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Ultrasonography is increasingly being performed by clinicians at the point of care, and nephrologists are no exception. This Core Curriculum illustrates how ultrasonography can be incorporated into clinical decision making across the spectrum of kidney disease to optimize the care nephrologists provide to patients. Sonography is valuable in outpatient and inpatient settings for the diagnosis and management of acute and chronic kidney disease, evaluation of cystic disease, urinary obstruction, pain, hematuria, proteinuria, assessment of volume status, and in providing guidance for kidney biopsy. As kidney disease advances, ultrasound is useful in the placement and maintenance of temporary and permanent access for dialysis. After kidney transplantation, ultrasonography is critical for evaluation of allograft dysfunction and for biopsies. Sonography skills expedite patient care and enhance the practice of nephrology and are relatively easily acquired with training. It is our hope that this curriculum will encourage nephrologists to learn and apply this valuable skill., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Hemodialysis solutions typically contain a high alkali concentration designed to counter interdialytic acidosis, but this could result in persistent alkalosis in some patients. The prevalence and significance of persistent alkalosis were therefore examined at four outpatient centers over a 10-year period., Methods: Alkalosis was defined as a pre-dialysis serum [HCO 3 ] ≥ 26 meq/L in >6 months of a 12-month period and was persistent if present in a majority of months thereafter. Control patients had a serum [HCO 3 ] of 19-23 meq/L > 6 of every 12 months. Standard, citrate-containing dialysate was used in all patients without adjustment of bicarbonate concentration., Results: 444 of 1271 patients had alkalosis that persisted in 73. Compared to control patients, persistently alkalotic patients were older, but gender, race, starting weight, comorbidities, and mortality did not differ. Dialysis dose was 7% greater, protein catabolic rate was 11% lower, and interdialytic weight gain was 29% lower, all p < 0.001. Persistently alkalotic patients had double the incidence of cardiac arrhythmias (p = 0.07) and a 20% greater intradialytic blood pressure decrease (p < 0.001)., Conclusions: Alkalosis is common in hemodialysis patients and can be persistent, likely due to decreased protein catabolic rate and increased dialysis dose, and may have detrimental cardiovascular effects., (© 2022 Wiley Periodicals LLC.)

Background and Objectives: Point-of-care ultrasound (POCUS)-performed by a clinician during a patient encounter and used in patient assessment and care planning-has many potential applications in nephrology. Yet, US nephrologists have been slow to adopt POCUS, which may affect the training of nephrology fellows. This study sought to identify the current state of POCUS training and implementation in nephrology fellowships., Design, Setting, Participants, & Measurements: Concise survey instruments measuring attitudes toward POCUS, its current use, fellow competence, and POCUS curricula were disseminated to ( 1 ) 912 US nephrology fellows taking the 2021 Nephrology In-Training Examination and ( 2 ) 229 nephrology training program directors and associate program directors. Fisher exact, chi-squared, and Wilcoxon rank sum tests were used to compare the frequencies of responses and the average responses between fellows and training program directors/associate program directors when possible., Results: Fellow and training program directors/associate program directors response rates were 69% and 37%, respectively. Only 38% of fellows (240 respondents) reported receiving POCUS education during their fellowship, and just 33% of those who did receive POCUS training reported feeling competent to use POCUS independently. Similarly, just 23% of training program directors/associate program directors indicated that they had a POCUS curriculum in place, although 74% of training program directors and associate program directors indicated that a program was in development or that there was interest in creating a POCUS curriculum. Most fellow and faculty respondents rated commonly covered POCUS topics-including dialysis access imaging and kidney biopsy-as "important" or "very important," with the greatest interest in diagnostic kidney ultrasound. Guided scanning with an instructor was the highest-rated teaching strategy. The most frequently reported barrier to POCUS program development was the lack of available instructors., Conclusions: Despite high trainee and faculty interest in POCUS, the majority of current nephrology fellows are not receiving POCUS training. Hands-on training guided by an instructor is highly valued, yet availability of adequately trained instructors remains a barrier to program development., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022&#95;09&#95;21&#95;CJN01850222.mp3., (Copyright © 2022 by the American Society of Nephrology.)

