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Biomedical subjects

F Scolari

Publications and source records attributed to F Scolari.

At least 19 recordsLinked to original sources
PubMed2006

Cis and trans regulatory elements in NPHS2 promoter: implications in proteinuria and progression of renal diseases.

Podocin (NPHS2) expression in podocytes is associated with variable degrees of proteinuria and progression to renal failure in different glomerular diseases that suggests different expression profiles in NPHS2 promoter. Three functional polymorphisms in NPHS2 promoter (-51T, -116T, and -535 insCTTTTTT(3)) were found determining strong downregulation (-73, -59, and -82%, respectively) of the reporter gene expression when transfected in podocytes. Electrophoretic mobility shift assay experiments showed that all wild-type variants (-51G, -116C, and -535 insCTTTTTT(2)) formed specific DNA-protein complexes with podocyte nuclear extracts that were abolished by the presence of the rare forms (-51T, -116T, and -535 insCTTTTTT(3)). In the case of -51G, upstream stimulatory factor-1 (USF1) was identified as the specific trans element in accord to binding inhibition experiments and USF1 RNAi silencing. Haplotype analysis of 204 normal controls and 545 patients with renal diseases (308 immunoglobulin (Ig)A nephropathy and 237 focal segmental glomerulosclerosis) evidenced that -116/-51 and -535/P2OL formed two blocks in strong linkage disequilibrium in both normal and pathological cohorts. The high NPHS2 promoter profile -116C/-51G haplotype was more frequent in patients with IgA nephropathy (P-value=0.005) and was associated with a better clinical outcome in terms of proteinuria and creatinine levels. Overall our study describes functional variants of NPHS2 promoter and characterizes trans-acting elements that modulate podocin expression in the kidney. High producer NPHS2 promoter haplotypes seem protective in patients with chronic glomerular diseases.

Adolescent↗
PubMed2006

Glomerular clusterin is associated with PKC-alpha/beta regulation and good outcome of membranous glomerulonephritis in humans.

Mechanisms for human membranous glomerulonephritis (MGN) remain elusive. Most up-to-date concepts still rely on the rat model of Passive Heymann Nephritis that derives from an autoimmune response to glomerular megalin, with complement activation and membrane attack complex assembly. Clusterin has been reported as a megalin ligand in immunodeposits, although its role has not been clarified. We studied renal biopsies of 60 MGN patients by immunohistochemistry utilizing antibodies against clusterin, C5b-9, and phosphorylated-protien kinase C (PKC) isoforms (pPKC). In vitro experiments were performed to investigate the role of clusterin during podocyte damage by MGN serum and define clusterin binding to human podocytes, where megalin is known to be absent. Clusterin, C5b-9, and pPKC-alpha/beta showed highly variable glomerular staining, where high clusterin profiles were inversely correlated to C5b-9 and PKC-alpha/beta expression (P=0.029), and co-localized with the low-density lipoprotein receptor (LDL-R). Glomerular clusterin emerged as the single factor influencing proteinuria at multivariate analysis and was associated with a reduction of proteinuria after a follow-up of 1.5 years (-88.1%, P=0.027). Incubation of podocytes with MGN sera determined strong upregulation of pPKC-alpha/beta that was reverted by pre-incubation with clusterin, serum de-complementation, or protein-A treatment. Preliminary in vitro experiments showed podocyte binding of biotinilated clusterin, co-localization with LDL-R and specific binding inhibition with anti-LDL-R antibodies and with specific ligands. These data suggest a central role for glomerular clusterin in MGN as a modulator of inflammation that potentially influences the clinical outcome. Binding of clusterin to the LDL-R might offer an interpretative key for the pathogenesis of MGN in humans.

Adult↗
PubMed2006

Familial aggregation of primary glomerulonephritis in an Italian population isolate: Valtrompia study.

