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BACKGROUND: Hypertension affects 25-30% of the world population. Hydrochlorothiazide (HCTZ) is among the most used and cheapest medications but was in 2018 labeled with a warning stating increased risk of non-melanoma skin cancer (NMSC). This study describes geographical differences in the association between HCTZ and NMSC in a perspective of hypertensive heart disease (HHD). METHODS: We conducted a systematic literature search (PubMed, Embase, Clinicaltrial.gov, and Clinicaltrial.eu) using PICO/PECO acronyms including case-control, cohort, and randomized controlled trials. We constructed a rate ratio of disability-adjusted life years (DALY) for HHD/NMSC in global burden of disease (GBD) regions. RESULTS: No increased risk of NMSC with use of HCTZ was found in Taiwan, India, and Brazil. A small (hazard ratio (HR)/odds ratio (OR) ≤ 1.5) but significantly increased risk was seen in Canada, USA, and Korea. An increased risk (1.5 < HR/OR ≤ 2.5) in Iceland, Spain, and Japan and a highly increased risk (HR/OR > 2.5 in UK, Denmark, Netherlands, and Australia. HHD is associated with a more than 10-fold DALY rate compared with NMSC in 13 of 21 GBD regions corresponding 77.2% of the global population. In none of these 13 regions were there an increased risk of HCTZ-associated NMSC. CONCLUSIONS: Despite limited information from many countries, our data point to large geographical differences in the association between HCTZ and NMSC. In all GBD regions, except Australasia, HHD constitutes a more than 5-fold DALY rate compared to NMSC. This disproportionate risk should be considered before avoiding HCTZ as part of the antihypertensive treatment.

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Fibromuscular dysplasia (FMD) is a disease of the musculature of arterial walls leading to stenoses, aneurysms, and dissections. The purpose of this report was to summarize the evidence for (1) one-time routine imaging from brain-to-pelvis and (2) lifelong antiplatelet therapy, for example, aspirin, for patients diagnosed with FMD as suggested by an international consensus report from 2019. PubMed was systematically searched, and the evidence providing a basis for the current consensus points, as well as articles published since, were reviewed. In four registries evaluating patients with FMD, the prevalence of multivessel involvement, aneurysms, and dissections was reported to be 43.5%-66.3%, 21.6%-30.6%, and 5.6%-28.1%, respectively. Any antiplatelet drug was used in 72.9% of patients, and aspirin was prescribed in up to 70.2% of patients. Based on the high prevalence of vascular manifestations, their associated morbidity, and the potential for endovascular or surgical intervention, the suggestion of one-time brain-to-pelvis screening with computed tomography angiography or magnetic resonance angiography is well supported. Contrarily, the evidence to support the consensus statement of lifelong antiplatelet therapy to all patients in the absence of contraindications is more uncertain since a beneficial effect has not been demonstrated specifically in patients with fibromuscular dysplasia. Therefore, until the efficacy and safety of primary thromboprophylaxis have been demonstrated in this patient group specifically, it may be equally appropriate to only use antiplatelet agents in patients with a clear indication after individual evaluation according to risk factors for thrombotic and thromboembolic complications.

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INTRODUCTION: Hemodialysis treatment using standard dialysate bicarbonate concentrations cause transient metabolic alkalosis possibly associated with hemodynamic instability. The aim of this study was to perform a detailed comparison of high and low dialysate bicarbonate in terms of blood pressure, intradialytic hemodynamic parameters, orthostatic blood pressure, and electrolytes. METHODS: Fifteen hemodialysis patients were examined in a single-blind, randomized, controlled, crossover study. Participants underwent a 4-h hemodialysis session with dialysate bicarbonate concentration of 30 or 38 mmol/L with 1 week between interventions. Blood pressure was monitored throughout hemodialysis, while cardiac output, total peripheral resistance, stroke volume, and central blood volume were assessed with ultrasound dilution technique (Transonic). Orthostatic blood pressure was measured pre- and post-hemodialysis. FINDINGS: With similar ultrafiltration (UF) volume (2.6 L), systolic blood pressure (SBP) tended to decrease more during high dialysate bicarbonate compared to low dialysate bicarbonate; the mean (95% confidence interval) between treatment differences in SBP were: 8 (-4; 20) mmHg (end of hemodialysis) and 7 (0; 15) mmHg (post-hemodialysis). Stroke volume decreased whereas total peripheral resistance increased significantly more during high dialysate bicarbonate compared to low dialysate bicarbonate with mean between treatment differences: Stroke volume: 12 (1; 23) mL; Total peripheral resistance: -2.9 (-5.3; -0.5) mmHg/(L/min). Cardiac output tended to decrease more with high dialysate bicarbonate compared to low dialysate bicarbonate with mean between treatment difference 0.7 (0.0; 1.4) L/min. High dialysate bicarbonate caused alkalosis, hypocalcemia, and lower plasma potassium, whereas patients remained normocalcemic with normal pH during low dialysate bicarbonate. Orthostatic blood pressure response after dialysis did not differ significantly. DISCUSSION: The use of high dialysate bicarbonate compared to low dialysate bicarbonate was associated with hypocalcemia, alkalosis, and a more pronounced hypokalemia. During hemodialysis with UF, a better preservation of blood pressure, stroke volume, and cardiac output may be achieved with low dialysate bicarbonate compared to high dialysate bicarbonate.