Purpose: Measurements of breast arterial calcifications (BAC) can offer a personalized, non-invasive approach to risk-stratify women for cardiovascular diseases such as heart attack and stroke. We aim to detect and segment breast arterial calcifications in mammograms accurately and suggest novel measurements to quantify detected BAC for future clinical applications., Methods: To separate BAC in mammograms, we propose a lightweight fine vessel segmentation method Simple Context U-Net (SCU-Net). Due to the large image size of mammograms, we adopt a patch-based way to train SCU-Net and obtain the final whole-image-size results by stitching patchwise results together. To further quantify calcifications, we test five quantitative metrics to inspect the progression of BAC for subjects: sum of mask probability metric ( P M ), sum of mask area metric ( A M ), sum of mask intensity metric ( S I M ), sum of mask area with threshold intensity metric T A M X , and sum of mask intensity with threshold X metric T S I M X . Finally, we demonstrate the ability of the metrics to longitudinally measure calcifications in a group of 26 subjects and evaluate our quantification metrics compared with calcified voxels and calcium mass on breast CT for 10 subjects., Results: Our segmentation results are compared with state-of-the-art network architectures based on recall, precision, accuracy, F1 score/Dice score, and Jaccard index evaluation metrics and achieve corresponding values of 0.789, 0.708, 0.997, 0.729, and 0.581 for whole-image-size results. The quantification results all show >95% correlation between quantification measures on predicted masks of SCU-Net as compared to the groundtruth and measurement of calcification on breast CT. For the calcification quantification measurement, our calcification volume (voxels) results yield R 2 -correlation values of 0.834, 0.843, 0.832, 0.798, and 0.800 for the P M , A M , S I M , T A M 100 , T S I M 100 metrics, respectively; our calcium mass results yield comparable R 2 -correlation values of 0.866, 0.873, 0.840, 0.774, and 0.798 for the same metrics., Conclusions: Simple Context U-Net is a simple method to accurately segment arterial calcification retrospectively on routine mammograms. Quantification of the calcifications based on this segmentation in the retrospective cohort study has sufficient sensitivity to detect the normal progression over time and should be useful for future research and clinical applications., (© 2021 American Association of Physicists in Medicine.)

Patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD) experience an increased risk of cerebrovascular disease and cognitive dysfunction. Hemodialysis (HD), a major modality of renal replacement therapy in ESKD, can cause rapid changes in blood pressure, osmolality, and acid-base balance that collectively present a unique stress to the cerebral vasculature. This review presents an update regarding cerebral blood flow (CBF) regulation in CKD and ESKD and how the maintenance of cerebral oxygenation may be compromised during HD. Patients with ESKD exhibit decreased cerebral oxygen delivery due to anemia, despite cerebral hyperperfusion at rest. Cerebral oxygenation further declines during HD due to reductions in CBF, and this may induce cerebral ischemia or "stunning." Intradialytic reductions in CBF are driven by decreases in cerebral perfusion pressure that may be partially opposed by bicarbonate shifts during dialysis. Intradialytic reductions in CBF have been related to several variables that are routinely measured in clinical practice including ultrafiltration rate and blood pressure. However, the role of compensatory cerebrovascular regulatory mechanisms during HD remains relatively unexplored. In particular, cerebral autoregulation can oppose reductions in CBF driven by reductions in systemic blood pressure, while cerebrovascular reactivity to CO 2 may attenuate intradialytic reductions in CBF through promoting cerebral vasodilation. However, whether these mechanisms are effective in ESKD and during HD remain relatively unexplored. Important areas for future work include investigating potential alterations in cerebrovascular regulation in CKD and ESKD and how key regulatory mechanisms are engaged and integrated during HD to modulate intradialytic declines in CBF.

