Reliability of rubidium-82 PET/CT for renal perfusion determination in healthy subjects.

BACKGROUND: Changes in renal perfusion may play a pathophysiological role in hypertension and kidney disease, however to date, no method for renal blood flow (RBF) determination in humans has been implemented in clinical practice. In a previous study, we demonstrated that estimation of renal perfusion based on a single positron emission tomography/computed tomography (PET/CT) scan with Rubidium-82 (82Rb) is feasible and found an approximate 5% intra-assay coefficient of variation for both kidneys, indicative of a precise method.This study's aim was to determine the day-to day variation of 82Rb PET/CT and to test the method's ability to detect increased RBF induced by infusion of amino acids. METHODS: Seventeen healthy subjects underwent three dynamic 82Rb PET/CT scans over two examination days comprising: Day A, a single 8-minute dynamic scan and Day B, two scans performed before (baseline) and after RBF stimulation by a 2-hour amino acid-infusion. The order of examination days was determined by randomization. Time activity curves for arterial and renal activity with a 1-tissue compartment model were used for flow estimation; the K1 kinetic parameter representing renal 82Rb clearance. Day-to-day variation was calculated based on the difference between the unstimulated K1 values on Day A and Day B and paired t-testing was performed to compare K1 values at baseline and after RBF stimulation on Day B. RESULTS: Day-to-day variation was observed to be 5.5% for the right kidney and 6.0% for the left kidney (n = 15 quality accepted scans). K1 values determined after amino acid-infusion were significantly higher than pre-infusion values (n = 17, p = 0.001). The mean percentage change in K1 from baseline was 13.2 ± 12.9% (range - 10.4 to 35.5) for the right kidney; 12.9 ± 13.2% (range - 15.7 to 35.3) for the left kidney. CONCLUSION: Day-to-day variation is acceptably low. A significant K1 increase from baseline is detected after application of a known RBF stimulus, indicating that 82Rb PET/CT scanning can provide a precise method for evaluation of RBF and it is able to determine changes herein. CLINICAL TRIAL REGISTRATION: EU Clinical Trials Register, 2017-005008-88. Registered 18/01/2018.

Effect of sodium nitrite on renal function and sodium and water excretion and brachial and central blood pressure in healthy subjects: a dose-response study.

Sodium nitrite (NaNO2) is converted to nitric oxide (NO) in vivo and has vasodilatory and natriuretic effects. Our aim was to examine the effects of NaNO2 on hemodynamics, sodium excretion, and glomerular filtration rate (GFR). In a single-blinded, placebo-controlled, crossover study, we infused placebo (0.9% NaCl) or 0.58, 1.74, or 3.48 µmol NaNO2·kg-1·h-1 for 2 h in 12 healthy subjects, after 4 days of a standard diet. Subjects were supine and water loaded. We measured brachial and central blood pressure (BP), plasma concentrations of renin, angiotensin II, aldosterone, arginine vasopressin (P-AVP), and plasma nitrite (P-[Formula: see text]), GFR by Cr-EDTA clearance, fractional excretion of sodium (FENa) free water clearance (CH2O), and urinary excretion rate of guanosine 3',5'-cyclic monophosphate (U-cGMP). The highest dose reduced brachial systolic BP (5.6 mmHg, P = 0.003), central systolic BP (5.6 mmHg, P = 0.035), and CH2O (maximum change from 3.79 to 1.27 ml/min, P = 0.031) and increased P-[Formula: see text] (from 0.065 to 0.766 µmol/l, P < 0.001), while reducing U-cGMP (from 444 to 247 pmol/min, P = 0.004). GFR, FENa, P-AVP, and the components in the renin-angiotensin-aldosterone system did not change significantly. In conclusion, intravenous NaNO2 induced a dose-dependent reduction of brachial and central BP. The hemodynamic effect was not mediated by the renin-angiotensin-aldosterone system. NaNO2 infusion resulted in a vasopressin-independent decrease in CH2O and urine output but no change in urinary sodium excretion or GFR. The lack of increase in cGMP accompanying the increase in [Formula: see text] suggests a direct effect of nitrite or nitrate on the renal tubules and vascular bed with little or no systemic conversion to NO.

