Proprotein convertase subtilisin/kexin type 9 targets megalin in the kidney proximal tubule and aggravates proteinuria in nephrotic syndrome.

Proteinuria is a prominent feature of chronic kidney disease. Interventions that reduce proteinuria slow the progression of chronic kidney disease and the associated risk of cardiovascular disease. Here, we propose a mechanistic coupling between proteinuria and proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulator of cholesterol and a therapeutic target in cardiovascular disease. PCSK9 undergoes glomerular filtration and is captured by megalin, the receptor responsible for driving protein reabsorption in the proximal tubule. Accordingly, megalin-deficient mice and patients carrying megalin pathogenic variants (Donnai Barrow syndrome) were characterized by elevated urinary PCSK9 excretion. Interestingly, PCSK9 knockout mice displayed increased kidney megalin while PCSK9 overexpression resulted in its reduction. Furthermore, PCSK9 promoted trafficking of megalin to lysosomes in cultured proximal tubule cells, suggesting that PCSK9 is a negative regulator of megalin. This effect can be accelerated under disease conditions since either genetic destruction of the glomerular filtration barrier in podocin knockout mice or minimal change disease (a common cause of nephrotic syndrome) in patients resulted in enhanced tubular PCSK9 uptake and urinary PCSK9 excretion. Pharmacological PCSK9 inhibition increased kidney megalin while reducing urinary albumin excretion in nephrotic mice. Thus, glomerular damage increases filtration of PCSK9 and concomitantly megalin degradation, resulting in escalated proteinuria.

In a real-life setting, risk factors, coronary artery calcium score, and coronary stenosis at computed tomography angiography are associated with major adverse cardiovascular events and all-cause mortality among kidney transplant candidates.

Kidney failure is associated with an increased risk of cardiovascular disease and death. This single-center, a retrospective study evaluated the association between risk factors, coronary artery calcium score (CACS), coronary computed tomography angiography (CTA), major adverse cardiovascular events (MACEs), and all-cause mortality in kidney transplant candidates. Data on clinical risk factors, MACE, and all-cause mortality were collected from patient records. A total of 529 kidney transplant candidates were included (median follow-up of 4.7 years). CACS was evaluated in 437 patients and CTA in 411. Both the presence of ≥3 risk factors, CACS of ≥400, as well as multiple-vessel stenoses or left main artery disease predicted MACE (hazard ratio, 2.09; [95% confidence interval, 1.35-3.23]; 4.65 [2.20-9.82]; 3.70 [1.81-7.57]; 4.90 [2.40-10.01]) and all-cause mortality (harad ratio, 4.44; [95% confidence interval, 2.54-7.76]; 4.47 [2.22-9.02]; 2.82 [1.34-5.94]; 5.41 [2.81-10.41]) in univariate analyses. Among patients eligible for CACS and CTA (n = 376), only CACS and CTA were associated with both MACE and all-cause mortality. In conclusion, risk factors, CACS, and CTA provide information on the risk of MACE and mortality in kidney transplant candidates. An additional value of CACS and CTA compared with risk factors was observed for the prediction of MACE in a subpopulation undergoing both CACS and CTA.

Patient-reported outcome (PRO) measurements in chronic and malignant diseases: ten years' experience with PRO-algorithm-based patient-clinician interaction (telePRO) in AmbuFlex.

BACKGROUND: Patient-reported Outcome (PRO) measures may be used as the basis for out-patient follow-up instead of fixed appointments. The patients attend follow-up from home by filling in questionnaires developed for that specific aim and patient group (telePRO). The questionnaires are handled in real time by a specific algorithm, which assigns an outcome color reflecting clinical need. The specific questionnaires and algorithms (named solutions) are constructed in a consensus process with clinicians. We aimed to describe AmbuFlex' telePRO solutions and the algorithm outcomes and variation between patient groups, and to discuss possible applications and challenges. METHODS: TelePRO solutions with more than 100 processed questionnaires were included in the analysis. Data were retrieved together with data from national registers. Characteristics of patients, questionnaires and outcomes were tabulated for each solution. Graphs were constructed depicting the overall and within-patient distribution of algorithm outcomes for each solution. RESULTS: From 2011 to 2021, 29 specific telePRO solutions were implemented within 24 different ICD-10 groups. A total of 42,015 patients were referred and answered 171,268 questionnaires. An existing applicable instrument with cut-off values was available for four solutions, whereas items were selected or developed ad hoc for the other solutions. Mean age ranged from 10.7 (Pain in children) to 73.3 years (chronic kidney disease). Mortality among referred patients varied between 0 (obesity, asthma, endometriosis and pain in children) and 528 per 1000 patient years (Lung cancer). There was substantial variation in algorithm outcome across patient groups while different solutions within the same patient group varied little. DISCUSSION: TelePRO can be applied in diseases where PRO can reflect clinical status and needs. Questionnaires and algorithms should be adapted for the specific patient groups and clinical aims. When PRO is used as replacement for clinical contact, special carefulness should be observed with respect to patient safety.

