No abstract

Abstract. Except for hereditary disease, genetic factors that contribute to the development of renal epithelial tumors are unknown. There is a possibility that the MDR1 encoded plasma membrane transporter P-glycoprotein (PGP) influences the risk of development of renal neoplasms. PGP is known to be involved in uptake, binding, transport, and distribution of xenobiotics. There is evidence that the MDR1 C3435T polymorphism drives expression and modulates disease risk. In an explorational case-control study, constitutional genotype frequencies were established at MDR1 C3435T of 537 healthy control subjects and compared with those of 212 patients with renal epithelial tumors. There were 179 clear cell renal cell carcinoma (CCRCC) and 33 tumors collectively assigned as non-CCRCC. In a second study, genotypes of another 150 healthy control subjects and 50 patients with three non-CCRCC types (26 papillary RCC, 11 chromophobe RCC, and 13 renal oncocytic adenoma) were compared. PCR-restriction fragment length polymorphism-based analysis of constitutional DNA, and statistical analysis were applied. PGP expression was analyzed by quantitative immunohistochemistry. The explorational study showed a significant association between T allele frequency and the occurrence of tumors (P ϭ 0.007). When tumors were histopathologically distinguished into frequent CCRCC and less frequent non-CCRCC, both patient groups contributed to this effect with a seemingly strong influence by the latter (P ϭ 0.0419). The second study established the T allele as a risk factor especially for non-CCRCC (P ϭ 0.0005) with the highest risk for homozygote TT allele carriers (P Ͻ 0.0001). Independently, MDR1C3435T genotype associated variations in PGP expression were shown in normal renal parenchyma with a 1.5-fold difference of median values (TT, 1.9; CC, 2.8; P ϭ 0.0065). The data provide evidence for PGP to influence the susceptibility to develop renal epithelial tumors by virtue of its MDR1 C3435T polymorphism and changes in expression. Especially T and TT carriers are at risk for developing non-CCRCC, i.e., papillary and chromophobe RCC as well as oncocytic adenomas.Renal epithelial tumors contribute approximately 3% to the overall cancer incidence and mortality. Renal cell carcinomas (RCC) compose clear cell RCC (CCRCC) in 75% to 80%, papillary (chromophilic) RCC in 10%, and chromophobe RCC in 5%. Others include granular cell carcinoma, spindle cell carcinoma, and duct Bellini and unclassified carcinomas (1). There are also benign oncocytic and papillary adenomas, which account for approximately 5% of all renal epithelial neoplasms. Although the molecular origins of these histologic subentities have been identified, i.e., mutations and hypermethylations of the VHL and RASSF1A tumor suppressor genes in CCRCC (2-5), mutations of the MET proto-oncogene in papillary RCC (6,7), and loci for hereditary chromophobe RCC and oncocytic adenoma on chromosome 17p11.2 (8), their cause and interindividual differences in susceptibility remain elusive.It is interes...

These data indicate that during the regeneration processes, developmental paradigms may be recapitulated in order to restore mature kidney function.

The Pax genes comprise a family of transcription factors active in specific tissues during embryonic development and are associated with at least three developmental mutations in mouse and man. In the developing kidney, Pax-2 is expressed in the induced mesenchyme, in the ureter epithelium, and in early epithelial structures derived from the mesenchyme. Pax-2 expression is repressed upon terminal differentiation of the renal tubule epithelium, but persists in the undifferentiated epithelium of human Wilms' tumours. We have produced a dominant gain-of-function mutation in transgenic mice by deregulating the expression of the mouse Pax-2 gene. The data obtained with four independently derived transgenic embryos and with one transgenic line demonstrate that deregulated Pax-2 expression results in histologically abnormal and dysfunctional renal epithelium with properties similar to congenital nephrotic syndrome. Thus, repression of Pax-2 is required for normal kidney development and persistent expression of Pax-2 may restrict the differentiation potential of renal epithelial cells.

Long-term technical and clinical results after directional atherectomy of femoro-popliteal lesions are in favor of de novo lesions compared with restenotic lesions.

Percutaneous stent-angioplasty has become an accepted therapy for the treatment of atherosclerotic renal artery stenosis (RAS) because of higher acute and long-term success rates compared with balloon angioplasty alone. Restenosis rates after successful renal stent placement vary from 6 to 20% and depend mainly on the definition of restenosis and the vessel diameter of the renal artery or stent. We recommend that restenosis should be defined as >70%. The safety and efficacy of drug-eluting stents for the treatment of RAS is poorly defined. The currently partially published GREAT study (Palmaz Genesis peripheral stainless steel balloon expandable stent: comparing a sirolimus-coated vs. a bare stent in REnal Artery Treatment) examined the effect of a sirolimus-coated stent on restenosis rate in 102 patients and found a relative risk reduction of angiographic binary in-stent restenosis by 50% (7% versus 14%, P = ns). Given the lack of outcome data, the considerable expenses associated with drug-eluting stents, morbidity, and cost associated with prolonged dual antithrombotic therapy, the use of drug-eluting stents in RAS should be restricted to clinical trials. This is a review on restenosis rate following renal stenting, its definition, and the potential use for implantation of a drug-eluting stent in RAS, which so far for this indication is not yet commercially available.

No abstract

The conversion of mesenchyme to epithelium during the embryonic development of the mammalian kidney requires reciprocal inductive interactions between the ureter and the responding metanephric mesenchyme. The Pax-2 gene is activated in the mesenchyme in response to induction and is subsequently down-regulated in more differentiated cells derived from the mesenchyme. Pax-2 belongs to a family of genes, at least three of which encode morphogenetic regulatory transcription factors. In order to determine the role of Pax-2 during kidney development, we have generated a loss- of-function phenotype using antisense oligonucleotides in mouse kidney organ cultures. These oligonucleotides can specifically inhibit Pax-2 protein accumulation in kidney mesenchyme cells, where the intracellular concentrations are maximal. The kidney organ cultures were stained with uvomurulin and laminin antibodies as markers for epithelium formation. With significantly reduced Pax-2 protein levels, kidney mesenchyme cells fail to aggregate and do not undergo the sequential morphological changes characteristic of epithelial cell formation. The data demonstrate that Pax-2 function is required for the earliest phase of mesenchyme-to-epithelium conversion.