Hereditary factors are suspected to contribute to the pathogenesis of sporadic primary glomerulonephritis, but their contribution is difficult to delineate in the general population. We studied the prevalence of primary glomerulonephritis in an isolated population from the extreme northern Valtrompia valley, Northern Italy. Investigation of medical records, community urinary screening program and molecular characterization of the population's ancestry were performed; genealogies of affected individuals were researched. Forty-three patients with primary glomerulonephritis were identified: 25 had biopsy-proven disease (11 immunoglobulin A (IgA) nephropathy; eight mesangial proliferative glomerulonephritis without IgA deposits; four focal segmental glomerular sclerosis; two membranous nephropathy), and 18 had clinical glomerulonephritis. All 43 patients originated from three mountain villages (Collio, San Colombano, and Bovegno). In contrast, we found only four cases of primary glomerulonephritis in two nearby villages (Pezzaze and Tavernole) that shared similar population histories and lifestyles, demonstrating heterogeneity of risk factors for glomerulonephritis (P=3 x 10(-5)). All 43 affected individuals could be traced back to common ancestors (XVI-XVII centuries), enabling the construction of three large pedigree including three parent-child affected pairs and five affected siblings pairs. Molecular data showed lower genetic diversity and increased inbreeding in the Valtrompia population compared to the control population. Molecular and genealogical evidence of limited set of founders and the absence of shared nephritogenic environmental factors suggest that our patients share a common genetic susceptibility to the development of primary glomerulonephritis. Further molecular study of our families will offer the possibility to shed light on the genetic background underlying these glomerular disorders.

Adult↗
PubMed2001

Identification of the gene for oral-facial-digital type I syndrome.

Oral-facial-digital type 1 syndrome (OFD1 [MIM 311200]) is transmitted as an X-linked dominant condition with lethality in males and is characterized by malformations of the face, oral cavity, and digits, and by a highly variable expressivity even within the same family. Malformation of the brain and polycystic kidneys are commonly associated with this disorder. The locus for OFD1 was mapped by linkage analysis to a 12-Mb interval, flanked by markers DXS85 and DXS7105 in the Xp22 region. To identify the gene responsible for this syndrome, we analyzed several transcripts mapping to the region and found mutations in OFD1 (formerly named "Cxorf5/71-7a"), encoding a protein containing coiled-coil alpha-helical domains. Seven patients with OFD1, including three with familial and four with sporadic cases, were analyzed. Analysis of the familial cases revealed a missense mutation, a 19-bp deletion, and a single base-pair deletion leading to a frameshift. In the sporadic cases, we found a missense (de novo), a nonsense, a splice, and a frameshift mutation. RNA in situ studies on mouse embryo tissue sections show that Ofd1 is developmentally regulated and is expressed in all tissues affected in OFD1 syndrome. The involvement of OFD1 in oral-facial-digital type I syndrome demonstrates an important role of this gene in human development.

Abnormalities, Multiple↗
PubMed2001

Clinical and morphological features of kidney involvement in primary Sjögren's syndrome.

BACKGROUND: Primary Sjögren's syndrome is a connective tissue disorder affecting primarily the lacrimal and salivary glands, resulting in xerophtalmia and xerostomia. Extraglandular manifestations are frequent and may include renal involvement. METHODS: We studied the prevalence and nature of kidney involvement in 60 Italian patients with primary Sjögren's syndrome, diagnosed according to the European classification criteria. The following renal laboratory tests were performed in all patients: electrolytes in serum and in 24-h urine, creatinine in serum and in 24-h urine, venous pH and HCO(3)(-), urinalysis, urine culture, urinary osmolality and urine pH. A water deprivation test was performed in patients with morning urine osmolalities below the reference values adjusted for age. An oral ammonium chloride loading test was performed in patients with urine pH above 5.5 from morning samples. Renal biopsy was performed in patients with renal involvement. RESULTS: Sixteen patients (27%) had laboratory evidence of tubular and/or glomerular dysfunction. A variable degree of creatinine clearance reduction was found in eight patients (13%); frank distal tubular acidosis in three (5%); hypokalaemia in four (7%); and pathological proteinuria in 12 (20%). Urine concentrating capacity was defective in 10 out of 48 (21%) tested patients. Only four patients presented with overt clinical manifestations, including hypokalaemic tetraparesis (1), nephrotic syndrome (2), recurrent renal stones with flank pain and haematuria (1). In two patients, signs of renal involvement preceded the onset of sicca syndrome. Renal biopsies from nine patients showed tubulo-interstitial nephritis in six and glomerular disease in three. Patients with renal involvement had a significantly shorter disease duration compared with patients without renal abnormalities. CONCLUSIONS: Kidney involvement is a frequent extraglandular manifestation of primary Sjögren's syndrome. It is rarely overt and may precede the onset of subjective sicca syndrome.

