Mandy Turner

Impaired phosphate tolerance revealed with an acute oral challenge

Elevated serum phosphate is consistently linked with cardiovascular disease (CVD) events and mortality in the setting of normal and impaired kidney function. However, serum phosphate does not often exceed the upper limit of normal until glomerular filtration rate (GFR) falls below 30 mL/min/m2. It was hypothesized that the response to an oral, bioavailable phosphate load will unmask impaired phosphate tolerance, a maladaptation not revealed by baseline serum phosphate concentrations. In this study, rats with varying kidney function as well as normo‐phosphatemic human subjects, with inulin‐measured GFR (13.2 to 128.3mL/min), received an oral phosphate load. Hormonal and urinary responses were evaluated over 2 hours. Results revealed that the more rapid elevation of serum phosphate was associated with subjects and rats with higher levels of kidney function, greater responsiveness to acute changes in parathyroid hormone (PTH), and significantly more urinary phosphate at 2 hours. In humans, increases in urinary phosphate to creatinine ratio did not correlate with baseline serum phosphate concentrations but did correlate strongly to early increase of serum phosphate. The blunted rise in serum phosphate in rats with CKD was not the result of altered absorption. This result suggests acute tissue deposition may be altered in the setting of kidney function impairment. Early recognition of impaired phosphate tolerance could translate to important interventions, such as dietary phosphate restriction or phosphate binders, being initiated at much higher levels of kidney function than is current practice.

A novel quantitative approach to the measurement of abdominal aortic calcification as applied to the Canadian Multicenter Osteoporosis Study (CaMOS)

BACKGROUND AND AIMS Lateral spine radiographs provide an inexpensive resource for characterizing abdominal aortic calcification (AAC). A widely accepted measurement of AAC is the semi-quantitative technique generated by the Framingham Heart Study (F-AAC-24). We sought to develop an analytical method to quantify ACC (QAAC) on lateral spine radiographs and compare the finding to conventional subjective measurements. METHODS Severity of AAC was quantified by measuring pixel intensities in the user-defined region of the aorta with internal standardization to the vertebral endplates and background calibration to the density of the vertebral body. The association between bone mineral density (BMD) measured by dual energy X-ray absorptiometry (DXA) and AAC measured by QAAC, F-AAC-24 and a modified Framingham score (F-AAC-12) was determined in 110 participants of the Canadian Multicenter Osteoporosis Study (CaMOS). RESULTS The inter-observer reliability for the QAAC was slightly higher than with the visual and semi-quantitative Framingham method and the pseudo-colored images illustrate the potential to meaningfully resolve severity of calcification. There was a significant negative association between QAAC and BMD measures of the hip and spine. This association remained significant after adjustment for age, sex, estimated glomerular filtration rate, phosphate and hypertension. Significant predictors of F-ACC-12 and 24 included age and hypertension. CONCLUSIONS The QAAC is a reproducible approach to measuring AAC. Whether it is capable of monitoring subtle calcific changes over time requires further study. This technique could be applied to large studies that seek to determine the impact of interventions that modify bone density as a treatment for vascular calcification and cardiovascular disease in the general population.

The Vitamin K Metabolome in Chronic Kidney Disease

The purpose of this review is to summarize the research to date on the impact of chronic kidney disease (CKD) on the vitamin K metabolome. Vitamin K-dependent proteins contribute to cardiovascular disease (CVD) prevention via the prevention of ectopic mineralization. Sub-clinical vitamin K deficiency is common in CKD patients, and evidence suggests that it may contribute to the CVD burden in this population. Research from animal models suggests that CKD alters tissue measures of the two predominant forms of vitamin K: KI and MK-4. The expression and/or activity of enzymes that regulate the recycling of vitamin K and the carboxylation of vitamin K-dependent proteins also appear to be altered in CKD. Evidence suggests that statins, a common pharmaceutical prescribed to CKD patients to prevent cardiovascular events, may impact the metabolism of vitamin K and therefore contribute to its relative inefficiency at preventing CVD in this population as kidney disease progresses. Human research on the tissue vitamin K metabolome in CKD patients is lacking.

Acute Tissue Mineral Deposition in Response to a Phosphate Pulse in Experimental CKD: VASCULAR MINERAL ACCRUAL IN CKD

Pathogenic accumulation of calcium (Ca) and phosphate (PO4) in vasculature is a sentinel of advancing cardiovascular disease in chronic kidney disease (CKD). This study sought to characterize acute distribution patterns of radiolabeled 33PO4 and 45Ca in cardiovascular tissues of rats with CKD (0.25% dietary adenine). The disposition of 33PO4 and 45Ca was assessed in blood and 36 tissues after a 10‐minute intravenous infusion of one of the following: (i) PO4 pulse + tracer 33PO4; (ii) PO4 pulse + tracer 45Ca; or (iii) saline + tracer 45Ca in CKD and non‐CKD animals. After the infusion, 33PO4 in blood was elevated (2.3× at 10 minutes, 3.5× at 30 minutes, p < 0.05) in CKD compared with non‐CKD. In contrast, there was no difference in clearance of 45Ca from the blood. Compared with controls, CKD rats had a markedly increased 33PO4 incorporation in several tissues (skeletal muscle, 7.8×; heart, 5.5×), but accrual was most pronounced in the vasculature (24.8×). There was a significant, but smaller, increase in 45Ca accrual in the vasculature of CKD rats (1.25×), particularly in the calcified rat, in response to the acute phosphate load. Based on the pattern of tissue uptake of 33PO4 and 45Ca, this study revealed that an increase in circulating PO4 is an important stimulus for the accumulation of these minerals in vascular tissue in CKD. This response is further enhanced when vascular calcification is also present. The finding of enhanced vascular mineral deposition in response to an acute PO4 pulse provides evidence of significant tissue‐specific susceptibility to calcification.

Validation of a routine two‐sample iohexol plasma clearance assessment of GFR and an evaluation of common endogenous markers in a rat model of CKD

Endogenous markers of kidney function are insensitive to early declines in glomerular filtration rate (GFR) and in rodent models, validated, practical alternatives are unavailable. In this study, we determined GFR by modeling the plasma clearance of two compounds, iohexol and inulin, and compared the findings to common endogenous markers. All plasma clearance methods of both iohexol and inulin detected a decline in renal function weeks prior to any increase in endogenous marker. Iohexol plasma clearance and inulin plasma clearance had a very high agreement and minimal bias when using 12‐sample models. However, only iohexol could be accurately simplified to a two‐sample, one‐compartment estimation strategy. Following an IV injection of low‐dose iohexol and two timed blood samples at 30 and 90 min, one can accurately approximate a complex 12‐sample strategy of plasma clearance. This method is simple enough to use in routine, longitudinal analysis of larger cohort animal studies.