Persistent low-grade inflammation and premature ageing are hallmarks of the uremic phenotype and contribute to impaired health status, reduced quality of life, and premature mortality in chronic kidney disease (CKD). Because there is a huge global burden of disease due to CKD, treatment strategies targeting inflammation and premature ageing in CKD are of particular interest. Several distinct features of the uremic phenotype may represent potential treatment options to attenuate the risk of progression and poor outcome in CKD. The nuclear factor erythroid 2-related factor 2 (NRF2)–kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1 (KEAP1) signaling pathway, the endocrine phosphate-fibroblast growth factor-23–klotho axis, increased cellular senescence, and impaired mitochondrial biogenesis are currently the most promising candidates, and different pharmaceutical compounds are already under evaluation. If studies in humans show beneficial effects, carefully phenotyped patients with CKD can benefit from them.

Objective: The relation between inflammatory markers, adiposity and disease is under extensive study. Here we tested the hypothesis that the immunomodulatory protein pentraxin 3 (PTX3) is associated with adiposity in the general population.Methods: Serum PTX3 concentrations, body mass index (BMI), waist circumference (WC) and fat depots, as quantified by dual‐energy X‐ray absorptiometry and magnetic resonance imaging, were assessed in three community‐based cohorts: ULSAM, n = 790, mean age 78 years; PIVUS, n = 1003, mean age 70 years, women 50%; and the NORDIET‐trial, n = 86, mean age 53 years, women 63%. Participants were re‐examined after 5 years (PIVUS, n = 804) or following a 6‐week randomized controlled dietary intervention (NORDIET).Results: PTX3 levels were inversely associated with BMI and WC as well as with total and visceral fat (P < 0.05 for all; adjusted for age, inflammatory biomarkers and cardiovascular risk factors). The association between PTX3 and BMI appeared even stronger in nonobese individuals. A decrease in BMI over 5 years as well as weight loss following the NORDIET intervention were associated with increased serum PTX3 concentrations (P < 0.001).Conclusions: These consistent data support an inverse association between circulating PTX3 and anthropometrical measures, calling for further mechanistic studies of the link between PTX3 and fat.

Witasp A, Carrero JJ, Heimbürger O, Lindholm B, Hammarqvist F, Stenvinkel P, Nordfors L (Karolinska Institutet, Stockholm, Sweden). Increased expression of pro‐inflammatory genes in abdominal subcutaneous fat in advanced chronic kidney disease patients. J Intern Med 2011; 269: 410–419. Objectives. Low‐grade systemic inflammation, oxidative stress and peripheral insulin resistance are intimately associated and contribute to the increased risk of cardiovascular complications in advanced chronic kidney disease (CKD). Because altered adipose tissue activities have previously been linked to pathophysiological processes in various inflammatory and metabolic diseases we hypothesized that the uraemic milieu in patients with CKD may interact with the adipose tissue, provoking an unfavourable shift in its transcriptional output. Design. Twenty‐one adipokine mRNAs were quantified in abdominal subcutaneous adipose tissue (SAT) biopsies and serum/plasma concentrations of inflammatory markers and related protein products were measured. Setting. The study was conducted at the Karolinska University Hospital, Huddinge, and Karolinska Institutet, Stockholm, Sweden. Subjects. Thirty‐seven patients with CKD [15 women, median 58 (interquartile range 49–65) years] and nine nonuraemic individuals [four women, age 62 (45–64) years] were recruited prior to initiation of peritoneal dialysis catheter insertion or elective hernia repair/laparoscopic cholecystectomy, respectively. Results. Even after correction for body mass index, SAT from patients showed a significant upregulation of inflammatory pathway genes interleukin 6 (3.0‐fold, P = 0.0002) and suppressor of cytokine signalling 3 (2.5‐fold, P = 0.01), as well as downregulation of leptin (2.0‐fold, P = 0.03) and the oxidative stress genes uncoupling protein 2 (1.5‐fold, P = 0.03) and cytochrome b‐245, alpha polypeptide (1.5‐fold, P = 0.005), in relation to controls. Conclusions. These gene expression differences suggest that inflammatory and oxidative stress activities may be important features of the intrinsic properties of uraemic adipose tissue, which may have significant effects on the uraemic phenotype.