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BACKGROUND: Sodium-glucose-cotransporter 2 inhibitors (SGLT2is) have revolutionized the treatment of type 2 diabetes mellitus (DM2) and chronic kidney disease (CKD), reducing the risk of cardiovascular and renal end points by up to 40%. The underlying mechanisms are not fully understood. OBJECTIVE: The study aims to examine the effects of empagliflozin versus placebo on renal hemodynamics, sodium balance, vascular function, and markers of the innate immune system in patients with DM2, DM2 and CKD, and nondiabetic CKD. METHODS: We conducted 3 double-blind, crossover, randomized controlled trials, each with identical study protocols but different study populations. We included patients with DM2 and preserved kidney function (estimated glomerular filtration rate >60 mL/min/1.73 m2), DM2 and CKD, and nondiabetic CKD (both with estimated glomerular filtration rate 20-60 mL/min/1.73 m2). Each participant was randomly assigned to 4 weeks of treatment with either 10 mg of empagliflozin once daily or a matching placebo. After a wash-out period of at least 2 weeks, participants were crossed over to the opposite treatment. End points were measured at the end of each treatment period. The primary end point was renal blood flow measured with 82Rubidium positron emission tomography-computed tomography (82Rb-PET/CT). Secondary end points include glomerular filtration rate measured with 99mTechnetium-diethylene-triamine-pentaacetate (99mTc-DTPA) clearance, vascular function assessed by forearm venous occlusion strain gauge plethysmography, measurements of the nitric oxide (NO) system, water and sodium excretion, body composition measurements, and markers of the complement immune system. RESULTS: Recruitment began in April 2021 and was completed in September 2022. Examinations were completed by December 2022. In total, 49 participants completed the project: 16 participants in the DM2 and preserved kidney function study, 17 participants in the DM2 and CKD study, and 16 participants in the nondiabetic CKD study. Data analysis is ongoing. Results are yet to be published. CONCLUSIONS: This paper describes the rationale, design, and methods used in a project consisting of 3 double-blind, crossover, randomized controlled trials examining the effects of empagliflozin versus placebo in patients with DM2 with and without CKD and patients with nondiabetic CKD, respectively. TRIAL REGISTRATION: EU Clinical Trials Register 2019-004303-12; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004303-12, EU Clinical Trials Register 2019-004447-80; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004447-80, EU Clinical Trials Register 2019-004467-50; https://www.clinicaltrialsregister.eu/ctr-search/search?query=and+2019-004467-50. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/56067.

