C. T. Paul Krediet

Activation of the renin-angiotensin system may initiate chronic kidney disease. We hypothesised that renal hypoxia is a consequence of hemodynamic changes induced by angiotensin II and occurs prior to development of severe renal damage. Male Sprague-Dawley rats were infused continuously with angiotensin II (350 ng/kg/min) for 8 days. Mean arterial pressure (n = 5), cortical (n = 6) and medullary (n = 7) oxygenation (pO₂) were continuously recorded by telemetry and renal tissue injury was scored. Angiotensin II increased arterial pressure gradually to 150 ± 18 mmHg. This was associated with transient reduction of oxygen levels in renal cortex (by 18 ± 2%) and medulla (by 17 ± 6%) at 10 ± 2 and 6 ± 1 hours, respectively after starting infusion. Thereafter oxygen levels normalised to pre-infusion levels and were maintained during the remainder of the infusion period. In rats receiving angiotensin II, adding losartan to drinking water (300 mg/L) only induced transient increase in renal oxygenation, despite normalisation of arterial pressure. In rats, renal hypoxia is only a transient phenomenon during initiation of angiotensin II-induced hypertension.

Purpose There is ample evidence that systemic sympathetic neural activity contributes to the progression of chronic kidney disease, possibly by limiting renal blood flow and thereby inducing renal hypoxia. Up to now there have been no direct observations of this mechanism in humans. We studied the effects of systemic sympathetic activation elicited by a lower body negative pressure (LBNP) on renal blood flow (RBF) and renal oxygenation in healthy humans. Methods Eight healthy volunteers (age 19–31 years) were subjected to progressive LBNP at − 15 and − 30 mmHg, 15 min per level. Brachial artery blood pressure was monitored intermittently. RBF was measured by phase-contrast MRI in the proximal renal artery. Renal vascular resistance was calculated as the MAP divided by the RBF. Renal oxygenation (R2*) was measured for the cortex and medulla by blood oxygen level dependent (BOLD) MRI, using a monoexponential fit. Results With a LBNP of − 30 mmHg, pulse pressure decreased from 50 ± 10 to 43 ± 7 mmHg; MAP did not change. RBF decreased from 1152 ± 80 to 1038 ± 83 mL/min to 950 ± 67 mL/min at − 30 mmHg LBNP (p = 0.013). Heart rate and renal vascular resistance increased by 38 ± 15% and 23 ± 8% (p = 0.04) at − 30 mmHg LBNP, respectively. There was no change in cortical or medullary R2* (20.3 ± 1.2 s⁻¹ vs 19.8 ± 0.43 s⁻¹; 28.6 ± 1.1 s⁻¹ vs 28.0 ± 1.3 s⁻¹). Conclusion The results suggest that an increase in sympathetic vasoconstrictor drive decreases kidney perfusion without a parallel reduction in oxygenation in healthy humans. This in turn indicates that sympathetic activation suppresses renal oxygen demand and supply equally, thus allowing adequate tissue oxygenation to be maintained.

Background: Renal hypoxia, implicated as crucial factor in onset and progression of chronic kidney disease, may be attributed to reduced nitric oxide becausenitric oxidedilates vasculature and inhibits mitochondrial oxygen consumption. We hypothesized that chronicnitric oxidesynthase inhibition would induce renal hypoxia.Methods and Results: Oxygen‐sensitive electrodes, attached to telemeters, were implanted in either renal cortex (n=6) or medulla (n=7) in rats. After recovery and stabilization, baseline oxygenation (pO₂) was recorded for 1 week. To inhibitnitric oxidesynthase, N‐ω‐nitro‐l‐arginine (L‐NNA; 40 mg/kg/day) was administered via drinking water for 2 weeks. A separate group (n=8), instrumented with blood pressure telemeters, followed the same protocol. L‐NNA rapidly induced hypertension (165±6 versus 108±3 mm Hg;PP2, after initially dipping, returned to baseline and then increased. MedullarypO₂decreased progressively (up to −19±6% versus baseline;P2was decreased (3.7 [2.2–5.3] versus 7.9 [7.5–8.4];P2were unaltered. Terminal glomerular filtration rate (1374±74 versus 2098±122 μL/min), renal blood flow (5014±336 versus 9966±905 μL/min), and sodium reabsorption efficiency (13.0±0.8 versus 22.8±1.7 μmol/μmol) decreased (allP2shows transient changes, medullarypO₂decreased progressively. Chronic L‐NNA leads to decreased renal perfusion and sodium reabsorption efficiency, resulting in progressive medullary hypoxia, suggesting that juxtamedullary nephrons are potentially vulnerable to prolonged nitric oxide depletion.

