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Skeletal vascular perfusion is altered in chronic kidney disease.

ABSTRACT: Patients with chronic kidney disease (CKD) are at an alarming risk of cardiovascular disease and fracture-associated mortality. CKD has been shown to have negative effects on vascular reactivity and organ perfusion. Although alterations in bone blood flow are linked to dysregulation of bone remodeling and mass in multiple conditions, changes to skeletal perfusion in the setting of CKD have not been explored. The goal of this study was to establish the effect of CKD on skeletal perfusion in a rat model of CKD. In two experiments with endpoints at 30 and 35 weeks of age, respectively, normal (NL) and Cy/+ (CKD) animals (n = 6/group) underwent in vivo intra-cardiac fluorescent microsphere injection to assess bone tissue perfusion. These two separate time points aimed to describe skeletal perfusion at 30 and 35 weeks based on previous studies demonstrating significant progression of hyperparthyroid bone disease during this timeframe. CKD animals had blood urea nitrogen (BUN) levels significantly higher than NL at both 30 and 35 weeks. At 30 weeks, perfusion was significantly higher in the femoral cortex (+259%, p < 0.05) but not in the tibial cortex (+140%, p = 0.11) of CKD animals relative to NL littermates. Isolated tibial marrow perfusion at 30 weeks showed a trend toward being higher (+183%, p = 0.08) in CKD. At 35 weeks, perfusion was significantly higher in both the femoral cortex (+173%, p < 0.05) and the tibial cortex (+241%, p < 0.05) in CKD animals when compared to their normal littermates. Isolated tibial marrow perfusion (-57%, p <0.05) and vertebral body perfusion (-71%, p <0.05) were lower in CKD animals. The current study demonstrates two novel findings regarding bone perfusion in an animal model of high turnover CKD. First, cortical bone perfusion in CKD animals is higher than in normal animals. Second, alterations in bone marrow perfision differed among the stages of CKD and were distinct from perfusion to the cortical bone. Determining whether these changes in bone perfusion are drivers, propagators, or consequences of skeletal deterioration in CKD will necessitate further work.

SUBMITTER: Aref MW

PROVIDER: S-EPMC6020396 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:An association between lower bone mineral density (BMD) and presence of vascular calcification (VC) has been reported in several studies. Chronic kidney disease (CKD) causes detrimental disturbances in the mineral balance, bone turnover, and development of severe VC. Our group has previously demonstrated expression of Wnt inhibitors in calcified arteries of CKD rats. Therefore, we hypothesized that the CKD-induced VC via this pathway signals to bone and induces bone loss. To address this novel hypothesis, we developed a new animal model using isogenic aorta transplantation (ATx). Severely calcified aortas from uremic rats were transplanted into healthy rats (uremic ATx). Transplantation of normal aortas into healthy rats (normal ATx) and age-matched rats (control) served as control groups. Trabecular tissue mineral density, as measured by μCT, was significantly lower in uremic ATx rats compared with both control groups. Uremic ATx rats showed a significant upregulation of the mineralization inhibitors osteopontin and progressive ankylosis protein homolog in bone. In addition, we found significant changes in bone mRNA levels of several genes related to extracellular matrix, bone turnover, and Wnt signaling in uremic ATx rats, with no difference between normal ATx and control. The bone histomorphometry analysis showed significant lower osteoid area in uremic ATx compared with normal ATx along with a trend toward fewer osteoblasts as well as more osteoclasts in the erosion lacunae. Uremic ATx and normal ATx had similar trabecular number and thickness. The bone formation rate did not differ between the three groups. Plasma biochemistry, including sclerostin, kidney, and mineral parameters, were similar between all three groups. ex vivo cultures of aorta from uremic rats showed high secretion of the Wnt inhibitor sclerostin. In conclusion, the presence of VC lowers BMD, impairs bone metabolism, and affects several pathways in bone. The present results prove the existence of a vasculature to bone tissue cross-talk. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Project description:BackgroundEvidence indicates that reducing dietary salt may reduce the incidence of heart disease and delay decline in kidney function in people with chronic kidney disease (CKD). This is an update of a review first published in 2015.ObjectivesTo evaluate the benefits and harms of altering dietary salt for adults with CKD.Search methodsWe searched the Cochrane Kidney and Transplant Register of Studies up to 6 October 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.Selection criteriaRandomised controlled trials comparing two or more levels of salt intake in adults with any stage of CKD.Data collection and analysisTwo authors independently assessed studies for eligibility, conducted risk of bias evaluation and evaluated confidence in the evidence using GRADE. Results were summarised using random effects models as risk ratios (RR) for dichotomous outcomes or mean differences (MD) for continuous outcomes, with 95% confidence intervals (CI).Main resultsWe included 21 studies (1197 randomised participants), 12 in the earlier stages of CKD (779 randomised participants), seven in dialysis (363 randomised participants) and two in post-transplant (55 randomised participants). Selection bias was low in seven studies, high in one and unclear in 13. Performance and detection biases were low in four studies, high in two, and unclear in 15. Attrition and reporting biases were low in 10 studies, high in three and unclear in eight. Because duration of the included studies was too short (1 to 36 weeks) to test the effect of salt restriction on endpoints such as death, cardiovascular events or CKD progression, changes in salt intake on blood pressure and other secondary risk factors were examined. Reducing salt by mean -73.51 mmol/day (95% CI -92.76 to -54.27), equivalent to 4.2 g or 1690 mg sodium/day, reduced systolic/diastolic blood pressure by -6.91/-3.91 mm Hg (95% CI -8.82 to -4.99/-4.80 to -3.02; 19 studies, 1405 participants; high certainty evidence). Albuminuria was reduced by 36% (95% CI 26 to 44) in six studies, five of which were carried out in people in the earlier stages of CKD (MD -0.44, 95% CI -0.58 to -0.30; 501 participants; high certainty evidence). The evidence is very uncertain about the effect of lower salt intake on weight, as the weight change observed (-1.32 kg, 95% CI -1.94 to -0.70; 12 studies, 759 participants) may have been due to fluid volume, lean tissue, or body fat. Lower salt intake may reduce extracellular fluid volume in the earlier stages of CKD (-0.87 L, 95% CI -1.17 to -0.58; 3 studies; 187 participants; low certainty evidence). The evidence is very uncertain about the effect of lower salt intake on reduction in antihypertensive dose (RR 2.45, 95% CI 0.98 to 6.08; 8 studies; 754 participants). Lower salt intake may lead to symptomatic hypotension (RR 6.70, 95% CI 2.40 to 18.69; 6 studies; 678 participants; moderate certainty evidence). Data were sparse for other types of adverse events.Authors' conclusionsWe found high certainty evidence that salt reduction reduced blood pressure in people with CKD, and albuminuria in people with earlier stage CKD in the short-term. If such reductions could be maintained long-term, this effect may translate to clinically significant reductions in CKD progression and cardiovascular events. Research into the long-term effects of sodium-restricted diet for people with CKD is warranted.

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Skeletal vascular perfusion is altered in chronic kidney disease.

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