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.Kidney International advance online publication, 1 April 2015; doi:10.1038/ki.2015.71.
Matrix Gla protein (MGP) is an inhibitor of vascular calcification but its mechanism of action and pathogenic role are unclear. This was examined in cultured rat aortas and in a model of vascular calcification in rats with renal failure. Both carboxylated (GlaMGP) and uncarboxylated (GluMGP) forms were present in aorta and disappeared during culture with warfarin. MGP was also released into the medium and removed by ultracentrifugation, and similarly affected by warfarin. In a high-phosphate medium, warfarin increased aortic calcification but only in the absence of pyrophosphate, another endogenous inhibitor of vascular calcification. Although GlaMGP binds and inactivates bone morphogenic protein (BMP)-2, a proposed mediator of vascular calcification through up-regulation of the osteogenic transcription factor runx2, neither warfarin, BMP-2, nor the BMP-2 antagonist noggin altered runx2 mRNA content in aortas, and noggin did not prevent warfarin-induced calcification. Aortic content of MGP mRNA was increased 5-fold in renal failure but did not differ between calcified and noncalcified aortas. Immunoblots showed increased GlaMGP in noncalcified (5-fold) and calcified (20-fold) aortas from rats with renal failure, with similar increases in GluMGP. We conclude that rat aortic smooth muscle produces both GlaMGP and GluMGP in tissue-bound and soluble, presumably vesicular, forms. MGP inhibits calcification independent of BMP-2-driven osteogenesis and only in the absence of pyrophosphate, consistent with direct inhibition of hydroxyapatite formation. Synthesis of MGP is increased in renal failure and deficiency of GlaMGP is not a primary cause of medial calcification in this condition.
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 m2) and 137 subjects with CKD (eGFR < 90 ml/min per 1.73 m2). 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 m2 (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.
The relationship between kidney function and liver function has been investigated largely in the context of pathologic changes in advanced liver failure, and little is known about any physiologic responses to hepatic failure. Because both organs are responsible for clearing metabolic by-products, there may be renal compensation for decreased hepatic clearance. This possibility is supported by the fact that both kidney size and glomerular filtration rate vary with other alterations in metabolic demand, such as changes in body size or protein intake.1, 2 Our frequent finding of large kidneys during sonography in patients with end-stage liver disease supported the possibility that renal hypertrophy was occurring. This was investigated by measuring renal parenchymal volume (RPV) on computed tomography scans and examining autopsy findings in patients with or without end-stage liver disease and no clinical or radiologic evidence of intrinsic renal disease.
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.
Background and objectives: The significance of renal parenchymal volume and the factors that influence it are poorly understood.
Design, setting, participants, & measurements: Renal parenchymal volume (RPV) was measured on contrast-enhanced CT scans after exclusion of sinus fat and vessels in 224 healthy subjects evaluated as kidney donors and in a separate cohort of 22 severely obese individuals before and after 6 months of weight loss. GFR was measured by iohexol clearance in 76 of the transplant donors. RPV was correlated with age, GFR, and various anthropometric parameters.
Results: In potential transplant donors, RPV correlated with body surface area (BSA; r = 0.68) and was 7% larger in men but did not vary with age or race. Gender and body size were independent determinants of RPV. RPV correlated well with GFR (r = 0.62) and accounted for almost all of the variability in a model of GFR that included age, race, gender, and body surface area. GFR correlated more strongly with RPV than with creatinine-based equations. The same relationship between RPV and BSA was observed in obesity, and RPV decreased with weight loss.
Conclusions: In healthy adults younger than 65 years, renal parenchymal volume is governed by body size and gender but not age or race and is strongly correlated with GFR. This indicates that renal parenchymal volume varies to meet metabolic demand and is closely linked to renal function.
Background and objectives: Because previous studies have not distinguished between intimal (atherosclerotic) and medial vascular calcification, the prevalence and clinical significance of either condition in chronic or end-stage kidney disease (CKD or ESKD) are unknown. We hypothesized that breast arterial calcification (BAC) is exclusively medial and that mammography can serve as a useful marker of generalized medial calcification in CKD and ESKD.
Design, setting, participants, & measurements: Arterial calcification was identified histologically in breast tissue or visually in mammograms and radiographs of extremities from patients with CKD or ESKD.
Results: Medial calcification but no intimal calcification was present in all 16 specimens from patients with CKD or ESKD. In 71 women with ESKD, BAC was present on mammograms in 63% compared with 17% in women without renal insufficiency matched for age, race, and diabetes (P < 0.001). Age and ESKD duration were significant, independent predictors of BAC. BAC was also present in 36% of mammograms from the same patients performed 5.5 ± 0.7 years before the onset of ESKD (P < 0.05 versus control) but in only 14% of patients with stage 3 CKD. Comparison of mammograms and extremity radiographs revealed that BAC was present in over 90% of patients with peripheral arterial calcification (PAC), and PAC was observed in less than 6% of patients without BAC.
Conclusions: BAC is a specific and useful marker of medial vascular calcification in CKD, and its prevalence is markedly increased in ESKD and advanced CKD.
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 m2 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.
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 Ca2+ (Ka = 10.9 ± 1.0 × 10−6 M−1) that resulted in a 4% decrease in ionized Ca2+ in culture medium at 5 mM thiosulfate and a corresponding 5% increase in the solubility product for calcium–phosphate. Adjustment of the total Ca2+ 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.
Extracellular inorganic pyrophosphate (ePPi) is an important endogenous inhibitor of vascular calcification, but it is not known whether systemic or local vascular PPi metabolism controls calcification. To determine the role of ePPi in vascular smooth muscle, we identified the pathways responsible for ePPi production and hydrolysis in rat and mouse aortas and manipulated them to demonstrate their role in the calcification of isolated aortas in culture. Rat and mouse aortas contained mRNA for ectonucleotide pyrophosphatase/phosphodiesterases (NPP1–3), the putative PPi transporter ANK, and tissue-nonspecific alkaline phosphatase (TNAP). Synthesis of PPi from ATP in aortas was blocked by β,γ-methylene-ATP, an inhibitor of NPPs. Aortas from mice lacking NPP1 (Enpp1−/−) did not synthesize PPi from ATP and exhibited increased calcification in culture. Although ANK-mediated transport of PPi could not be demonstrated in aortas, aortas from mutant (ank/ank) mice calcified more in culture than did aortas from normal (ANK/ANK) mice. Hydrolysis of PPi was reduced 25% by β,γ-methylene-ATP and 50% by inhibition of TNAP. Hydrolysis of PPi was increased in cells overexpressing TNAP or NPP3 but not NPP1 and was not reduced in Enpp1−/− aortas. Overexpression of TNAP increased calcification of cultured aortas. The results show that smooth muscle NPP1 and TNAP control vascular calcification through effects on synthesis and hydrolysis of ePPi, indicating an important inhibitory role of locally produced PPi. Smooth muscle ANK also affects calcification, but this may not be mediated through transport of PPi. NPP3 is identified as an additional pyrophosphatase that could influence vascular calcification.