Recommended calcium intake in adults and children with chronic kidney disease-a European consensus statement.

Mineral and bone disorders (MBD) are common in patients with chronic kidney disease (CKD), contributing to significant morbidity and mortality. For several decades, the first-line approach to controlling hyperparathyroidism in CKD was by exogenous calcium loading. Since the turn of the millennium, however, a growing awareness of vascular calcification risk has led to a paradigm shift in management and a move away from calcium-based phosphate binders. As a consequence, contemporary CKD patients may be at risk of a negative calcium balance, which, in turn, may compromise bone health, contributing to renal bone disease and increased fracture risk. A calcium intake below a certain threshold may be as problematic as a high intake, worsening the MBD syndrome of CKD, but is not addressed in current clinical practice guidelines. The CKD-MBD and European Renal Nutrition working groups of the European Renal Association (ERA), together with the CKD-MBD and Dialysis working groups of the European Society for Pediatric Nephrology (ESPN), developed key evidence points and clinical practice points on calcium management in children and adults with CKD across stages of disease. These were reviewed by a Delphi panel consisting of ERA and ESPN working groups members. The main clinical practice points include a suggested total calcium intake from diet and medications of 800-1000 mg/day and not exceeding 1500 mg/day to maintain a neutral calcium balance in adults with CKD. In children with CKD, total calcium intake should be kept within the age-appropriate normal range. These statements provide information and may assist in decision-making, but in the absence of high-level evidence must be carefully considered and adapted to individual patient needs.

No Detectable Coagulation Activation After Vitamin K (MK-7) Supplementation in Patients on Dialysis With Functional Vitamin K Deficiency: A One-Year Randomized, Placebo-Controlled Study.

OBJECTIVE: Patients on dialysis treatment have poor functional vitamin K status, and this may increase the risk of vascular calcification. Vitamin K supplementation may therefore be relevant in patients on dialysis, but the procoagulant effects have not been studied. We evaluated effects of menaquinone-7 (MK-7) supplementation on biomarkers of coagulation in patients on dialysis. METHODS: Double-blinded, placebo-controlled study in 123 patients on dialysis randomized to 52 weeks of vitamin K (MK-7, 360 µg/daily, n = 61) or placebo (n = 62). Measurements at baseline and after 52 weeks of intervention included thrombin generation (endogenous thrombin potential, peak thrombin concentration, time to peak, and lag time); clot activities of vitamin K-dependent coagulation factors (F) II, VII, IX, and X; prothrombin fragment 1 + 2 (F1+2); and proteins induced by vitamin K absence II (PIVKA-II). Between-group differences (vitamin K vs. placebo) at 52 weeks were determined with an analysis of covariance. Within-group changes in vitamin K and placebo groups were analyzed with a paired t-test. Vascular adverse events and serious adverse events were registered based on hospital records, laboratory data, and participant interviews and compared between groups using Fisher's exact test or Pearson's Chi-Squared test. RESULTS: A between-group difference at 52 weeks was observed for PIVKA-II (P < .001). PIVKA-II decreased significantly from baseline to 52 weeks in the vitamin K group, but not in the placebo group. We observed no between-group differences or within-group changes for biomarkers of coagulation, except for FVII clot activity which was reduced in the placebo group (P = .04), and no between-group differences in adverse events and serious adverse events. CONCLUSION: One year of vitamin K supplementation in patients on dialysis has no detectable effects on biomarkers of coagulation activation, clot activities of vitamin K-dependent coagulation factors, and vascular events or death, indicating no procoagulant effects of this treatment.

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 ).

The Danish newborn standard and the International Fetal and Newborn Growth Consortium for the 21st Century newborn standard: a nationwide register-based cohort study.