Adult↗
PubMed2001

Polymorphisms in the promoter region and at codon 54 of the MBL2 gene are not associated with IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) occurs sporadically in unrelated individuals. Several different polymorphic genes have been investigated in recent years in order to demonstrate their possible association with IgAN. Three recent, different studies with conflicting conclusions have discussed the role of the mannose binding lectin (MBL), a serum lectin involved in natural immunity, in the IgAN pathogenesis by examination of MBL deposits in biopsies. In the present study we investigated several polymorphisms of the MBL gene located in the promoter region and in the first exon. METHODS: MBL polymorphism detection was performed in 22 Italian patients with familial IgA nephropathy and in 138 Italian patients with the sporadic form of the disease. The polymorphisms in the MBL2 promoter region and in the exon 1 were investigated, respectively, by direct sequencing and by amplification refractory mutation system-polymerase chain reaction on genomic DNA collected from peripheral blood. Seventy-four unrelated healthy subjects matched for ethnic origin were used as controls. RESULTS: Allelic and genotypic frequencies of the polymorphisms at position -550, -328, -221 and at codon 54 did not show any differences between patients and controls. Similar frequency distributions of these polymorphisms were also found in the subgroups of IgAN patients subdivided according to the clinical manifestations and the progression of the disease. CONCLUSIONS: This study indicates that the analysed polymorphisms of the MBL gene do not appear to be primarily involved in the susceptibility and severity of IgAN.

Adolescent↗
PubMed2001

Direct effect of the correction of acidosis on plasma parathyroid hormone concentrations, calcium and phosphate in hemodialysis patients: a prospective study.

BACKGROUND: Metabolic acidosis contributes to renal osteodystrophy and together with hyperphosphatemia, hypocalcemia and altered vitamin D metabolism may result in increased levels of intact parathyroid hormone (iPTH) and metastatic calcifications. However, the impact of the correction of metabolic acidosis on iPTH levels and calcium-phosphate metabolism is still controversial. STUDY DESIGN: The effects of the correction of metabolic acidosis on serum concentrations of iPTH, calcium (Ca), phosphate (PO(4)) and alkaline phosphatase were prospectively studied. Twelve uremic patients on maintenance hemodialysis (HD) for 49 months (median; range 6-243 months) with serum bicarbonate levels < or =20 mmol/l were studied before and after 3 months of oral sodium bicarbonate supplementation. Predialysis serum bicarbonate, arterial pH, ionized calcium, plasma sodium, plasma potassium, serum creatinine, hemoglobin, K(t)/V, postdialysis body weight, predialysis systolic and diastolic blood pressure were also evaluated before and after correction. RESULTS: Serum bicarbonate levels and arterial pH increased respectively from 19.3 +/- 0.6 to 24.4 +/- 1.2 mmol/l (p < 0.0001) and 7.34 +/- 0.03 to 7.40 +/- 0.02 (p < 0.001). iPTH levels decreased significantly from 399 +/- 475 to 305 +/- 353 pg/ml (p = 0.026). No changes in total serum Ca, plasma PO(4), serum akaline phosphatase, K(t)/V, serum creatinine, hemoglobin, body weight, predialysis systolic and diastolic blood pressures were observed. iCa decreased significantly. CONCLUSIONS: Our study demonstrates that the correction of metabolic acidosis in chronic HD patients reduces iPTH concentrations in HD patients with secondary hyperparathyroidism possibly by a direct effect on iPTH secretion.

Acid-Base Equilibrium↗
PubMed2000

A prospective randomized trial on azathioprine addition to cyclosporine versus cyclosporine monotherapy at steroid withdrawal, 6 months after renal transplantation.

BACKGROUND: Many attempts have been made to withdraw steroid therapy in renal transplant patients in order to avoid its many side effects. Results have been, so far, controversial. In this randomized prospective study, we compare the efficacy of azathioprine adjuncts to cyclosporine at the time of steroid withdrawal, 6 months after transplantation, versus Cyclosporine monotherapy, in preventing acute rejection. METHODS: One hundred and sixteen kidney transplant patients with good and stable renal function (creatininemia <2 mg/dl) received, in the first 6 months, cyclosporine + steroid. They were then randomized into two groups (A and B), and steroid therapy was withdrawn over 2 months. Group A (58 patients) continued on cyclosporine monotherapy, whereas group B (58 patients) added azathioprine (1 mg/kg/day) at the beginning of randomization and continued on cyclosporine + azathioprine. In both groups, patients resumed steroid therapy at the first episode of acute rejection. Follow-up after randomization was 5.3+/-1.6 years. RESULTS: After 5 years, the incidence of steroid resumption was 57% in group A and 29% in group B (P<0.02); of those, 68% and 88% of them were within 6 months from randomization. Anti-rejection therapy was always successful. Five-year patient and graft survival rates were 90% and 88% in group A and 100% and 91% in group B. Creatininemia did not differ, at follow-up. Side effects differed only for mild and reversible leukopenia caused by azathioprine in group B. CONCLUSION: Cyclosporine plus azathioprine is more effective than cyclosporine monotherapy in reducing the incidence of acute rejection after steroid withdrawal. Graft loss as a result of chronic rejection, mild in both groups, did not differ. Steroid withdrawal is feasible and advantageous, and the addition of azathioprine allowed 71% of our selected patients to remain steroid-free.

