The Effect of Magnesium Supplementation on Vascular Calcification in CKD: A Randomized Clinical Trial (MAGiCAL-CKD).

SIGNIFICANCE STATEMENT: Magnesium prevents vascular calcification in animals with CKD. In addition, lower serum magnesium is associated with higher risk of cardiovascular events in CKD. In a randomized, double-blinded, placebo-controlled trial, the authors investigated the effects of magnesium supplementation versus placebo on vascular calcification in patients with predialysis CKD. Despite significant increases in plasma magnesium among study participants who received magnesium compared with those who received placebo, magnesium supplementation did not slow the progression of vascular calcification in study participants. In addition, the findings showed a higher incidence of serious adverse events in the group treated with magnesium. Magnesium supplementation alone was not sufficient to delay progression of vascular calcification, and other therapeutic strategies might be necessary to reduce the risk of cardiovascular disease in CKD. BACKGROUND: Elevated levels of serum magnesium are associated with lower risk of cardiovascular events in patients with CKD. Magnesium also prevents vascular calcification in animal models of CKD. METHODS: To investigate whether oral magnesium supplementation would slow the progression of vascular calcification in CKD, we conducted a randomized, double-blinded, placebo-controlled, parallel-group, clinical trial. We enrolled 148 subjects with an eGFR between 15 and 45 ml/min and randomly assigned them to receive oral magnesium hydroxide 15 mmol twice daily or matching placebo for 12 months. The primary end point was the between-groups difference in coronary artery calcification (CAC) score after 12 months adjusted for baseline CAC score, age, and diabetes mellitus. RESULTS: A total of 75 subjects received magnesium and 73 received placebo. Median eGFR was 25 ml/min at baseline, and median baseline CAC scores were 413 and 274 in the magnesium and placebo groups, respectively. Despite plasma magnesium increasing significantly during the trial in the magnesium group, the baseline-adjusted CAC scores did not differ significantly between the two groups after 12 months. Prespecified subgroup analyses according to CAC>0 at baseline, diabetes mellitus, or tertiles of serum calcification propensity did not significantly alter the main results. Among subjects who experienced gastrointestinal adverse effects, 35 were in the group receiving magnesium treatment versus nine in the placebo group. Five deaths and six cardiovascular events occurred in the magnesium group compared with two deaths and no cardiovascular events in the placebo group. CONCLUSIONS: Magnesium supplementation for 12 months did not slow the progression of vascular calcification in CKD, despite a significant increase in plasma magnesium. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov ( NCT02542319 ).

Associations of Serum Uromodulin and Urinary Epidermal Growth Factor with Measured Glomerular Filtration Rate and Interstitial Fibrosis in Kidney Transplantation.

INTRODUCTION: Noninvasive biomarkers that reflect tubular health and allow early recognition of accelerated graft fibrosis development are warranted. Serum uromodulin (sUmod) and urinary epidermal growth factor (uEGF) originate from kidney tubules and may reflect functional nephron mass. The aim of this study was to investigate the associations between sUmod and uEGF with measured glomerular filtration rate (mGFR) and kidney allograft interstitial fibrosis percentage (IF%) score. METHODS: sUmod and uEGF measurements, mGFR by iohexol-clearance and kidney allograft biopsies were obtained from kidney transplant recipients (KTRs) included in the Omega-3 fatty acids in Renal Transplantation (ORENTRA) trial at 8 weeks (baseline) and at 1 year after transplantation (end of study). Associations were analyzed with univariable and multivariable linear regression. RESULTS: Ninety patients at baseline and 48 patients at end of study had complete study variable assessments. uEGF normalized to urinary creatinine (uEGF/Cr) was associated with mGFR both at baseline (standardized ß-coefficient [Std. ß-coeff] = 0.457 [p = <0.001]) and at end of study (Std. ß-coeff = 0.637 [p = <0.001]). sUmod was only associated with mGFR at end of study (Std. ß-coeff = 0.443 [p = 0.002]). uEGF/Cr, sUmod, and mGFR were associated with graft IF% score both at baseline (Std. ß-coeff = -0.349 [p = 0.001], -0.274 [p = 0.009] and -0.289 [p = 0.006], respectively) and at end of study (Std. ß-coeff = -0.365 [p = 0.011], -0.347 [p = 0.016] and -0.405 [p = 0.004], respectively). The results remained largely unchanged in multivariable analysis. CONCLUSION: uEGF/Cr and sUmod were associated with mGFR and graft IF% score. Our results indicate a possible role of uEGF/Cr and sUmod in the follow-up of KTRs.

