Estimates show approximately 10% of children with hypoplastic kidneys are linked to the disease. Many different histological abnormalities have been noted, including:
decrease in nephron number associated with hypertrophy
focal segmental glomerulosclerosis
interstitial fibrosis and tubular atrophy
multicystic dysplastic kidneyUp to one-third of diagnosed patients develop end stage kidney disease, which may lead to complete kidney failure. Causes
Pax2 mutations
The majority of mutations occur in exons 2,3 and 4, which encode the paired domain and frame shift mutations that lead to a null allele. The missense mutations appear to disrupt hydrogen bonds, leading to decreased transactivation of Pax2, but do not seem to effect nuclear localization, steady state mRNA levels, or the ability of Pax2 to bind to its DNA consensus sequence. Mutations related to the disease have also been noted in exons 7,8, and 9, with milder phenotypes than the other mutations. Recent studies
Pax2 is expressed in the kidney, midbrain, hindbrain, cells in the spinal column, developing ear and developing eye. Homozygous negative Pax2 mutation is lethal, but heterozygote mutants showed many symptoms of papillorenal syndrome, including optic nerve dysplasia with abnormal vessels emerging from the periphery of the optic cup and small dysplasic kidneys. It is shown that Pax2 is under upstream control of Shh in both mice and zebrafish, which is expressed in the precordal plate. Other genes
Approximately half of patients with papillorenal syndrome do not have defects in the Pax2. This suggests that other genes play a role in the development of the syndrome, though few downstream effectors of Pax2 have been identified.
showed that risk for MDR-TB is three times higher among recreational drug users than non-users. Shin et al.s study demonstrated that alcohol usage was linked to poorer outcomes in MDR-TB treatment; they also noted that a majority of subjects within their study (many of whom regularly used alcohol) were nevertheless cured by their aggressive treatment regimen.Non-compliance with treatment plans is often cited as a contributor to MDR-TB transmission and mortality. Indeed, of the 80 newly released TB-infected inmates in Fry et al.s study, 73.8% did not report visiting a community dispensary for further treatment. Ruddy et al. cite release from facilities as one of the main causes of interruption in prisoners TB treatment, in addition to non-compliance within the prison and upon reintegration into civilian life. Fry et al.s study also listed side effects of TB treatment medications (especially in HIV positive individuals), financial worries, housing insecurities, family problems, and fear of arrest as factors that prevented some prisoners from properly adhering to TB treatment. They also note that some researchers have argued that the short-term gains TB-positive prisoners receive, such as better food or work exclusion, may dis-incentivize becoming cured. In their World Health Organization article, Gelmanova et al. posit that non-adherence to TB treatment indirectly contributes to bacterial resistance. Although ineffective or inconsistent treatment does not "create" resistant strains, mutations within the high bacterial load in non-adherent prisoners can cause resistance. Nachega & Chaisson argue that inadequate TB control programs are the strongest driver of MDR-TB incidence.