Adrenal Cortex Hormones↗
PubMed2000

IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22-23.

End-stage renal disease (ESRD) is a major public health problem, affecting 1 in 1,000 individuals and with an annual death rate of 20% despite dialysis treatment. IgA nephropathy (IgAN) is the most common form of glomerulonephritis, a principal cause of ESRD worldwide; it affects up to 1.3% of the population and its pathogenesis is unknown. Kidneys of people with IgAN show deposits of IgA-containing immune complexes with proliferation of the glomerular mesangium (Fig. 1). Typical clinical features include onset before age 40 with haematuria and proteinuria (blood and protein in the urine), and episodes of gross haematuria following mucosal infections are common; 30% of patients develop progressive renal failure. Although not generally considered a hereditary disease, striking ethnic variation in prevalence and familial clustering, along with subclinical renal abnormalities among relatives of IgAN cases, have suggested a heretofore undefined genetic component. By genome-wide analysis of linkage in 30 multiplex IgAN kindreds, we demonstrate linkage of IgAN to 6q22-23 under a dominant model of transmission with incomplete penetrance, with a lod score of 5.6 and 60% of kindreds linked. These findings for the first time indicate the existence of a locus with large effect on development of IgAN and identify the chromosomal location of this disease gene.

Chromosome Mapping↗
PubMed2000

Cholesterol crystal embolism: A recognizable cause of renal disease.

Cholesterol crystal embolism, sometimes separately designated atheroembolism, is an increasing and still underdiagnosed cause of renal dysfunction antemortem in elderly patients. Renal cholesterol crystal embolization, also known as atheroembolic renal disease, is caused by showers of cholesterol crystals from an atherosclerotic aorta that occlude small renal arteries. Although cholesterol crystal embolization can occur spontaneously, it is increasingly recognized as an iatrogenic complication from an invasive vascular procedure, such as manipulation of the aorta during angiography or vascular surgery, and after anticoagulant and fibrinolytic therapy. Cholesterol crystal embolism may give rise to different degrees of renal impairment. Some patients show only a moderate loss of renal function; in others, severe renal failure requiring dialysis ensues. An acute scenario with abrupt and sudden onset of renal failure may be observed. More frequently, a progressive loss of renal function occurs over weeks. A third clinical form of renal atheroemboli has been described, presenting as chronic, stable, and asymptomatic renal insufficiency. The renal outcome may be variable; some patients deteriorate or remain on dialysis, some improve, and some remain with chronic renal impairment. In addition to the kidneys, atheroembolization may involve the skin, gastrointestinal system, and central nervous system. Renal atheroembolic disease is a difficult and controversial diagnosis for the protean extrarenal manifestations of the disease. In the past, the diagnosis was often made postmortem. However, in the last decade, awareness of atheroembolic renal disease has improved, enabling us to make a correct premortem diagnosis in a number of patients. Correct diagnosis requires the clinician to be alert to the possibility. The typical patient is a white man aged older than 60 years with a baseline history of hypertension, smoking, and arterial disease. The presence of a classic triad characterized by a precipitating event, acute or subacute renal failure, and peripheral cholesterol crystal embolization strongly suggests the diagnosis. The confirmatory diagnosis can be made by means of biopsy of the target organs, including kidneys, skin, and the gastrointestinal system. Thus, Cinderella and her shoe now can be well matched during life. Patients with renal atheroemboli have a dismal outlook. A specific treatment is lacking. However, it is an important diagnosis to make because it may save the patient from inappropriate treatment. Finally, recent data suggest that an aggressive therapeutic approach with patient-tailored supportive measures may be associated with a favorable clinical outcome.

Adult↗
PubMed2000

Suprarenal aortic cross-clamping in elective abdominal aortic aneurysm surgery.