Increasing incidence and improved survival in ANCA-associated vasculitis-a Danish nationwide study.

BACKGROUND: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) carries a high risk of morbidity and mortality, with outcomes modified by treatment and an incidence that may be increasing. We examined temporal changes in incidence and mortality during 2000-15 using nationwide healthcare registries. METHODS: Patients with incident AAV were identified using International Classification of Diseases Version 10 (ICD10) codes and grouped according to inclusion year (Period 1: 2000-04, Period 2: 2005-09, Period 3: 2010-15). Log link cumulative incidence regression adjusted for age, sex, renal function, cardiovascular disease, diabetes, hypertension and advanced disease severity were used to model survival. RESULTS: We identified 1631 patients (52% male), corresponding to an incidence of 18.5 persons/million/year (Period 1: 15.1, Period 2: 18.5, Period 3: 21.4). The slope of incident serologic ANCA testing was steeper than that of AAV (P = 0.002). Mean [standard deviation (SD)] age was 60.2 (16.7) years and mean (SD) follow-up was 6.8 (4.7) years. A total of 571 (35%) patients died (5-year mortality of 22.1%), with an absolute risk ratio (ARR) for Periods 2 and 3 compared with Period 1 of 0.80 [confidence interval (CI) 0.65-0.98, P = 0.031] and 0.39 (CI 0.31-0.50, P < 0.001). About 274 patients developed end-stage renal disease (ESRD) [16.8% (Period 1: 23.3%, Period 2: 17.6%, Period 3: 12.5%)], with ARR decreasing over time: Period 2 0.61 (CI 0.42-0.87, P = 0.007) and Period 3 0.57 (CI 0.39-0.83, P = 0.003). The overall risk of death associated with ESRD or chronic kidney disease was 1.74 (CI 1.29-2.37, P < 0.001) and 1.58 (CI 1.21-2.07, P < 0.001). CONCLUSIONS: Incidence of ANCA testing and AAV diagnosis increased over the test period. Falls over time in mortality and ESRD risk may relate to earlier diagnosis and changes in treatment practice.

Urine soluble CD163 (sCD163) as biomarker in glomerulonephritis: stability, reference interval and diagnostic performance.

OBJECTIVES: Soluble (s) CD163 is a well-established macrophage biomarker, and recent data suggests urine sCD163 to reflect disease activity in crescentic glomerulonephritis (GN). Other types of GN may also be associated with glomerular inflammation but the potential usefulness of urine sCD163 as a general biomarker of GN remains unaddressed. METHODS: An in-house sCD163 enzyme-linked immunosorbent assay (ELISA) was validated for urinary use and compared to a frequently used commercial ELISA. The pre-analytical stability of urine sCD163 was assessed and a reference interval was established according to the CLSI guidelines using specimens from 253 healthy individuals. Urine samples from 64 patients with different types of renal disorders were also analysed. RESULTS: Urine sCD163 was highly stable during storage. An upper reference limit of 5.1 µg/L (1.9 µg/mmol, normalised to creatinine) was established using the in-house ELISA. Urine sCD163 was generally increased in GN patients (3.9 µg/mmol, p<0.0001, AUROC=0.97) and decreased upon treatment, but did not perform better than urine albumin (AUROC=1.00). Patients with proliferative GN had higher urine sCD163/albumin (p=0.0001) ratio. The commercial assay had a higher detection limit, and patient levels were 4-6 times lower than in the in-house assay. CONCLUSIONS: Urine sCD163 is a stable biomarker that can be measured with acceptable accuracy using our in-house ELISA. Its pre-analytical characteristics makes it a reliable biomarker and our findings point towards the use of urine sCD163 as a biomarker of specific subtypes of GN.

Sex Differences in the Association Between Bone Mineral Density and Coronary Artery Disease in Patients Referred for Cardiac Computed Tomography.