Osteoprotegerin predicts cardiovascular events in patients treated with haemodialysis.

BACKGROUND: Disturbances in bone mineral metabolism are associated with increased mortality and cardiovascular events (CVEs). However, the association between bone-associated protein biomarkers, mortality and CVEs independent of cytokine activation remains unknown. This study aimed to investigate bone-associated protein biomarkers and the association with inflammatory cytokines and cardiovascular (CV) outcomes. METHODS: This prospective study enrolled haemodialysis patients in Denmark between December 2010 and March 2011. Using a proximity extension proteomics assay, nine bone-associated proteins were examined: cathepsin D (CTSD), cathepsin L1 (CTSL1), dickkopf-related protein 1, fibroblast growth factor 23, leptin, osteoprotegerin (OPG), receptor activator of nuclear factor kappa-Β ligand, TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptor 2 (TRAIL-R2). The importance of the bone-associated protein markers was evaluated by a random forest (RF) algorithm. The association between bone-associated proteins with all-cause death, CV death and CVEs was analysed in multivariable Cox models adjusted for age, gender, comorbidities, laboratory data and dialysis duration. RESULTS: We enrolled 331 patients [63.7% men; mean age, 65 years (standard deviation 14.6)] in a prospective cohort study with 5 years of follow-up. When adjusting for confounders, CTSL1 remained associated with all-cause death and four biomarkers were associated with CVEs. However, the association between bone markers and the outcomes was attenuated after adjusting for inflammatory proteins and only OPG remained associated with CVEs in the adjusted model. Evaluating the importance of bone markers by RF, OPG was the most important marker related to CVEs. OPG also improved the prediction of CVEs in integrated discrimination improvement and net reclassification improvement analyses. CONCLUSIONS: OPG, a well-known bone biomarker, was associated with CVEs independent of cytokine activity. In contrast, the association between CVEs and the remaining three bone-associated proteins (TRAIL-R2, CTSD and CTSL1) was affected by cytokine inflammation activity.

Growth Differentiation Factor 15 Provides Prognostic Information Superior to Established Cardiovascular and Inflammatory Biomarkers in Unselected Patients Hospitalized With COVID-19.

BACKGROUND: Growth differentiation factor 15 (GDF-15) is a strong prognostic marker in sepsis and cardiovascular disease (CVD). The prognostic value of GDF-15 in coronavirus disease 2019 (COVID-19) is unknown. METHODS: Consecutive, hospitalized patients with laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and symptoms of COVID-19 were enrolled in the prospective, observational COVID Mechanisms Study. Biobank samples were collected at baseline, day 3 and day 9. The primary end point was admission to the intensive care unit or death during hospitalization, and the prognostic performance of baseline and serial GDF-15 concentrations were compared with that of established infectious disease and cardiovascular biomarkers. RESULTS: Of the 123 patients enrolled, 35 (28%) reached the primary end point; these patients were older, more often had diabetes, and had lower oxygen saturations and higher National Early Warning Scores on baseline. Baseline GDF-15 concentrations were elevated (>95th percentile in age-stratified healthy individuals) in 97 (79%), and higher concentrations were associated with detectable SARS-CoV-2 viremia and hypoxemia (both P<0.001). Patients reaching the primary end point had higher concentrations of GDF-15 (median, 4225 [IQR, 3197-5972] pg/mL versus median, 2187 [IQR, 1344-3620] pg/mL, P<0.001). The area under the receiver operating curve was 0.78 (95% CI, 0.70-0.86). The association between GDF-15 and the primary end point persisted after adjusting for age, sex, race, body mass index, estimated glomerular filtration rate, previous myocardial infarction, heart failure, and atrial fibrillation (P<0.001) and was superior and incremental to interleukin-6, C-reactive protein, procalcitonin, ferritin, D-dimer, cardiac troponin T, and N-terminal pro-B-type natriuretic peptide. Increase in GDF-15 from baseline to day 3 was also greater in patients reaching the primary end point (median, 1208 [IQR, 0-4305] pg/mL versus median, -86 [IQR, -322 to 491] pg/mL, P<0.001). CONCLUSIONS: GDF-15 is elevated in the majority of patients hospitalized with COVID-19, and higher concentrations are associated with SARS-CoV-2 viremia, hypoxemia, and worse outcome. The prognostic value of GDF-15 was additional and superior to established cardiovascular and inflammatory biomarkers. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04314232.