Effect of tolvaptan on renal water and sodium excretion and blood pressure during nitric oxide inhibition: a dose-response study in healthy subjects.

BACKGROUND: Tolvaptan is a selective vasopressin receptor antagonist. Nitric Oxide (NO) promotes renal water and sodium excretion, but the effect is unknown in the nephron's principal cells. In a dose-response study, we measured the effect of tolvaptan on renal handling of water and sodium and systemic hemodynamics, during baseline and NO-inhibition with L-NMMA (L-NG-monomethyl-arginine). METHODS: In a randomized, placebo-controlled, double blind, cross over study, 15 healthy subjects received tolvaptan 15, 30 and 45 mg or placebo. L-NMMA was given as a bolus followed by continuous infusion during 60 min. We measured urine output (UO), free water clearance (CH2O), fractional excretion of sodium (FENa), urinary aquaporin-2 channels (u-AQP2) and epithelial sodium channels (u-ENaCγ), plasma vasopressin (p-AVP) and central blood pressure (cBP). RESULTS: During baseline, FENa was unchanged. Tolvaptan decreased u-ENaCγ dose-dependently and increased p-AVP threefold, whereas u-AQP2 was unchanged. During tolvaptan with NO-inhibition, UO and CH2O decreased dose-dependently. FENa decreased dose-independently and u-ENaCγ remained unchanged. Central BP increased equally after all treatments. CONCLUSIONS: During baseline, fractional excretion of sodium was unchanged. During tolvaptan with NO-inhibition, renal water excretion was reduced dose dependently, and renal sodium excretion was reduced unrelated to the dose, partly via an AVP dependent mechanism. Thus, tolvaptan antagonized the reduction in renal water and sodium excretion during NO-inhibition. Most likely, the lack of decrease in AQP2 excretion by tolvaptan could be attributed to a counteracting effect of the high level of p-AVP. TRIAL REGISTRATION: Clinical Trial no: NCT02078973 . Registered 1 March 2014.

Effects of atorvastatin on systemic and renal NO dependency in patients with non-diabetic stage II-III chronic kidney disease.

AIMS: Clinical trials suggest that statins have beneficial effects on the cardiovascular system independent from their cholesterol lowering properties. In patients with chronic kidney disease stage II-III, we tested the hypothesis that atorvastatin increased systemic and renal nitric oxide (NO) availability using L-N(G) -monomethyl arginine (L-NMMA) as an inhibitor of NO production. METHODS: In a randomized, placebo-controlled, crossover study patients were treated with atorvastatin for 5 days with standardized diet and fluid intake. Glomerular filtration reate (GFR), fractional excretions of sodium (FENa ), urinary excretion of aquaporin-2 (u-AQP2) and epithelial sodium channels (u-ENaCγ ), vasoactive hormones (renin, angiotensin II, aldosterone, arginine vasopressin, endothelin-1 and brain natriuretic peptide) and central blood pressure (BP) estimated by applanation tonometry were measured before and after systemic administration of the NO inhibitor L-NMMA. RESULTS: Atorvastatin caused a significant reduction in U-ENaCγ , but sodium excretion, C H 2 O , FENa and u-AQP2 were not changed by atorvastatin. L-NMMA reduced renal effect variables, including GFR, FENa and u-ENaCγ and increased brachial BP and central BP to a similar extent during both treatments. Vasoactive hormones were changed in the same way by L-NMMA during atorvastatin and placebo treatment. CONCLUSION: During, atorvastatin and placebo treatment, inhibition of nitric oxide synthesis induced the same response in brachial and central blood pressure, GFR, renal tubular function and vasoactive hormones. Thus, the data do not support that atorvastatin changes nitric oxide availability in patients with mild nephropathy. The reduced u-ENaC may reflect changes in sodium absorption in the nephron induced by atorvastatin.

Effect of vasopressin antagonism on renal handling of sodium and water and central and brachial blood pressure during inhibition of the nitric oxide system in healthy subjects.