Introduction: Medial arterial calcification is a common and progressive lesion in end-stage renal disease that is associated with poor cardiovascular outcomes. Whether this lesion can be arrested or reversed is unknown, and was examined retrospectively by measuring progression of breast arterial calcification before and after kidney transplantation., Methods: Arterial calcification was measured on serial mammograms from patients with previous kidney transplantation and compared to measurements performed before transplantation or in patients on the active waitlist. Serum creatinine >2.0 mg/dl after transplantation or warfarin use were exclusions., Results: Median (interquartile range) progression of arterial calcification was 12.9 mm/breast per year (5.9 to 32.6) in 34 patients before or awaiting transplantation compared to just 1.2 mm/breast per year (-0.54 to 5.1) in 34 patients after transplantation ( P  < 0.001). Slowing of progression was also seen in longitudinal analyses of patients with mammograms performed both before and after transplantation. Duration of end-stage renal disease before transplantation but not age, diabetes, baseline calcification, or serum chemistries correlated with progression after transplantation. Significant regression was not observed in any patient., Conclusion: In this first quantitative study of the effect of kidney transplantation, medial arterial calcification appeared to slow to rates seen in patients with normal renal function, indicating that the effect of renal failure may be completely abrogated. Overall, however, there was no significant regression, suggesting that calcification is irreversible and emphasizing the importance of prevention. Duration of pretransplant end-stage renal disease but not baseline calcification was a determinant of progression, consistent with cumulative, permanent changes to arteries that promote calcification., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Objective: Warfarin is associated with medial arterial calcification in humans, but the magnitude and specificity of this effect and the role of other risk factors are unknown. Using serial mammograms, progression of arterial calcification was compared in women receiving no anticoagulants, warfarin, or other anticoagulants, and before, during, and after warfarin use. Approach and Results: Warfarin users with mammograms were identified by computerized searches of medical records that included renal function and diabetes mellitus. Lengths of calcified arterial segments were measured, with progression expressed as millimeters per breast per year and presented as medians and interquartile range (IQR). In women with normal renal function (estimated glomerular filtration rate >60 mL/minute per 1.73 m 2 ), progression was 3.9-fold greater in warfarin users: 9.9 (3.8-16) versus 2.5 (0.7-6.7) in controls, P =0.0003, but not increased in users of other anticoagulants. In longitudinal analyses, progression increased from 2.1 (IQR, 0.3-3.9) to 13.8 (IQR, 7.8-38.7; P =0.011) after starting warfarin (n=11) and decreased from 8.8 (IQR, 1.1-10) to 1.9 (IQR, -10 to 6.7; P =0.024) after discontinuation of warfarin (n=13). Progression of calcification was similar in warfarin users with chronic kidney disease (7.3 [IQR, 3.6-17], n=29) but markedly accelerated in warfarin users with end-stage renal disease (47 [IQR, 31-183], n=11; P =0.0002). Progression was similar in diabetic and nondiabetic warfarin users (10.1 [IQR, 3.8-24] versus 7.8 [IQR, 3.6-15]) and did not correlate with age ( r =0.09) or duration of warfarin therapy ( r =0.12)., Conclusions: Warfarin significantly accelerates medial arterial calcification in humans. This effect is markedly augmented in end-stage renal disease.

Competing Interests: W.C. O’Neill derives income from training courses in sonography, reports personal fees from Childrens Healthcare of Atlanta outside the submitted work, and receives garnt support from the National Institutes of Health and the American Heart Association unrelated to this work. All remaining authors have nothing to disclose.

A variety of criteria exist for histopathologic diagnosis of calciphylaxis, also known as calcific uremic arteriolopathy but data on their specificity are limited. To assess this, histologic findings of 38 skin biopsies performed for a suspicion of calcific uremic arteriolopathy were compared with histologic findings in skin obtained from healthy margins of 43 amputations in patients with end-stage renal disease (ESRD) without evidence of calcific uremic arteriolopathy. Abnormalities in small arteries or arterioles were present in 35% of amputation specimens and 55% of skin biopsies, and among these only thrombosis but not calcification was significantly more prevalent in skin biopsies. The prevalence of extravascular calcification did not differ. Vascular lesions were more common in skin biopsies from patients with high clinical suspicion of calcific uremic arteriolopathy (81%), significantly driven by increases in both calcification and thrombosis, compared to amputations (35%). The combination of medial calcification and thrombosis was six-fold more prevalent in high-suspicion skin biopsies than in amputation specimens. The location of affected vessels did not differ. In two autopsy cases, some but not all findings of involved skin were also present in uninvolved skin. Thus, histopathologic findings historically associated with calcific uremic arteriolopathy can also occur in viable tissue from unaffected patients with ESRD, calling into question the specificity of individual histologic findings for calcific uremic arteriolopathy. However, the combination of medial calcification and thrombosis was rare in unaffected patients and may provide a higher degree of specificity., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Introduction: Medial arterial calcification is common in chronic kidney disease (CKD) and portends poor clinical outcomes, but its progression relative to the severity of CKD and the role of other risk factors is unknown because of the lack of reliable quantification., Methods: Calcification of breast arteries detected by mammography, which is exclusively medial and correlates with medial calcification in peripheral arteries and with cardiovascular outcomes, was used to measure the progression of medial arterial calcification in women with CKD and end-stage renal disease (ESRD). Measurements showed intra- and interobserver correlations of 0.98, an interstudy variability of 8% to 11%, and a correlation with computed tomographic measurements of 0.92., Results: Progression of calcification was measured in 60 control subjects (estimated glomerular filtration rate (eGFR) ≥ 90 ml/min per 1.73 m 2 ) and 137 subjects with CKD (eGFR < 90 ml/min per 1.73 m 2 ). Progression in control subjects was linear over time and independent of age. The rate of progression was increased in CKD but only at eGFR < 40 ml/min per 1.73 m 2 (median, 8.1 vs. 3.9 mm/breast/yr in controls; P  = 0.006). Progression accelerated markedly in subjects with ESRD (median, 20 mm/breast/yr; n = 36), but did not differ from controls after kidney transplantation (n = 25). Diabetes significantly augmented progression in subjects with CKD and ESRD but not in controls., Conclusion: Mammography is a convenient and reliable method to measure the progression of medial arterial calcification. Progression does not increase until advanced stages of CKD, accelerates markedly in ESRD, and returns to control rates after kidney transplantation. Diabetes significantly increases progression in CKD and ESRD.

