Gerwin E. Engels

Short-term Effects of Tolvaptan in Individuals With Autosomal Dominant Polycystic Kidney Disease at Various Levels of Kidney Function

BACKGROUND A recent study showed that tolvaptan, a vasopressin V2 receptor antagonist, decreased total kidney volume (TKV) growth and estimated glomerular filtration rate (GFR) loss in autosomal dominant polycystic kidney disease (ADPKD) with creatinine clearance≥60mL/min. The aim of our study was to determine whether the renal hemodynamic effects and pharmacodynamic efficacy of tolvaptan in ADPKD are dependent on GFR. STUDY DESIGN Clinical trial with comparisons before and after treatment. SETTING & PARTICIPANTS Patients with ADPKD with a wide range of measured GFRs (mGFRs; 18-148 mL/min) in a hospital setting. INTERVENTION Participants were studied at baseline and after 3 weeks of treatment with tolvaptan given in increasing dosages, if tolerated (doses of 60, 90, and 120mg/d in weeks 1, 2, and 3, respectively). OUTCOMES Change in markers for aquaresis (free-water clearance, urine and plasma osmolality, 24-hour urine volume, and plasma copeptin) and kidney injury (TKV and kidney injury biomarkers). MEASUREMENTS GFR was measured by (125)I-iothalamate clearance; TKV, by magnetic resonance imaging; biomarker excretion, by enzyme-linked immunosorbent assay; and osmolality, by freezing point depression. RESULTS In 27 participants (52% men; aged 46±10 years; mGFR, 69±39mL/min; TKV, 2.15 [IQR, 1.10-2.77] L), treatment with tolvaptan led to an increase in urine volume and free-water clearance and a decrease in urine osmolality, TKV, and kidney injury marker excretion. Changes in urine volume and osmolality with treatment were less in participants with lower baseline mGFRs (both P<0.01). However, change in fractional free-water clearance was greater at lower baseline mGFRs (P=0.001), suggesting that participants with decreased GFRs responded more to tolvaptan per functioning nephron. LIMITATIONS Limited sample size, no control group. CONCLUSIONS In patients with ADPKD with decreased kidney function, response to tolvaptan is lower for TKV, urinary volume, and osmolality, but larger for fractional free-water clearance. This latter finding suggests that patients with ADPKD with lower GFRs might benefit from long-term treatment with tolvaptan, as has been observed for patients with preserved GFRs.

In vitro hemocompatibility testing: The importance of fresh blood

The use of unactivated blood for hemocompatibility testing is essential to obtain reliable results. Here, the authors study the influence of heparinized whole blood storage time and temperature on blood activation and evaluate the importance of initiating hemocompatibility tests within 4 h of blood collection. Blood from healthy volunteers was collected and analyzed with minimal delay, after 30 min and after 60 min of storage at room temperature, 30 or 37 °C. In addition, blood was analyzed after 1, 2, or 4 h of storage at room temperature. Platelet count, mean platelet volume, platelet binding capacity to collagen and thromboxane B2 were measured to assess platelet function, complement complex C5b-9 and elastase were measured to assess activation of the inflammatory response system, and thrombin-antithrombin III was measured to assess activation of the coagulation system. Furthermore, free hemoglobin was measured in platelet poor plasma as an indicator for red blood cell damage. The authors found that storage at 30 °C significantly increased platelet and coagulation activity after 60 min and storage at 37 °C significantly increased platelet, coagulation, and white blood cell activity after 60 min. Storage at room temperature significantly decreased platelet binding to collagen after 4 h and increased platelet activity after 1 h onward and white blood cell activity after 4 h. Their results show that short-term storage of heparinized whole blood significantly influences biomarkers over time, especially at 30 and 37 °C compared to room temperature. However, blood stored at room temperature for 4 h is also affected. In particular, platelet function and white blood cell activity are significantly influenced after 4 h of stationary storage at room temperature; therefore, the authors propose that hemocompatibility tests should be initiated well within 4 h of blood collection, preferably within 2 h.

Skin and Plasma Autofluorescence During Hemodialysis: A Pilot Study

Skin autofluorescence (AF) is related to the accumulation of advanced glycation end products (AGEs) and is one of the strongest prognostic markers of mortality in hemodialysis (HD) patients. The aim of this pilot study was to investigate whether changes in skin AF appear after a single HD session and if they might be related to changes in plasma AF. Skin and plasma AF were measured before and after HD in 35 patients on maintenance HD therapy (nine women and 26 men, median age 68 years, range 33-83). Median dialysis time was 4 h (range 3-5.5). Skin AF was measured noninvasively with an AGE Reader, and plasma AF was measured before and after HD at 460 nm after excitation at 370 nm. The HD patients had on average a 65% higher skin AF value than age-matched healthy persons (P < 0.001). Plasma AF was reduced by 14% (P < 0.001), whereas skin AF was not changed after a single HD treatment. No significant influence of the reduced plasma AF on skin AF levels was found. This suggests that the measurement of skin AF can be performed during the whole dialysis period and is not directly influenced by the changes in plasma AF during HD.

Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan

BACKGROUND AND OBJECTIVES Recent animal experiments suggest that dysregulation of the EGF receptor pathway plays a role in the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD). Research on EGF receptor ligands in humans with ADPKD is lacking. EGF receptor ligands were measured in patients with ADPKD at baseline and after treatment with a vasopressin V2 receptor antagonist (V2RA) because this information might provide a rationale for future V2RA combination therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Blood and urine concentrations of the EGF receptor ligands heparin-binding (HB)-EGF, EGF, and TGF-α were measured by ELISAs in 27 patients with ADPKD who participated in a single-center study investigating a V2RA in 2011-2013 and in 27 controls who were selected from a general population-based observational study. Cyst fluid concentrations were also measured. In patients with ADPKD, ligands were measured at baseline, after 3-week treatment with a V2RA, and 3 weeks after drug withdrawal. The measured GFR (mGFR) was determined by iothalamate infusion, and total kidney volume was measured by magnetic resonance imaging. RESULTS Urinary HB-EGF excretion and plasma concentration were higher in patients with ADPKD than in controls (median, 1.4 [interquartile range, 1.2-1.9] versus 0.6 [0.4-0.8] µg/24 hours [P<0.001] and 157.9 [83.1-225.9] versus 77.2 [37.2-174.3] pg/ml [P=0.04]). In contrast, urinary EGF excretion and plasma EGF concentration were lower in patients with ADPKD, whereas TGF-α did not differ between patients and controls. Higher HB-EGF excretion was correlated with more severe disease, assessed as lower mGFR (r=-0.39; P=0.05), higher total kidney volume (r=0.39; P=0.05), and higher urinary excretion of albumin and heart-type fatty acid-binding protein, whereas higher EGF excretion and TGF-α excretion were negatively correlated with disease severity. During V2RA treatment, HB-EGF excretion increased (from 1.4 [1.2-1.9] to 2.4 [2.1-3.1] µg/24 hours; P<0.001). CONCLUSION In patients with ADPKD, higher urinary HB-EGF excretion is correlated with more severe disease. Whether this association is causal needs to be investigated in intervention studies.

Novel polyurethanes with interconnected porous structure induce in vivo tissue remodeling and accompanied vascularization

Tissue engineering and regenerative medicine have furnished a vast range of modalities to treat either damaged tissue or loss of soft tissue or its function. In most approaches, a temporary porous scaffold is required to support tissue regeneration. The scaffold should be designed such that the turnover synchronizes with tissue remodeling and regeneration at the implant site. Segmented polyester urethanes (PUs) used in this study were based on epsilon-caprolactone (CL) and co-monomers D,L-lactide (D,L-L) and gamma-butyrolactone (BL), and 1,4-butanediisocyanate (BDI). In vitro, the PUs were nontoxic and haemocompatible. To test in vivo biocompatibility, the PUs were further processed into porous structures and subcutaneously implanted in rats for a period up to 21 days. Tissue remodeling and scaffold turnover was associated with a mild tissue response. The tissue response was characterized by extensive vascularization through the interconnected pores, with low numbers of macrophages on the edges and stroma formation inside the pores of the implants. The tissue ingrowth appeared to be related to the extent of microphase separation of the PUs and foam morphology. By day 21, all of the PU implants were highly vascularized, confirming the pores were interconnected. Degradation of P(CL/D,L-L)-PU was observed at this time, whereas the other two PU types remained intact. The robust method reported here of manufacturing and processing, good mechanical properties, and in vivo tissue response of the porous P(CL/D,L-L)-PU and PBCL-PU makes them excellent candidates as biomaterials with an application for soft tissue remodeling, for example, for cardiovascular regeneration.

Intraoperative cell salvage during cardiac surgery is associated with reduced postoperative lung injury

OBJECTIVES In addition to its blood-sparing effects, intraoperative cell salvage may reduce lung injury following cardiac surgery by removing cytokines, neutrophilic proteases and lipids that are present in cardiotomy suction blood. To test this hypothesis, we performed serial measurements of biomarkers of the integrity of the alveolar-capillary membrane, leucocyte activation and general inflammation. We assessed lung injury clinically by the duration of postoperative mechanical ventilation and the alveolar arterial oxygen gradient. METHODS Serial measurements of systemic plasma concentrations of interleukin-6 (IL-6), myeloperoxidase, elastase, surfactant protein D (SP-D), Clara cell 16 kD protein (CC16) and soluble receptor for advanced glycation endproducts (sRAGEs) were performed on blood samples from 195 patients who underwent cardiac surgery with the use of a cell salvage (CS) device (CS, n = 99) or without (CONTROL, n = 96). RESULTS Postoperative mechanical ventilation time was shorter in the CS group than in the CONTROL group [10 (8-15) vs 12 (9-18) h, respectively, P = 0.047]. The postoperative alveolar arterial oxygen gradient, however, was not different between groups. After surgery, the lung injury biomarkers CC16 and sRAGEs were lower in the CS group than in the CONTROL group. Biomarkers of systemic inflammation (IL-6, myeloperoxidase and elastase) were also lower in the CS group. Finally, mechanical ventilation time correlated with CC16 plasma concentrations. CONCLUSIONS The intraoperative use of a cell salvage device resulted in less lung injury in patients after cardiac surgery as assessed by lower concentrations of lung injury markers and shorter mechanical ventilation times.