BACKGROUND: Tolvaptan is a selective vasopressin receptor antagonist (V2R) that increases free water excretion. We wanted to test the hypotheses that tolvaptan changes both renal handling of water and sodium and systemic hemodynamics during basal conditions and during nitric oxide (NO)-inhibition with L-NG-monomethyl-arginine (L-NMMA). METHODS: Nineteen healthy subjects were enrolled in a randomized, placebo-controlled, double-blind, crossover study of two examination days. Tolvaptan 15 mg or placebo was given in the morning. L-NMMA was given as a bolus followed by continuous infusion during 60 minutes. We measured urine output(UO), free water clearance (CH2O), fractional excretion of sodium (FENa), urinary aquaporin-2 channels (u-AQP2) and epithelial sodium channels (u-ENaCγ), plasma vasopressin (p-AVP), central and brachial blood pressure(cBP, bBP). RESULTS: During baseline conditions, tolvaptan caused a significant increase in UO, CH2O and p-AVP, and FENa was unchanged. During L-NMMA infusion, UO and CH2O decreased more pronounced after tolvaptan than after placebo (-54 vs.-42% and -34 vs.-9% respectively). U-AQP2 decreased during both treatments, whereas u-ENaCγ decreased after placebo and increased after tolvaptan. CBP and bBP were unchanged. CONCLUSION: During baseline conditions, tolvaptan increased renal water excretion. During NO-inhibition, the more pronounced reduction in renal water excretion after tolvaptan indicates that NO promotes water excretion in the principal cells, at least partly, via an AVP-dependent mechanism. The lack of decrease in u-AQP2 by tolvaptan could be explained by a counteracting effect of increased plasma vasopressin. The antagonizing effect of NO-inhibition on u-ENaC suggests that NO interferes with the transport via ENaC by an AVP-dependent mechanism.

Self-Performed Dietary Sodium Reduction and Blood Pressure in Patients With Essential Hypertension: A Randomized Clinical Trial.

BACKGROUND: Hypertension is the leading risk factor for cardiovascular disease worldwide. Patients with blood pressure (BP) response to dietary sodium reduction are referred to as "salt sensitive." Salt sensitivity (SS) might be due to differences in sodium storage capacity and the erythrocyte SS examines this capacity of the red blood cells. This study aimed to test the effect of a self-performed sodium reduced diet on BP in patients with essential hypertension and examine whether erythrocyte SS predicts SS. METHODS AND RESULTS: Seventy-two patients with hypertension were included and randomized 2:1 to either sodium reduction or a control group for 4 weeks. Blood samples, 24-hour BP measurement, and 24-hour urine collection were performed before and after. The intervention group received advice on how to lower sodium intake. Urinary sodium excretion decreased 66 mmol (95% CI, -96 to -37 mmol) in the intervention group compared with the control group. Systolic 24-hour BP decreased 9 mm Hg after low-sodium diet compared with the control group (95% CI, -13 to -4 mm Hg). Similarly, the difference in reduction in diastolic BP between the groups was 5 mm Hg (95% CI, -8 to -1 mm Hg). We found no correlation between erythrocyte SS at baseline and decrease in 24-hour BP, neither systolic nor diastolic (P=0.66 and P = 0.84). CONCLUSIONS: Self-performed sodium reduction was feasible and led to decrease in 24-hour BP of 9/5 mm Hg compared with a control group. The erythrocyte SS did not correlate to the change in BP after lowering sodium intake. REGISTRATION: URL: https://clinicaltrials.gov; Unique Identifier: NCT05165823.

Effects of Empagliflozin in Type 2 Diabetes With and Without Chronic Kidney Disease and Nondiabetic Chronic Kidney Disease: Protocol for 3 Crossover Randomized Controlled Trials (SiRENA Project).

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.

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.

Effects of atorvastatin on systemic and renal nitric oxide in healthy man.