Atherosclerosis and osteoporosis are both common and preventable diseases. Evidence supports a link between coronary artery disease (CAD) and low bone mineral density (BMD). This study aimed to assess the association between thoracic spine BMD and CAD in men and women with symptoms suggestive of CAD. This cross-sectional study included 1487 (mean age 57 years (range 40-80), 47% men) patients referred for cardiac computed tomography (CT). Agatston coronary artery calcium score (CACS), CAD severity (no, mild, moderate, and severe), vessel involvement (no, 1-, 2-, and 3/left main disease), and invasive measurements were evaluated. BMD of three thoracic vertebrae was measured using quantitative CT. We used the American college of radiology cut-off values for lumbar spine BMD to categorize patients into very low (<80 mg/cm3), low (80-120 mg/cm3), or normal BMD (>120 mg/cm3). BMD as a continuous variable was included in the linear regression analyses to assess associations between CACS (CACS=0, CACS 1- 399, and CACS ≥ 400) and BMD, and CAD severity and BMD. Significant lower BMD was present with increasing CACS and stenosis degree unadjusted. Multivariate linear regression analyses in women revealed a significant correlation between BMD and CACS groups (ß = -4.06, p<0.05), but no correlation between BMD and CAD severity (ß = -1.59, p = 0.14). No association was found between BMD and CACS (ß = -1.50, p = 0.36) and CAD severity (ß = 0.07, p = 0.94) in men. BMD is significantly correlated to CACS after adjusting for confounders in women, but not in men, suggesting a possible sex difference in pathophysiology.

Thoracic Bone Mineral Density Derived from Cardiac CT Is Associated with Greater Fracture Rate.

Background Osteoporosis is a prevalent, under-diagnosed, and treatable disease associated with increased fracture risk. Bone mineral density (BMD) derived from cardiac CT may be used to determine fracture rate. Purpose To assess the association between fracture rate and thoracic BMD derived from cardiac CT. Materials and Methods This prospective cohort study included consecutive participants referred for cardiac CT for evaluation of ischemic heart disease between September 2014 and March 2016. End of follow-up was June 30, 2018. In all participants, volumetric BMD of three thoracic vertebrae was measured by using quantitative CT software. The primary and secondary outcomes were any incident fracture and any incident osteoporosis-related fracture registered in the National Patient Registry, respectively. Hazard ratios were assessed by using BMD categorized as very low (<80 mg/cm3), low (80-120 mg/cm3), or normal (>120 mg/cm3). The study is registered at ClinicalTrials.gov (identifier: NCT02264717). Results In total, 1487 participants (mean age, 57 years ± 9; age range, 40-80 years; 52.5% women) were included, of whom 179 (12.0%) had very low BMD. During follow-up (median follow-up, 3.1 years; interquartile range, 2.7-3.4 years; range, 0.2-3.8 years), 80 of 1487 (5.3%) participants were diagnosed with an incident fracture and in 31 of 80 participants, the fracture was osteoporosis related. In unadjusted Cox regressions analyses, very low BMD was association with a greater rate of any fracture (hazard ratio, 2.6; 95% confidence interval [CI]: 1.4, 4.7; P = .002) and any osteoporosis-related fracture (hazard ratio, 8.1; 95% CI: 2.4, 26.7; P = .001) compared with normal BMD. After adjusting for age and sex, very low BMD remained associated with any fracture (hazard ratio, 2.1; 95% CI: 1.1, 4.2) and any osteoporosis-related fracture (hazard ratio, 4.0; 95% CI: 1.1, 14.6). Conclusion Routine cardiac CT can be used to help measure thoracic bone mineral density (BMD) to identify individuals who have low BMD and a greater fracture rate. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Bredella in this issue.

Association between circulating proprotein convertase subtilisin/kexin type 9 levels and prognosis in patients with severe chronic kidney disease.