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BACKGROUND: Chronic kidney disease (CKD) is associated with accelerated vascular calcification and increased central systolic blood pressure when measured invasively (invCSBP) relative to cuff-based brachial systolic blood pressure (cuffSBP). The contribution of aortic wall calcification to this phenomenon has not been clarified. We, therefore, examined the effects of aortic calcification on cuffSBP and invCSBP in a cohort of patients representing all stages of CKD. METHODS: During elective coronary angiography, invCSBP was measured in the ascending aorta with a fluid-filled catheter with simultaneous recording of cuffSBP using an oscillometric device. Furthermore, participants underwent a non-contrast computed tomography scan of the entire aorta with observer-blinded calcification scoring of the aortic wall ad modum Agatston. RESULTS: We included 168 patients (mean age 67.0 ±â€…10.5, 38 females) of whom 38 had normal kidney function, while 30, 40, 28, and 32 had CKD stages 3a, 3b, 4, and 5, respectively. Agatston scores adjusted for body surface area ranged from 48 to 40,165. We found that invCSBP increased 3.6 (95% confidence interval 1.4-5.7) mm Hg relative to cuffSBP for every 10,000-increment in aortic Agatston score. This association remained significant after adjustment for age, diabetes, antihypertensive treatment, smoking, eGFR, and BP level. No such association was found for diastolic BP. CONCLUSIONS: Patients with advanced aortic calcification have relatively higher invCSBP for the same cuffSBP as compared to patients with less calcification. Advanced aortic calcification in CKD may therefore result in hidden central hypertension despite apparently well-controlled cuffSBP. ClinicalTrials.gov identifier: NCT04114695.

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Introduction: Central aortic blood pressure (BP) could be a better risk predictor than brachial BP. This study examined whether invasively measured aortic systolic BP improved outcome prediction beyond risk prediction by conventional cuff-based office systolic BP in patients with and without chronic kidney disease (CKD). Methods: In a prospective, longitudinal cohort study, aortic and office systolic BPs were registered in patients undergoing elective coronary angiography (CAG). CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2. Multivariable Cox models were used to determine the association with incident myocardial infarction (MI), stroke, and death. Results: Aortic and office systolic BPs were available in 39,866 patients (mean age: 64 years; 58% males; 64% with hypertension) out of which 6605 (17%) had CKD. During a median follow-up of 7.2 years (interquartile range: 4.6-10.1 years), 1367 strokes (CKD: 353), 1858 MIs (CKD: 446), and 7551 deaths (CKD: 2515) occurred. CKD increased the risk of stroke, MI, and death significantly. Office and aortic systolic BP were both associated with stroke in non-CKD patients (adjusted hazard ratios with 95% confidence interval per 10 mm Hg: 1.08 [1.05-1.12] and 1.06 [1.03-1.09], respectively) and with MI in patients with CKD (adjusted hazard ratios: 1.08 [1.03-1.13] and 1.08 [1.04-1.12], respectively). There was no significant difference between prediction of outcome with office or aortic systolic BP when adjusted models were compared with C-statistics. Conclusion: Regardless of CKD status, invasively measured central aortic systolic BP does not improve the ability to predict outcome compared with brachial office BP measurement.

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Ambulatory blood pressure monitoring (ABPM) may be stressful and associated with discomfort, possibly influenced by the number of cuff inflations. We compared a low frequency (LF-ABPM) regimen with one cuff inflation per hour, with a high frequency (HF-ABPM) regimen performed according to current guidelines using three cuff-inflations per hour during daytime and two cuff-inflations during night time. In a crossover study, patients underwent ABPMs with both frequencies, in a randomized order, within an interval of a few days. Patients reported pain (visual analogue scale from 0 to 10) and sleep disturbances after each ABPM. The primary endpoint was the difference in mean 24 h systolic BP (SBP) between HF-ABPM and LF-ABPM. A total of 171 patients were randomized, and data from 131 (age 58 ± 14 years, 47% females, 24% normotensive, 53% mildly hypertensive, and 22% moderately-severely hypertensive) completing both ABPMs were included in the analysis. Mean SBP was 137.5 mmHg (95% CI, 134.8;140.2) for HF-ABPM and 138.2 mmHg (95%CI, 135.2;141.1) for LF-ABPM. The 95% limits of agreement were -15.3 mmHg and +14.0 mmHg. Mean 24 h SBP difference between HF-ABPM and LF-ABPM was -0.7 mmHg (95%CI, -2.0;0.6). Coefficients of variation were similar for LF-ABPM and HF-ABPM. Pain scores (median with interquartile range), for HF-ABPM and LF-ABPM were 1.5 (0.6;3.0) and 1.3 (0.6;2.9) during daytime, and 1.3 (0.4:3.4) and 0.9 (0.4;2.0) during nighttime (P < 0.05 for both differences). We conclude that LF-ABPM and HF-ABPM values are in good agreement without any clinically relevant differences in BP. Furthermore, LF-ABPM causes a relatively modest reduction in procedure-related pain.