Severe Acute Respiratory Syndrome Coronavirus 2 RNA in Plasma Is Associated With Intensive Care Unit Admission and Mortality in Patients Hospitalized With Coronavirus Disease 2019.

The clinical significance of severe acute respiratory syndrome coronavirus 2 RNA in the circulation is unknown. In this prospective cohort study, we detected viral RNA in the plasma of 58 of 123 (47%) patients hospitalized with coronavirus disease 2019. RNA was detected more frequently, and levels were higher, in patients who were admitted to the intensive care unit and/or died.

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.

Relative and absolute cancer risks among Nordic kidney transplant recipients-a population-based study.

Kidney transplant recipients (KTRs) have an increased cancer risk compared to the general population, but absolute risks that better reflect the clinical impact of cancer are seldom estimated. All KTRs in Sweden, Norway, Denmark, and Finland, with a first transplantation between 1995 and 2011, were identified through national registries. Post-transplantation cancer occurrence was assessed through linkage with cancer registries. We estimated standardized incidence ratios (SIR), absolute excess risks (AER), and cumulative incidence of cancer in the presence of competing risks. Overall, 12 984 KTRs developed 2215 cancers. The incidence rate of cancer overall was threefold increased (SIR 3.3, 95% confidence interval [CI]: 3.2-3.4). The AER of any cancer was 1560 cases (95% CI: 1468-1656) per 100 000 person-years. The highest AERs were observed for nonmelanoma skin cancer (838, 95% CI: 778-901), non-Hodgkin lymphoma (145, 95% CI: 119-174), lung cancer (126, 95% CI: 98.2-149), and kidney cancer (122, 95% CI: 98.0-149). The five- and ten-year cumulative incidence of any cancer was 8.1% (95% CI: 7.6-8.6%) and 16.8% (95% CI: 16.0-17.6%), respectively. Excess cancer risks were observed among Nordic KTRs for a wide range of cancers. Overall, 1 in 6 patients developed cancer within ten years, supporting extensive post-transplantation cancer vigilance.

Plasma marine n-3 polyunsaturated fatty acids and cardiovascular risk factors: data from the ACE 1950 study.

PURPOSE: A high intake of marine n-3 polyunsaturated fatty acids (PUFAs) might improve cardiovascular (CV) health. We conducted a cross-sectional study to investigate associations between plasma phospholipid levels of marine n-3 PUFAs and CV risk factors, educational level, physical activity and smoking habits. METHODS: A total of 3706 individuals from a general population, all born in 1950 and residing in Akershus County, Norway, were included in this study. The main statistical approach was multivariable adjusted linear regression. RESULTS: Plasma marine n-3 PUFA levels ranged from 2.7 to 20.3 wt%, with a median level of 7.7 wt% (interquartile range 4.3-11.1 wt%). High levels of plasma marine n-3 PUFAs were associated with lower serum triglycerides [Standardized regression coefficient (Std.ß-coeff.) - 0.14, p < 0.001], body mass index (Std. ß-coeff. -0.08, p < 0.001), serum creatinine (Std. ß-coeff. -0.03, p = 0.05), C-reactive protein levels (Std. ß-coeff. - 0.03, p = 0.04), higher levels of serum high-density lipoprotein cholesterol (Std. ß-coeff. 0.08, p < 0.001) and low-density lipoprotein cholesterol (Std. ß-coeff. 0.04, p = 0.003). High levels of plasma marine n-3 PUFAs were also associated with lower glycated hemoglobin (Std. ß-coeff. - 0.04, p = 0.01), however, only in individuals without diabetes. We found no associations between plasma marine n-3 PUFA levels and fasting plasma glucose or carotid intima-media thickness. High levels of plasma marine n-3 PUFAs were associated with higher educational level, more physical activity and lower prevalence of smoking. CONCLUSION: In this cross-sectional study of Norwegian individuals born in 1950, high levels of plasma marine n-3 PUFAs were favourably associated with several CV risk factors, suggesting that fish consumption might improve CV health.

