 years old because of retinal detachment due to bilateral retinal angiomatosis. Direct gene sequencing showed a deletion-insertion in exon 3, starting from nucleotide 499 of the coding sequence (c.499-504 delinstT) in a heterozygous status; it causes a frame-shift and creates a premature stop at codon 170. The genetic study of the unaffected parents and of the unaffected brother confirmed the diagnosis of de novo VHL disease with the dentification of a new germline mutation, never reported in the literature. The patient showed normal kidney function and she did not show other organ lesions or clinical manifestations of VHL disease. She was successfully submitted to renal parenchymal sparing-surgery. In conclusion, it is important to test for germline mutations in VHL patients with the involvement of one organ or a pair of organs. Once the mutation is found in the proband, all family members can be easily tested for the documented mutation. The early identification of VHL patients is very important for clinical and genetic reasons.     

Correlation of lipoprotein(a) levels and myocardial stress thallium scintigraphy pattern in different entities of CHD severity

BACKGROUND: Higher levels of lipoprotein(a) confer an increased risk for coronary heart disease (CHD). Apo-E genotype (APO-E) also plays a role, the APO-E epsilon 4 allele being associated with CHD. Furthermore, higher Lp(a) concentrations are correlated with APO-E epsilon 4 allele presence. The study was performed to investigate the relationship of Lp(a) and APO-E with the functional status of coronary arteries as evaluated by myocardial scintigraphy. PATIENTS AND METHODS: We studied 70 patients (27 F and 43 M; mean age: 55 +/- 6 yrs.) consecutively referred for CHD, and 50 normal sex and age-matched controls. Total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apo-AI, apo-B, Lp(a) levels (ELISA), Lp(a) isoforms (Immuno Blotting) and APO-E (PCR) were measured in all subjects. Only CHD patients underwent a myocardial tomographic stress thallium scintigraphy (201Tl-SPECT); the SPECT pattern was classified as follows: no perfusion defects (unstable angina group = 1), reversible defects at stress images (ischemia group = 2), fixed defects (infarction group = 3). RESULTS: Lp(a) medians were significantly higher than controls in group 1 (p < 0.05), 2 (p < 0.001) and 3 (p = 0.00). Low molecular weight isoforms (B, S1, S2) were significantly more frequent in all CHD-patients vs. controls (p < 0.05), whereas APO-E genotypes did not differ among controls and patients. Multiple regression analysis showed family history (p < 0.001) to be the only independent predictive variable of CHD severity correlated to the scintigraphic pattern. CONCLUSION: Among the considered biological parameters in our patients only Lp(a) plasma levels are related to the entity of ischemic cardiac wall damage as evaluated by 201Tl-SPECT.     

Therapeutic effect of spa therapy and short wave therapy in knee osteoarthritis: a randomized,single blind,controlled trial

Spa therapy and short wave therapy are two of the most commonly used non-pharmacological approaches for osteoarthritis. The aim of this study was to assess their efficacy in comparison to conventional therapy in patients with osteoarthritis of the knee in a single blind, randomized, controlled trial. Seventy-four outpatients were enrolled; 30 patients were treated with a combination of daily local mud packs and arsenical ferruginous mineral bath water from the thermal resort of Levico Terme (Trento, Italy) for 3 weeks; 24 patients were treated with short wave therapy for the same period and 20 patients continued regular, routine ambulatory care. Patients were assessed at baseline, upon completion of the 3-week treatment period, and 12 weeks later. Spa therapy and short wave therapy both demonstrated effective symptomatic treatment in osteoarthritis of the knee at the end of the treatment, but only the spa therapy was shown to have efficacy persistent over time. Our study demonstrated the superiority of arsenical ferruginous spa therapy compared to short wave therapy in the treatment of osteoarthritis of the knee, probably in relationship to the specific effects of the minerals in this water.     

Racial difference in endothelial function: role of the infective burden

There is much evidence to suggest the existence of racial differences between blacks and whites in the behaviour of endothelial function. Infective state, sustained by viral or bacterial agents, may injure the endothelial surface favouring the onset and progression of atherosclerotic process, mainly by an inflammatory mechanism. The aim of the study was to investigate endothelial function, expressed as brachial flow-mediated vasodilation (FMV), in black and white healthy subjects, along with antibody titer to cytomegalovirus, hepatitis virus (B, C), herpes virus-1 and 2, Epstein-Barr, Chlamydia pneumoniae and the expression of adhesion molecules. We enrolled 22 young (mean age 27+/-8 years) healthy subjects of black race (10 males) and 20 healthy young subjects (10 males, mean age 28+/-9 years) of white race. Total infectious burden (TIB) was defined as the number of serological positive infections. Black subjects have a reduced brachial FMV (6.9+/-3.5% versus 11.6+/-3.0%, p<0.01) and increased values of hsCRP (0.35+/-0.15 mg/dL versus 0.07+/-0.08 mg/dL, p<0.05), white cells (8578+/-1041/mmc versus 5833+/-998/mmc, p<0.01) and adhesion molecules (respectively: sVCAM-1 945+/-142 versus 779+/-93, sICAM-1 534+/-107 ng/mL versus 325+/-80 ng/mL; both p<0.01) in comparison to white subjects. The total infectious burden in black race was significantly higher than in white race (5+/-1 versus 2+/-1, p<0.01). At the univariate analysis, brachial FMV was significantly related to the levels of adhesion molecules (respectively: sVCAM-1 r=-0.49; sICAM-1 r=-0.50, both p<0.05), hsCRP (r=-0.47, p<0.05) and white blood cells (r=-0.43, p<0.05). TIB was associated with brachial FMV (r=-0.64, p<0.05), sVCAM-1 (r=0.55, p<0.05) and hsCRP (r=0.47, p<0.05). At the multivariate analysis the only predictive variables for brachial FMV were hsCRP, TIB and brachial diameter (respectively: beta=-0.49, -0.19, -0.54, all p<0.05). This study confirms that endothelial reactivity is impaired in young African black patients; moreover its behavior is strictly related to the inflammatory state and to the total infectious burden.     

Myokine—Irisin—and Its Effects Linking Bone and Muscle Function

Irisin is a myokine secreted by the skeletal muscle during physical activity both in mice and humans. Its first identified role was to activate the browning response in white adipocytes, subsequently triggering non-shivering thermogenesis; therefore, Irisin has raised great expectations as a potential target in the treatment of obesity. In 2015, we demonstrated that Irisin plays a central role in the control of bone mass, driving positive effects on cortical mineral density and bone mechanical properties. This effect on the bone was triggered using an Irisin dosage 70 times lower than the one needed to induce the browning response, suggesting that the skeleton is the primary target organ of this myokine. Moreover, our studies also highlighted the autocrine effect of Irisin on the skeletal muscle, overall suggesting that Irisin plays a fundamental role in the physiology of the musculoskeletal system. More recently, we demonstrated the efficacy of Irisin in preventing and restoring bone and muscle losses in a mouse model affected by disuse-induced osteoporosis and muscular atrophy. Hopefully, if future investigations will be confirmed in humans, it may lead to develop an Irisin-based therapy for physically disable or bedridden patients and it might also represent a countermeasure for astronauts subjected to microgravity.