Pathologic cardiovascular calcification is associated with a number of conditions and is a common complication of chronic kidney disease. Because ambient calcium and phosphate levels together with properties of the vascular matrix favor calcification even under normal conditions, endogenous inhibitors such as pyrophosphate play a key role in prevention. Genetic diseases and animal models have elucidated the metabolism of extracellular pyrophosphate and demonstrated the importance of pyrophosphate deficiency in vascular calcification. Therapies based on pyrophosphate metabolism have been effective in animal models, including renal failure, and hold promise as future therapies to prevent vascular calcification., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Sonography is increasingly being performed by clinicians and has applications throughout the spectrum of nephrology, including acute and chronic renal failure, urinary obstruction, cystic disease, pain, hematuria, transplantation, kidney biopsy, temporary and permanent vascular access, and assessment of fluid status. The skill is relatively easily acquired, expedites patient care, and enhances the practice of nephrology. However, the lack of exposure in most training programs remains a major obstacle., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

A number of histologic changes are associated with the medial arterial calcification that occurs in chronic kidney disease, leading to several different hypotheses concerning the underlying mechanism. Careful timing of these changes in relation to the onset of the calcification, as reported in this issue of the journal, can shed light on which changes are pathogenic as opposed to secondary in reaction to the calcification., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The incidence of renal malignancies is markedly increased in end-stage renal disease and appears to be related to the development of acquired cystic kidney disease. Identification and evaluation of simple cysts, complex cysts, and solid masses in these patients rely on imaging studies, including ultrasonography, computed tomography, and magnetic resonance imaging, each of which has advantages and disadvantages. While there are no published data to support screening of ESRD patients, this seems appropriate in at least some patients, based on patient characteristics and the presence or absence of acquired cystic kidney disease. The optimal frequency and modality remain to be determined., (© 2017 Wiley Periodicals, Inc.)

Chronic decline in renal function is accompanied by deterioration of bone structure and function and progressive calcification of the vascular system. Both disease states have been linked with increased morbidity and mortality in chronic kidney disease. The severe alterations of mineral metabolism inherent with loss of renal function have an impact on vascular calcification development and progression, and several investigators have focused on ways to reduce their impact on vascular health. Imaging has contributed an important role in the assessment of vascular calcification, and the impact of various interventions aimed at curbing their progression., (© 2017 Wiley Periodicals, Inc.)

The extent to which vascular calcification is reversible and the possible mechanisms are unclear. To address this, calcified aortas from uremic mice were transplanted orthotopically into normal mice, and the calcium content, histology, and minerals of the allografts were compared with the nontransplanted donor aorta. Calcium content decreased immediately after transplantation but remained constant thereafter, with 68% ± 12% remaining after 34 weeks. X-ray diffraction showed the presence of apatite in both donor aortas and allografts. Osteoclasts were absent in the allografts and there was no expression of the macrophage marker CD11b, the osteoclast marker tartrate-resistant acid phosphatase, or carbonic anhydrase II. The initial loss of calcium was less in heavily calcified aortas and was associated with an increase in the Ca/P ratio from 1.49 to 1.63, consistent with a loss of nonapatitic calcium. The results indicate that vascular calcification persists after reversal of uremia, because of a lack of active resorption of apatite. This failure to resorb established calcifications may contribute to the severity of vascular calcification and suggests that therapy should be aimed at prevention., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Summary: Calcium supplements have been associated with increased cardiovascular risk, but the mechanism is unknown. We investigated the effects of calcium supplements on the propensity of serum to calcify, based on the transition time of primary to secondary calciprotein particles (T50). Changes in serum calcium were related to changes in T50., Introduction: Calcium supplements have been associated with increased cardiovascular risk; however, it is unknown whether this is related to an increase in vascular calcification., Methods: We investigated the acute and 3-month effects of calcium supplements on the propensity of serum to calcify, based on the transition time of primary to secondary calciprotein particles (T50), and on three possible regulators of calcification: fetuin-A, pyrophosphate and fibroblast growth factor-23 (FGF23). We randomized 41 postmenopausal women to 1 g/day of calcium as carbonate, or to a placebo containing no calcium. Measurements were performed at baseline and then 4 and 8 h after their first dose, and after 3 months of supplementation. Fetuin-A, pyrophosphate and FGF23 were measured in the first 10 participants allocated to calcium carbonate and placebo who completed the study., Results: T50 declined in both groups, the changes tending to be greater in the calcium group. Pyrophosphate declined from baseline in the placebo group at 4 h and was different from the calcium group at this time point (p = 0.04). There were no other significant between-groups differences. The changes in serum total calcium from baseline were significantly related to changes in T50 at 4 h (r = -0.32, p = 0.05) and 8 h (r = -0.39, p = 0.01), to fetuin-A at 3 months (r = 0.57, p = 0.01) and to pyrophosphate at 4 h (r = 0.61, p = 0.02)., Conclusions: These correlative findings suggest that serum calcium concentrations modulate the propensity of serum to calcify (T50), and possibly produce counter-regulatory changes in pyrophosphate and fetuin-A. This provides a possible mechanism by which calcium supplements might influence vascular calcification.

