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.

Elevated intraneural vascularization of the median nerve proximal to the arteriovenous fistula in hemodialysis patients suspected of carpal tunnel syndrome: A case series.

Patients with end-stage kidney disease may require creation of an arteriovenous fistula in order to receive hemodialysis treatment. The creation may result in several complications, including carpal tunnel syndrome. Early diagnosis and treatment are essential to relieve symptoms, prevent permanent nerve damage, and improve quality of life. However, the sensory and motor disturbances resembling carpal tunnel syndrome could be related to other etiologies than external compression of the median nerve underneath the transverse ligament. This case report presents eight patients with a radiocephalic arteriovenous fistula, who all had symptoms of carpal tunnel syndrome. Ultrasonographic examination showed a segmental intraneural hypervascularization of a large vessel inside the median nerve proximal to the wrist and arteriovenous fistula anastomosis with garland-like course as well as multiple flow velocities. The neurophysiological findings showed a significant decreased velocity in the ipsilateral forearm to the arteriovenous fistula.

Intravascular volumes and the influence on anemia assessed by a carbon monoxide rebreathing method in patients undergoing maintenance hemodialysis.

INTRODUCTION: Fluid overload is a major challenge in hemodialysis patients and might cause hypervolemia. We speculated that hemodialysis patients reaching dry weight could have undetected hypervolemia and low hemoglobin (Hb) concentration (g/dL) due to hemodilution. METHODS: The study included hemodialysis patients (n = 22) and matched healthy controls (n = 22). Blood volume, plasma volume, red blood cell volume, and total Hb mass were determined using a carbon monoxide (CO)-rebreathing method in hemodialysis patients reaching dry weight and controls. Blood volume measurements were also obtained by a dual-isotope labeling technique in a subgroup for validation purposes. FINDINGS: In the hemodialysis group, the median specific blood volume was 89.3 mL/kg (interquartile range [IQR]: 76.7-95.4 mL/kg) and was higher than in the control group (79.9 mL/kg [IQR: 70.4-88.0 mL/kg]; p < 0.037). The median specific plasma volume was 54.7 mL/kg (IQR: 47.1-61.0 mL/kg) and 44.0 mL/kg (IQR: 38.7-49.5 mL/kg) in the hemodialysis and control groups, respectively (p < 0.001). Hb concentration was lower in hemodialysis patients (p < 0.001), whereas no difference in total Hb mass was observed between groups (p = 0.11). A correlation was found between blood volume measured by the CO-rebreathing test and the dual-isotope labeling technique in the control group (r = 0.83, p = 0.015), but not the hemodialysis group (r = 0.25, p = 0.60). DISCUSSION: The hemodialysis group had increased specific blood volume at dry weight due to high plasma volume, suggesting a hypervolemic state. However, correlation was not established against the dual-isotope labeling technique underlining that the precision of the CO-rebreathing test should be further validated. The total Hb mass was similar between hemodialysis patients and controls, unlike Hb concentration, which emphasizes that Hb concentration is an inaccurate marker of anemia among hemodialysis patients.

Cardiac arrhythmia and hypoglycaemia in patients receiving haemodialysis with and without diabetes (the CADDY study): protocol for a Danish multicentre cohort study.

INTRODUCTION: Patients receiving haemodialysis are at increased risk of arrhythmias and sudden cardiac death, but data on arrhythmia burden and the pathophysiology remain limited. Among potential risk factors, hypoglycaemia is proposed as a possible trigger of lethal arrhythmias. The development of implantable loop recorders (ILR) and continuous glucose monitoring (CGM) enables long-term continuous ECG and glycaemic monitoring. The current article presents the protocol of a study aiming to increase the understanding of arrhythmias and risk factors in patients receiving haemodialysis. The findings will provide a detailed exploration of the burden and nature of arrhythmias in these patients including the potential association between hypoglycaemia and arrhythmias. METHODS AND ANALYSIS: The study is an investigator-initiated, prospective, multicentre cohort study recruiting 70 patients receiving haemodialysis: 35 with diabetes and 35 without diabetes. Participants are monitored with ILRs and CGM for 18 months follow-up. Data collection further includes a monthly collection of predialysis blood samples and dialysis parameters. The primary outcome is the presence of clinically significant arrhythmias defined as a composite of bradycardia, ventricular tachycardia, or ventricular fibrillation. Secondary outcomes include the characterisation of clinically significant arrhythmias and other arrhythmias, glycaemic characteristics, and mortality. The data analyses include an assessment of the association between arrhythmias and hypoglycaemia and hyperglycaemia, baseline clinical variables, and parameters related to kidney failure and the haemodialysis procedure. ETHICS AND DISSEMINATION: The study has been approved by the Ethics Committee of the Capital Region of Denmark (H-20069767). The findings will be presented at national and international congresses as well as in international peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT04841304.