BACKGROUND: It is a matter of debate whether 1 universal standard, such as the International Fetal and Newborn Growth Consortium for the 21st Century standard, can be applied to all populations. OBJECTIVE: The primary objective was to establish a Danish newborn standard based on the criteria of the International Fetal and Newborn Growth Consortium for the 21st Century standard to compare the percentiles of these 2 standards. A secondary objective was to compare the prevalence and risk of fetal and neonatal deaths related to small for gestational age defined by the 2 standards when used in the Danish reference population. STUDY DESIGN: This was a register-based nationwide cohort study. The Danish reference population included 375,318 singletons born at 33 to 42 weeks of gestation in Denmark between January 1, 2008, and December 31, 2015. The Danish standard cohort included 37,811 newborns who fulfilled the criteria of the International Fetal and Newborn Growth Consortium for the 21st Century standard. Birthweight percentiles were estimated using smoothed quantiles for each gestational week. The outcomes included birthweight percentiles, small for gestational age (defined as a birthweight of 3rd percentile), and adverse outcomes (defined as either fetal or neonatal death). RESULTS: At all gestational ages, the Danish standard median birthweights at term were higher than the International Fetal and Newborn Growth Consortium for the 21st Century standard median birthweights: 295g for females and 320 g for males. Therefore, the estimates of the prevalence rate of small for gestational age within the entire population were different: 3.9% (n=14,698) using the Danish standard vs 0.7% (n=2640) using the International Fetal and Newborn Growth Consortium for the 21st Century standard. Accordingly, the relative risk of fetal and neonatal deaths among small-for-gestational-age fetuses differed by SGA status defined by the different standards (4.4 [Danish standard] vs 9.6 [International Fetal and Newborn Growth Consortium for the 21st Century standard]). CONCLUSION: Our finding did not support the hypothesis that 1 universal standard birthweight curve can be applied to all populations.

Far infrared treatment on the arteriovenous fistula induces changes in sVCAM and sICAM in patients on hemodialysis.

INTRODUCTION: There is a substantial risk of developing stenosis and dysfunction in the arteriovenous fistula (AVF) in patients on hemodialysis (HD). Far infrared radiation (FIR) is a non-invasive local intervention with a potentially beneficial effect on AVF patency. The underlying mechanism is not clear. It was hypothesized that a single FIR treatment reduces factors of inflammation and promotes endothelial vasodilators in the AVF. METHODS: Forty HD patients with an AVF were included in an open-label intervention study. Patients were randomized to receive either FIR (FIR group) or no FIR (control group). Blood samples were drawn directly from the AVF and from a peripheral vein in the non-AVF arm before (T0) and 40 min after (T40) treatment during a HD session. The changes [median (interquartile range)] in circulating factors of inflammation, endothelial function and vasoreactivity during FIR were measured. RESULTS: In the AVF a single FIR treatment during dialysis resulted in a significantly diminished decrease in soluble vascular cell adhesion molecule, sVCAM [-31.6 (-54.3; 22.1) vs -89.9 (-121.6; -29.3), P = .005] and soluble intercellular adhesion molecule, sICAM [-24.2 (-43.5; 25.3) vs -49 (-79.9; -11.6), P = .02] compared with the control group. Other factors, such as interleukins, nitrite, nitrate and tumor necrosis factor 1, also declined during dialysis, but with no significant differences related to FIR in either the AVF or the non-AVF arm. CONCLUSION: A single FIR treatment attenuated the decrease in sVCAM and sICAM in the AVF compared with a control group during HD. Findings do not support the hypothesis of a vaso-protective effect of FIR. The long-term effects of FIR on the AVF are unknown.

Vitamin K supplementation and bone mineral density in dialysis: results of the double-blind, randomized, placebo-controlled RenaKvit trial.

