Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Early onset of puberty: Tracking genetic and environmental factors

Under physiological conditions, factors affecting the genetic control of hypothalamic functions are predominant in determining the individual variations in timing of pubertal onset. In pathological conditions, however, these variations can involve different genetic susceptibility and the interaction of environmental factors. The high incidence of precocious puberty in foreign children migrating to Belgium and the detection in their plasma of a long-lasting 1,1,1-trichloro-2,2-bis(4-chlorophenyl) ethane (DDT) residue suggest the potential role of environmental endocrine disrupting chemicals in the early onset of puberty. This hypothesis was confirmed by experimental data showing thattemporary exposure of immature female rats to DDT in vivo results in early onset of puberty. We compared the gene expression profile of hypothalamic hamartoma associated or not with precocious puberty in order to identify gene networks responsible for both hamartoma-dependent sexual precocity and the onset of normal human puberty. In conclusion, pathological variations in the timing of puberty may provide unique information about the interactions of either environmental conditions or genetic susceptibility with the hypothalamic mechanism controlling the onset of sexual maturation, as shown by examples of precocious puberty following exposure to endocrine disrupters or due to hypothalamic hamartoma. Copyright (c) 2005 S. Karger AG, Basel

Epigenetic control of female puberty

The timing of puberty is controlled by many genes. The elements coordinating this process have not, however, been identified. Here we show that an epigenetic mechanism of transcriptional repression times the initiation of female puberty in rats. We identify silencers of the Polycomb group (PcG) as major contributors to this mechanism, and show that PcG proteins repress Kiss1, a puberty-activating gene. Hypothalamic expression of two key PcG genes, Eed and Cbx7, decreases and methylation of their promoters increases preceding puberty. Inhibiting DNA methylation blocks both events and results in pubertal failure. The pubertal increase in Kiss1 is accompanied by EED loss from the Kiss1 promoter and enrichment of histone H3 modifications associated with gene activation. Preventing the eviction of EED from the Kiss1 promoter disrupts pulsatile GnRH release, delays puberty, and compromises fecundity. Our results identify epigenetic silencing as a novel mechanism underlying the neuroendocrine control of female puberty