elastin and Kidney-Failure--Chronic

Patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) have significant cardiovascular morbidity and mortality that is in part due to the development of vascular calcification. Vascular calcification is an active, highly regulated process that shares many similarities with normal bone formation. New discoveries related to extracellular vesicles, microRNAs, and calciprotein particles continue to reveal the mechanisms that are involved in the initiation and progression of vascular calcification in CKD. Further innovations in these fields are critical for the development of biomarkers and therapeutic options for patients with CKD and ESRD.

Topics: Calcium; Disease Progression; Elastin; Humans; Kidney Failure, Chronic; Muscle, Smooth, Vascular; Phosphorus; Renal Insufficiency, Chronic; Risk Factors; Vascular Calcification

This article reviews the diseases that may show epidermal perforation as a histologic feature. Many of these represent examples of transepithelial elimination (TEE), a mechanism by which the skin rids itself of abnormal substances. After a review of disorders in which perforation is an occasional finding, four diseases that have been considered essential perforating disorders are discussed: elastosis perforans serpiginosa (EPS), reactive perforating collagenosis (RPC), perforating folliculitis (PF), and Kyrle 's disease (KD). A review of the literature, including recent reports of perforating diseases associated with chronic renal failure, suggests that there may be considerable clinical and histologic overlap among PF, KD, and the adult form of "perforating collagenosis." A working classification for the perforating disorders is suggested.

Topics: Collagen Diseases; Elastic Tissue; Elastin; Folliculitis; Granuloma; Humans; Keratosis; Kidney Failure, Chronic; Microscopy, Electron; Pseudoxanthoma Elasticum; Skin; Skin Diseases

Topics: Amino Acid Sequence; Animals; Bone and Bones; Bone Regeneration; Calcium Radioisotopes; Chronic Kidney Disease-Mineral and Bone Disorder; Collagen; Depression, Chemical; Elastin; Humans; Hydroxyproline; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Microscopy, Electron; Parathyroid Hormone; Proline; Stimulation, Chemical; Structure-Activity Relationship; Tritium; Uremia

Arterial medial calcification (AMC), a hallmark of vascular disease in uremic patients, is highly correlated with serum phosphate levels and cardiovascular mortality. To determine the mechanisms of AMC, mice were made uremic by partial right-side renal ablation (week 0), followed by left-side nephrectomy at week 2. At 3 weeks, mice were switched to a high-phosphate diet, and various parameters of disease progression were examined over time. Serum phosphate, calcium, and fibroblast growth factor 23 (FGF-23) were up-regulated as early as week 4. Whereas serum phosphate and calcium levels declined to normal by 10 weeks, FGF-23 levels remained elevated through 16 weeks, consistent with an increased phosphate load. Elastin turnover and vascular smooth muscle cell (VSMC) phenotype change were early events, detected by week 4 and before AMC. Both AMC and VSMC loss were significantly elevated by week 8. Matrix metalloprotease 2 (MMP-2) and cathepsin S were present at baseline and were significantly elevated at weeks 8 and 12. In contrast, MMP-9 was not up-regulated until week 12. These findings over time suggest that VSMC phenotype change and VSMC loss (early phosphate-dependent events) may be necessary and sufficient to promote AMC in uremic mice fed a high-phosphate diet, whereas elastin degradation might be necessary but is not sufficient to induce AMC (because elastin degradation occurred also in uremic mice on a normal-phosphate diet, but they did not develop AMC).

Topics: Animals; Calcinosis; Cell Death; Diet; Disease Models, Animal; Disease Progression; Elastin; Enzyme Activation; Fibroblast Growth Factor-23; Immunohistochemistry; Kidney Failure, Chronic; Matrix Metalloproteinases; Mice; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Phosphates; Time Factors; Tunica Media; Uremia