Background: Matrix Gla protein is a vitamin K-dependent inhibitor of vascular calcification. Warfarin use is associated with increased breast arterial calcification, but whether this is reflective of other arteries or occurs in men is unclear. In this study, the prevalence of calcification in peripheral arteries was compared in patients with and without warfarin therapy., Methods and Results: This retrospective matched cohort study assessed 430 patients with radiographs performed during or after warfarin therapy who were identified by a computerized search of medical records. Each patient was matched to a patient without warfarin exposure based on age, sex, and diabetes status. Patients with warfarin exposure <1 month, history of end-stage renal disease, or serum creatinine >2.0 mg/dl were excluded. Radiographs were reviewed visually for arterial calcification. The prevalence of arterial calcification was 44% greater in patients with versus without warfarin use (30.2% versus 20.9%, P=0.0023) but not on radiographs performed before warfarin therapy (26.4% versus 22.4%, n=156) or prior to 5 years of warfarin therapy. The increase was noted only in the ankle and foot, was limited to a medial pattern of calcification, and was similar in men and women., Conclusions: Warfarin use is associated with lower extremity arterial calcification in both men and women independent of age, sex, diabetes status, and other patient characteristics. This may have implications for the choice of therapies for long-term anticoagulation., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Hypocalcemia is common in advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD), and it is standard practice to correct this back to the normal range, presumably to prevent symptomatic hypocalcemia and help control hyperparathyroidism. However, there are few studies to support this approach, and recent data suggest that this promotes vascular calcification and adynamic bone disease. Whether setting a lower target will improve outcomes has not been tested, but existing data suggest that this may have minimal risks and substantial potential benefits and should be explored., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The presence of bone tissue in calcified arteries may provide insights into the pathophysiology and potential reversibility of calcification, but the prevalence, distribution, and determinants of bone and osteoclasts in calcified arteries are unknown. Specimens of 386 arteries from lower limb amputations in 108 patients were examined retrospectively. Calcification was present in 282 arteries from 89 patients, which was medial in 64%, intimal in 9%, and both in 27%. Bone was present in 6% of arteries, essentially all of which were heavily calcified. Multiple sampling revealed that the true prevalence of bone in heavily calcified arteries was 25%. Bone was more common in medial rather than intimal calcifications (10% vs 3%, p=0.03) but did not vary with artery location (above vs below the knee). Heavily calcified arteries with bone were more likely to come from patients who were older (p=0.04), had diabetes (p=0.06), or were receiving warfarin (p=0.06), but there was no association with gender or renal failure. Bone was almost always adjacent to calcifications, along the periphery, but never within. Staining for the bone-specific proteins osteocalcin and osterix was noted in 20% and 45% of heavily calcified arteries without visible bone. Osteoclasts were present in 4.9% of arteries, all of which were heavily calcified and most of which contained bone. The frequent absence of bone in heavily calcified vessels and the histologic pattern strongly suggests a secondary rather than primary event. Recruitment of osteoclasts to vascular calcifications can occur but is rare, suggesting a limited capacity to reverse calcifications., (© The Author(s) 2015.)