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Purpose: To investigate the interplay between chronic kidney disease (CKD) and coronary artery disease (CAD) on the incidence of cardiovascular events in patients with suspected chronic coronary syndrome (CCS). Patients and Methods: Patients with suspected CCS who underwent first-time coronary angiography in Western Denmark between 2003 and 2016 were included in this cohort study. Moreover, an age- and sex-matched general population cohort was established. Patients were stratified according to estimated glomerular filtration rate (eGFR). Presence of CAD was defined as ≥1 obstructive stenosis or non-obstructive diffuse disease. Major adverse cardiovascular events (MACE) were defined as a composite of myocardial infarction, ischemic stroke, and cardiac death. Results: A total of 42,611 patients were included with a median follow-up of 7.3 years. Patients without and with CAD had MACE rates per 100 person-years that were 0.52 and 1.67 for eGFR ≥90 mL/min/1.73 m2, 0.68 and 2.09 for eGFR 60-89 mL/min/1.73 m2, 1.27 and 3.85 for eGFR 30-59 mL/min/1.73 m2, and 2.27 and 6.92 for eGFR <30 mL/min/1.73 m2. Comparing to eGFR ≥90 mL/min/1.73 m2, the adjusted incidence rate ratios for MACE were 1.29 (1.10-1.51) for eGFR 60-89 mL/min/1.73 m2, 1.86 (1.49-2.33) for eGFR 30-59 mL/min/1.73 m2, and 3.57 (1.92-6.67) for eGFR <30 mL/min/1.73 m2 in patients without CAD, and 1.11 (1.03-1.20), 1.71 (1.55-1.90), and 2.46 (1.96-3.09) in patients with CAD. The inverse relationship between kidney function and risk of MACE was confirmed when comparing patients with and without CAD to matched individuals in the general population. Conclusion: Absence of CAD is a strong negative predictor of major adverse cardiovascular events in patients with CKD.

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BACKGROUND AND AIMS: Obstructive sleep apnea (OSA) may accelerate arterial calcification, but the relation remains unexplored in diabetic kidney disease (DKD). We examined the associations between OSA, coronary calcification and large artery stiffness in patients with DKD and reduced renal function. METHODS: Patients with type 2 diabetes, estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 and urine albumin-creatinine ratio (UACR) > 30 mg/g were tested for OSA quantified by the apnea-hypopnea index (AHI, events/hour). Patients without OSA (AHI< 5) were compared to patients with moderate (AHI 15-29) or severe (AHI ≥30) OSA and underwent computed tomography angiography with coronary Agatston scoring (CAS) to quantify coronary calcification. Arterial stiffness was determined as carotid-femoral pulse wave velocity (PWV). RESULTS: Among 114 patients with acceptable AHI recordings had 43 no OSA, 33 mild OSA and 38 moderate-severe OSA. Mean age of the 74 patients completing the study was 71.5 ± 9.4 years (73% males), eGFR 32.2 ± 12.3 ml/min/1.73 m2 and UACR 533 (192-1707) mg/g. CAS (ln-transformed) was significantly higher in patients with OSA compared to patients without (6.6 ± 1.7 vs. 5.6 ± 2.4, p = 0.04), and the same was observed for PWV (11.9 ± 2.7 vs. 10.5 ± 2.2 m/s, p = 0.02). In multivariable linear regression analyses adjusted for sex, age, body mass index, UACR, and mean arterial pressure, moderate-severe OSA remained significantly associated with PWV but not with CAS. Dominance analysis revealed OSA as the third and second most important factor relative to CAS and PWV respectively. CONCLUSIONS: In DKD patients, moderate-severe OSA is a significant predictor of arterial stiffness but is not independently associated with coronary calcification.