Clinical studies have demonstrated that 50% of individuals with chronic renal disease (CRD) die of cardiovascular causes, including advanced calcific arterial and valvular disease; however, the mechanisms of accelerated calcification in CRD remain obscure, and no therapies can prevent disease progression. We recently demonstrated in vivo that inflammation triggers cardiovascular calcification. In vitro evidence also indicates that elastin degradation products may promote osteogenesis. Here, we used genetically modified mice and molecular imaging to test the hypothesis in vivo that cathepsin S (catS), a potent elastolytic proteinase, accelerates calcification in atherosclerotic mice with CRD induced by 5/6 nephrectomy.. Apolipoprotein-deficient (apoE(-/-))/catS(+/+) (n=24) and apoE(-/-)/catS(-/-) (n=24) mice were assigned to CRD and control groups. CRD mice had significantly higher serum phosphate, creatinine, and cystatin C levels than those without CRD. To visualize catS activity and osteogenesis in vivo, we coadministered catS-activatable and calcification-targeted molecular imaging agents 10 weeks after nephrectomy. Imaging coregistered increased catS and osteogenic activities in the CRD apoE(-/-)/catS(+/+) cohort, whereas CRD apoE(-/-)/catS(-/-) mice exhibited less calcification. Quantitative histology demonstrated greater catS-associated elastin fragmentation and calcification in CRD apoE(-/-)/catS(+/+) than CRD apoE(-/-)/catS(-/-) aortas and aortic valves. Notably, catS deletion did not cause compensatory increases in RNA levels of other elastolytic cathepsins or matrix metalloproteinases. Elastin peptide and recombinant catS significantly increased calcification in smooth muscle cells in vitro, a process further amplified in phosphate-enriched culture medium.. The present study provides direct in vivo evidence that catS-induced elastolysis accelerates arterial and aortic valve calcification in CRD, providing new insight into the pathophysiology of cardiovascular calcification.

Topics: Animals; Aorta; Aortic Valve; Aortic Valve Stenosis; Apolipoproteins E; Calcinosis; Carotid Artery Diseases; Cathepsins; Cells, Cultured; Creatinine; Cystatin C; Elastin; Humans; Kidney Failure, Chronic; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Muscle, Smooth, Vascular; Nephrectomy; Osteogenesis; Phosphates; Tunica Intima; Tunica Media

Calcification of the media of arteries is common in patients with end-stage renal disease (ESRD) undergoing haemodialysis and is a major cause of arteriosclerosis. The aim of this study was to clarify the role of glycoxidative modification of elastin in the calcification of aortic media in this group of patients.. Samples of tunica media were obtained from non-atherosclerotic areas of the aortas of cadavers of seven non-diabetic patients with ESRD (age 65.5 +/- 10.6 years) and 10 age-matched controls (age 61.1 +/- 10.3 years). The localization of pentosidine, a major glycoxidation product, and calcium deposits in the media were examined using immunohistochemical and von Kossa staining, followed by orcein staining for elastin fibres. Tissue levels of pentosidine and calcium were measured in elastase-digested media using reversed high-performance liquid chromatography and atomic absorption spectrophotometry, respectively.. In aortic media, but not intima, immunostained pentosidine was observed along elastin fibres or in the extracellular spaces between them. Early calcification was manifest as small punctate calcified deposits along elastin fibres in the media. Advanced calcification was found as large, confluent calcified deposits in extracellular spaces between elastin fibres. Double staining showed co-localization of pentosidine and calcified deposits in the media. Both the staining density of pentosidine and calcification were more prominent in ESRD patients than in controls. The mean medial contents of both elastin-associated pentosidine and calcium were significantly higher in ESRD patients than in controls. In ESRD patients, the level of calcium in elastase-digested media correlated significantly with pentosidine levels, which increased in parallel with the duration of haemodialysis.. Our results indicate that glycoxidative modification of elastin in aortic media may be involved in the enhancement of medial calcification in ESRD patients on haemodialysis.

Topics: Aged; Aorta; Arginine; Calcinosis; Calcium; Elastin; Female; Humans; Immunohistochemistry; Kidney Failure, Chronic; Lysine; Male; Middle Aged; Tunica Media

