Pyrophosphate, alkaline phosphatase, and vascular calcification.
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Alkaline Phosphatase↗
Biomedical subjects
W Charles O'Neill
Publications and source records attributed to W Charles O'Neill.
B-mode sonography in acute renal failure.
B-mode sonography is an extremely useful and cost-effective method to eliminate urinary obstruction as a cause of acute renal failure and should be performed on all patients in whom obstruction is likely or in whom the cause of renal failure is not apparent. The threshold should be reduced in patients with solitary kidneys and sonography is probably indicated in all transplant patients. Sonography has very little utility in the management of other patients with acute renal failure. Although sonographic changes do occur in acute tubular necrosis, they are difficult to detect in the absence of baseline studies and are nonspecific.
Acute Kidney Injury↗
An assessment of statin safety by nephrologists.
Recently, concerns regarding potential adverse effects of the statins on the kidney have been raised. The Kidney Expert Panel of the National Lipid Association's (NLA) Safety Task Force, made up of 3 nephrologists, was convened to review all of the currently available evidence pertinent to determining whether statins cause kidney injury, independent of the known, rare mechanisms of rhabdomyolysis and allergic, drug-induced, interstitial nephritis. The Panel reviewed published and unpublished evidence and found none that suggested that statins, when used in doses currently approved by the US Food and Drug Administration (FDA), cause kidney injury.
Dose-Response Relationship, Drug↗
Reduced plasma pyrophosphate levels in hemodialysis patients.
Pyrophosphate (PPi) is a known inhibitor of hydroxyapatite formation and has been shown to inhibit medial vascular calcification in vitamin D-toxic rats. It was demonstrated recently that endogenous production of PPi prevents calcification of rat aorta that are cultured in high concentrations of calcium and phosphate. For determining whether PPi metabolism is altered in hemodialysis patients, plasma levels and dialytic clearance of PPi were measured in stable hemodialysis patients. Predialysis plasma [PPi] was 2.26 +/- 0.19 microM in 38 clinically stable hemodialysis patients compared with 3.26 +/- 0.17 in 36 normal subjects (P < 0.01). Approximately 30% of plasma PPi was protein bound, and this was not altered in dialysis patients. There was a weak inverse correlation with age in normal individuals but not in dialysis patients. Plasma [PPi] in dialysis patients was correlated with plasma [PO4(3-)] (r = 0.56) but not with [Ca2+], parathyroid hormone, or the dose of dialysis, and levels did not vary between interdialytic periods of 2 and 3 d. Plasma [PPi] decreased 32 +/- 5% after standard hemodialysis in 17 patients. In vitro clearance of PPi by a 2.1-m2 cellulose acetate dialyzer was 36%, and the mean PPi removal in five patients was 43 +/- 5 micromol, consistent with a similar in vivo clearance. Cleared PPi was greater than the plasma pool but less than the estimated extracellular fluid pool. Erythrocyte PPi content decreased 24 +/- 4%, indicating that intracellular PPi is removed as well. It is concluded that plasma [PPi] is reduced in hemodialysis patients and that PPi is cleared by dialysis. Plasma levels in some patients were below those that have previously been shown to prevent calcification of vessels in culture, suggesting that altered PPi metabolism could contribute to vascular calcification in hemodialysis patients.
Adult↗
Sonographic assessment of the severity and progression of autosomal dominant polycystic kidney disease: the Consortium of Renal Imaging Studies in Polycystic Kidney Disease (CRISP).
BACKGROUND: The accuracy and precision of ultrasonography (US) in assessing the severity of autosomal dominant polycystic kidney disease (ADPKD) is unknown. METHODS: US and magnetic resonance imaging (MRI) were performed at baseline and 1 year on 230 subjects with ADPKD. Ellipsoid volume was calculated from US length, width, and depth, and sequential transverse images were used to measure total and cystic volume directly. These were compared with MRI measurements of kidney volume and cystic volume. RESULTS: Variability between different sonographers ranged from 18% to 42%. Correlations between US and MRI volume were 0.88 and 0.89. The SD of the discrepancy from MRI ranged from 21% to 33% and was unrelated to kidney size or body mass. Kidney length was the most reproducible measurement, and its correlation with MRI volume was 0.84. All patients with an US volume less than 700 cm3 had an MRI volume less than 1,000 cm3, and all patients with an US volume greater than 1,700 cm3 had an MRI volume greater than 1,000 cm3. Increases in volume after 1 year were 12% +/- 36% for the ellipsoid method, 6% +/- 29% for the direct method, and 4.2% +/- 7.2% for MRI. Correlation between US and MRI measurement of fractional cyst volume was 0.80. CONCLUSION: Sonographic measurement of kidney volume in patients with ADPKD is inaccurate and lacks the precision necessary to measure short-term disease progression. However, sonography can provide an estimate of kidney volume that reflects severity and prognosis in individual patients.