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INTRODUCTION: Chronic kidney disease (CKD) is associated with cardiovascular disease (CVD) and death. Albuminuria is an established risk factor, but additional biomarkers predicting CKD progression or CVD are needed. Arterial stiffness is an easily measurable parameter that has been associated with CVD and mortality. We evaluated the ability of carotid-femoral pulse wave velocity (PWV) and urine albumin-creatinine (UAC) ratio to predict CKD progression, cardiovascular events, and mortality in a cohort of CKD patients. METHODS: In CKD stage 3-5 patients, PWV and UAC were measured at baseline. CKD progression was defined as 50% decline in estimated glomerular filtration rate (eGFR), initiation of dialysis, or renal transplantation. A composite endpoint was defined as CKD progression, myocardial infarction, stroke, or death. Endpoints were analyzed using Cox regression analysis adjusted for possible confounders. RESULTS: We included 181 patients (median age 69 [interquartile range 60-75] years, 67% males) with a mean eGFR of 37 ± 12 mL/min/1.73 m2 and UAC 52 (5-472) mg/g. Mean PWV was 10.6 m/s. Median follow-up until first event was 4 (3-6) years with 44 and 89 patients reaching a CKD progression or composite endpoint, respectively. UAC (g/g) significantly predicted both CKD progression (HR 1.5 [1.2; 1.8]) and composite endpoints (HR 1.4 [1.1; 1.7]) in adjusted Cox regression. In contrast, PWV (m/s) was not associated with neither CKD progression (HR 0.99 [0.84; 1.18]) nor the composite endpoint (HR 1.03 [0.92; 1.15]). CONCLUSION: In an aging CKD population, UAC predicted both CKD progression and a composite endpoint of CKD progression, cardiovascular events, or death, while PWV did not.

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BACKGROUND: Living kidney donors (LKDs) are at increased risk of chronic kidney disease, whereas transplant recipients experience progressive reduction of graft function. We examined the predictive value of quantitative stereology on renal function in LKDs and recipients of living donor kidneys, based on perioperative biopsies from the donated kidney. METHODS: Cortex volume of both donor kidneys was determined by contrast-enhanced computed tomography and single-kidney glomerular filtration rate (GFR) by 51 chrome-EDTA clearance together with renography. Glomerular density was used to estimate total glomeruli number in addition to glomerular volume, glomerular sclerosis, kidney fibrosis, and arteriole dimensions. GFR measurements were repeated 1 y after transplantation in both LKDs and recipients. Associations between GFR at follow-up and cortex volume and histomorphometric parameters after adjustment of age, gender, body mass index, smoking status, 24-h blood pressure, and single-kidney GFR were examined. RESULTS: We included 49 LKDs (age, 51 ± 12 y) and 51 recipients (age, 44 ± 13 y). At follow-up, GFR was 71 ± 16 mL/min in LKDs and 61 ± 18 mL/min in recipients with hyperfiltration being more prominent in LKDs (30.4%) as compared to recipients (16.4%; P < 0.05). One-year GFR in donors correlated to cortex volume ( P < 0.001) but not to any histological parameters, whereas GFR in recipients correlated to the amount of interstitial fibrosis ( P < 0.01) but not to other histological parameters or cortex volume. CONCLUSIONS: Kidney cortex volume, but not renal histology parameters, predicts 1-y renal outcome in LKDs. In contrast, the amount of interstitial fibrosis, but not cortex volume, predicts 1-y graft function in recipients.

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The immunomodulatory and regenerative properties of mesenchymal stromal cells (MSCs) make MSC therapy a promising therapeutic strategy in kidney disease. A targeted MSC administration via the renal artery offers an efficient delivery method with limited spillover to other organs. Although local administration alleviates safety issues with MSCs in systemic circulation, it introduces new safety concerns in the kidneys. In a porcine model, we employed intra-renal arterial infusion of ten million allogenic adipose tissue-derived MSCs. In order to trigger any potential adverse events, a higher dose (hundred million MSCs) was also included. The kidney function was studied by magnetic resonance imaging after the MSC infusion and again at two weeks post-treatment. The kidneys were assessed by single kidney glomerular filtration rate (skGFR) measurements, histology and inflammation, and fibrosis-related gene expression. None of the measured parameters were affected immediately after the administration of ten million MSCs, but the administration of one hundred million MSCs induced severe adverse events. Renal perfusion was reduced immediately after MSC administration which coincided with the presence of microthrombi in the glomeruli and signs of an instant blood-mediated inflammatory reaction. At two weeks post-treatment, the kidneys that were treated with one hundred million MSCs showed reduced skGFR, signs of tissue inflammation, and glomerular and tubular damage. In conclusions, the intra-renal administration of ten million MSCs is well-tolerated by the porcine kidney. However, higher concentrations (one hundred million MSCs) caused severe kidney damage, implying that very high doses of intra-renally administered MSCs should be undertaken with caution.