INTRODUCTION: this retrospective study was undertaken to evaluate whether suprarenal aortic cross-clamping increased the perioperative mortality and morbidity as compared to infrarenal clamping, in order to create the rationale for a more extensive application of this apparently more traumatic manoeuvre. MATERIALS AND METHODS: in a series of 734 elective aortic substitutions for abdominal aneurysm (AA), performed consecutively from January 1992 to June 1999, aortic cross-clamping was performed at a suprarenal level in 56 juxtarenal aneurysms, i.e. aneurysms extending to the lower edge of the renal arteries (8%, Group 1), and at an infrarenal level in 634 subrenal aneurysms (92%, Group 2). When analysing preoperative data, the diameter of aneurysms was larger in Group 1 than in Group 2 (p<0. 005). No significant differences were found between the two groups as regards age, sex, postinfarction cardiomyopathy, chronic obstructive pulmonary disease, chronic renal insufficiency and ASA classification of operative risks. RESULTS: the average time of renal exclusion in the juxtarenal aneurysms was 20 min (range 12-35 min). There is no difference between the two groups as regards the time of aortic clamping (mean 50 vs. 60 min) or the need for homologous blood transfusion (7% vs. 11% of patients). Perioperative (30 days) mortality did not differ: 3.6% vs. 1.9% (n.s.); nor did the incidence of acute myocardial infarction (3.6% vs. 2.3%). Renal function deteriorated in 8 (14%) vs. 0 (0%) (p<0.001) and 1 patient (2%) required permanent dialysis, as compared to 0% in Group 2. The incidence of ischaemic colitis was also significantly higher in Group 1 (7%) than in Group 2 (2%, p<0.01). CONCLUSION: this data shows that suprarenal clamping, which is necessary for the radical treatment of juxtarenal aortic aneurysms, can be performed with a low risk.

Aged↗
PubMed2000

Evidence of further genetic heterogeneity in autosomal dominant medullary cystic kidney disease.

BACKGROUND: Autosomal dominant medullary cystic kidney disease is a genetically heterogeneous nephropathy with clinical and morphological features similar to recessively inherited juvenile nephronophthisis. Recently, a second gene locus on chromosome 16p12, MCKD2 has been mapped [1] in addition to the known locus on chromosome 1q21 (MCKD1) [2]. In a previous study we have excluded linkage for three caucasian families to the MCKD1 locus [3]. METHODS: Haplotype analysis was performed on 72 individuals (including 24 affected subjects), using a set of seven microsatellite markers spanning the critical region on chromosome 16p12-p13 of about 10.5 cM. RESULTS: We report on haplotype analysis of closely linked markers to the MCKD2 locus in the previously studied families and two additional families. CONCLUSION: In all five families the association of MCKD2 with the disease was excluded by a multipoint LOD score <-2, thus suggesting the involvement of a third MCKD locus.

Chromosome Mapping↗
PubMed1999

Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria.

BACKGROUND: Stratum 2 of the Ramipril Efficacy in Nephropathy (REIN) study has already shown that in patients with chronic nephropathies and proteinuria of 3 g or more per 24 h, angiotensin-converting enzyme (ACE) inhibition reduced the rate of decline in glomerular filtration and halved the combined risk of doubling of serum creatinine or end-stage renal failure (ESRF) found in controls on placebo plus conventional antihypertensives. In REIN stratum 1, reported here, 24 h proteinuria was 1 g or more but less than 3 g per 24 h. METHODS: In stratum 1 of this double-blind trial 186 patients were randomised to a ramipril or a control (placebo plus conventional antihypertensive therapy) group targeted at achieving a diastolic blood pressure of less than 90 mm Hg. The primary endpoints were change in glomerular filtration rate (GFR) and time to ESRF or overt proteinuria (> or =53 g/24 h). Median follow-up was 31 months. FINDINGS: The decline in GFR per month was not significantly different (ramipril 0.26 [SE 0.05] mL per min per 1.73m2, control 0.29 [0.06]). Progression to ESRF was significantly less common in the ramipril group (9/99 vs 18/87) for a relative risk (RR) of 2.72 (95% CI 1.22-6.08); so was progression to overt proteinuria (15/99 vs 27/87, RR 2.40 [1.27-4.52]). Patients with a baseline GFR of 45 mL/min/1.73 m2 or less and proteinuria of 1.5 g/24 h or more had more rapid progression and gained the most from ramipril treatment. Proteinuria decreased by 13% in the ramipril group and increased by 15% in the controls. Cardiovascular events were similar. As expected, the rate of decline in GFR and the frequency of ESRF were much lower in stratum 1 than they had been in stratum 2. INTERPRETATION: In non-diabetic nephropathies, ACE inhibition confers renoprotection even to patients with non-nephrotic proteinuria.

Adult↗
PubMed1999

Pseudoporphyria induced by nabumetone.

Nabumetone is a nonsteroidal anti-inflammatory drug, which has only rarely been associated with photosensitivity. We report a case of bullous lesions arising over photoexposed areas in a patient treated with nabumetone.

Anti-Inflammatory Agents, Non-Steroidal↗