Adolescent↗
Correlation of renal histopathology with sonographic findings.
BACKGROUND: Judgments about irreversible renal disease are frequently based on the sonographic appearance of the kidneys. However, the sensitivity and specificity of sonography in identifying chronic, irreversible disease have never been determined, and the specific pathologic changes that increase renal cortical echogenicity have not been defined. METHODS: We retrospectively compared sonographic parameters (length, quantitative echogenicity, cortical thickness, and parenchymal thickness) to biopsy findings of glomerular sclerosis, tubular atrophy, interstitial fibrosis, and interstitial inflammation in 207 patients. RESULTS: Echogenicity showed the strongest correlation with all 4 histologic parameters (r= 0.28-0.35). Renal size was significantly correlated with glomerular sclerosis (r=-0.26) and tubular atrophy (r= 0.20). Parenchymal thickness, but not cortical thickness, correlated with tubular atrophy (r=-0.23). By multivariate analysis, tubular atrophy and interstitial inflammation, but not interstitial fibrosis, were significant determinants of cortical echogenicity. Severe chronic disease (>50% sclerosed glomeruli or a score of 3 out of 5 or greater for tubular atrophy or interstitial fibrosis) was present in 69% and 47% of patients with combined renal length <20 cm and >20 cm, respectively (P= <0.05). For cortical echogenicity >1.0 (>liver echogenicity) and </=1.0, the proportions of severe disease were 66% and 30%, respectively (P < 0.001). Severe disease was present in 86% of patients with combined renal length <20 cm and cortical echogenicity >1.0. CONCLUSION: Cortical echogenicity is the sonographic parameter that correlates best with renal histopathology. Although size or echogenicity alone are poor predictors of chronic irreversible disease, the likelihood of treatable disease in small kidneys with increased cortical echogenicity is very low.
Adolescent↗
Phosphate-induced vascular calcification: role of pyrophosphate and osteopontin.
Hyperphosphatemia is thought to underlie medial vascular calcification in advanced renal failure, but calcification can occur in other conditions in the absence of hyperphosphatemia, indicating that additional factors are important. To identify these factors, a model of medial calcification in rat aorta in vitro was developed. Aortic rings from rats were incubated in serum-free medium for 9 d, and calcification was measured as incorporation of (45)Ca and confirmed by histology and x-ray diffraction. No calcification occurred in normal vessels despite elevated free Ca(2+) and PO(4)(3-) concentrations of 1.8 mM and 3.8 mM, respectively, but mechanical injury resulted in extensive calcification in the media. Co-incubation studies revealed that normal aortas produced a soluble inhibitor of calcification in injured vessels that was destroyed by alkaline phosphatase. Culture of normal aortas with alkaline phosphatase resulted in calcification of the elastic lamina identified as hydroxyapatite by x-ray diffraction. This effect of alkaline phosphatase was not due to dephosphorylation of osteopontin (OPN), and calcification was not increased in aortas from OPN-deficient mice. The inhibitor was identified as pyrophosphate on the basis of the calcification induced in aortas cultured with inorganic pyrophosphatase, the inhibition of calcification in injured aortas by pyrophosphate, and the production of inhibitory levels of pyrophosphate by normal aortas. No calcification occurred under any conditions at a normal PO(4)(3-) concentration. It is concluded that elevated concentrations of Ca(2+) and PO(4)(3-) are not sufficient for medial vascular calcification because of inhibition by pyrophosphate. Alkaline phosphatase can promote calcification by hydrolyzing pyrophosphate, but OPN is not an endogenous inhibitor of calcification in rat aorta.
Alkaline Phosphatase↗
Reduced renal function in patients with simple renal cysts.