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.

A question to the physician from a patient on hemodialysis: Would it be safe to run a marathon? A case report.

A patient on maintenance hemodialysis asked his physician if it would be safe for him to run a marathon. For healthy persons, studies show that it is relatively safe. Very few data are available on patients on hemodialysis performing out of center endurance exercise. To address this question, we conducted a clinical study to investigate the electrolyte derangements during different running distances. Our main concern was development of hyperkalemia. We present a case of an anuric hemodialysis patient, who ran eight different runs with a maximum distance of 32.2 km. Blood was analyzed before and after the runs. We did not find severe hyperkalemia at any point. According to this study, we found no signs of increased risk.

Acute hemodynamic changes during far infrared treatment of the arteriovenous fistula in hemodialysis patients.

BACKGROUND: The arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis (HD) treatment and preservation of a stable vascular access is crucial. Long term Far Infrared Radiation (FIR) has been found to increase access flow together with an enhanced maturation and patency of the AVF. The acute effects of FIR on access flow have been sparsely described and the results are contradictory, perhaps due to differences in measurement conditions and other factors of importance for access flow. METHODS: Twenty patients in HD with an AVF were included. Each patient was randomized to receive either FIR (FIR group) or no FIR (control group). The acute changes in access flow were investigated in both groups on the second dialysis day of the week and during the first 1.5 h of the dialysis session. Concomitant changes in hemodynamic parameters of importance for access flow were also explored. RESULTS: There was no significant change in access flow in the FIR group compared with the control group (median (Interquartile Range)) (-10 (-413.8; 21.3) ml/min vs -17.5 (-83.8; 76.3) ml/min, p = 0.58). There was no significant difference in any of the hemodynamic parameters between the FIR and the control group; cardiac output (-0.7 (-1.2; -0.2) l/min vs -0.4 (-0.9; 0.1) l/min, p = 0.58), cardiac index (-0.3 (-0.5; -0.1)) l/min/m2 vs -0.3 (-0.4; 0) l/min/m2, p = 0.68), mean arterial pressure (5.5 (-1.8; 8.4) mmHg vs 1.5 (-3; 6.3) mmHg, p = 0.35) and total peripheral resistance (2 (1.8; 3.4) mmHg × min/l vs 1 (-0.3; 3.1) mmHg × min/l, p = 0.12). CONCLUSION: In this trial, with a highly standardized set-up, one session of FIR did not result in any acute changes in access flow. This was not due to differences in the hemodynamic parameters between the groups.

Stable incidence and survival of arteriovenous fistulas over 39 years: A long-term national cohort study.

INTRODUCTION: The age and number of comorbidities in the hemodialysis population has increased over time. This may influence the construction and survival of the arteriovenous fistula (AVF). The present study explored the incidence and survival of AVFs over a period of 39 years. METHODS: A retrospective cohort study was conducted based on Danish registries. Incident hemodialysis patients between 1977 and 2015 were included. The incidence of AVF and factors associated with the construction of an AVF were described. Risk factors for AVF survival and repair were explored by Kaplan Meier and Cox proportional hazard analysis. RESULTS: The total number of arteriovenous accesses (AVF and arteriovenous grafts) were 10,187 and there were 4201 central venous catheters (CVC). No significant difference in the proportion of AVFs during the 39 years was seen. Age and renal diagnosis did not influence the proportion of AVFs. Patients with CVCs were found to have a significantly higher prevalence of comorbidities (p < 0.01). AVF survival remained stable during the 39 years. The first constructed AVF had the best survival, 35% still functioning after 15 years. Factors such as brachiocephalic AVF, female sex, and diabetic nephropathy increased the risk of AVF failure (Odds Ratio (OR): 2.46, 95% Confidence Interval (CI) (2.29-2.65), 1.17 (1.10-1.25), and 1.21 (1.12-1.3)), respectively. CONCLUSION: Despite an older dialysis population, the proportion and survival of the AVF in the Danish dialysis population has not changed, probably because of increased awareness of AVF as the first choice of vascular access and improved surveillance, surgery, and repair.