BACKGROUND: Vitamin K deficiency is highly prevalent in patients on dialysis and may contribute to their low bone mineral density (BMD) and increased risk of fracture. This study investigated the effect of menaquinone-7 (MK-7) supplementation on BMD in patients on chronic dialysis. METHODS: In a multicentre, double-blind, placebo-controlled intervention trial, 123 patients on chronic dialysis were randomised to a daily oral supplement of either MK-7 360 µg or placebo for 2 years. BMD of the distal radius (1/3, mid, ultradistal and total), femoral neck, lumbar spine (L1-L4) and whole body was assessed by dual-energy X-ray absorptiometry. Serum levels of vitamin K1 and MK-7 and plasma levels of total osteocalcin, dephosphorylated-uncarboxylated matrix Gla protein and protein induced by vitamin K absence II were measured to assess vitamin K status. RESULTS: After 2 years, an accelerated BMD loss of the 1/3 distal radius was found with MK-7 supplementation {mean difference of changes relative to placebo -0.023 g/cm2 [95% confidence interval (CI) -0.039 to -0.008]}, whereas the decrease in lumbar spine BMD seen in the placebo group was prevented [mean difference of changes between groups 0.050 g/cm2 (95% CI 0.015-0.085)]. No significant effects were observed at the remaining skeletal sites. Vitamin K status strongly improved in MK-7-supplemented participants. CONCLUSION: Compared with placebo, an accelerated BMD loss of the 1/3 distal radius was found after 2 years of MK-7 supplementation, whereas a decline in lumbar spine BMD was prevented. As such, MK-7 supplementation might modify BMD site-specifically in patients on dialysis. In aggregate, our findings do not support MK-7 supplementation to preserve bone in patients on dialysis.

Combination therapy with immune check point inhibitors and acute kidney injury.

BACKGROUND: Immune checkpoint inhibitors have revolutionized the treatment of metastatic renal cell carcinoma and malignant melanoma but are also associated with a risk of severe side effects. Nephrotoxicity is an immune checkpoint inhibitor-related adverse effect, but acute kidney injury (AKI) can also be caused by other more common conditions. This study aimed to describe the incidence and causes of AKI in patients treated with combination therapy of immune checkpoint inhibitors. MATERIAL AND METHODS: This retrospective cohort study included 200 patients receiving ipilimumab and nivolumab for either metastatic renal cell carcinoma or malignant melanoma at the Department of Oncology at Copenhagen University Hospital, Herlev between 1 January 2019 and 31 December 2020. The incidence and cause of AKI within 6 months after treatment was determined. RESULTS: In the 96 patients treated for malignant melanoma 15 patients (16%) had an episode of AKI. Two of these patients had potential immune checkpoint inhibitor-related AKI both of which received treatment with a proton pump inhibitor (PPI). Of the 104 included patients with metastatic renal cell carcinoma 26 patients (25%) developed AKI. Five of these patients had potential immune checkpoint inhibitor-related AKI. Treatment with PPI before the development of AKI occurred in 4 out of these 5 patients. CONCLUSION: Patients receiving combination therapy with checkpoint inhibitors are at high risk of AKI, but different causes of AKI should always be considered. Use of PPI concurrently with ICIs is likely to increase the risk of AKI.

Associations Between Albuminuria, Estimated GFR and Cardiac Phenotype in a Cohort with Chronic Kidney Disease: The CPH-CKD ECHO Study.

OBJECTIVE: Echocardiographic findings in chronic kidney disease (CKD) vary. We sought to estimate the prevalence of abnormal cardiac structure and function in patients with CKD and their association to estimated glomerular filtration rate (eGFR) and urine albumin/creatinine ratio (UACR). METHODS: We prospectively enrolled 825 outpatients with non-dialysis-dependent CKD, mean age 58± 13 yrs, and 175 matched healthy controls, mean age 60±12 yrs. Echocardiography included assessment of left ventricular (LV) hypertrophy, LV ejection fraction (LVEF), global longitudinal strain (GLS) and diastolic dysfunction according to ASE/EACVI guidelines. RESULTS: LV hypertrophy was found in 9% of patients vs. 1.7% of controls (p=0.005) was independently associated with UACR (p=0.002). Median LVEF was 59.4% (IQR 55.2, 62.8) in patients vs. 60.8% (57.7, 64.1) in controls (p=0.002). GLS was decreased in patients with eGFR <60ml/min/1.73m² (-17.6%±3.1%) vs. patients with higher eGFR (19.0%±2.2%, p<0.001), who were similar to controls. Diastolic dysfunction was detected in 55% of patients and in 34% of controls. LIMITATIONS: Non-random sampling, cross-sectional analysis. CONCLUSIONS: We report lower prevalence of hypertrophy than previous studies, but similar measurements of systolic and diastolic function. Cardiac remodeling in CKD may be influenced by treatment modalities, demographics, comorbidities and renal pathology.

