Age- and sex-adjusted linear regression analyses demonstrating relationships of bilirubin with thyroid hormones, components of the metabolic syndrome, insulin, insulin resistance and total cholesterol.

<p>HDL, high density lipoprotein; HOMA-IR, homeostasis model assessment-insulin resistance; β, standardized regression coefficient. Bilirubin, TSH, glucose, insulin and HOMA-IR and triglycerides were log transformed.</p

Graphical presentation of the interaction of free T₄ with insulin resistance on bilirubin.

<p>The standardized regression coefficients of the interaction term obtained by multivariable linear regression analysis as shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090886#pone-0090886-t003" target="_blank">Table 3</a>, model 3 is used.</p

Multivariable linear regression models demonstrating the interaction between free T₄ and insulin resistance on bilirubin.

<p>HOMA-IR, Homeostasis model assessment-insulin resistance; AST, Aspartate aminotransferase; ALT, Alanine aminotransferase; β, standardized regression coefficient. Bilirubin, HOMA-IR, AST and ALT were log transformed.</p

Clinical characteristics, glucose, insulin, insulin resistance, lipids, transaminases, and thyroid hormones in 1854 subjects.

<p>Data in mean ± SD or in median (interquartile range). BMI, body mass index; HOMA-IR, homeostasis model assessment-insulin resistance; HDL, high density lipoprotein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; β, standardized regression coefficient. <i>P</i>-values for linear trend are shown. Bilirubin, glucose, insulin, HOMA-IR, triglycerides, TSH, AST and ALT were log transformed.</p

Quantification of surface area of all lymph vessels counted in proteinuric kidneys over time.

<p>All double positive lymph vessels have been divided into four categories based on their size. At 6 weeks, small, middle-size and large lymph vessels were present in close association with larger blood vessels, however there were almost no very small LV, indicating no lymph vessel formation. Over time, the number of very small LV significantly increased up to week 24. Besides, the number of small, middle-size and large LV increased between week 6–12 and/or between weeks 24–30, implying growth and enlargement of LV in these time frames. (**p<0.01; ***p<0.001).</p

Interstitial lymph vessel induction precedes interstitial fibrosis.

<p>Double staining of podoplanin (lymph vessels) with the interstitial collagens types I and III shows the induction of lymph vessels from 12 weeks onwards, whereas interstitial fibrosis is only evident at week 30. (Bar = 100 µm).</p

Development of proteinuria (A) and focal glomerulosclerosis (B) over time in unilateral Adriamycin-induced nephropathy.

<p>(*p<0.05, **p<0.01, ***p<0.001); (A) versus week 0; (B) versus week 6.</p

Antiproteinuric intervention strongly prevents renal lymphangiogenesis.

<p>Lymphatic vessel number was significantly higher in the kidneys of proteinuric rats than in rats receiving anti-proteinuric treatment. Representative images of interstitial lymphatic vessels (arrows) in the kidney of proteinuric (A) compared to treated animals (B). Quantification showed a significant reduction of lymph vessel number upon anti-proteinuric treatment (C), whereas efficacy of ACE inhibition on proteinuria is shown in D. Dashed line shows the mean number of cortical lymphatic vessels in kidneys of healthy rats. (Bar = 100 µm, **p<0.01, ***p<0.001).</p

Identification of tubulo-interstitial lymph vessels.

<p>Podoplanin positive tubulo-interstitial vessel-like structures (indicated by black arrows) were present in the kidneys of saline-injected rats adjacent to large and middle-size arteries (A), and barely observed in cortical interstitial area, even in proteinuric kidneys at week 6 (B), however were clearly induced in the kidneys of adriamycin-injected rats at 12 weeks (C). Interstitial localization of these podoplanin-positive vessels becomes clear by the recognition of PAS-positive tubules. Double staining for podoplanin and LYVE-1 (D–F) and for podoplanin and VEGFR3 (G–I) confirmed interstitial podoplanin positive structures to be lymphatic endothelial cells, both in large and small lymphatic vessels. (Bar = 100 µm).</p

Quantitative immunohistochemical analysis of tubulo-interstitial damage markers in proteinuric, non-proteinuric and saline-injected rats over time.

<p>Lymphangiogenesis (A), measured as lymph vessel number per medium power field (MPF/200×); osteopontin staining (B), quantified as % positive staining per cortical field; myofibroblasts (C), quantified as % positive staining for α-smooth muscle-cell actin per cortical field; interstitial (ED-1)-positive macrophages (D), numbers per cortical field; interstitial collagen type I deposition (E), quantified as % staining per cortical field; and interstitial collagen type III deposition (F), quantified as % staining per cortical field (*p<0.05, **p<0.01, ***p<0.001 versus week 6, and for collagen III only week 12 versus week 30 was significant).</p