BACKGROUND: Chronic kidney disease is a risk factor for premature development of coronary atherosclerosis and mortality. A high level of proprotein convertase subtilisin/kexin type 9 (PCSK9) is a recently recognized cardiovascular risk factor and has become the target of effective inhibitory treatment. In 167 kidney transplantation candidates, we aimed to: (i) compare levels of PCSK9 with those of healthy controls, (ii) examine the association between levels of PCSK9 and low-density lipoprotein cholesterol (LDL-c) and the degree of coronary artery disease (CAD) and (iii) evaluate if levels of PCSK9 predict major adverse cardiac events (MACE) and mortality. METHODS: Kidney transplant candidates (n = 167) underwent coronary computed tomography angiography (CCTA) and invasive coronary angiography (ICA) before transplantation. MACE and mortality data were extracted from the Western Denmark Heart Registry, a review of patient records and patient interviews. A group of 79 healthy subjects were used as controls. RESULTS: Mean PCSK9 levels did not differ between healthy controls and kidney transplant candidates. In patients not receiving lipid-lowering therapy, PCSK9 correlated positively with LDL-c (rho = 0.24, P < 0.05). Mean PCSK9 was similar in patients with and without obstructive CAD at both CCTA and ICA. In a multiple regression analysis, PCSK9 was associated with neither LDL-c (ß=-6.45, P = 0.44) nor coronary artery calcium score (ß=2.17, P = 0.84). During a follow-up of 3.7 years, PCSK9 levels were not associated with either MACE or mortality. CONCLUSIONS: The ability of PCSK9 levels to predict cardiovascular disease and prognosis does not seem to apply to a cohort of kidney transplant candidates.

Hemodynamic Response to Glucose-Insulin Infusion and Meals during Hemodialysis.

INTRODUCTION: Intradialytic nutrition may improve nutritional status and reduce mortality in patients on maintenance hemodialysis (HD) but has been associated with adverse events, mainly hemodynamic instability. Some dialysis centers therefore restrict intradialytic meals. In 2 clinical studies, we investigated the effects of intradialytic glucose-insulin infusion (GII) and meal intake on blood pressure (BP), pulse wave velocity (PWV), pulse wave analysis (PWA), and cardiac output (CO). PWA yielded augmentation index standardized with heart rate 75 (AIx@HR75). METHODS: In the GII study, 12 nondiabetic HD patients had BP, PWV, PWA, and CO measured during 3 HD sessions: standard HD, HD with glucose infusion, and HD with GII. In the Meal study, 12 nondiabetic patients had BP and PWA measured on 3 study days: meal alone (non-HD), meal and HD, 2 meals and HD. Twelve matched healthy controls completed the non-HD day. FINDINGS: In the GII study, glucose or GII had no additional effects on hemodynamic parameters compared with standard HD. HD resulted in a decrease in systolic BP of 13%, in diastolic BP of 9%, in AIx@HR75 of 17%, and CO of 18%. PWV was reduced by only 5%. In the Meal study, a meal alone did not change BP, whereas the combined influence of HD and meal intake reduced systolic BP with 22% and diastolic BP with 19%. Furthermore, AIx@HR75 decreased by 37% on HD days and by 36% in controls, but was unaffected on non-HD days. DISCUSSION: In the GII study, HD significantly reduced BP, AIx@75, and CO, whereas PWV remained almost constant. No additional effects were observed by concomitant GII during HD. BP reductions seemed larger in the Meal study compared with the GII study. Taken together, HD per se appears as the main discriminant for intradialytic hypotension but in hemodynamically unstable patients the timing and route of nutrition provision should be considered carefully.

Feasibility of Opportunistic Screening for Low Thoracic Bone Mineral Density in Patients Referred for Routine Cardiac CT.

Despite being a frequent and treatable disease, osteoporosis remains under-diagnosed worldwide. Our study aim was to characterize the bone mineral density (BMD) status in a group of patients with symptoms suggestive of coronary artery disease (CAD) with low/intermediate risk profile undergoing routine cardiac computed tomography (CT) to rule out CAD. This cross-sectional study used prospectively acquired data from a large consecutively included cohort. Participants were referred for cardiac CT based on symptoms of CAD. Quantitative CT (QCT) dedicated software was used to obtain BMD measurements in 3 vertebrae starting from the level of the left main coronary artery. We used the American College of Radiology cut-off values for lumbar spine QCT to categorize patients into very low (<80 mg/cm3), low (80-120 mg/cm3), or normal BMD (>120 mg/cm3). Analyses included 1487 patients. Mean age was 57 years (range 40-80), and 52% were women. The number of patients with very low BMD was 105 women (14%, 105/773) and 74 men (10%, 74/714). The majority of patients with very low BMD was not previously diagnosed with osteoporosis (87%) and received no anti-osteoporotic treatment (90%). Opportunistic screening in patients referred for cardiac CT revealed a substantial number of patients with very low BMD. The majority of these patients was not previously diagnosed with osteoporosis and received no anti-osteoporotic treatment. Identification of these patients could facilitate initiation of anti-osteoporotic treatment and reduce the occurrence of osteoporosis-related complications.

PR3-ANCA-associated vasculitis is associated with a specific motif in the peptide-binding cleft of HLA-DP molecules.