Effects of marine n-3 fatty acid supplementation in renal transplantation: A randomized controlled trial.

Marine n-3 fatty acids (FAs) may exert beneficial effects on inflammation, fibrosis, and endothelial function, which could preserve renal graft function. In this randomized controlled trial, 132 Norwegian renal transplant recipients received either 2.6 g of marine n-3 FAs or olive oil (control) daily for 44 weeks, in addition to standard care. Thirty patients did not complete the trial. The primary endpoint was change (Δ) in measured glomerular filtration rate (mGFR) during follow-up. We found no significant difference in Δ mGFR between the marine n-3 FA group and controls (6.7 vs 3.8 mL/min per 1.73 m2 , P = .15). Significant beneficial effects from marine n-3 FA supplementation were, however, seen in secondary endpoints plasma triglycerides, plasma high-sensitivity C-reactive protein, and brachial artery flow-mediated dilation. In the per-protocol population, the renal graft indices percent interstitial fibrosis and Chronic Allograft Damage Index also were significantly lower in the marine n-3 FA group. The cumulative incidence of adverse events did not differ between the marine n-3 FA group (n = 218) and controls (n = 240). In conclusion, marine FA supplementation did not improve renal function compared with controls, but was safe, lowered plasma triglyceride and high-sensitivity C-reactive protein levels, and improved endothelial function (Clinical.Trials.gov identifier NCT01744067).

A Fully Automated Method for the Determination of Serum Belatacept and Its Application in a Pharmacokinetic Investigation in Renal Transplant Recipients.

BACKGROUND: Belatacept (Nulojix; Bristol-Myers Squibb, New York, NY) is a biological immunosuppressive drug used for the prophylaxis of acute rejection after renal transplantation. Few studies have described belatacept pharmacokinetics, and the effect of therapeutic drug monitoring has not been investigated. We have developed a drug-capture assay (using drug target) to measure belatacept in serum and applied this assay in a pharmacokinetic study in renal transplant recipients. METHODS: CD80 was used to trap belatacept onto streptavidin-coated wells. Captured drug was quantified using Eu-labeled protein A and time-resolved fluorescence. The assay was applied in a pilot pharmacokinetic study in renal transplanted patients receiving belatacept infusions. Belatacept serum concentrations were determined at several time points between belatacept infusions. A simple population pharmacokinetic model was developed to visualize measured and predicted belatacept serum concentrations. RESULTS: The assay range was 0.9-30 mg/L with accuracy within 91%-99% and coefficients of variation ranging from 1.2% to 3.6%. Predilution extended the measurement range to 130 mg/L with an accuracy of 90% and coefficients of variation of 3.8%. Samples were stable during storage at 4°C for 15 days and during 2 freeze-thaw cycles. Belatacept concentrations were determined in a total of 203 serum samples collected during 26 infusion intervals from 5 renal transplant recipients. The population pharmacokinetic model visualized both measured and predicted concentrations. CONCLUSIONS: We have developed an automated, accurate, and precise assay for the determination of belatacept serum concentrations. The assay was successfully applied in a pharmacokinetic study in renal transplant recipients receiving belatacept infusions.

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.

Trans-fatty Acids and Survival in Renal Transplantation.

OBJECTIVE: High consumption of trans-fatty acids (TFAs) is associated with increased mortality. DESIGN AND METHODS: Observational cohort study of 1.988 Norwegian renal transplant recipients with a median follow-up time of 9.6 years. We assessed multivariable adjusted associations between plasma levels of industrial and ruminant TFAs with patient and graft survival. Plasma phospholipid fatty acid levels were determined by gas chromatography at 10 weeks after transplantation. RESULTS: During follow-up, there were 595 deaths, and 805 grafts were lost. Plasma industrial TFA levels dropped from 0.3 wt% in years 1999-2004 to reach a plateau of 0.2 wt% from year 2005 and beyond, whereas plasma levels of ruminant TFAs remained stable throughout the study period. In the former era (years 1999 to 2004, n = 902), we found multivariable adjusted associations between plasma industrial TFA levels and mortality (hazard ratio 4.44, P = .02) and graft loss (hazard ratio 4.22, P = .01). In the latter era (years 2005 to 2011, n = 1,086), there were no associations between plasma industrial TFA levels and patient or graft survival. Plasma ruminant TFAs were not associated with mortality or graft loss in either eras. CONCLUSION: In this Norwegian transplant cohort, plasma industrial TFA levels dropped from around 0.3 wt% in the former era to 0.2 wt% in the latter era. While plasma industrial TFA was significantly associated with survival in the former era, no associations were found with survival in the latter era. This finding suggests that lowering industrial TFA consumption from modest to low levels could possibly influence health beneficially after renal transplantation.