Autosomal dominant polycystic kidney disease (ADPKD) is marked by gradual renal cyst and kidney enlargement and ultimately renal failure. Magnetic resonance-based, height-adjusted total kidney volume (htTKV) over 600 cc/m predicts the development of CKD stage 3 within 8 years in the Consortium for Radiologic Imaging in Polycystic Kidney Disease cohort. Here we compared simultaneous ultrasound and magnetic resonance imaging to determine whether ultrasound and kidney length (KL) predict future CKD stage 3 over longer periods of follow-up. A total of 241 ADPKD patients, 15-46 years, with creatinine clearance of 70 ml/min and above had iothalamate clearance, magnetic resonance, and ultrasound evaluations. Participants underwent an average of five repeat clearance measurements over a mean follow-up of 9.3 years. Ultrasound and magnetic resonance-based TKV and KL were compared using Bland-Altman plots and intraclass correlations. Each measure was tested to predict future CKD stage 3. Relatively strong intraclass correlations between ultrasound and magnetic resonance were found for both htTKV and KL (0.81 and 0.85, respectively). Ultrasound and magnetic resonance-based htTKV and KL predicted future CKD stage 3 similarly (AUC of 0.87, 0.88, 0.87, and 0.88, respectively). An ultrasound kidney length over 16.5 cm and htTKV over 650 ml/min had the best cut point for predicting the development of CKD stage 3. Thus, kidney length alone is sufficient to stratify the risk of progression to renal insufficiency early in ADPKD using either ultrasound or magnetic resonance imaging.

Medial vascular calcification (MVC) is a pathological phenomenon that causes vascular stiffening and can lead to heart failure; it is common to a variety of conditions, including aging, chronic kidney disease, diabetes, obesity, and a variety of rare genetic diseases. These conditions share the common feature of tissue-nonspecific alkaline phosphatase (TNAP) upregulation in the vasculature. To evaluate the role of TNAP in MVC, we developed a mouse model that overexpresses human TNAP in vascular smooth muscle cells in an X-linked manner. Hemizygous overexpressor male mice (Tagln-Cre(+/-) ; Hprt(ALPL) (/Y) or TNAP-OE) show extensive vascular calcification, high blood pressure, and cardiac hypertrophy, and have a median age of death of 44 days, whereas the cardiovascular phenotype is much less pronounced and life expectancy is longer in heterozygous (Tagln-Cre(+/-) ; Hprt(ALPL) (/-) ) female TNAP-OE mice. Gene expression analysis showed upregulation of osteoblast and chondrocyte markers and decreased expression of vascular smooth muscle markers in the aortas of TNAP-OE mice. Through medicinal chemistry efforts, we developed inhibitors of TNAP with drug-like pharmacokinetic characteristics. TNAP-OE mice were treated with the prototypical TNAP inhibitor SBI-425 or vehicle to evaluate the feasibility of TNAP inhibition in vivo. Treatment with this inhibitor significantly reduced aortic calcification and cardiac hypertrophy, and extended lifespan over vehicle-treated controls, in the absence of secondary effects on the skeleton. This study shows that TNAP in the vasculature contributes to the pathology of MVC and that it is a druggable target., (© 2014 American Society for Bone and Mineral Research.)

Objective: The histopathology of peripheral arterial disease and the accompanying calcification are poorly defined, and it is not known whether this varies according to different risk factors., Approach and Results: Sections from 176 upper and lower leg arteries were examined histologically in specimens from amputations of 60 patients with peripheral arterial disease, of whom 58% had diabetes mellitus, 35% had end-stage renal disease, and 48% had a history of smoking. The most common findings were calcification of the media (72% of arteries) and intimal thickening without lipid (68% of arteries), with the presence of atheromas in only 23% of arteries. Intimal calcification occurred in 43% and was generally much less extensive than medial calcification. Nonatheromatous intimal thickening was frequently severe, resulting in complete occlusion in some vessels. The absence of lipid and macrophages was confirmed by staining with oil red O and staining for CD68. Other than a greater prevalence and severity of medial calcification in end-stage renal disease, the findings did not differ between diabetics, patients with end-stage renal disease, or smokers., Conclusions: The results indicate that the majority of arteries in patients with peripheral arterial disease have a vascular lesion that is distinct from atherosclerosis, suggesting a different pathogenesis. This pattern does not differ substantially between patients with different risk factors for peripheral arterial disease. The bulk of vascular calcification in the lower extremities is medial rather than intimal., (© 2014 American Heart Association, Inc.)

Medial arterial calcification is common in advanced kidney disease but its impact on cardiovascular disease is uncertain because imaging techniques used to date cannot reliably distinguish it from atherosclerotic calcification. We have previously shown that breast arterial calcification (BAC) is exclusively medial and is a marker of generalized medial calcification in end-stage renal disease (ESRD). Therefore, the presence of BAC on mammograms in 202 women with ESRD (mean duration 4.1 years) was correlated with cardiovascular events to determine the clinical significance of medial arterial calcification. BAC was found in 58% of the study participants and was significantly associated with age, diabetes, and ESRD duration. Both coronary artery (27 vs. 15%) and peripheral arterial disease (PAD; 19 vs. 4%) were more likely in patients with BAC but only the latter persisted after accounting for other factors (odds ratio 4.6; 95% confidence interval 1.2-15). In 142 women without clinical events before mammography, BAC was associated with a greater incidence of new PAD events (13 vs. 3%) but not coronary artery disease events (11 vs. 11%). Thus, BAC is strongly and independently associated with PAD in women with ESRD and may be predictive of clinical events. This suggests that medial arterial calcification is a clinically significant lesion that may contribute to the accelerated PAD in ESRD.

