Exploring reasons for state-level variation in incidence of dialysis-requiring acute kidney injury (AKI-D) in the United States

Background: There is considerable state-level variation in the incidence of dialysis-requiring acute kidney injury (AKI-D). However, little is known about reasons for this geographic variation. Methods: National cross-sectional state-level ecological study based on State Inpatient Databases (SID) and the Behavioral Risk Factor Surveillance System (BRFSS) in 2011. We analyzed 18 states and six chronic health conditions (diabetes mellitus [diabetes], hypertension, chronic kidney disease [CKD], arteriosclerotic heart disease [ASHD], cancer (excluding skin cancer), and chronic obstructive pulmonary disease [COPD]). Associations between each of the chronic health conditions and AKI-D incidence was assessed using Pearson correlation and multiple regression adjusting for mean age, the proportion of males, and the proportion of non-Hispanic whites in each state. Results: The state-level AKI-D incidence ranged from 190 to 1139 per million population. State-level differences in rates of hospitalization with chronic health conditions (mostly \u3c 3-fold difference in range) were larger than the state-level differences in prevalence for each chronic health condition (mostly \u3c 2.5-fold difference in range). A significant correlation was shown between AKI-D incidence and prevalence of diabetes, ASHD, and COPD, as well as between AKI-D incidence and rate of hospitalization with hypertension. In regression models, after adjusting for age, sex, and race, AKI-D incidence was associated with prevalence of and rates of hospitalization with five chronic health conditions - diabetes, hypertension, CKD, ASHD and COPD - and rates of hospitalization with cancer. Conclusions: Results from this ecological analysis suggest that state-level variation in AKI-D incidence may be influenced by state-level variations in prevalence of and rates of hospitalization with several chronic health conditions. For most of the explored chronic conditions, AKI-D correlated stronger with rates of hospitalizations with the health conditions rather than with their prevalences, suggesting that better disease management strategies that prevent hospitalizations may translate into lower incidence of AKI-D

Zebrafish IGF genes: gene duplication, conservation and divergence, and novel roles in midline and notochord development.

Insulin-like growth factors (IGFs) are key regulators of development, growth, and longevity. In most vertebrate species including humans, there is one IGF-1 gene and one IGF-2 gene. Here we report the identification and functional characterization of 4 distinct IGF genes (termed as igf-1a, -1b, -2a, and -2b) in zebrafish. These genes encode 4 structurally distinct and functional IGF peptides. IGF-1a and IGF-2a mRNAs were detected in multiple tissues in adult fish. IGF-1b mRNA was detected only in the gonad and IGF-2b mRNA only in the liver. Functional analysis showed that all 4 IGFs caused similar developmental defects but with different potencies. Many of these embryos had fully or partially duplicated notochords, suggesting that an excess of IGF signaling causes defects in the midline formation and an expansion of the notochord. IGF-2a, the most potent IGF, was analyzed in depth. IGF-2a expression caused defects in the midline formation and expansion of the notochord but it did not alter the anterior neural patterning. These results not only provide new insights into the functional conservation and divergence of the multiple igf genes but also reveal a novel role of IGF signaling in midline formation and notochord development in a vertebrate model

A proposed model for the evolution of multiple IGF genes in zebrafish.

<p>It is postulated that an insulin-like gene (ILP) identified in Amphioxus is the likely ancestor of modern vertebrate insulin/IGFs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007026#pone.0007026-Chan1" target="_blank">[2]</a>. This ancestral gene subsequently duplicated to form distinct insulin (INS) and IGF, as found in early agnathan vertebrates <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007026#pone.0007026-Nagamatsu1" target="_blank">[3]</a>. The second round (2R) of whole-genome duplication gives rise to distinct IGF-1 and IGF-2 genes found in all gnathosomes <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007026#pone.0007026-Duguay1" target="_blank">[4]</a>. The “fish specific” third round (3R) whole-genome duplication results in four distinct IGF genes, as found in zebrafish in this study. The duplicated IGF genes have evolved overlapping yet distinct functions by attaining differential regulatory mechanisms of gene expression, different peptide structure, and different biological activities.</p

All four zebrafish <i>igf</i> genes are functional.

<p>(A) Microinjection of each of the 4 zebrafish IGF mRNA into zebrafish embryo resulted in elevated Akt phospholylation. GFP, IGF-1a, -1b, -2a, and -2b mRNA was injected into zebrafish embryos at 1-2 cell stage. The injected embryos were raised to shield and 15 somite stages. Lysates were prepared and subjected to SDS-PAGE followed by immunoblot analysis using antibodies against total and phosphorylated Akt (Akt-P). (B) Densitometric analysis result of (A). The phosphorylated Akt/total Akt ratio was calculated and expressed as % of the control (GFP mRNA injected) group. Grey bars represent the shield stage groups, and dark bars represent the 15 somite stage groups. Values are means±SE (n = 3). *<i>p</i><0.01 compared with the control group.</p