Weight Loss Challenges in Achieving Transplant Eligibility in Patients With Kidney Failure: A Qualitative Study.

Rationale & Objective: Patients with kidney failure need kidney replacement therapy to maximize survival. Kidney transplant is a superior mode of kidney replacement therapy for most individuals with kidney failure. Patients with obesity often are not approved for kidney transplant until they lose sufficient weight, as obesity may complicate the surgical procedure, and the risk of graft loss increases with a higher body mass index. To help potential kidney transplant recipient candidates lose weight, further knowledge of their thoughts, feelings, and attitudes is needed. Study Design: Qualitative study with semistructured interviews and an exploratory research design, guided by qualitative content analysis. Setting & Participants: Patients at a hospital in Denmark required to lose weight to achieve kidney transplant eligibility. Analytical Approach: From patients' responses, we identified descriptive themes using a phenomenological approach. The factors affecting outcomes were derived reflexively from these themes. Results: Ten interviews were analyzed. Experiences of obesity and weight-loss attempts were described across 4 themes; (1) restrictions and exhaustion, (2) hope and hopelessness, (3) support and self-discipline, and (4) motivation based on severity. A major motivating factor to achieving weight loss in the studied group of patients was their declining kidney function and the fact that kidney transplant cannot be considered until sufficient weight loss is achieved. Limitations: Thematic saturation was reached after an unexpectedly low number of participants. The patients were only interviewed once and over the phone. Conclusions: Patients with obesity who are seeking kidney transplant need additional help with the dietary restrictions brought on by kidney disease. They need assistance bridging between a kidney-friendly diet and a sustainable diet that will ensure weight loss. These patients also express not wanting to feel alone in their weight-loss battle. They are looking for help and support to achieve weight loss.

Flow reduction of a high-flow arteriovenous fistula in a hemodialysis patient reveals changes in natriuretic and renin-angiotensin system hormones of relevance for kidney function.

Arteriovenous fistulas (AVFs) are iatrogenic vascular connections established to allow high-flow intravascular access for patients with chronic kidney disease requiring hemodialysis. The left-right flow shunt results in changes in extracellular fluid volume and blood pressure-controlling hormones that could affect the residual kidney function. We present a case where a female patient with a brachiocephalic AVF had a fistula flow of >4 L/min. To reduce the flow, a banding procedure was performed. The patient was examined prior to banding and 1 and 2 weeks thereafter. Banding resulted in a marked decrease in AVF flow from >4 to 1 L/min and was associated with reductions in N-terminal pro-brain natriuretic peptide of 51% and 67% at 1- and 2-weeks post-banding, respectively. Mid-regional pro-atrial natriuretic peptide concentrations were reduced post-banding by 17% after 1 week and 25% after 2 weeks. After 1 week, renin, angiotensin II, and aldosterone levels in plasma decreased transiently by 44%, 47%, and >86%, respectively, and returned to pre-banding levels after 2 weeks. Creatinine clearance tended to decrease while blood pressure and total body water increased 2 weeks after banding. This indicates that high-flow AVF is associated with increased natriuretic peptides and hormones of the renin-angiotensin-aldosterone system, that may balance each other regarding fluid retention and hypertension and support remaining kidney function.

Developments in the Histopathological Classification of ANCA-Associated Glomerulonephritis.