Determination of Tacrolimus Concentration and Protein Expression of P-Glycoprotein in Single Human Renal Core Biopsies.

BACKGROUND: Tacrolimus (TAC) is currently the cornerstone of immunosuppressive protocols for renal transplant recipients. Despite therapeutic whole blood monitoring, TAC is associated with nephrotoxicity, and it has been hypothesized that intrarenal accumulation of TAC and/or its metabolites are involved. As TAC is a substrate of P-glycoprotein (P-gp), the expression and activity of this efflux transporter could influence the levels of TAC in renal tissue. The primary aim of this study was to develop and validate a method for quantification of TAC in tissue homogenates from single human renal core biopsies. The secondary aim was to provide measures of P-gp expression and of the demethylated metabolites of TAC in the same renal biopsy. METHODS: Human renal tissue, with and without clinical TAC exposure, was used for method development and validation. Homogenates were prepared with bead-beating, and concentrations of TAC and its demethylated metabolites were analyzed with liquid chromatography tandem mass spectrometry after protein precipitation. A Western blot method was used for semiquantification of P-gp expression in the homogenates. The final methods were applied to renal core biopsies from 2 transplant patients. RESULTS: The TAC assay showed within- and between-run mean accuracy between 99.7% and 107% and coefficients of variation ≤6.7%. Matrix effects were nonsignificant, and samples were stable for 3 months preanalytically when stored at -80°C. TAC concentrations in the renal core biopsies were 62.6 and 43.7 pg/mg tissue. The methods for measurement of desmethyl-TAC and P-gp expression were suitable for semiquantification in homogenates from renal core biopsies. CONCLUSIONS: These methods may be valuable for the elucidation of the pharmacokinetic mechanisms behind TAC-induced nephrotoxicity in renal transplant recipients.

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.

Plasma n-6 Polyunsaturated Fatty Acid Levels and Survival in Renal Transplantation.

OBJECTIVE: The major n-6 polyunsaturated fatty acids linoleic acid (LA) and arachidonic acid (AA) play a role in inflammation and glucose metabolism, which could affect patient and renal transplant survival. DESIGN AND METHODS: In this single center cohort study of 1988 Norwegian renal transplant recipients, we assessed associations between plasma levels of LA and AA at baseline, measured by gas chromatography, and patient and graft survival, as well as inflammation and cardiovascular risk markers. RESULTS: During follow-up (median of 9.6 years), 595 patients died and 805 renal transplants were lost, either due to recipient death or graft failure. In multivariable survival analysis, we found no associations with mortality for plasma levels of LA (hazard ratios: 0.99, 95% confidence intervals: 0.96-1.01) or AA (hazard ratios: 1.01, 95% confidence intervals: 0.96-1.06). No associations were found for cardiovascular mortality, overall graft loss, or death-censored graft loss. Plasma glucose, proglycemic marker chemerin, and proinflammatory marker growth differentiation factor 15 were inversely associated with plasma LA and positively associated with plasma AA levels in multivariable analysis. CONCLUSIONS: We found no associations between plasma levels of LA or AA and patient or graft survival. Plasma levels of LA and proglycemic indices were inversely associated, signaling a possible beneficial effect of LA consumption for prevention of posttransplantation diabetes mellitus.

Development of Kidney Transplant Fibrosis Is Inversely Associated With Plasma Marine Fatty Acid Level.