The effect of increasing dialysate magnesium on calciprotein particles, inflammation and bone markers: post hoc analysis from a randomized controlled clinical trial.

BACKGROUND: The formation of calciprotein particles (CPPs) may be an important component of the humoral defences against ectopic calcification. Although magnesium (Mg) has been shown to delay the transition of amorphous calcium-/phosphate-containing primary CPP (CPP-1) to crystalline apatite-containing secondary CPP (CPP-2) ex vivo, effects on the endogenous CPP pool are unknown. METHODS: We used post hoc analyses from a randomized double-blind parallel-group controlled clinical trial of 28 days treatment with high dialysate Mg of 2.0 mEq/L versus standard dialysate Mg of 1.0 mEq/L in 57 subjects undergoing maintenance hemodialysis for end-stage kidney disease. CPP load, markers of systemic inflammation and bone turnover were measured at baseline and follow-up. RESULTS: After 28 days of treatment with high dialysate Mg, serum total CPP (-52%), CPP-1 (-42%) and CPP-2 (-68%) were lower in the high Mg group (all P < 0.001) but were unchanged in the standard dialysate Mg group. Tumour necrosis factor-α (-20%) and interleukin-6 (-22%) were also reduced with high dialysate Mg treatment (both P < 0.01). High dialysate Mg resulted in higher levels of bone-specific alkaline phosphatase (a marker of bone formation) (+17%) but lower levels of tartrate-resistant acid phosphatase 5 b (a marker of bone resorption; -33%) (both P < 0.01). Inflammatory cytokines and bone turnover markers were unchanged in the standard dialysate Mg group over the same period. CONCLUSIONS: In this exploratory analysis, increasing dialysate Mg was associated with reduced CPP load and systemic inflammation and divergent changes in markers of bone formation and resorption.

Placental transverse relaxation time (T2) estimated by MRI: Normal values and the correlation with birthweight.

INTRODUCTION: Placental transverse relaxation time (T2) assessed by MRI may have the potential to improve the antenatal identification of small for gestational age. The aims of this study were to provide normal values of placental T2 in relation to gestational age at the time of MRI and to explore the correlation between placental T2 and birthweight. MATERIAL AND METHODS: A mixed cohort of 112 singleton pregnancies was retrieved from our placental MRI research database. MRI was performed at 23.6-41.3 weeks of gestation in a 1.5T system (TE (8): 50-440 ms, TR: 4000 ms). Normal pregnancies were defined by uncomplicated pregnancies with normal obstetric outcome and birthweight deviation within ±1 SD of the expected for gestational age. The correlation between placental T2 and birthweight was investigated using the following outcomes; small for gestational age (birthweight ≤-2 SD of the expected for gestational age) and birthweight deviation (birthweight Z-scores). RESULTS: In normal pregnancies (n = 27), placenta T2 showed a significant negative linear correlation with gestational age (r = -.91, P = .0001) being 184 ms ± 15.94 ms (mean ± SD) at 20 weeks of gestation and 89 ms ± 15.94 ms at 40 weeks of gestation. Placental T2 was significantly reduced among small-for-gestational-age pregnancies (mean Z-score -1.95, P < .001). Moreover, we found a significant positive correlation between placenta T2 deviation (Z-score) and birthweight deviation (Z-score) (R2  = .26, P = .0001). CONCLUSIONS: This study provides normal values of placental T2 to be used in future studies on placental MRI. Placental T2 is closely related to birthweight and may improve the antenatal identification of small-for-gestational-age pregnancies.