Rationale: Vascular calcification is a prominent feature of late‐stage diabetes, renal and cardiovascular disease (CVD), and has been linked to adverse events. Recent studies in patients reported that plasma levels of osteomodulin (OMD), a proteoglycan involved in bone mineralisation, associate with diabetes and CVD. We hypothesised that OMD could be implicated in these diseases via vascular calcification as a common underlying factor and aimed to investigate its role in this context.Methods and results: In patients with chronic kidney disease, plasma OMD levels correlated with markers of inflammation and bone turnover, with the protein present in calcified arterial media. Plasma OMD also associated with cardiac calcification and the protein was detected in calcified valve leaflets by immunohistochemistry. In patients with carotid atherosclerosis, circulating OMD was increased in association with plaque calcification as assessed by computed tomography. Transcriptomic and proteomic data showed that OMD was upregulated in atherosclerotic compared to control arteries, particularly in calcified plaques, where OMD expression correlated positively with markers of smooth muscle cells (SMCs), osteoblasts and glycoproteins. Immunostaining confirmed that OMD was abundantly present in calcified plaques, localised to extracellular matrix and regions rich in α‐SMA⁺ cells. In vivo, OMD was enriched in SMCs around calcified nodules in aortic media of nephrectomised rats and in plaques from ApoE^−/− mice on warfarin. In vitro experiments revealed that OMD mRNA was upregulated in SMCs stimulated with IFNγ, BMP2, TGFβ1, phosphate and β‐glycerophosphate, and by administration of recombinant human OMD protein (rhOMD). Mechanistically, addition of rhOMD repressed the calcification process of SMCs treated with phosphate by maintaining their contractile phenotype along with enriched matrix organisation, thereby attenuating SMC osteoblastic transformation. Mechanistically, the role of OMD is exerted likely through its link with SMAD3 and TGFB1 signalling, and interplay with BMP2 in vascular tissues.Conclusion: We report a consistent association of both circulating and tissue OMD levels with cardiovascular calcification, highlighting the potential of OMD as a clinical biomarker. OMD was localised in medial and intimal α‐SMA⁺ regions of calcified cardiovascular tissues, induced by pro‐inflammatory and pro‐osteogenic stimuli, while the presence of OMD in extracellular environment attenuated SMC calcification.

Context: The mechanisms behind postoperative insulin resistance and impaired glucose utilization are not fully understood. Objective: In this study, we aimed to specifically evaluate the transcription profile of genes in the insulin and adipokine signaling pathways in sc and omental adipose tissue after surgical injury. Design: Relative expression of 21 target genes was analyzed in both sc and omental adipose tissue sampled at the beginning and at the end of operation. Setting: The study was conducted at a university-affiliated hospital. Patients: Twelve nondiabetic patients [seven females; age, 65 (range, 46–72) yr; body mass index, 24.8 (16.5–29.8) kg/m²] undergoing major abdominal surgery were included. Main Outcome Measurements: The changes in mRNA levels were analyzed. Results: After surgery, both sc and omental adipose tissue mRNA levels of genes involved in the IL6 and nicotinamide phosphoribosyltransferase pathways were increased, whereas mRNA levels of insulin receptor substrate 1 and adiponectin were reduced (P < 0.05). TNF pathway genes were differently regulated between sc and omental adipose tissue, and glucose transporter 4 mRNA levels were decreased only in omental adipose tissue. Conclusions: The transcriptional output of pivotal inflammatory and insulin signaling pathway genes is altered after surgery, and this pattern differs between different fat depots. This could be of importance for the metabolic aberrations associated to postsurgical complications, such as insulin resistance and hyperglycemia.

Morphological alterations at the kidney filtration barrier increase intrinsic capillary wall permeability resulting in albuminuria. However, automated, quantitative assessment of these morphological changes has not been possible with electron or light microscopy. Here we present a deep learning-based approach for segmentation and quantitative analysis of foot processes in images acquired with confocal and super-resolution fluorescence microscopy. Our method, Automatic Morphological Analysis of Podocytes (AMAP), accurately segments podocyte foot processes and quantifies their morphology. AMAP applied to a set of kidney diseases in patient biopsies and a mouse model of focal segmental glomerulosclerosis allowed for accurate and comprehensive quantification of various morphometric features. With the use of AMAP, detailed morphology of podocyte foot process effacement was found to differ between categories of kidney pathologies, showed detailed variability between diverse patients with the same clinical diagnosis, and correlated with levels of proteinuria. AMAP could potentially complement other readouts such as various omics, standard histologic/electron microscopy and blood/urine assays for future personalized diagnosis and treatment of kidney disease. Thus, our novel finding could have implications to afford an understanding of early phases of kidney disease progression and may provide supplemental information in precision diagnostics.