Glycoxidation and lipid peroxidation products accumulate in collagen of various tissues in haemodialysis patients with end-stage renal disease (ESRD). The purpose of this study was to test the hypothesis that increased glycoxidation and lipid peroxidation of aortic elastin is implicated in the cardiovascular complications, particularly atherosclerosis, of chronic haemodialysis patients.. Post-mortem aortic samples were obtained from 16 deceased subjects, including chronic haemodialysis patients (group 1 n=6, age 64.7+/-11.4 years) and control subjects (group 2 n=10, age 61.1+/-10.4 years). The samples were divided into three vessel wall sites: atherosclerotic intima, lesion-free intima, and media. They were sequentially treated with 0.01 M phosphate-buffered saline, collagenase, and elastase to obtain three fractions, namely soluble (SF), collagen (CF), and elastin (EF) fractions, respectively. Using spectrophotofluorometry, the pentosidine- and malondialdehyde (MDA)-linked fluorescence of these fractions was measured at wavelengths 335/385 and 390/460 (excitation/emission), respectively.. Samples from haemodialysis patients (group 1) exhibited a significant increase in both pentosidine- and MDA-linked fluorescence of EF in atherosclerotic intima, lesion-free intima, and media samples, compared with samples from control subjects (group 2). In group 1, the levels of pentosidine- and MDA-linked fluorescence of EF were highest in atherosclerotic intima among the three aortic sites. Interestingly, in both groups, the levels of pentosidine- and MDA-linked fluorescence of EF were significantly higher than those of CF in all aortic sites. There was a strong correlation between the levels of pentosidine- and MDA-linked fluorescence in CF and EF for all aortic sites. In group 1, the pentosidine- and MDA-linked fluorescence levels of EF correlated significantly with the duration of haemodialysis in lesion-free intima and media.. Our study provides the first biochemical evidence for a close link between aortic elastin glycoxidation and lipid peroxidation. In addition, we demonstrated high levels of these products in the aortic elastin of haemodialysis patients with ESRD. Our findings support the hypothesis that modification of aortic elastin by glycoxidation and lipid peroxidation may contribute to the development of vascular complications, particularly atherosclerosis, in patients with end-stage renal failure.

Topics: Arteriosclerosis; C-Reactive Protein; Elastin; Fluorescence; Glycosylation; Humans; Kidney Failure, Chronic; Lipid Peroxidation; Malondialdehyde; Oxidation-Reduction; Renal Dialysis

A 31-year-old man who had been under regular hemodialysis for 6 months was diagnosed as Williams syndrome (WS) by fluorescence in situ hybridization (FISH) chromosomal analysis. The association of WS and chronic renal failure (CRF) is only rarely encountered. Endocrinological examinations revealed hypergonadotropic hypogonadism. Prolonged and exaggerated responses of adrenocorticotropin (ACTH) to insulin-induced hypoglycemia and corticotropin releasing hormone (CRH) were also noted. While most of the endocrinological abnormalities observed in this patient could be attributed to altered endocrine circumstances in CRF, some findings stand in contrast. Furthermore, the testicular biopsy specimen showed severe hypospermatogenesis. Endocrine disorders observed in this patient may be at least in part, responsible for various clinical features underlying WS.

Topics: Adult; Chromosomes, Human, Pair 7; Elastin; Hormones; Humans; Hypogonadism; Hypothalamo-Hypophyseal System; In Situ Hybridization, Fluorescence; Insulin; Kidney Failure, Chronic; Male; Pituitary Hormones, Anterior; Pituitary-Adrenal System; Renal Dialysis; Testis; Uremia; Williams Syndrome

Lung calcification was detected in four out of 29 long-term dialysed patients on whom postmortem examinations were performed between 1967 and 1980. On light microscopy, calcification showed either a finely granular and linear localization along the alveolar septa, or a coarse and widespread parenchymal distribution. Histochemical studies revealed evidence of calcium, magnesium and phosphate ions in the deposits. Ultrastructural examination of the less severely involved alveolar septa showed selective deposition of calcium salts within an increased amount of elastin. The deposits consisted of electron dense roundish granules with a concentric laminar structure. They appeared either single or conglomerated in polycyclic formations, supposedly representing the progressive steps of the mineralization process, at first localized within elastin and progressively spreading outside it. The high magnesium content of the deposits suggests that the serum concentration of this ion may play an important role in visceral calcification of long-term dialysed patients.

Topics: Adult; Calcinosis; Calcium; Elastin; Female; Humans; Kidney Failure, Chronic; Lung; Lung Diseases; Magnesium; Male; Middle Aged; Renal Dialysis