Understanding Bone Disease in Patients with Diabetic Kidney Disease: a Narrative Review.

PURPOSE OF REVIEW: Both diabetes and kidney disease associate with the development of bone disease and an increased risk of fragility fractures. The etiologies of bone disease in patients with diabetic kidney disease (DKD) are multiple and complex. This review explores the association between DKD and bone disease and discusses how the presence of both diabetes and kidney disease may impair bone quality and increase fracture risk. Diagnostic tools as well as future research areas are also discussed. RECENT FINDINGS: Patients with DKD have an increased risk of fragility fracture, most pronounced in patients with type 1 diabetes, and in DKD a high prevalence of adynamic bone disease is found. Recent studies have demonstrated disturbances in the interplay between bone regulating factors in DKD, such as relative hypoparathyroidism and alterations of bone-derived hormones including fibroblast growth factor-23 (FGF-23), sclerostin and klotho, which lead to bone disease. This review examines the current knowledge on bone disease in patients with DKD, clinical considerations for patient care, as well as subjects for future research.

Screening for small-for-gestational-age fetuses.

INTRODUCTION: It is well established that correct antenatal identification of small-for-gestational-age (SGA) fetuses reduces their risk of adverse perinatal outcome with long-term consequences. Ultrasound estimates of fetal weight (EFWus ) are the ultimate tool for this identification. It can be conducted as a "universal screening", that is, all pregnant women at a specific gestational age. However, in Denmark it is conducted as "selective screening", that is, only on clinical indication. The aim of this study was to assess the performance of the Danish national SGA screening program and the consequences of false-positive and false-negative SGA cases. MATERIAL AND METHODS: In this retrospective cohort study, we included 2928 women with singleton pregnancies with due dates in 2015. We defined "risk of SGA" by an EFWus  ≤ -15% of expected for the gestational age and "SGA" as birthweight ≤-22% of expected for gestational age. RESULTS: At birth, the prevalence of SGA was 3.3%. The overall sensitivity of the Danish screening program was 62% at a false-positive rate of 5.6%. Within the entire cohort, 63% had an EFWus compared with 79% of the SGA cases. The sensitivity was 79% for those born before 37 weeks of gestation but only 40% for those born after 40 weeks of gestation. The sensitivity was also associated with birthweight deviation; 73% among extreme SGA cases (birthweight deviation ≤-33%) and 55% among mild SGA (birthweight deviation between -22% and -27%). False diagnosis of SGA was associated with an increased rate of induction of labor (ORadj  = 2.51, 95% CI 1.70-3.71) and cesarean section (ORadj  = 1.44, 95% CI 0.96-2.18). CONCLUSIONS: The performance of the Danish national screening program for SGA based on selective EFWus on clinical indication has improved considerably over the last 20 years. Limitations of the program are the large proportion of women referred to ultrasound scan and the low performance post-term.

Risk of fracture in adults on renal replacement therapy: a Danish national cohort study.

BACKGROUND: Patients on dialysis treatment or living with a transplanted kidney have several risk factors for bone fracture, especially disturbances in mineral metabolism and immunosuppressive therapy. We describe the incidence of fracture in this retrospective national Danish cohort study and explore the influence of age, gender, comorbidity and prescribed medication. METHODS: By individual-level linkage between nationwide administrative registries, the risk of fracture was compared between the group of patients receiving chronic dialysis treatment and patients receiving their first renal transplant in the study period, using the Danish background population as reference group. All three groups were followed up until first fracture, emigration, death or end of study. Cox proportional hazard models with fracture as outcome were fitted to the data. RESULTS: The hazard ratio (HR) for any fracture was 3.14 [95% confidence interval (95% CI):2.97-3.31] in the dialysis group and 1.94 (95% CI: 1.72-2.18) in the renal transplanted group. The HR remained increased, but was modified by adjustment for age, gender, comorbidity and prior fracture [dialysis group: 1.85 (95% CI: 1.75-1.95); renal transplanted group: 1.82 (95% CI: 1.62-2.06)]. Prescribed diuretics, lipid-modifying agents and proton pump inhibitors also modulated the fracture risk. CONCLUSIONS: Patients on dialysis or living with a transplanted kidney have a significantly higher risk of fracture than the Danish background population. Differences in age, gender, drug use and comorbidity only partly explain this increased risk. Further studies are warranted to explore the reason for this increased fracture risk in patients on renal replacement therapy.

