Genetic approaches to human renal agenesis/hypoplasia and dysplasia

Congenital abnormalities of the kidney and urinary tract are frequently observed in children and represent a significant cause of morbidity and mortality. These conditions are phenotypically variable, often affecting several segments of the urinary tract simultaneously, making clinical classification and diagnosis difficult. Renal agenesis/hypoplasia and dysplasia account for a significant portion of these anomalies, and a genetic contribution to its cause is being increasingly recognized. Nevertheless, overlap between diseases and challenges in clinical diagnosis complicate studies attempting to discover new genes underlying this anomaly. Most of the insights in kidney development derive from studies in mouse models or from rare, syndromic forms of human developmental disorders of the kidney and urinary tract. The genes implicated have been shown to regulate the reciprocal induction between the ureteric bud and the metanephric mesenchyme. Strategies to find genes causing renal agenesis/hypoplasia and dysplasia vary depending on the characteristics of the study population available. The approaches range from candidate gene association or resequencing studies to traditional linkage studies, using outbred pedigrees or genetic isolates, to search for structural variation in the genome. Each of these strategies has advantages and pitfalls and some have led to significant discoveries in human disease. However, renal agenesis/hypoplasia and dysplasia still represents a challenge, both for the clinicians who attempt a precise diagnosis and for the geneticist who tries to unravel the genetic basis, and a better classification requires molecular definition to be retrospectively improved. The goal appears to be feasible with the large multicentric collaborative groups that share the same objectives and resources.     

Glomerulocystic kidney disease in hypomelanosis of Ito

Hypomelanosis of Ito (incontinentia pigmenti type I) was first described as a disorder characterized by unusual unilateral or bilateral cutaneous macular hypopigmented whorls, streaks and patches. Subsequently, neurologic, skeletal and ocular involvement were described. Kidney involvement has been reported only exceptionally. Here, we describe the case of a male infant with hypomelanosis of Ito with a prenatal diagnosis of bilateral enlargement of the kidneys, decreased corticomedullary differentiation and cysts located in the cortical and subcapsular regions. These findings were confirmed postnatally. The skin examination showed hypopigmented linear and round diffuse lesions located on the right leg and the arms. Ophthalmological examination showed anterior capsular and posterior subcapsular cataract of the left eye. Renal biopsy was characteristic of glomerulocystic kidney disease, whereas the skin biopsy confirmed the clinical diagnosis of hypomelanosis of Ito. Four other cases of kidney disease in hypomelanosis of Ito have been reported, including two cases characterized by cystic renal changes, indicating that gene abnormalities that cause hypomelanosis of Ito may also impair normal renal development, causing renal cystic changes.     

Analbuminemia Zonguldak: case report and mutational analysis

OBJECTIVES: To document a new case of the rare disease analbuminemia and to study the molecular defect responsible for the trait. DESIGN AND METHODS: Single-strand conformational polymorphism (SSCP), heteroduplex analysis (HA), and DNA sequencing of the 14 exons and their flanking intron regions, as well as of the 5' and 3' UTR, of the albumin gene were conducted on DNA extracted from peripheral blood samples. RESULTS: DNA sequence analysis showed that the proband was homozygous, and his parents were both heterozygous, for a previously unreported 5180 T-->A transversion. This silent mutation creates at position 5180-81 a new AG dinucleotide, the invariant sequence encountered in all eukaryotic intron acceptor splice sites. This aberrant splice site near the 3'end of exon 5 might alter the normal splicing mechanism. No other mutation was found in the examined regions of the gene. CONCLUSIONS: Our results define a new molecular defect in the albumin gene.     

Direct effect of plasma permeability factors from patients with idiopatic FSGS on nephrin and podocin expression in human podocytes

The presence of circulating plasma factors (PF) altering renal permeability to proteins has been previously described in patients with focal segmental glomerulosclerosis (FSGS). Since these patients show reduced nephrin and podocin expression at renal biopsy, we evaluated the effect of serum and PF from patients with FSGS on nephrin and podocin expression in human podocytes. We studied 7 sera from patients with steroid-resistant FSGS, 3 from patients with nephrotic syndrome caused by non-immune disease, and 6 from healthy subjects. PF was prepared from plasmapheresis eluates of 2 patients with post-transplant recurrence of FSGS. Purification procedure was based on protein A Sepharose chromatography and differential precipitation in ammonium sulphate. Nephrin and podocin expression was semi-quantitatively evaluated by immunofluorescence. We found that serum and PF from FSGS patients rapidly induced redistribution and loss of nephrin in podocytes. This effect was associated with cytoskeleton redistribution and inhibited by cytochalasin B and sodium azide. On the contrary, podocin expression was unchanged after incubation with serum and PF from FSGS patients for short periods, but markedly reduced at 24 h. Our results demonstrate that serum and PF from FSGS patients may directly affect nephrin and podocin in human podocytes, thus providing new insights into the mechanisms causing proteinuria in FSGS.     

Prognostic significance of estrogen receptor determination in primary breast cancer

The authors report on 767 consecutive primary Stage I-II breast cancer cases followed-up from 3 to 8 years. The estrogen receptor (ER) content was determined in all cases and did not influence the treatment choice. A correlation was attempted between ER and menstrual or pathological nodal status (N) or the 5-year disease-free survival (DFS). ER was correlated with menopausal status ER+ cases being more frequent in postmenopausal patients, whereas no correlation was observed between ER and nodal status. In absence of nodal involvement (N-) the prognosis was not influenced by the ER status. A significantly better DFS was evident for ER+ respect to ER- patients in the N+ series but such a correlation is questionable as the adjuvant treatment (hormone or chemotherapy) given to such patients may have influenced the DFS according to the ER status. According to the present study, ER determination should not be used as a discriminant in the performance of adjuvant postoperative treatment based on a prognostic judgment.     

Evaluation of percutaneous transhepatic balloon dilatation of benign biliary strictures in high-risk patients

During the period from 1979 through 1984, 17 patients with benign biliary strictures underwent percutaneous transhepatic balloon dilatation. All patients presented with either hyperbilirubinemia and acute cholangitis, a history of intermittent chills and fever, or both. Balloon dilatation was most successful in those patients with intrahepatic strictures, sclerosing cholangitis, strictured biliary enteric anastomoses, and distal common bile duct strictures with retained calculi. Two patients with postsurgical common bile duct injury had treatment failure 3 and 18 months after dilatation and subsequently underwent elective hepaticojejunostomy. Although our longest treatment success is now more than 4 1/2 years in an 83 year old woman who is 15 years posthepaticojejunostomy, the mean follow-up of the entire group has only been 2 years. On the basis of our early experience and that of others, we now recommend an initial attempt at balloon dilatation in most patients with postsurgical benign biliary strictures. Further technical advances and longer follow-up in present and future series may certainly broaden the appeal of this nonoperative procedure.