Publications

Earlier recognition of chronic kidney disease (CKD) could slow progression, prevent complications, and reduce cardiovascular-related outcomes. However, current estimates of CKD awareness indicate that both patient- and provider-level awareness remain unacceptably low. Many of the factors that are possibly associated with CKD awareness, which could help guide implementation of awareness efforts, have yet to be fully examined. Also, little is known regarding whether increased patient or provider awareness improves clinical outcomes, or whether there are possible negative consequences of awareness for CKD patients. Further research is necessary to continue to design and refine awareness campaigns aimed at both patients and providers, but there is an immediate need for dissemination of basic CKD information, given both the high prevalence of CKD and its risk factors and the low estimated awareness of CKD.

PURPOSE OF REVIEW

To provide a brief review of methods used in genetic epidemiology studies, an update of recent significant findings in genome-wide studies of kidney disease, and a discussion of the clinical implications of these findings.

RECENT FINDINGS

Recent developments in genetic epidemiology methodologies, specifically the use of genome-wide panels of single nucleotide polymporphisms (SNPs) for association analyses, have yielded exciting insights into the underlying pathogenesis of chronic kidney disease and its progression. The two most notable and promising genetic discoveries are those of MYH9 and UMOD, both of which have been replicated in separate populations.

SUMMARY

Genomic studies have the potential to yield exciting new areas of biological research, potential targets for treatment, and ultimately markers of disease risk. This review addresses recent genetic studies and their implications in chronic kidney disease care.

BACKGROUND

Previously, we found that mast cell tryptases and carboxypeptidase A3 (CPA3) are differentially expressed in the airway epithelium in asthmatic subjects. We also found that asthmatic subjects can be divided into 2 subgroups ("T(H)2 high" and "T(H)2 low" asthma) based on epithelial cell gene signatures for the activity of T(H)2 cytokines.

OBJECTIVES

We sought to characterize intraepithelial mast cells (IEMCs) in asthma.

METHODS

We performed gene expression profiling in epithelial brushings and stereology-based quantification of mast cell numbers in endobronchial biopsy specimens from healthy control and asthmatic subjects before and after treatment with inhaled corticosteroids (ICSs). We also performed gene expression and protein quantification studies in cultured airway epithelial cells and mast cells.

RESULTS

By means of unsupervised clustering, mast cell gene expression in the airway epithelium related closely to the expression of IL-13 signature genes. The levels of expression of mast cell genes correlate positively with lung function improvements with ICSs. IEMC density was 2-fold higher than normal in subjects with T(H)2-high asthma compared with that seen in subjects with T(H)2-low asthma or healthy control subjects (P = .015 for both comparisons), and these cells were characterized by expression of tryptases and CPA3 but not chymase. IL-13 induced expression of stem cell factor in cultured airway epithelial cells, and mast cells exposed to conditioned media from IL-13-activated epithelial cells showed downregulation of chymase but no change in tryptase or CPA3 expression.

CONCLUSION

IEMC numbers are increased in subjects with T(H)2-high asthma, have an unusual protease phenotype (tryptase and CPA3 high and chymase low), and predict responsiveness to ICSs. IL-13-stimulated production of stem cell factor by epithelial cells potentially explains mast cell accumulation in T(H)2-high asthmatic epithelium.

A major source of air pollution exposure in the developing world is smoke due to inefficient cooking with biomass fuels in poorly ventilated homes. Biomass fuel refers to any recently living plant- and/or animal-based material that is deliberately burned by humans as fuel, including wood, crop residues, and animal dung. The levels of exposure to particulate matter in such homes are often at least an order of magnitude higher than the highest concentrations that occur in the ambient air of the developed world. Because roughly half the world's population cooks daily with unprocessed biomass fuel, the potential public health impact is huge. The World Health Organization has estimated that indoor air pollution from solid fuel use is responsible for 2.6% of the total global burden of disease and between 1.5 and 2 million deaths each year, primarily due to acute lower respiratory infection in young children and chronic obstructive pulmonary disease in adult women. Major limitations of the existing epidemiologic literature include lack of actual exposure measurements, lack of longitudinal studies, inadequate exposure-response information, and few intervention studies. Ongoing research in Guatemala is attempting to address these data gaps.

Twenty-four-hour dietary recalls are used frequently to study homebound older adults' eating behaviors. However, the reliability and predictive validity of this method have not been established in this population. The purpose of this study was to examine whether homebound older adults provide reliable and valid measures of total energy intake in 24-hour dietary recalls. Two hundred thirty homebound older adults were interviewed in their homes using a questionnaire to assess eating behaviors and factors that could affect those behaviors. Participants completed three 24-hour dietary recalls at baseline and again at 6-month follow-up. Two subsamples were identified for analyses. For participants who were not hospitalized during the 6-month interval and had their weight measured at both assessments (n=52), sufficient test-retest reliability of energy intake was observed (r=0.59), but energy intake deficiencies relative to estimated energy requirements did not predict actual weight loss (r=0.08). When this sample was supplemented with 91 participants who experienced any adverse event (weight loss of 2.5% or more, hospitalization, institutionalization, or mortality) in the 6-month period (n=143), adverse events were more likely to occur for those with insufficient energy intake (odds ratio 3.49, P=0.009), and in white participants compared to African-American participants (odds ratio 3.13, P=0.016). Adequate test-retest reliability of the 24-hour dietary recall was demonstrated, but additional research with larger samples and longer follow-up intervals is needed to better evaluate the predictive validity of energy intake measures for this population.

BACKGROUND

Autophagy is characterized by the sequestration of cytoplasm and organelles into multimembrane vesicles and subsequent degradation by the cell's lysosomal system. It is linked to many physiological functions in human cells including stress response, protein degradation, organelle turnover, caspase-independent cell death and tumor suppression. Malignant transformation is frequently associated with deregulation of autophagy and several tumor suppressors can modulate autophagic processes. The tumor suppressor p53 can induce autophagy after metabolic or genotoxic stress through transcriptionally-dependent and -independent mechanisms. In this study we expand on the former mechanism by functionally characterizing a p53 family target gene, ISG20L1 under conditions of genotoxic stress.

RESULTS

We identified a p53 target gene, ISG20L1, and show that transcription of the gene can be regulated by all three p53 family members (p53, p63, and p73). We generated an antibody to ISG20L1 and found that it localizes to the nucleolar and perinucleolar regions of the nucleus and its protein levels increase in a p53- and p73-dependent manner after various forms of genotoxic stress. When ectopically expressed in epithelial cancer-derived cell lines, ISG20L1 expression decreased clonogenic survival without a concomitant elevation in apoptosis and this effect was partially rescued in cells that were ATG5 deficient. Knockdown of ISG20L1 did not alter 5-FU induced apoptosis as assessed by PARP and caspase-3 cleavage, sub-G1 content, and DNA laddering. Thus, we investigated the role of ISG20L1 in autophagy, a process commonly associated with type II cell death, and found that ISG20L1 knockdown decreased levels of autophagic vacuoles and LC3-II after genotoxic stress as assessed by electron microscopy, biochemical, and immunohistochemical measurements of LC3-II.

CONCLUSIONS

Our identification of ISG20L1 as a p53 family target and discovery that modulation of this target can regulate autophagic processes further strengthens the connection between p53 signaling and autophagy. Given the keen interest in targeting autophagy as an anticancer therapeutic approach in tumor cells that are defective in apoptosis, investigation of genes and signaling pathways involved in cell death associated with autophagy is critical.