The influence of vitamin D analogs on calcification modulators, N-terminal pro-B-type natriuretic peptide and inflammatory markers in hemodialysis patients: a randomized crossover study.

BACKGROUND: The risk of cardiovascular disease is tremendously high in dialysis patients. Dialysis patients treated with vitamin D analogs show decreased cardiovascular morbidity and mortality compared with untreated patients. We examined the influence of two common vitamin D analogs, alfacalcidol and paricalcitol, on important cardiovascular biomarkers in hemodialysis patients. Anti-inflammatory effects and the influence on regulators of vascular calcification as well as markers of heart failure were examined. METHODS: In 57 chronic hemodialysis patients enrolled in a randomized crossover trial comparing paricalcitol and alfacalcidol, we examined the changes in osteoprotegerin, fetuin-A, NT-proBNP, hs-Crp, IL-6 and TNF-α, during 16 weeks of treatment. RESULTS: NT-proBNP and osteoprotegerin increased comparably in the paricalcitol and alfacalcidol-treated groups. Fetuin-A increased significantly in the alfacalcidol-treated group compared with the paricalcitol-treated group (difference 32.84 µmol/l (95% C.I.; range 0.21-67.47)) during the first treatment period. No difference was found between the groups during the second treatment period, and IL-6, TNF-α and hs-Crp were unchanged in both treatment groups. CONCLUSIONS: Paricalcitol and alfacalcidol modulate regulators of vascular calcification. Alfacalcidol may increase the level of the calcification inhibitor fetuin-A. We did not find any anti-inflammatory effect or difference in changes of NT-proBNP. TRIAL REGISTRY: ClinicalTrials.gov NCT00469599 May 3 2007.

Long-term cardiovascular events, graft failure, and mortality in kidney transplant recipients.

BACKGROUND: Kidney transplant recipients are at increased risks of cardiovascular events, but contemporary risk estimates are sparse. Using the Danish nationwide administrative databases, we quantified 1- and 5-year risks of cardiovascular disease and kidney failure among all first-time kidney transplant recipients (2005-2018) and age- and sex-matched controls (1:10 ratio). METHODS: Cumulative 1- and 5-year incidence of cardiovascular events (myocardial infarction, stroke, or heart failure), kidney failure (re-transplantation or need for dialysis >30 days post-transplant), and mortality following transplantation were calculated until maximally Dec 31, 2018. RESULTS: A total of 2,565 kidney transplant recipients (median age 50.5 [25-75th percentile 40.2-60.7] years, 37 % females) and 25,650 controls were included. 1-year cumulative incidence of myocardial infarction, stroke, or heart failure was 2.6 % (95 % confidence interval 1.9 %-3.2 %) among kidney transplant recipients versus 0.5 % (0.4 %-0.5 %) in controls. Cumulative 5-year risk estimates for the same endpoints were 8.3 % (7.1 %-9.5 %) for the transplant patients, and 2.6 % (2.3 %-2.8 %) among controls, respectively. For the kidney transplant cohort, cumulative mortality was 2.2 % (1.7 %-2.8 %) and 10.3 % (9.0 %-11.6 %) at 1- and 5 years, respectively, versus 0.5 % (0.4 %-0.6 %) and 3.0 % (2.7 %-3.2 %) for controls. The cumulative incidence of dialysis and re-transplantation was 6.1 % (5.2 %-7.1 %) at 1 year and 16.3 % (14.7 %-17.9 %) at 5 years, respectively. CONCLUSIONS: Despite the benefits of transplantation, kidney transplant recipients continue to have significant long-term cardiovascular disease, end-stage kidney disease, and mortality risks even with contemporary medical management. Better cardiovascular preventive strategies are warranted to improve prognosis in this segment of patients.