Statin treatment improves endothelial function but the effects of statins on renal nitric oxide have not been clarified. In this crossover study, 26 healthy subjects received atorvastatin 80 mg per day or placebo for 5 days. After 5 days of treatment, L-N(G)-monomethyl arginine caused a similar increase in blood pressure and decrease in urine output and glomerular filtration rate. The decrease in fractional excretion of sodium to L-N(G)-monomethyl arginine was more pronounced after atorvastatin treatment. Atorvastatin did not change the response to several vasoactive hormones. The results indicate that atorvastatin increase renal nitric oxide, which may explain a part of the pleiotropic effects of statins.

Effect of nitric oxide inhibition on blood pressure and renal sodium handling: a dose-response study in healthy man.

Nitric oxide (NO) is a ubiquitous vasodilator and an important regulator of renal sodium excretion. To further investigate the role of NO in renal sodium handling, we studied the effects of the NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), in a crossover dose-response study. During NO inhibition mean arterial pressure increased dose-dependently and reached a plateau after 20 minutes of infusion. On the contrary, the fractional excretion of sodium was reduced equally in all three L-NMMA doses. This indicates that sodium excretion is highly sensitive to even small changes in renal NO bioavailability in healthy human.

Urothelial Carcinoma in an Allograft kidney.

Patients who have been kidney transplanted have an increased risk of developing cancer. This case report presents a rarely described case in which a patient, who had received a kidney transplant from a deceased donor, was diagnosed with disseminated urothelial carcinoma originating from the allograft. After the removal of the allograft and the immunosuppressive treatment, there was regression in the cancer. Unfortunately, it was not a complete regression of the urothelial cancer and the patient died. This case indicates that there is a risk of getting cancer from the transplanted kidney from a deceased donor, but also that the immunosuppressive treatment can contribute to the development of this cancer.

[SGLT2 inhibitorsfor treatment of chronic kidney disease without diabetes or heart failure].

This review summarises the current knowledge of electroconvulsive therapy (ECT) which is still the most potent and fast-acting antidepressant intervention. The modern procedure is safe when general precautions are taken. Cognitive side effects are transient in most patients, and concerns about side effects should not prevent relevant use. Due to the prognostic benefits of rapid remission, ECT should, in relevant patients, be considered early in the treatment course. Patients should be offered maintenance pharmacotherapy, and, in high-risk cases, tapering of the acute ECT course or maintenance ECT, in order to reduce the risk of relapse.

Effect of furosemide on body composition and urinary proteins that mediate tubular sodium and sodium transport-A randomized controlled trial.

BACKGROUND: Furosemide inhibits the sodium potassium chloride cotransporter (NKCC2) in the thick ascending limb of the loop of Henle and increases urinary water and sodium excretion. This study investigates the effect of furosemide on body composition estimated with multifrequency bioimpedance spectroscopy (BIS) technique and urinary proteins from NKCC2. METHODS: This study is a randomized, placebo-controlled, crossover study where healthy subjects received either placebo or 40 mg furosemide on two separate occasions, where body composition with BIS, renal function, proteins from tubular proteins that mediate sodium and water transport, and plasma concentrations of vasoactive hormones were measured before and after intervention. RESULTS: We observed an expected increased diuresis with a subsequent reduction in bodyweight of (-1.51 ± 0.36 kg, p < .001) and extracellular water (ECW; -1.14 ± 0.23 L, p < .001) after furosemide. We found a positive correlation between the decrease in ECW and a decrease in bodyweight and a negative correlation between the decrease in ECW and the increase in urinary output. Intracellular water (ICW) increased (0.47 ± 0.28 L, p < .001). Urinary excretion of NKCC2 increased after furosemide and the increase in NKCC2 correlated with an increase in urine output and a decrease in ECW. CONCLUSION: We found BIS can detect acute changes in body water content but the method may be limited to estimation of ECW. BIS demonstrated that furosemide increases ICW which might be explained by an extracellular sodium loss. Finally, urinary proteins from NKCC2 increases after furosemide with a good correlation with diuresis end the decrease in ECW.

[Diabetic muscle infarction as a rare cause of acute onset leg pain].