Objective: Matrix gla protein is a vitamin K-dependent inhibitor of medial arterial calcification whose synthesis and activity are blocked by warfarin. Warfarin induces arterial calcification in experimental models, but whether this occurs in humans is unclear. This was addressed by examining breast arterial calcification, which is exclusively medial and easily identified on mammograms., Approach and Results: Screening mammograms from women with current, past, or future warfarin use were examined for the presence of arterial calcification and compared with mammograms obtained in untreated women matched for age and diabetes mellitus. Women with a serum creatinine >2.0 mg/dL or a history of end-stage renal disease were excluded. In 451 women with mammograms performed after ≥1 month of warfarin therapy, the prevalence of arterial calcification was 50% greater than in 451 untreated women (39.0% versus 25.9%; P<0.0001). However, in 159 mammograms performed before warfarin therapy, the prevalence of arterial calcification was not increased (26.4% versus 25.8%). The increased prevalence varied with duration of treatment, from 25.0% for <1 year to 74.4% for >5 years. In a multivariable logistic model, only age and duration of warfarin, but not the period of time after stopping warfarin, were significant determinants of arterial calcification in women with current or past warfarin use., Conclusions: The prevalence of breast arterial calcification is increased in women with current or past warfarin use independent of other risk factors and conditions predating warfarin use. This effect appears to be cumulative and may be irreversible., (© 2014 American Heart Association, Inc.)

Plasma levels of pyrophosphate, an endogenous inhibitor of vascular calcification, are reduced in end-stage renal disease and correlate inversely with arterial calcification. However, it is not known whether the low plasma levels are directly pathogenic or are merely a marker of reduced tissue levels. This was tested in an animal model in which aortas were transplanted between normal mice and Enpp1(-/-) mice lacking ectonucleotide pyrophosphatase phosphodiesterase, the enzyme that synthesizes extracellular pyrophosphate. Enpp1(-/-) mice had very low plasma pyrophosphate and developed aortic calcification by 2 months that was greatly accelerated with a high-phosphate diet. Aortas of Enpp1(-/-) mice showed no further calcification after transplantation into wild-type mice fed a high-phosphate diet. Aorta allografts of wild-type mice calcified in Enpp1(-/-) mice but less so than the adjacent recipient Enpp1(-/-) aorta. Donor and recipient aortic calcium contents did not differ in transplants between wild-type and Enpp1(-/-) mice, demonstrating that transplantation per se did not affect calcification. Histology revealed medial calcification with no signs of rejection. Thus, normal levels of extracellular pyrophosphate are sufficient to prevent vascular calcification, and systemic Enpp1 deficiency is sufficient to produce vascular calcification despite normal vascular extracellular pyrophosphate production. This establishes an important role for circulating extracellular pyrophosphate in preventing vascular calcification.

Although kidney size can be important in the evaluation of renal disease, it has not been carefully studied and true volume is rarely measured, and good normative data are lacking. Wang et al. measured both cortical and medullary volumes in potential transplant donors and correlate these with physiologic, morphometric, and metabolic parameters. The results reveal interesting and potentially important correlations and differential responses between the two compartments, providing a framework for future investigation.

The pathophysiology of medial arterial calcification in chronic kidney disease (CKD) is unclear but has been ascribed to phenotypic changes in vascular smooth muscle, possibly in conjunction with intimal proliferation and atherosclerosis. As the prevalence of calcification in breast arteries is increased in women with CKD and end-stage renal disease (ESRD), this was examined histologically in mastectomy specimens from 19 women with CKD or ESRD. Arterial calcification was present in 18, was exclusively medial, and occurred in vessels as small as arterioles. Intimal thickening was common but unrelated to calcification. There was no evidence of atherosclerosis. The earliest calcification presented as small punctate lesions scattered throughout the media, often with calcification of the internal elastic lamina. Arterial calcification was present in all samples from an age- and diabetes-matched cohort without CKD but was much milder. While smooth muscle cell density was reduced one-third in arteries from patients with ESRD, the cells appeared normal, expressed SM22α, and exhibited no apoptosis. Staining for the bone-specific protein osteocalcin, the osteoblastic transcription factors Runx2 or osterix, or the chondrocytic transcription factor SOX9 was absent in regions of early calcification. Thus, medial calcification in breast arteries of patients with CKD can occur in the absence of smooth muscle cell apoptosis and/or osteogenic transdifferentiation. This suggests that the pathologic mineralization process may differ from one arterial type to the other.