Myocardial work in chronic kidney disease: insights from the CPH-CKD ECHO Study.

BACKGROUND: Myocardial work is a novel echocardiographic measure that offers detailed insights into cardiac mechanics. We sought to characterize cardiac function by myocardial work in patients with chronic kidney disease (CKD). METHODS: We prospectively enrolled 757 patients with non-dialysis-dependent CKD and 174 age- and sex-matched controls. Echocardiographic pressure-strain loop analysis was performed to acquire the global work index (GWI). Linear regressions were performed to investigate the association between estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) to GWI. RESULTS: Patients with CKD had a mean age of 57 years, 61% were men, and median eGFR was 42 mL/min/1.73 m2. Overall, no difference in GWI was observed between patients and controls (1879 vs. 1943 mmHg%, p = 0.06). However, a stepwise decline in GWI was observed for controls vs. patients with CKD without left ventricular hypertrophy vs. patients with CKD and left ventricular hypertrophy (GWI, 1943 vs. 1887 vs. 1789 mmHg%; p for trend = 0.030). In patients with CKD, eGFR was not associated with GWI by linear regression. However, diabetes modified this association (p for interaction = 0.007), such that per 10 mL/min/1.73 m2 decrease in eGFR, GWI decreased by 22 (9-35) mmHg% (p = 0.001) after multivariable adjustments in patients without diabetes, but with no association between eGFR and GWI in patients with diabetes. No association was observed between UACR and GWI. CONCLUSION: Patients with CKD and left ventricular hypertrophy exhibited lower myocardial work compared to matched controls. Furthermore, decreasing eGFR was associated with decreasing myocardial work only in patients without diabetes. No association to UACR was observed.

The role of aetiology in cardiac manifestations of chronic kidney disease: the CPH-CKD ECHO study.

PURPOSE: We investigated the associations between cardiac parameters and aetiologies of CKD in an exploratory study. METHODS: The study population consisted of 883 participants, 174 controls and 709 patients with aetiologies of CKD including diabetic nephropathy/renovascular KD in diabetes mellitus, hypertensive/renovascular nephropathy, tubulointerstitial nephritis, glomerulonephritis/vasculitis, polycystic KD (PKD), and CKD of unknown origin. Echocardiographic measures included left ventricular (LV) ejection fraction, global longitudinal, area, and radial strain, E/e' ratio, and LV mass index. These were compared between each aetiological group and controls in unadjusted and adjusted analysis. RESULTS: In unadjusted analysis, patients with diabetic nephropathy/renovascular KD in diabetes mellitus, had impaired LV ejection fraction (Median [IQR]: 56% [49.9,60.69] vs. 60.8% [57.7,64.1]), global longitudinal (mean ± SD: 13.1 ± 3.5% vs. 15.5 ± 2.6%), area (24.1 ± 5.8% vs. 28.5 ± 4.2%), and radial strain (36.2 ± 11.2% vs. 44.1 ± 9.7%), and increased LV mass index (89.1 g/m2 [71.8,104.9] vs. 69,0 g/m2 [57.9,80.8]) and E/e' ratio (10.6 [8.5,12.6] vs. 7 [5.8,8.3], p < 0.001 for all) compared with controls. Associations were similar for CKD of unknown origin. Patients with hypertensive/renovascular nephropathy had impaired global longitudinal and area strain, and higher E/e' ratio. Patients with glomerulonephritis/vasculitis had higher LV mass index, while patients with PKD had better global longitudinal strain than controls. All findings remained significant in adjusted analysis, except for the impaired global longitudinal strain in hypertensive/renovascular nephropathy. CONCLUSION: Glomerulonephritis/vasculitis, hypertensive/renovascular nephropathy, CKD of unknown origin, and diabetic nephropathy/renovascular KD in diabetes mellitus were increasingly associated with adverse cardiac findings, while PKD and tubulointerstitial nephritis were not. Aetiology might play a role regarding the cardiac manifestations of CKD.