OBJECTIVE(S): We assessed associations between plasma levels of polyunsaturated fatty acids (PUFAs) and degree of inflammation and interstitial fibrosis in transplanted kidneys. DESIGN: The design of the study was single center cohort study. SUBJECTS: A study population of 156 patients who received a kidney transplant at Oslo University Hospital during 2010. MAIN OUTCOME MEASURE: Kidney transplant biopsies were obtained at 2 months and 1 year after transplantation. Degree of inflammation and interstitial fibrosis in the cortex of transplanted kidneys were estimated semi-quantitatively. Plasma phospholipid fatty acids levels were measured in a stable phase 2 months posttransplant. We used multivariate linear regression to assess associations between plasma levels of PUFAs and degree of inflammation and interstitial fibrosis at 2 months and 1 year postoperatively and change in degree of interstitial fibrosis during the first year after transplantation, adjusting for inflammation and fibrosis risk factors. RESULTS: Higher plasma marine n-3 PUFA levels were associated with less development of interstitial fibrosis in the kidney transplant (unstandardized ß-coefficient -1.12, standardized ß-coefficient -0.18, P = .03) during the first year after transplantation. Plasma levels of alpha linoleic acid, linoleic acid, and arachidonic acid were not associated with development of interstitial fibrosis. No associations were found between plasma levels of PUFAs and inflammation inside fibrotic areas or outside fibrotic areas in the kidney transplant at neither 2 months nor 1 year postoperatively. Linolenic acid levels in plasma were positively associated with change in renal function during the first year after transplantation. CONCLUSION: The inverse association between plasma marine n-3 PUFA levels and development of interstitial fibrosis during the first year after kidney transplantation suggests that marine fatty acid consumption might halt progression of fibrosis.

Acute glomerulonephritis triggered by parvovirus B19. / Akutt glomerulonefritt utløst av parvovirus B19.

Background: Para- and post-infectious glomerulonephritis may be caused by various microbiological agents. We present a case of parvovirus B19 infection causing a post-infectious glomerulonephritis. Case presentation: A 30-year-old woman was admitted to hospital after four weeks of fever, flank pain and general oedema. Laboratory measurements showed elevated creatinine and alanine aminotransferase, whereas haemoglobin, albumin and thrombocyte levels were low. The urine analyses were positive for both haematuria and proteinuria. Ultrasound and CT scan of the thorax and abdomen showed multiple increased lymphoid nodes, bilateral pleural effusion, periportal oedema and ascites. C3 was low, and C4 normal. Additional immunological laboratory tests were negative. Viral serology was positive for parvovirus B19 immunoglobulin M and immunoglobulin G, confirming glomerulonephritis triggered by infection. The patient's symptoms resolved without any specific treatment, and a few months later creatinine had normalised. Interpretation: This case report illustrates the importance of microbiological laboratory work-up to further investigate acute kidney failure of unknown cause.

Early introduction of oral paricalcitol in renal transplant recipients. An open-label randomized study.

In stable renal transplant recipients with hyperparathyroidism, previous studies have indicated that vitamin D agonist treatment might have anti-proteinuric effects. Animal studies indicate possible anti-fibrotic and anti-inflammatory effects. Early introduction of paricalcitol in de novo renal transplant recipients might reduce proteinuria and prevent progressive allograft fibrosis. We performed a single-center, prospective, randomized, open-label trial investigating effects of paricalcitol 2 µg/day added to standard care. Participants were included 8 weeks after engraftment and followed for 44 weeks. Primary end point was change in spot urine albumin/creatinine ratio. Exploratory microarray analyses of kidney biopsies at study end investigated potential effects on gene expression. Secondary end points included change in glomerular filtration rate (GFR), pulse wave velocity (PWV), and endothelial function measured by peripheral arterial tonometry as reactive hyperemia index (RHI). Seventy-seven de novo transplanted kidney allograft recipients were included, 37 receiving paricalcitol. Paricalcitol treatment lowered PTH levels (P = 0.01) but did not significantly reduce albuminuria (P = 0.76), change vascular parameters (PWV; P = 0.98, RHI; P = 0.33), or influence GFR (P = 0.57). Allograft gene expression was not influenced. To summarize, in newly transplanted renal allograft recipients, paricalcitol reduced PTH and was well tolerated without negatively affecting kidney function. Paricalcitol did not significantly reduce/prevent albuminuria, improve parameters of vascular health, or influence allograft gene expression.

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 .