OBJECTIVES: This study aimed to characterize the association between HLA alleles and ANCA-associated vasculitis (AAV) in a genetically homogeneous population, and to analyse the contribution of specific HLA molecule amino acid sequences to the risk of AAV. METHODS: We included 187 Danish patients with AAV and 1070 healthy controls. All were HLA typed at two-field resolution. The association of HLA alleles to PR3- or MPO-AAV was analysed. The contribution of the dominant molecular motifs of the HLA-DPB1 molecule to the risk of AAV was investigated by association studies that included specific amino acid sequences of the hypervariable regions in exon 2. RESULTS: Ninety-four percent of patients with PR3-AAV were carriers of HLA-DPB1*04:01 while all patients with PR3-AAV were carriers of an HLA-DPB1*04 allele, and 85% were homozygous. This was significantly more than in the control group (P < 0.0001). The association was even stronger when HLA-DPB1*04:02 and -DPB1*23:01 were included. HLA-DPB1*04:01, -DPB1*04:02 and -DPB1*23:01 share amino acids in positions 8-9, 69, 76 and 84-87 within the hypervariable regions, but only positions 69 and 84-87 contributed significantly to the disease risk. HLA-DRB1*15 was associated with an increased risk of developing PR3-AAV, while HLA-DRB1*04, -DRB1*07 and -DQB1*03 were associated with a reduced risk of kidney involvement in PR3-AAV. MPO-AAV was only weakly associated with HLA class I alleles. CONCLUSION: PR3-AAV is strongly associated with the HLA-DPB1 alleles HLA-DPB1*04:01, -DPB1*04:02 and -DPB1*23:01, which share amino acid sequences crucial for the peptide-binding groove.

Aortic Calcification Affects Noninvasive Estimates of Central Blood Pressure in Patients with Severe Chronic Kidney Disease.

BACKGROUND: Central blood pressure (BP) assessed noninvasively considerably underestimates true invasively measured aortic BP in chronic kidney disease (CKD) patients. The difference between the estimated and the true aortic BP increases with decreasing estimated glomerular filtration rates (eGFR). The present study investigated whether aortic calcification affects noninvasive estimates of central BP. METHODS: Twenty-four patients with CKD stage 4-5 undergoing coronary angiography and an aortic computed tomography scan were included (63% males, age [mean ± SD ] 53 ± 11 years, and eGFR 9 ± 5 mL/min/1.73 m2). Invasive aortic BP was measured through the angiography catheter, while non-invasive central BP was obtained using radial artery tonometry with a SphygmoCor® device. The Agatston calcium score (CS) in the aorta was quantified on CT scans using the CS on CT scans. RESULTS: The invasive aortic systolic BP (SBP) was 152 ± 23 mm Hg, while the estimated central SBP was 133 ± 20 mm Hg. Ten patients had a CS of 0 in the aorta, while 14 patients had a CS >0 in the aorta. The estimated central SBP was lower than the invasive aortic SBP in patients with aortic calcification compared to patients without (mean difference 8 mm Hg, 95% CI 0.3-16; p = 0.04). The brachial SBP was lower than the aortic SBP in patients with aortic calcification compared to patients without (mean difference 10 mm Hg, 95% CI 2-19; p = 0.02). CONCLUSION: In patients with advanced CKD the presence of aortic calcification is associated with a higher difference between invasively measured central aortic BP and non-invasive estimates of central BP as compared to patients without calcifications.

Remote follow-up using patient-reported outcome measures in patients with chronic kidney disease: the PROKID study - study protocol for a non-inferiority pragmatic randomised controlled trial.