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Background Estimated pulse wave velocity (ePWV) calculated by equations using age and blood pressure has been suggested as a new marker of mortality and cardiovascular risk. However, the prognostic potential of ePWV during long-term follow-up in patients with symptoms of stable angina remains unknown. Methods and Results In this study, ePWV was calculated in 25 066 patients without diabetes, previous myocardial infarction (MI), stroke, heart failure, or valvular disease (mean age 63.7±10.5 years, 58% male) with stable angina pectoris undergoing elective coronary angiography during 2003 to 2016. Multivariable Cox models were used to assess the association with incident all-cause mortality, MI, and stroke. Discrimination was assessed using Harrell´s C-index. During a median follow-up period of 8.5 years (interquartile range 5.5-11.3 years), 779 strokes, 1233 MIs, and 4112 deaths were recorded. ePWV was associated with all-cause mortality (hazard ratio [HR] per 1 m/s, 1.13; 95% CI, 1.05-1.21) and MI (HR per 1 m/s 1.23, 95% CI, 1.09-1.39) after adjusting for age, systolic blood pressure, body mass index, smoking, estimated glomerular filtration rate, Charlson Comorbidity Index score, antihypertensive treatment, statins, aspirin, and number of diseased coronary arteries. Compared with traditional risk factors, the adjusted model with ePWV was associated with a minor but likely not clinically relevant increase in discrimination for mortality, 76.63% with ePWV versus 76.56% without ePWV, P<0.05. Conclusions In patients with stable angina pectoris, ePWV was associated with all-cause mortality and MI beyond traditional risk factors. However, the added prediction of mortality was not improved to a clinically relevant extent.

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Background The aim of this study was to prospectively evaluate the effects of renal artery stenting in consecutive patients with severe atherosclerotic renal artery stenosis and high-risk clinical presentations as defined in a national protocol developed in 2015. Methods and Results Since the protocol was initiated, 102 patients have been referred for revascularization according to the following high-risk criteria: severe renal artery stenosis (≥70%) with true resistant hypertension, rapidly declining kidney function, or recurrent heart failure/sudden pulmonary edema. At baseline, the mean 24-hour ambulatory systolic blood pressure was 166.2 mm Hg (95% CI, 162.0-170.4), the defined daily dose of antihypertensive medication was 6.5 (95% CI, 5.8-7.3), and the estimated glomerular filtration rate was 41.1 mL/min per 1.73m2 (95% CI, 36.6-45.6). In 96 patients with available 3-month follow-up data, mean 24-hour ambulatory systolic blood pressure decreased by 19.6 mm Hg (95% CI, 15.4-23.8; P<0.001), the defined daily dose of antihypertensive medication was reduced by 52% (95% CI, 41%-62%; P<0.001), and estimated glomerular filtration rate increased by 7.8 mL/min per 1.73m2 (95% CI, 4.5-11.1; P<0.001). All changes persisted after 24 month follow-up. Among 17 patients with a history of hospitalization for acute decompensated heart failure, 14 patients had no new episodes after successful revascularization. Conclusions In this prospective cohort study, we observed a reduction in blood pressure and antihypertensive medication, an increase in estimated glomerular filtration rate, and a decrease in new hospital admissions attributable to heart failure/sudden pulmonary edema after renal artery stenting. Registration URL: https://clinicaltrials.gov. Identifier: NCT02770066.

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OBJECTIVE: Uremic myopathy is a condition seen in end-stage renal disease (ESRD), characterized by muscle weakness and muscle fatigue, in which the pathophysiology is uncertain. The aim of this study was to assess the role of abnormal serum constituents in ESRD patients by relating them to the excitability properties of the tibialis anterior muscle, at rest and during electrically induced muscle activation, by recording muscle velocity recovery cycles (MVRC) and frequency ramp responses. METHODS: Eighteen ESRD patients undergoing hemodialysis were evaluated by blood sample, MVRC, and frequency ramp (before and near the end of dialysis treatment), quantitative electromyography, and nerve conduction studies. Patients were compared to 24 control subjects. RESULTS: In patients, muscle relative refractory period, early supernormality, late supernormality after 5 conditioning stimuli, and latency of the last of 15 and 30 frequency ramp pulses were strongly associated with potassium levels (p < 0.01), showing depolarization before and normalization in the end of hemodialysis. CONCLUSIONS: In ESRD patients, the muscle membrane is depolarized, mainly due to hyperkalemia. SIGNIFICANCE: Since normal muscle fatigue has been attributed to potassium-induced depolarization, it seems likely that this mechanism is also a major cause of the exaggerated muscle fatigue and weakness in ESRD patients.