BACKGROUND: Sporadic renal cysts not associated with genetic polycystic disorders are common and generally thought to be of no clinical significance. Since multiple cysts frequently develop in end-stage renal disease (ESRD), we tested the hypothesis that cysts that are solitary or few in number are an early manifestation of reduced renal function. METHODS: We evaluated 561 hospitalized patients who underwent contrast-enhanced, abdominal computed tomography (CT) and correlated clinical characteristics and parameters of renal function with the presence or absence of renal cysts. RESULTS: Age ranged from 16 to 100 years, mean serum creatinine concentration was 0.88 mg/dL (range 0.4 to 2.1 mg/dL), and mean estimated creatinine clearance was 94 mL/min/1.73 m(2) (range 22 to 218 mL/min/1.73 m(2)). The presence of cysts was significantly correlated with older age (P < 0.001), higher serum creatinine concentration (P < 0.002), and lower estimated creatinine clearance (P < 0.001). In a multivariate analysis, including age and gender, estimated creatinine clearance still correlated with the presence of cysts (P= 0.009). When patients were grouped by age, estimated creatinine clearance correlated with cysts in patients <40 years and 40 to 59 years, but not in patients 60 to 79 years or > or =80 years. There was no association of cysts with hypertension or proteinuria. In patients with cysts, serum creatinine increased progressively but not significantly with cyst number, and did not correlate with size or distribution of cysts. Renal parenchymal volume was slightly but not significantly reduced in patients with cysts. CONCLUSION: The presence of kidney cysts, even single cysts, is associated with reduced renal function in hospitalized patients younger than 60 years. This relationship may be obscured by the reduced renal function and the high incidence of cysts in older patients. These results suggest that acquired cystic kidney disease may begin early in the course of renal disease and that underlying renal disease should be considered in individuals with renal cysts prior to age 60 years.
Adolescent↗
Blood pressure regulates the activity and function of the Na-K-2Cl cotransporter in vascular smooth muscle.
The Na-K-2Cl cotransporter (NKCC1) is one of several transporters that have been linked to hypertension, and its inhibition reduces vascular smooth muscle tone and blood pressure. NKCC1 in the rat aorta is stimulated by vasoconstrictors and inhibited by nitrovasodilators, and this is linked to the contractile state of the smooth muscle. To determine whether blood pressure also regulates NKCC1, we examined the acute effect of hypertension on NKCC1 in rats after aortic coarctation. In the hypertensive aorta (28-mmHg rise in mean blood pressure), an increase in NKCC1 activity (measured as bumetanide-sensitive (86)Rb efflux) was apparent by 16 h and reached a plateau of 62% greater than control at 48 h. In contrast, there was a slight decrease in NKCC1 activity in the hypotensive aorta (21% decrease in mean blood pressure). Measurement of NKCC1 mRNA by real-time PCR revealed a fivefold increase in the hypertensive aorta compared with the hypotensive aorta or sham aorta. The inhibition by bumetanide of isometric force response to phenylephrine was significantly greater in the hypertensive aorta than in the control aorta or hypotensive aorta. We conclude that NKCC1 in rat aortic smooth muscle is regulated by blood pressure, most likely through changes in transporter abundance. This upregulation of NKCC1 is associated with a greater contribution to force generation in the hypertensive aorta. This is the first demonstration that NKCC1 in vascular smooth muscle is regulated by blood pressure and indicates that this transporter is important in the acute response of vascular smooth muscle to hypertension.
Animals↗
Nephron number and primary hypertension.
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Humans↗
Aldosterone regulates the Na-K-2Cl cotransporter in vascular smooth muscle.
Aldosterone increases cation transport and contractility of vascular smooth muscle, but the specific transporter involved and how it is linked to smooth muscle tone is unknown. Because the Na-K-2Cl cotransporter (NKCC1) contributes to vascular smooth muscle contraction and is regulated by vasoactive compounds, we sought to determine whether this transporter is a target of aldosterone in rat aorta. Treatment of adrenalectomized rats with aldosterone for 7 days resulted in a 63% increase in NKCC1 activity as measured by bumetanide-sensitive efflux of 86Rb+. Treatment of normal aortas in culture with aldosterone for 3 and 7 days resulted in 29% and 47% increases in NKCC1 activity, respectively. Aldosterone had no acute effect on 86Rb+ efflux. Stimulation of NKCC1 was blocked by spironolactone, a mineralocorticoid receptor antagonist, but not by RU38486, a glucocorticoid receptor antagonist. Aldosterone did not augment the stimulation of NKCC1 by phenylephrine and did not increase NKCC1 mRNA as determined by real-time polymerase chain reaction. We conclude that aldosterone regulates the Na-K-2Cl cotransporter in vascular smooth muscle through classic mineralocorticoid receptors but not through changes in the abundance of NKCC1 mRNA. This could account for the increase in Na+, K+, and Cl- fluxes previously observed in vascular smooth muscle from mineralocorticoid-treated animals and may contribute to increased vascular tone.
Adrenalectomy↗
Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort.
BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by gradual renal enlargement and cyst growth prior to loss of renal function. Standard radiographic imaging has not provided the resolution and accuracy necessary to detect small changes in renal volume or to reliably measure renal cyst volumes. The Consortium for Radiologic Imaging Studies in Polycystic Kidney Disease (CRISP) is longitudinally observing ADPKD individuals using high-resolution magnetic resonance (MR) imaging to determine if change in renal and cyst volumes can be detected over a short period of time, and if they correlate with decline in renal function early in disease. METHODS: Standardization studies were conducted in phantoms and four subjects at each participating clinical center. After, in the full-scale protocol, healthy ADPKD individuals 15 to 45 years old with creatinine clearance>70 mL/min underwent standardized MR renal imaging, renal iothalamate clearance, comprehensive clinical evaluation, and determination of 24-hour urinary albumin and electrolyte excretion. Stereology was used from T1-weighted images to quantify renal volume, and region-growing thresholding was used from T2-weighted images to determine cyst volume. Renal structures were evaluated in relation to demographic, clinical, and biochemical variables using means/medians, standard deviations, and Pearson correlations. RESULTS: Reliability coefficients for MR renal and cyst volume measurements in phantoms were 99.9% and 89.2%, respectively. In the full-scale protocol, 241 ADPKD individuals (145 women and 96 men) were enrolled. Total renal, cyst, and % cyst volume were significantly greater in each decade group. Hypertensive individuals demonstrated greater renal, cyst, and % cyst volume than normotensive subjects. Age-adjusted renal (r = -0.31, P < 0.0001), cyst (r = -0.36, P < 0.0001), and % cyst volume (r = -0.35, P < 0.0001) were inversely related to glomerular filtration rate (GFR). Age-adjusted renal volume (r = 0.42, P < 0.0001), cystic (r = 0.39, P < 0.0001, and % cyst volume (r = 0.41, P < 0.0001) were related with urinary albumin excretion. CONCLUSION: MR measures of renal and cyst volume are reliable and accurate in patients with ADPKD. ADPKD is characterized by significant cystic involvement that increases with age. Structure (renal and cyst volume) and function (GFR) are inversely related and directly related with the presence of hypertension and urinary albumin excretion in individuals with normal renal function.
Adolescent↗
Reduced kidney size in patients with simple renal cysts.
BACKGROUND: Renal cysts frequently occur in the absence of genetic diseases but their significance is unknown. Since multiple cysts develop in many patients with advanced renal disease, we tested the hypothesis that isolated cysts are associated with early nephron loss. METHODS: All inpatient and outpatient sonograms performed by the Renal Division since 1995 were reviewed and, after exclusion of duplicate studies, patients with genetic cystic disorders, complex cysts, hydronephrosis, peripelvic cysts, end-stage renal disease and transplanted kidneys, 2526 were selected for this study, of which 385 had one or more cysts. Maximum renal length was used as an indication of size, and renal function was estimated by serum creatinine concentration. RESULTS: Both right and left kidney length were significantly less in patients with cysts (P < 0.0001), independent of which kidney contained the cyst(s). Renal lengths were less in patients with multiple cysts as opposed to single cysts but not in patients with bilateral cysts as compared to unilateral cysts. Cysts were twice as frequent in solitary kidneys than in dual kidneys (P = 0.01). In outpatients matched for age and gender, those with cysts had a higher serum creatinine concentration but with borderline significance (P = 0.06). Multivariate analysis revealed that age, gender, and renal length were each independent variables and together accounted for one third of the incidence of cysts. CONCLUSION: Kidney size is reduced in patients with simple renal cysts noted on renal sonography, and cysts may be associated with reduced renal function. This suggests that isolated cysts are an indication of nephron loss in patients with renal abnormalities.
Age Distribution↗
Seminars in nephrology. Introduction.
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Humans↗
Sonography of the kidney and urinary tract.
Sonography has become integral to the evaluation and management of patients with renal disease. Although many of the procedures discussed in this issue are not feasible for all nephrologists, sonography clearly is. It is convenient and saves time, both for the physician and the patient, and the equipment is not expensive. It is not a difficult skill to learn, as evidenced by the growing number of nephrologists who have learned it, and it greatly enhances the practice of nephrology. Even nephrologists who do not plan to acquire this skill should be familiar with it to understand the indications and limitations, and to participate in its interpretation. Sonography, both the performance and interpretation, is an acquired skill that requires hands-on training, supervision, and practice, and thus cannot be learned solely by reading. Therefore, the goal here is not to teach sonography but rather to provide a basic overview of sonography, discuss its role in nephrology, and present information relevant to incorporating sonography into a nephrology practice.
Humans↗