Diabetic muscle infarction (DMI) is a rare microvascular complication with spontaneous necrosis of skeletal musculature, most often localised to the thigh. DMI presents as an acute onset of pain in a muscle or muscle group. DMI is probably underdiagnosed because of its rareness and many differential diagnoses, why patients often undergo unnecessary and invasive diagnostic testing. The condition can be diagnosed with magnetic resonance imaging and the treatment is supportive with analgesics, bedrest and glycaemic control. We present two cases of DMI in patients with long-standing Type 1 diabetes.

Estimation of renal perfusion based on measurement of rubidium-82 clearance by PET/CT scanning in healthy subjects.

BACKGROUND: Changes in renal blood flow (RBF) may play a pathophysiological role in hypertension and kidney disease. However, RBF determination in humans has proven difficult. We aimed to confirm the feasibility of RBF estimation based on positron emission tomography/computed tomography (PET/CT) and rubidium-82 (82Rb) using the abdominal aorta as input function in a 1-tissue compartment model. METHODS: Eighteen healthy subjects underwent two dynamic 82Rb PET/CT scans in two different fields of view (FOV). FOV-A included the left ventricular blood pool (LVBP), the abdominal aorta (AA) and the majority of the kidneys. FOV-B included AA and the kidneys in their entirety. In FOV-A, an input function was derived from LVBP and from AA, in FOV-B from AA. One-tissue compartmental modelling was performed using tissue time activity curves generated from volumes of interest (VOI) contouring the kidneys, where the renal clearance of 82Rb is represented by the K1 kinetic parameter. Total clearance for both kidneys was calculated by multiplying the K1 values with the volume of VOIs used for analysis. Intra-assay coefficients of variation and inter-observer variation were calculated. RESULTS: For both kidneys, K1 values derived from AA did not differ significantly from values obtained from LVBP, neither were significant differences seen between AA in FOV-A and AA in FOV-B, nor between the right and left kidneys. For both kidneys, the intra-assay coefficients of variation were low (~ 5%) for both input functions. The measured K1 of 2.80 ml/min/cm3 translates to a total clearance for both kidneys of 766 ml/min/1.73 m2. CONCLUSION: Measurement of renal perfusion based on PET/CT and 82Rb using AA as input function in a 1-tissue compartment model is feasible in a single FOV. Based on previous studies showing 82Rb to be primarily present in plasma, the measured K1 clearance values are most likely representative of effective renal plasma flow (ERPF) rather than estimated RBF values, but as the accurate calculation of total clearance/flow is very much dependent on the analysed volume, a standardised definition for the employed renal volumes is needed to allow for proper comparison with standard ERPF and RBF reference methods.

Non-parathyroid hypercalcemia associated with paraffin oil injection in 12 younger male bodybuilders: a case series.

INTRODUCTION: Injection of paraffin oil to augment muscles size is a troubling phenomenon known to cause a foreign body reaction with formation of granulomas. In a few case reports, long-term side effects have been reported in terms of hypercalcemia and renal failure. METHODS: We identified a case series of 12 male bodybuilders presenting with non-parathyroid hypercalcemia who previously had injected paraffin oil to increase muscles size. RESULTS: At admission, all patients had moderate-to-severe hypercalcemia with suppressed PTH levels and impaired renal function. Calcitriol levels were within the normal range or slightly elevated. Follow-up measurements showed marked hypercalciuria with nearly normal levels of bone turnover markers. A correlation was found between levels of peptidyl dipeptidase and calcitriol (R = 0.812, P = 0.050). Treatment with antiresorptive agents seemed less effective than glucocorticoids, which resulted in a significantly lowering of ionized calcium levels and improved renal function, although no patients were cured by this treatment. Immunosuppression with azathioprine or mycophenolate may have a glucocorticoid-saving effect. One patient had surgery with removal of affected muscle tissue, without any apparent effect on plasma calcium levels. CONCLUSION: The hypercalcemia and associated hypercalciuria seems to be due to an intestinal hyperabsorption of calcium. It remains to be elucidated, whether an increased calcitriol synthesis within granulomas is the only (main) mechanism by which intestinal calcium absorption is increased. Glucocorticoids seem most appropriate as the first choice for treatment. Bodybuilders should be warned against use of intramuscular oil injections (and other substances), as this may have severe adverse health consequences.