Catheter-based renal sympathetic denervation (RDN) has been considered a potential treatment for therapy resistant hypertension (RHT). However, in a randomized placebo-controlled trial, RDN did not lead to a substantial blood pressure (BP) reduction. We hypothesized that variation in the reported RDN efficacy might be explained by incomplete nerve disruption as assessed by renal 123I–meta-iodobenzylguanidine (123I–mIBG) scintigraphy. In 21 RHT patients (median age 60 years), we performed 123I–mIBG scintigraphy before and 6 weeks after RDN. Additionally, we assessed changes in BP (24 h day, night, and average), plasma- and urinary-catecholamines and plasma renin activity (PRA) before and after RDN. Planar scintigraphy was performed at 15 min and 4 h after 123I–mIBG administration. The ratio of the mean renal (specific) counts vs. muscle (non-specific) counts represented 123I–mIBG uptake. Renal 123I–mIBG washout was calculated between 15 min and 4 h. After RDN office-based systolic BP decreased from 172 to 153 mmHg (p = 0.036), while diastolic office BP (p = 0.531), mean 24 h systolic and diastolic BP (p = 0.602, p = 0.369, respectively), PRA (p = 0.409) and plasma catecholamines (p = 0.324) did not significantly change post-RDN. Following RDN, 123I–mIBG renal uptake at 15 min was 3.47 (IQR 2.26–5.53) compared to 3.08 (IQR 2.79–4.95) before RDN (p = 0.289). Renal 123I–mIBG washout did not change post-RDN (p = 0.230). In addition, there was no significant correlation between the number of denervations and the renal 123I–mIBG parameters. No changes were observed in renal 123I–mIBG uptake or washout at 6 weeks post-RDN. These observations support incomplete renal denervation as a possible explanation for the lack of RDN efficacy.

Purpose A patient was identified with severe metabolic acidosis, a high anion gap and 5-oxoproline accumulation, probably caused by the simultaneous use of paracetamol (acetaminophen) and flucloxacillin. We wanted to investigate the necessity to control the interaction between both drugs with an automatic alert system. Methods To investigate the relevance of the interaction of paracetamol and flucloxacillin, a retrospective study was conducted. Data on paracetamol and flucloxacillin prescriptions and laboratory data (pH, Na⁺, HCO₃ ⁻, Cl⁻, albumin and 5-oxoproline levels) were combined to assess the prevalence of acidosis, calculate the anion gap and analyse 5-oxoproline levels in clinically admitted patients using both drugs simultaneously. Results In the 2-year study period, approximately 53,000 admissions took place in our hospital. One thousand and fifty-seven patients used paracetamol and flucloxacillin simultaneously, of which 51 patients (4.8%) had a serum pH ≤ 7.35. One patient, the same patient as presented in the case report, had a high anion gap and a toxic level of 5-oxoproline. Conclusion The prevalence of metabolic acidosis is very low and the only patient identified with the interaction was recognised during normal clinical care. We conclude that automatic alerts based on simultaneous use of paracetamol and flucloxacillin will generate too many signals. To recognise patients earlier and prevent severe outcomes, a warning system (clinical rule) based on paracetamol, flucloxacillin and pH measurement may be helpful. Early calculation of the anion gap can narrow the differential diagnosis of patients with metabolic acidosis and measurement of 5-oxoproline can explain acidosis due the interaction of paracetamol and flucloxacillin.

Blood pressure, renal hemodynamics, electrolyte and water excretion all display diurnal oscillation. Disturbance of these patterns is associated with hypertension and chronic kidney disease. Kidney oxygenation is dependent on oxygen delivery and consumption that in turn are determined by renal hemodynamics and metabolism. We hypothesized that kidney oxygenation also demonstrates 24-h periodicity. Telemetric oxygen-sensitive carbon paste electrodes were implanted in Sprague-Dawley rats (250-300g), either in renal medulla (n=9) or cortex (n=7). Arterial pressure (MAP) and heart rate (HR) were monitored by telemetry in a separate group (n=8). Data from 5 consecutive days were analyzed for rhythmicity by cosinor analysis. Diurnal electrolyte excretion was assessed by metabolic cages. During lights-off, oxygen levels increased to 105.3±2.1% in cortex and 105.2±3.8% in medulla. MAP was 97.3±1.5 mmHg and HR was 394.0±7.9 bpm during lights-off phase and 93.5±1.3 mmHg and 327.8±8.9 bpm during lights-on. During lights-on, oxygen levels decreased to 94.6±1.4% in cortex and 94.2±8.5% in medulla. There was significant 24-h periodicity in cortex and medulla oxygenation. Potassium excretion (1737±779 vs. 895±132 μmol/12h, P=0.005) and the distal Na+/K+ exchange (0.72±0.02 vs. 0.59±0.02 P<0.001) were highest in the lights-off phase, this phase difference was not found for sodium excretion (P=0.4). It seems that oxygen levels in the kidneys follow the pattern of oxygen delivery, which is known to be determined by renal blood flow and peaks in the active phase (lights-off).