Comparing changes in plasma and skin autofluorescence in low-flux versus high-flux hemodialysis

Background Tissue advanced glycation end products (AGE) are increased in hemodialysis (HD) patients, especially those with cardiovascular complications. Skin autofluorescence (skin-AF) can noninvasively estimate the accumulation of AGE in tissue. The aim was to clarify whether HD using a high-flux (HF) dialyzer favors plasma- or skin-AF removal compared to low-flux (LF) dialysis. Material and methods 28 patients were treated with either an HF-HD or LF-HD but otherwise unchanged conditions in a cross-over design. A glucose containing dialysate was used. Skin-AF was measured noninvasively with an AGE reader before and after HD. Fluorescence (370 nm/465 nm) of plasma (p-AF) was determined as total and nonprotein-bound fractions. Correction for hemoconcentrations were made using the change in serum albumin. Paired and nonpaired statistical analyses were used. Results Skin-AF was unchanged after LF- and HF-dialysis. Total, free, and protein- bound p-AF was reduced after a single LF-HD by 21%, 28%, and 17%, respectively (P<.001). After HF HD total and free p-AF was reduced by 5% and 15%, respectively (P<.001), while protein bound values were unchanged. The LF-HD resulted in a more pronounced reduction of p-AF than did HF HD (P<.001). Serum albumin correlated inversely with p-AF in HF-HD. Conclusions In the dialysis settings used there was no significant change in skin AF after dialysis, with LF or with HF dialysis. Although only limited reduction in plasma fluorescence was observed, this was more pronounced when performing LF dialysis. These data are not in overwhelming support of the use of HF dialysis in the setting used in this study.

Biomarkers of Lung Injury in Cardiothoracic Surgery

Diagnosis of pulmonary dysfunction is currently almost entirely based on a vast series of physiological changes, but comprehensive research is focused on determining biomarkers for early diagnosis of pulmonary dysfunction. Here we discuss the use of biomarkers of lung injury in cardiothoracic surgery and their ability to detect subtle pulmonary dysfunction in the perioperative period. Degranulation products of neutrophils are often used as biomarker since they have detrimental effects on the pulmonary tissue by themselves. However, these substances are not lung specific. Lung epithelium specific proteins offer more specificity and slowly find their way into clinical studies.

The effect of pulsatile cardiopulmonary bypass on lung function in elderly patients

Purpose Cardiopulmonary bypass is still a major cause of lung injury and delay in pulmonary recovery after cardiac surgery. Although it has been shown that pulsatile flow induced by intra-aortic balloon pumping is beneficial for preserving lung function, it is not clear if the same beneficial effect can be accomplished with pulsatile flow generated in the extracorporeal circuit. Therefore, we investigated the effect of pulsatile flow, produced by a centrifugal pump, on lung function in elderly patients. Methods Serial measurements of lung biomarkers Clara cell 16 kD protein, surfactant protein D, and elastase were performed on blood samples from 37 elderly patients (≥75 years) who underwent elective aortic valve replacement surgery with CPB, either with pulsatile perfusion or continuous perfusion. Pulmonary function was assessed by postoperative ventilation time, the arterial blood oxygenation (PaO2/FiO2), the alveolar-arterial oxygen gradient (Aa-O2 gradient) and the pulmonary vascular resistance indexed by body surface area (PVRi). Results There was no difference in lung function between both groups, as assessed by the postoperative ventilation time, the PaO2/FiO2 ratio, and the Aa-O2 gradient. The PVRi, however, was significantly lower in the pulsatile perfusion group 15 mins after the administration of protamine (p<0.05). The plasma concentrations of the lung biomarkers increased during surgery and peaked at 1 h ICU, there were however no differences between groups. Conclusions Pulsatile flow does not seem beneficial to postoperative lung function in elderly patients. Moreover, pulsatile flow does not affect lung function on a subclinical level as assessed by lung biomarkers.

Skin and Plasma Autofluorescence During Hemodialysis: A Pilot Study: Thoughts and Progress

Skin autofluorescence (AF) is related to the accumulation of advanced glycation end products (AGEs) and is one of the strongest prognostic markers of mortality in hemodialysis (HD) patients. The aim of this pilot study was to investigate whether changes in skin AF appear after a single HD session and if they might be related to changes in plasma AF. Skin and plasma AF were measured before and after HD in 35 patients on maintenance HD therapy (nine women and 26 men, median age 68 years, range 33-83). Median dialysis time was 4 h (range 3-5.5). Skin AF was measured noninvasively with an AGE Reader, and plasma AF was measured before and after HD at 460 nm after excitation at 370 nm. The HD patients had on average a 65% higher skin AF value than age-matched healthy persons (P < 0.001). Plasma AF was reduced by 14% (P < 0.001), whereas skin AF was not changed after a single HD treatment. No significant influence of the reduced plasma AF on skin AF levels was found. This suggests that the measurement of skin AF can be performed during the whole dialysis period and is not directly influenced by the changes in plasma AF during HD.