Ultrasound is commonly used in nephrology for diagnostic studies of the kidneys and lower urinary tract and to guide percutaneous procedures, such as insertion of hemodialysis catheters and kidney biopsy. Nephrologists must, therefore, have a thorough understanding of renal anatomy and the sonographic appearance of normal kidneys and lower urinary tract, and they must be able to recognize common abnormalities. Proper interpretation requires correlation with the clinical scenario. With the advent of affordable, portable scanners, sonography has become a procedure that can be performed by nephrologists, and both training and certification in renal ultrasonography are available.

Objective: Calcitriol and various analogs are commonly used to suppress secondary hyperparathyroidism in chronic kidney disease but may also exacerbate vascular calcification. Although this could be because of increased intestinal calcium and phosphate absorption, direct effects through vitamin D receptors (VDRs) on vascular smooth muscle have also been proposed., Approach and Results: The role of these receptors was investigated by examining gene regulation in rat aortas treated with calcitriol ex vivo and in vivo and by transplanting aortas from VDR-null (VDR(-/-)) mice into wild-type mice before induction of uremia and treatment with calcitriol. In cultured rat aortas, calcitriol increased the expression of mRNA for CYP24A1 but not mRNA for any bone-related or calcification-related genes. Gene expression in aortas in vivo was not altered by doses of calcitriol that promote calcification. Calcitriol markedly increased aortic calcification in uremic mice and this did not differ between VDR(-/-) aortic allografts and VDR(+/+) recipient aortas., Conclusions: Calcitriol promotes vascular calcification through a systemic action rather than through a direct vascular action.

Background: Thiosulfate has been shown to inhibit vascular calcification in uremic rats and may inhibit calcification in humans with end-stage renal disease but whether this is due to a systemic or local action is unknown. The underlying mechanism is also unclear but complexation of calcium ions has been proposed., Methods: In vitro assays were used to determine the effect of thiosulfate on vascular calcification and hydroxyapatite formation., Results: Thiosulfate (EC50: 1-2 mM) prevented calcification of injured or devitalized aortas but not uninjured aortas, and similar results were obtained with sulfate. There was no effect on reversal of calcification. Measurements with an ion-sensitive electrode (corrected for changes in ionic strength) revealed a very weak interaction between thiosulfate and Ca(2+) (K(a) = 10.9 ± 1.0 × 10(-6) M(-1)) that resulted in a 4% decrease in ionized Ca(2+) in culture medium at 5 mM thiosulfate and a corresponding 5% increase in the solubility product for calcium-phosphate. Adjustment of the total Ca(2+) concentration to account for this did not prevent the inhibition of aortic calcification by thiosulfate. Thiosulfate did not inhibit hydroxyapatite formation from seed crystals or the calcification of purified elastin and did not alter medium pH., Conclusions: Thiosulfate inhibits vascular calcification at millimolar concentrations through a direct extracellular effect that does not require intact smooth muscle cells but is related to cellular injury. This effect is not specific for thiosulfate since sulfate has similar properties. Inhibition cannot be explained by effects on ionized calcium, calcium-phosphate solubility, pH, oxidative stress or hydroxyapatite formation.

Background and Objectives: CKD is a risk factor for medial artery calcification, but the CKD stage at which this risk begins is unknown. Because breast arterial calcification (BAC) is a marker of generalized medial arterial calcification, mammography was used to detect medial arterial calcification in women with different CKD stages., Design, Setting, Participants, & Measurements: This was a retrospective, cross-sectional study of women with and without CKD matched for age and diabetes and identified from mammograms obtained in 2006-2011. BAC was scored as present or absent per visual inspection., Results: A total of 146 women with stage 3 CKD and 54 with stage 4/5 CKD were identified. An additional 21 patients with ESRD were identified and added to a previous cohort of 71 patients. Mean age was 64 years for CKD 3, 63 for CKD 4, and 59 for ESRD. Half of each group had diabetes. Compared with controls, the odds ratios for BAC were 1.44 in CKD 3 (95% confidence interval [CI], 0.82-2.53), 2.69 in CKD 4 (95% CI, 1.14-6.33), and 7.19 in ESRD (95% CI, 3.77-13.7) and did not differ with diabetic status or race. In a multivariable logistic model, age (P<0.001) and estimated GFR (P=0.005) were independent predictors of BAC. The odds ratio for BAC increased 4% for each milliliter per minute per 1.73 m(2) decrease in estimated GFR. The prevalence of BAC in CKD was increased in each decade of age over 49 years., Conclusions: CKD is an independent risk factor for medial arterial calcification.