Paraoxonase polymorphisms in CKD
Hundreds of papers on paraoxonase-1 in a variety of important clinical situations have been published, despite the knowledge of its specific biochemical function. Paraoxonase-1 was initially discovered as an esterase that hydrolyzes organophosphorus toxins. It was then proposed to be an antioxidant enzyme preventing lipid oxidation, but the evidence of this proposition is not compelling at present. However, a number of studies have found that polymorphisms of the enzyme are linked to systemic oxidative stress and cardiovascular events. Now, Ichikawa et al. present a study in which they genotyped seven single-nucleotide polymorphisms (SNPs) within the PON1 gene and determined their association with chronic kidney disease (CKD) in 2968 individuals from the general Japanese population. A missense SNP (rs662) with a G-to-A substitution leading to an amino acid substitution (G[Arg]/A[Gln]) was significantly associated with albuminuria and estimated glomerular filtration rate (eGFR), especially in women. The A/A genotype in women had the highest prevalence of albuminuria and the lowest values of adjusted eGFR. Remarkably, this association was not found in men. Importantly, when the authors measured serum PON1 activity, they found it to be lowest in subjects with the A/A genotype. The mechanism by which PON1 affects proteinuria and CKD will require further studies. See page 183.
PKD: new avenues of treatment
An explosion of research has taken place on the biology and therapeutics of polycystic kidney disease (PKD). The most exciting discovery is that most gene mutations in mice and humans that cause cystic disease code for proteins in the primary cilium. This finding has attracted many scientists who previously did not think of their work as being related to kidney disease. In a paper in this issue, Torres and Harris review the most recent advances in research on the biology of PKD. They discuss the proteins known to be involved in causing the disease and their interacting partners. They also present the ongoing clinical trials on the therapeutic advances to treat PKD. A related research paper in this issue by Gattone et al. discusses the use of rapamycin in the treatment of PKD in mice and measures the role of the mammalian target of rapamycin (mTOR) in causing the disease. These are indeed exciting times for PKD research. See pages 149 and 178.
Ghrelin increases appetite in ESRD patients
Many patients with end-stage renal disease (ESRD) are malnourished, partly because of loss of appetite. Recent advances in the control of satiety have revealed that ghrelin, a hormone secreted by the stomach, acts on the hypothalamus to affect food intake. Ashby et al. studied the effect of ghrelin administration on 12 malnourished dialysis patients for 1 week. The administration of ghrelin increased its concentration in the blood for 2 hours. Also, it immediately increased appetite and energy intake for the first meal after injection. Food diaries and observations of study meals revealed that this effect continued for 1 week when patients were given daily injections of ghrelin. Energy expenditure, measured with free-living pulse and motion monitors, was unchanged. This double-blind, crossover study shows that ghrelin produced a sustained increase in appetite and energy intake, indicating that ghrelin or drugs acting on its receptor could be excellent appetite enhancers for this difficult-to-treat population of patients. See page 199.