BACKGROUND: Outpatient care is steadily changing from hospital consultations to other platforms, such as phone consultation and online virtual clinics. It is prudent to maintain quality of care with such initiatives. Currently, patients with chronic kidney disease (CKD) have frequent scheduled visits, but it may be possible to optimise the frequency of hospital consultations using information from patient-reported outcome (PRO) questionnaires filled in at home (PRO-based follow-up). This approach may provide a more individually tailored follow-up based on actual needs for clinical attention. We aimed to evaluate the effectiveness of the quality of care, use of resources and patient outcomes associated with PRO-based follow-up in patients with CKD. METHODS: This study is a pragmatic, non-inferiority, randomised controlled trial in outpatients with CKD (Grove BE et al., Qual Life Res 27: S143, 2018). Newly referred patients with an estimated glomerular filtration rate (eGFR) of ≤40 ml/min 1.73m2 will be randomised to either: 1. PRO-based remote follow-up 2. PRO-based telephone consultation 3. Usual outpatient follow-up (control group) In the two intervention groups, a diagnosis-specific PRO questionnaire completed by the patient at home will substitute for usual outpatient follow-up visits. The PRO questionnaire will in part be used as a screening tool to identify patients in need of outpatient contact and to identify focus areas. Responses from the questionnaire will be processed according to a disease-specific algorithm and assigned green, yellow or red status according to patients' needs. The primary outcome will be loss of renal function evaluated by eGFR. Secondary outcomes are 1. Clinical outcomes, including initiation of acute dialyses, hospitalisation and mortality, 2. Utilisation of healthcare resources and 3. PRO measures, primarily quality of life (Euroqol EQ-5D) and illness perception (Brief Illness Perception Questionnaire (BIPQ). DISCUSSION: Benefits and possible drawbacks of the PRO-based follow-up will be evaluated. If PRO-based follow-up proves non-inferior to usual outpatient follow-up, a reorganisation of routine clinical practice in nephrology outpatient clinics may occur. Further, results may impact other patient groups with chronic conditions attending regular follow-up. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03847766 (Retrospectively registered on January 23, 2019).

Sclerostin is not associated with cardiovascular event or fracture in kidney transplantation candidates
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BACKGROUND: Sclerostin, a bone-derived protein, has been linked to cardiovascular calcifications in chronic kidney disease (CKD). The aim of this study was to investigate the associations between sclerostin and mineral and bone disorder in CKD, specifically whether sclerostin levels could predict cardiovascular event, fracture, or all-cause mortality. MATERIALS AND METHODS: Kidney transplantation candidates (n = 157) underwent computed tomography scans of the chest, abdomen, and pelvis. Calcification scores were calculated for coronary arteries, thoracic aorta, and the aortic and mitral valves. Volumetric bone mineral density (BMD) was measured at the spine and hip. Sclerostin and markers of bone turnover were determined from fasting blood samples. RESULTS: Compared to patients with a calcification score of 0, sclerostin levels were higher in patients with calcifications at the coronary arteries (+23%, p < 0.001) and the thoracic aorta (+27%, p = 0.001), but not in patients with calcifications at the aortic (+1%, p = 0.85) or mitral (+8%, p = 0.20) valves. During a median follow-up of 3.7 years, 28 patients had a major cardiovascular event, 19 patients sustained a fragility fracture, and 32 patients died. Sclerostin levels above the median did not predict major cardiovascular event (p = 0.15), fracture (p = 0.58), or mortality (p = 0.65). CONCLUSION: Sclerostin was positively associated with the presence of vascular calcifications, but was not predictive of events associated with mineral and bone disorder in a cohort of kidney transplantation candidates.
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Vertebral Bone Mineral Density Measured by Quantitative Computed Tomography With and Without a Calibration Phantom: A Comparison Between 2 Different Software Solutions.

Quantitative computed tomography (CT) can be used to quantify bone mineral density (BMD) in the spine from clinical CT scans. We aimed to determine agreement and precision of BMD measurements by 2 different methods: phantom-less internal tissue calibration and asynchronous phantom-based calibration in a cohort of patients with chronic kidney disease (CKD). Patients with CKD were recruited for CT angiography of the chest, abdomen, and pelvis. BMD was analyzed by 2 different software solutions using different calibration techniques; phantom-based by QCT Pro (Mindways Inc.) and phantom-less by Extended Brilliance Workspace (Philips Healthcare). Intraoperator reanalysis was performed on 53 patients (36%) for both methods. An interoperator reanalysis on 30 patients (20%) using the phantom-based method and 29 patients (19%) using the phantom-less method was made. XY- and Bland-Altman plots were used to evaluate method agreement. Phantom-based measured BMD was systematically higher than phantom-less measured BMD. Despite a small absolute difference of 3.3 mg/cm3 (CI: -0.2-6.9 mg/cm3) and a relative difference of 5.1% (CI: 2.2%-8.1%), interindividual differences were large, as seen by a wide prediction interval (PI: -47-40 mg/cm3). The Bland-Altman plot showed no systematic bias, apart from 5 outliers. Intraoperator variability was high for the phantom-less method (5.8%) compared to the phantom-based (0.8%) and the interoperator variability was also high for the phantom-less method (5.8%) compared to the phantom-based (1.8%). Despite high correlation between methods, the between-method difference on an individual level showed great variability. Our results suggest agreement between these 2 methods is insufficient to allow them to be used interchangeably in patients with CKD.