Renal hypoxia is thought to be an important pathophysiological factor in the progression of chronic kidney disease (CKD) and the associated hypertension. In a previous study among CKD patients, supplementation with 100% oxygen reduced sympathetic nerve activity (SNA) and lowered blood pressure (BP). We aimed to assess the underlying haemodynamic modulation and hypothesized a decreased systemic vascular resistance (SVR). To that end, 19 CKD patients were studied during 15-minute intervals of increasing partial oxygen pressure (ppO2) from room air (0.21 ATA) to 1.0 ATA and further up to 2.4 ATA, while continuously measuring finger arterial blood pressure (Finapres). Off-line, we derived indexes of SVR, cardiac output (CO) and baroreflex sensitivity from the continuous BP recordings (Modelflow). During oxygen supplementation, systolic and diastolic BP both increased dose-dependently from 128±24 and 72±19 mmHg respectively at baseline to 141±23 (p<0.001) and 80±21 mmHg (p<0.001) at 1.0ATA oxygen. Comparing baseline and 1.0 ATA oxygen, SVR increased from 1440±546 to 1745±710dyn·s/cm5 (p=0.009), heart rate decreased from 60±8 to 58±6 bpm (p<0.001) and CO from 5.0±1.3 to 4.6±1.1 L/min (p=0.02). Baroreflex sensitivity remained unchanged (13±13 to 15±12 ms/mmHg). These blood pressure effects were absent in a negative control group of eight young healthy subjects. We conclude that oxygen supplementation in CKD patients causes a non-baroreflex mediated increased in SVR and blood pressure.

Nephrol Dial Transplant 2016; 31(11): 1947–1956, doi: 10.1093/ndt/gfw225

Blood pressure (BP) decreases in the first weeks after Roux-and-Y gastric bypass surgery. Yet the pathophysiology of the BP-lowering effects observed after gastric bypass surgery is incompletely understood. We evaluated BP, systemic hemodynamics, and baroreflex sensitivity in 15 obese women[mean age 42 ± 7 standard deviation (SD) yr, body mass index 45 ± 6 kg/m²] 2 wk before and 6 wk following Roux-and-Y gastric bypass surgery. Six weeks after gastric bypass surgery, mean body weight decreased by 13 ± 5 kg (10%, P < 0.001). Office BP decreased from 137 ± 10/86 ± 6 to 128 ± 12/81 ± 9 mmHg ( P < 0.001, P < 0.01), while daytime ambulatory BP decreased from 128 ± 14/80 ± 9 to 114 ± 10/73 ± 6 mmHg ( P = 0.01, P = 0.05), whereas nighttime BP decreased from 111 ± 13/66 ± 7 to 102 ± 9/62 ± 7 mmHg ( P = 0.04, P < 0.01). The decrease in BP was associated with a 1.6 ± 1.2 l/min (20%, P < 0.01) decrease in cardiac output (CO), while systemic vascular resistance increased (153 ± 189 dyn·s·cm⁻⁵, 15%, P < 0.01). The maximal ascending slope in systolic blood pressure decreased (192 mmHg/s, 19%, P = 0.01), suggesting a reduction in left ventricular contractility. Baroreflex sensitivity increased from 9.0 [6.4–14.3] to 13.8 [8.5–19.0] ms/mmHg (median [interquartile range]; P < 0.01) and was inversely correlated with the reductions in heart rate ( R = −0.64, P = 0.02) and CO ( R = −0.61, P = 0.03). In contrast, changes in body weight were not correlated with changes in either BP or CO. The BP reduction following Roux-and-Y gastric bypass surgery is correlated with a decrease in CO independent of changes in body weight. The contribution of heart rate to the reduction in CO together with enhanced baroreflex sensitivity suggests a shift toward increased parasympathetic cardiovascular control. NEW & NOTEWORTHY The reason for the decrease in blood pressure (BP) in the first weeks after gastric bypass surgery remains to be elucidated. We show that the reduction in BP following surgery is caused by a decrease in cardiac output. In addition, the maximal ascending slope in systolic blood pressure decreased suggesting a reduction in left ventricular contractility and cardiac workload. These findings help to understand the physiological changes following gastric bypass surgery and are relevant in light of the increased risk of heart failure in these patients.