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Background: Mycophenolic acid (MPA) is a potent immunosuppressive agent used in solid organ transplantation. MPA exhibits large interindividual variation in dose-normalized plasma concentrations but is nevertheless usually prescribed as a fixed dose without use of therapeutic drug monitoring (TDM). Data on the effect of corticosteroid (CS) treatment on MPA concentrations during concomitant tacrolimus treatment remains sparse. Methods: Data is based on TDM of MPA area under the concentration curve (AUC) in 210 renal transplant recipients participating in the prospective, randomized, controlled, multi-center trial (SAILOR) where a steroid-free immunosuppressive regimen with mycophenolate mofetil (MMF) and low-dose tacrolimus was compared with a conventional prednisolone-based treatment regimen. Multilevel mixed-effects linear regression post-hoc analyses of MPA AUC was performed. Results: Median MPA AUC at baseline (within the first 2 weeks post-transplant) in patients taking 2 g MMF daily was 53 mg*h/L (interquartile range: 43-69 mg*h/L, min: 24-max: 117 mg*h/L). Between-patient variation in MPA AUC was up to 5-fold on the same MMF dose. Patients in the steroid-free group had 12.5% lower (95% CI; 3.2-20.9%, p = 0.01) MPA AUC levels at baseline compared to the steroid treated group. During follow-up (14 days-2 years post-transplant) there were no significant differences in MPA AUC between the groups with MPA AUC being 4.2% lower (95% CI: -4.8%-12,5%, p = 0.35) in the steroid-free vs standard treatment group in restricted analysis after multivariate adjustment for tacrolimus trough level, body weight, time after transplantation and MMF dose. MMF dose was positively correlated with MPA AUC (p < 0.001) whereas body weight was negatively correlated with MPA AUC (p < 0.001). MPA AUC was 0.4% (95% CI: 0.2-0.6%, p < 0.001) lower per 1 kg increase in weight. Tacrolimus trough levels had no significant effect on MPA AUC. Conclusion: Immunosuppression with CS during concomitant tacrolimus treatment was shortly after transplantation associated with a significantly higher MPA exposure but the effect was small and not maintained during follow-up. Low body weight was associated with higher MPA exposure, which suggests a potential for weight adjusted MMF dosing.

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PURPOSE: Hypertension is common in kidney transplant recipients (KTRs). For the evaluation of blood pressure (BP), 24-h ambulatory BP measurements (ABPM) are considered superior to usual office measurements but are also resource demanding and troublesome to many patients. We therefore evaluated the use of unattended automated office BP (AOBP) during the first year following living donor kidney transplantation and compared AOBP with ABPM as obtained 12 months after transplantation. MATERIALS AND METHODS: Data were retrieved from a cohort of 57 KTRs (mean age 45 ± 14 years, 75% males) who all received kidneys from living donors and had a good graft function (estimated glomerular filtration rate (eGFR) 52 ± 16 ml/min/1.73 m2 at 12 months). Unattended AOBP was measured at each visit to the outpatient clinic using the BpTru® device, while ABPM was obtained by Spacelabs® equipment before and 12 months after transplantation. RESULTS: AOBP remained stable from month 2 (130.2 ± 10.8/82.2 ± 7.8 mmHg) to month 12 (129.0 ± 12.8/83.1 ± 9.6 mmHg) post-transplantation. At 12 months follow-up, ambulatory daytime systolic BP was slightly higher than AOBP (132.7 ± 10.7 vs. 129.4 ± 12.2 mmHg, p = 0.04), while diastolic BP was similar (82.7 ± 7.7 vs. 82.0 ± 10.2 mmHg). Using Bland-Altman plots, 95% limits of agreements were -17.9 to 24.5 mmHg for systolic and -16.5 to 15.1 mmHg for diastolic BP. When considering a target BP of ≤130/<80 mmHg, 62% had sustained hypertension, 9% white coat hypertension and 11% masked hypertension. Using multiple linear regression analysis, only urine albumin-creatinine ratio tended to predict a higher systolic AOBP (p = 0.07). CONCLUSION: In a cohort of stable living donor KTRs, mean values of unattended AOBP using BpTru® are comparable to daytime ABPM with a misclassification rate of approximately 20%.

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