Postprandial Mineral Handling in Patients on Maintenance Hemodialysis.

OBJECTIVE: Patients on maintenance hemodialysis (HD) are unable to compensate for an enlarged mineral load with increased excretion of calcium and phosphate in the urine. Hence, excess calcium and phosphate must be neutralized by other mechanisms to avoid toxicity. The present study examined the acute handling of a mineral load in HD patients as compared with healthy subjects. DESIGN: Controlled intervention study. SUBJECTS: Twelve HD patients and 12 matched healthy subjects. INTERVENTION: After a weight-adjusted standardized meal, blood samples were collected for the following 9 hours for ionized calcium, phosphate, parathyroid hormone (PTH), and fibroblast growth factor-23 (FGF23). The fractional excretion of calcium and phosphate was measured in controls. The patients were not allowed to take phosphate binders 24 hours before the experiment, and the study was performed on a non-HD day. RESULTS: In healthy subjects, plasma calcium and phosphate did not change significantly from baseline, whereas HD patients demonstrated a decrease in plasma phosphate from 60 to 120 minutes by maximum 10% ([6; 13%], mean [95% confidence interval], P < .001) below baseline. PTH increased in both HD patients and controls and peaked 300 minutes after the meal 11% ([4; 19%], P < .004) above baseline in both groups. No changes in FGF23 were observed in HD patients, whereas FGF23 steadily decreased in controls, reaching nadir values at the end of the study 16% ([10; 21%], P < .001) below baseline. Control subjects demonstrated an immediate postprandial increase in the fractional excretion of both calcium and phosphate CONCLUSIONS: In HD patients, the mineral load paradoxically induced a decrease in plasma phosphate, whereas ionized calcium remained unchanged although PTH increased. These findings suggest that excess calcium and phosphate may be disposed of by mineral deposition, which may include soft tissue and vascular calcification.

Urine liver fatty acid binding protein and chronic kidney disease progression.

Excretion of the tubular protein liver fatty acid binding protein (L-FABP) is a potential novel biomarker of renal dysfunction. We examined whether urine L-FABP excretion adds prognostic information to the well-established risk markers, blood pressure (BP), albumin excretion and baseline GFR, regarding progression of chronic kidney disease (CKD). In a prospective study design a cohort of 74 stage 3-4 CKD patients (age 61 ± 13 years) were included. Glomerular filtration ratio (GFR, 51Cr-EDTA-clearance), 24-hour ambulatory BP, 24-hour urinary albumin/creatinine ratio (UAC) and urinary L-FABP/creatinine ratio (U-L-FABP/C) were determined at baseline and after 18 months of follow-up. For comparison 25 age-matched healthy controls were included. The U-L-FABP/C was elevated in CKD patients when compared to controls (mean U-L-FABP/C 2.3 [95% CI 1.7-2.9] µg/mmol vs 0.6 [0.5-0.7] µg/mmol, p < .001). In CKD patients, log U-L-FABP/C at baseline and at follow-up were positively associated (Pearson correlation coefficient r = 0.74, p < .001). Baseline log U-L-FABP/C was negatively correlated with baseline GFR (r = -0.32, p < .001) and directly correlated with UAC (r = 0.67, p < .001). The relative change in GFR from baseline to follow-up correlated with baseline UAC (p < .001), 24-hour systolic BP (p = 0.05) and log U-L-FABP/C (p < .001). Using multiple regression analysis adjusting for baseline GFR, UAC, BP, age and gender, baseline log U-L-FABP/C was associated with a decline in GFR only in patients with UAC <3 mg/mmol (n = 29, p = 0.001) and not in patients with UAC ≥3 mg/mmol (n = 44, p = 0.21). In conclusion urine L-FABP/C is permanently elevated in CKD patients, but only associated with GFR decline in those without albuminuria.

Bone turnover markers are associated with bone density, but not with fracture in end stage kidney disease: a cross-sectional study.