BACKGROUND AND OBJECTIVES: The histopathologic classification for ANCA-associated GN distinguishes four classes on the basis of patterns of injury. In the original validation study, these classes were ordered by severity of kidney function loss as follows: focal, crescentic, mixed, and sclerotic. Subsequent validation studies disagreed on outcomes in the crescentic and mixed classes. This study, driven by the original investigators, provides several analyses in order to determine the current position of the histopathologic classification of ANCA-associated GN. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A validation study was performed with newly collected data from 145 patients from ten centers worldwide, including an analysis of interobserver agreement on the histopathologic evaluation of the kidney biopsies. This study also included a meta-analysis on previous validation studies and a validation of the recently proposed ANCA kidney risk score. RESULTS: The validation study showed that kidney failure at 10-year follow-up was significantly different between the histopathologic classes (P<0.001). Kidney failure at 10-year follow-up was 14% in the crescentic class versus 20% in the mixed class (P=0.98). In the meta-analysis, no significant difference in kidney failure was also observed when crescentic class was compared with mixed class (relative risk, 1.15; 95% confidence interval, 0.94 to 1.41). When we applied the ANCA kidney risk score to our cohort, kidney survival at 3 years was 100%, 96%, and 77% in the low-, medium-, and high-risk groups, respectively (P<0.001). These survival percentages are higher compared with the percentages in the original study. CONCLUSIONS: The crescentic and mixed classes seem to have a similar prognosis, also after adjusting for differences in patient populations, treatment, and interobserver agreement. However, at this stage, we are not inclined to merge the crescentic and mixed classes because the reported confidence intervals do not exclude important differences in prognosis and because an important histopathologic distinction would be lost.

[Diabetes mellitus caused by cannabis oil].

The effects and side effects of medical cannabis are not well-established. In 2018, cannabis was approved as a medical drug in Denmark - giving all doctors the opportunity to subscribe medical cannabis to their patients. In this case report a 64-year-old kidney-transplanted woman started cannabis droplets due to chronic back pain, which resulted in increased appetite, weight gain and development of diabetes mellitus. Patients with an increased risk of developing diabetes may be more prone to this under the treatment with cannabis. Further studies are needed.

Apolipoprotein M in patients with chronic kidney disease.

BACKGROUND AND AIMS: Plasma apolipoprotein M (APOM) is bound to HDL-particles and has anti-atherogenic effects. The present study explored whether plasma APOM is reduced in patients with chronic kidney disease (CKD), and associated with cardiovascular disease (CVD). In addition, we tested the hypothesis that the excretion of APOM into the urine is increased in patients with kidney disease. METHODS: Plasma samples were collected from a cohort of patients with CKD stages 1 to 5D (N = 409) and controls (N = 35). Urine was collected from 47 subjects. Plasma APOM was measured with sandwich ELISA and urine APOM with competitive ELISA. RESULTS: Plasma APOM levels were reduced in patients with CKD stages 3-5D as compared to patients with CKD stages 1 + 2 and controls (p < 0.01). CKD patients with known CVD displayed even further reduction in plasma APOM levels than CKD patients without known CVD (p < 0.001). Fast-phase liquid chromatography showed that plasma APOM was primarily associated with HDL-cholesterol (HDL-C) across CKD stages. Accordingly, when plasma APOM values were corrected for HDL-C, a significant difference only persisted between patients with CKD stage 3 and stages 1 + 2 (p < 0.05), and the difference between CKD patients with and without known CVD disappeared. Urine APOM/creatinine ratio was not significantly increased in patients with kidney disease. CONCLUSIONS: The results show that the difference in plasma APOM levels observed between patients with mild and advanced CKD may mainly be due to differences in plasma HDL-C. Whether APOM plays a role in human uremic atherogenesis warrants further experimental studies.

[Primary membranous nephropathy presenting as relapsing ascites].

Ascites is common in patients with liver cirrhosis. It may present as a clinical manifestation in nephrotic syndrome in adults, typically with heart- or liver disease together with other oedema. We describe a 64-year-old male patient - with no liver or heart disease - with relapsing ascites and no other oedema, who was surprisingly diagnosed with primary membranous nephropathy (MN), and the autoantibody anti-PLA2R was positive. Through immunotherapy the ascites disappeared. Anti-PLA2R and anti-TSHD7A can be used in the diagnosis (primary/secondary MN) and may play a role in the treatment and prognosis.

Treatment of a soft tissue calcification in a patient receiving peritoneal dialysis.

Chronic Kidney Disease patients suffer from Mineral and Bone Disorder (CKD-MBD) leading to increased vascular and soft-tissue calcification. The prevalence of soft tissue calcification in dialysis patients is not well described, and most cases describe such calcifications in hemodialysis patients. We describe a case of a massive soft tissue calcification in the right gluteal region in a peritoneal dialysis patient. The patient had severe pain and were disabled. The treatment was converted to an intensive hemodialysis regimen with a minimal calcium load and high dose of cinacalcet. During the treatment, the calcification diminished rapidly from a diameter of 26.6 to 2.9 cm, and the patient symptoms were relieved, leaving the patient with no pain or restriction in mobilization.