Shared and Distinct Renal Transcriptome Signatures in 3 Standard Mouse Models of Chronic Kidney Disease.

INTRODUCTION: Several mouse models with diverse disease etiologies are used in preclinical research for chronic kidney disease (CKD). Here, we performed a head-to-head comparison of renal transcriptome signatures in standard mouse models of CKD to assess shared and distinct molecular changes in three mouse models commonly employed in preclinical CKD research and drug discovery. METHODS: All experiments were conducted on male C57BL/6J mice. Mice underwent sham, unilateral ureter obstruction (UUO), or unilateral ischemic-reperfusion injury (uIRI) surgery and were terminated two- and 6-weeks post-surgery, respectively. The adenine-supplemented diet-induced (ADI) model of CKD was established by feeding with adenine diet for 6 weeks and compared to control diet feeding. For all models, endpoints included plasma biochemistry, kidney histology, and RNA sequencing. RESULTS: All models displayed increased macrophage infiltration (F4/80 IHC) and fibrosis (collagen 1a1 IHC). Compared to corresponding controls, all models were characterized by an extensive number of renal differentially expressed genes (≥11,000), with a notable overlap in transcriptomic signatures across models. Gene expression markers of fibrosis, inflammation, and kidney injury supported histological findings. Interestingly, model-specific transcriptome signatures included several genes representing current drug targets for CKD, emphasizing advantages and limitations of the three CKD models in preclinical target and drug discovery. CONCLUSION: The UUO, uIRI, and ADI mouse models of CKD have significant commonalities in their renal global transcriptome profile. Model-specific renal transcriptional signatures should be considered when selecting the specific model in preclinical target and drug discovery.

Protocol for a randomised controlled trial comparing warfarin with no oral anticoagulation in patients with atrial fibrillation on chronic dialysis: the Danish Warfarin-Dialysis (DANWARD) trial.

INTRODUCTION: Atrial fibrillation is highly prevalent in patients on chronic dialysis. It is unclear whether anticoagulant therapy for stroke prevention is beneficial in these patients. Vitamin K-antagonists (VKA) remain the predominant anticoagulant choice. Importantly, anticoagulation remains inconsistently used and a possible benefit remains untested in randomised clinical trials comparing oral anticoagulation with no treatment in patients on chronic dialysis. The Danish Warfarin-Dialysis (DANWARD) trial aims to investigate the safety and efficacy of VKAs in patients with atrial fibrillation on chronic dialysis. The hypothesis is that VKA treatment compared with no treatment is associated with stroke risk reduction and overall benefit. METHODS AND ANALYSIS: The DANWARD trial is an investigator-initiated trial at 13 Danish dialysis centres. In an open-label randomised clinical trial study design, a total of 718 patients with atrial fibrillation on chronic dialysis will be randomised in a 1:1 ratio to receive either standard dose VKA targeting an international normalised ratio of 2.0-3.0 or no oral anticoagulation. Principal analyses will compare the risk of a primary efficacy endpoint, stroke or transient ischaemic attack and a primary safety endpoint, major bleeding, in patients allocated to VKA treatment and no treatment, respectively. The first patient was randomised in October 2019. Patients will be followed until 1 year after the inclusion of the last patient. ETHICS AND DISSEMINATION: The study protocol was approved by the Regional Research Ethics Committee (journal number H-18050839) and the Danish Medicines Agency (case number 2018101877). The trial is conducted in accordance with the Helsinki declaration and standards of Good Clinical Practice. Study results will be disseminated to participating sites, at research conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: NCT03862859, EUDRA-CT 2018-000484-86 and CTIS ID 2022-502500-75-00.