BACKGROUND: Fracture risk is increased in chronic kidney disease (CKD), but assessment of bone fragility remains controversial in these patients. This study investigated the associations between bone turnover markers, bone mineral density (BMD), and prevalent fragility fracture in a cohort of kidney transplantation candidates. METHODS: Volumetric BMD of spine and hip was measured by quantitative computed tomography. Parathyroid hormone (PTH), bone-specific alkaline phosphatase, procollagen type-1 N-terminal propeptide, tartrate resistant alkaline phosphatase, and C- and N-terminal telopeptides of type 1 collagen were analyzed from fasting morning blood samples. Fragility fractures included prevalent vertebral fractures and previous low-trauma clinical fractures. RESULTS: The fracture prevalence was 18% in 157 adult kidney transplant candidates. Fractured patients had reduced BMD and Z-score at both spine and hip. Levels of bone turnover markers were significantly higher in patients on maintenance dialysis than in pre-dialysis patients; but did not differ between patients with and without fracture. There were strong, positive correlations between PTH and all bone turnover markers. PTH was negatively associated with Z-score at lumbar spine and total hip; in contrast, bone turnover markers were only negatively associated with total hip Z-score. CONCLUSIONS: Bone turnover markers were negatively associated with bone density, but not associated with prevalent fracture in kidney transplantation candidates. The role of bone turnover markers in assessing bone fragility in CKD will require further investigation. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov with identifier NCT01344434 .

The relation between histopathological classification and renal outcome, ANCA subtype and treatment regimens in ANCA-associated vasculitis.

OBJECTIVES: ANCA-associated vasculitis (AAV) is associated with an increased risk of death and end stage renal disease (ESRD). The aim of this study was to examine the correlation between a histopathological classification and renal outcome and to describe the interaction with ANCA subtype and initial treatment. METHODS: Eighty-seven patients with AAV from 1999-2010 from two centres in Denmark were included in the study and had a 3 year follow-up. Data was collected retrospectively. The renal biopsies were reclassi ed into one of the following groups: crescentic, sclerotic, focal and mixed. RESULTS: Histopathologic groups were not associated with eGFR at three years. Age and baseline eGFR were independent prognostic for eGFR at three years. More patients in the crescentic group than in the mixed and focal groups developed ESRD (33%, 13% and 5% respectively). Patients reaching ESRD had few- er non-affected glomeruli (14 % vs. 34%, p=0.0014) and lower eGFR at baseline (7 vs. 21.7 ml/min/m(2), p<0.0001). At baseline MPO-ANCA positive patients were older, had more sclerotic glomeruli and had a lower eGFR after three years compared to PR3-ANCA positive patients. PR3-ANCA positive patients receiving plasma exchange (PE) improved eGFR more from baseline to three years than those not receiving PE (36 vs. 20 ml/min/m2, p=0.01). CONCLUSIONS: In our cohort most pa- tients in the crescentic group and fewer in the focal group reached ESRD. Age and baseline eGFR are prognostic of renal function after 3 years, as also in the PR3-ANCA positive subgroup initial treatment with PE.

Effect of Intravenous Contrast on Volumetric Bone Mineral Density in Patients with Chronic Kidney Disease.

Volumetric bone mineral density (vBMD) can be measured from clinical computed tomography (CT) scans, facilitating screening for osteoporosis. However, use of X-ray contrast media may influence vBMD analyses, and previous studies reported as much as a 30% increase in lumbar spine (LS) vBMD after contrast administration. At the total hip (TH), an increase of only 4.1% was reported, indicating less sensitivity to contrast enhancement at this site. This study aimed to investigate the changes in vBMD after intravenous contrast media administration at both the LS and proximal femur in patients with chronic kidney disease. Seventy-one patients underwent CT angiography of the chest, abdomen, and pelvis as part of the cardiac workup before kidney transplantation. vBMD of the LS and proximal femur were calculated before and after administration of 95 mL ioversol intravenously. XY- and Bland-Altman plots and paired Student's t-test were used to evaluate changes in vBMD. After contrast media administration vBMD increased both at the LS and proximal femur. Although the absolute difference was comparable, the relative difference was almost twice as high at the LS (10.2% [6.1-14.1]) compared to the TH (5.9% [2.4-9.3], p <0.001) and femoral neck (FN) (5.3% [0.5-9.9], p <0.001). Women had a greater increase in LS-vBMD than men (13.4 ± 8.0 vs 9.8 ± 4.8 mg/cc, p = 0.02). Based on FN T-scores, 11 patients (16%) changed osteoporotic status after contrast enhancement. In conclusion vBMD of the spine and hip increased after contrast media administration in a cohort of patients with chronic kidney disease. FN T-scores from contrast-enhanced clinical CT scans should therefore be interpreted with caution. The proximal femur may be the preferred region for vBMD analysis from clinical CT scans, as sensitivity to contrast enhancement seem less at this site. These results may not be applicable to other patient populations.