Hans O. Pinnschmidt

PLA2R antibody levels and clinical outcome in patients with membranous nephropathy and non-nephrotic range proteinuria under treatment with inhibitors of the renin-angiotensin system.

Patients with primary membranous nephropathy (MN) who experience spontaneous remission of proteinuria generally have an excellent outcome without need of immunosuppressive therapy. It is, however, unclear whether non-nephrotic proteinuria at the time of diagnosis is also associated with good prognosis since a reasonable number of these patients develop nephrotic syndrome despite blockade of the renin-angiotensin system. No clinical or laboratory parameters are available, which allow the assessment of risk for development of nephrotic proteinuria. Phospholipase A2 Receptor antibodies (PLA2R-Ab) play a prominent role in the pathogenesis of primary MN and are associated with persistence of nephrotic proteinuria. In this study we analysed whether PLA2R-Ab levels might predict development of nephrotic syndrome and the clinical outcome in 33 patients with biopsy-proven primary MN and non-nephrotic proteinuria under treatment with blockers of the renin-angiotensin system. PLA2R-Ab levels, proteinuria and serum creatinine were measured every three months. Nephrotic-range proteinuria developed in 18 (55%) patients. At study start (1.2±1.5 months after renal biopsy and time of diagnosis), 16 (48%) patients were positive for PLA2R-Ab. A multivariate analysis showed that PLA2R-Ab levels were associated with an increased risk for development of nephrotic proteinuria (HRu200a=u200a3.66; 95%CI: 1.39–9.64; pu200a=u200a0.009). Immunosuppressive therapy was initiated more frequently in PLA2R-Ab positive patients (13 of 16 patients, 81%) compared to PLA2R-Ab negative patients (2 of 17 patients, 12%). PLA2R-Ab levels are associated with higher risk for development of nephrotic-range proteinuria in this cohort of non-nephrotic patients at the time of diagnosis and should be closely monitored in the clinical management.

M-type Phospholipase A2 Receptor Autoantibodies and Renal Function in Patients with Primary Membranous Nephropathy

BACKGROUND AND OBJECTIVESnLoss of renal function in patients with primary membranous nephropathy cannot be reliably predicted by laboratory or clinical markers at the time of diagnosis. M-type phospholipase A2 receptor autoantibodies have been shown to be associated with changes in proteinuria. Their eventual effect on renal function, however, is unclear.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnIn this prospective, open, multicenter study, the potential role of M-type phospholipase A2 receptor autoantibodies levels on the increase of serum creatinine in 118 consecutive patients with membranous nephropathy and positivity for serum M-type phospholipase A2 receptor autoantibodies was analyzed. Patients were included in the study between April of 2010 and December of 2012 and observed until December of 2013. The clinical end point was defined as an increase of serum creatinine by ≥ 25% and serum creatinine reaching ≥ 1.3 mg/dl.nnnRESULTSnPatients were divided into tertiles according to their M-type phospholipase A2 receptor autoantibody levels at the time of inclusion in the study: tertile 1 levels=20-86 units/ml (low), tertile 2 levels=87-201 units/ml (medium), and tertile 3 levels ≥ 202 units/ml (high). The median follow-up time of all patients in the study was 27 months (interquartile range=18-33 months). The clinical end point was reached in 69% of patients with high M-type phospholipase A2 receptor autoantibodies levels (tertile 3) but only 25% of patients with low M-type phospholipase A2 receptor autoantibodies levels. The average time to reach the study end point was 17.7 months in patients with high M-type phospholipase A2 receptor autoantibodies levels and 30.9 months in patients with low M-type phospholipase A2 receptor autoantibodies levels. A multivariate Cox regression analysis showed that high M-type phospholipase A2 receptor autoantibodies levels-in addition to men and older age-are an independent predictor for progressive loss of renal function.nnnCONCLUSIONSnHigh M-type phospholipase A2 receptor autoantibodies levels were associated with more rapid loss of renal function in this cohort of patients with primary membranous nephropathy and therefore, could be helpful for treatment decisions.

Spontaneous remission of proteinuria is a frequent event in phospholipase A2 receptor antibody negative patients with membranous nephropathy

BACKGROUNDnPhospholipase A2 receptor antibodies (PLA2R-Ab) and thrombospondin type-1 domain-containing 7A antibodies (THSD7A-Ab) are present in 70-80% of patients with membranous nephropathy (MN). Little, however, is known about the pathogenesis of MN and the clinical outcome in PLA2R-Ab- and THSD7A-Ab-negative patients.nnnMETHODSnIn this prospective multicentre observational study, the clinical outcome of 37 patients with biopsy-proven MN who were negative for PLA2R-Ab and THSD7A-Ab in the serum was analysed.nnnRESULTSnA total of 198 patients were screened for inclusion in the study. Of these, 157 patients were positive for PLA2R-Ab and 4 patients for THSD7A-Ab. The remaining 37 patients were negative for both antibodies were and included in this study. Six patients died during the follow-up, five because of malignant diseases and one of an infection. One patient went into end-stage renal disease, and two patients were lost to follow-up. The remaining 28 patients were followed for at least 24 months (35.6 ± 8.9 months). Seventeen patients received immunosuppressive (IS) therapy, and 11 received supportive care only. At the end of the follow-up, 14 of the 17 patients treated with immunosuppressants and 10 of 11 patients on supportive therapy had a remission of proteinuria. The time to reach remission of proteinuria and serum creatinine levels at the end of the follow-up were not different between both groups. A univariate Cox regression analysis indicated that the use of immunosuppression did not alter the chance to reach a remission of proteinuria.nnnCONCLUSIONSnA high number of PLA2R-Ab- and THSD7A-Ab-negative patients with MN have a good prognosis and might not need IS therapy.

Morphology of Ruptured and Unruptured Intracranial Aneurysms

BACKGROUNDnIn addition to size and location, the morphology of intracranial aneurysms has been proposed to predict rupture. This study was undertaken to compare morphologic features between ruptured and unruptured aneurysms and identify those associated with greater risk of rupture.nnnMETHODSnBetween 2010 and 2014, 301 patients with subarachnoid hemorrhage and 204 with unruptured aneurysms were admitted to our hospital. Two investigators reviewed 3-dimensional angiograms of all aneurysms. Risk factors for rupture were identified. Morphology was classified into single-sac aneurysms with smooth margin, single-sac aneurysms with irregular margin, aneurysms with a daughter sac, and multilobulated aneurysms. The value of morphology in predicting rupture was tested with the use of logistic regression.nnnRESULTSnA total of 420 aneurysms met the inclusion criteria. Multilobulated aneurysm was the most frequent finding among ruptured aneurysms, followed by single sac with irregular margin, aneurysm with daughter sac, and single sac with smooth margin (44.9%, 25.9%, 18%, and 11.2%, respectively). Among unruptured aneurysms, single sac with smooth margin was the most frequent finding, followed by single sac with irregular margin, multilobulated aneurysm, and aneurysm with daughter sac (38.1%, 29.8%, 20.9%, and 11.2%, respectively). Morphology was an independent predictor of rupture (receiver operating characteristic-area under the curve 0.693, P < 0.001). Risk of rupture increased by factor of 3 (5, 95% confidence interval [CI] 1.6-5.3) from single sac with regular margin to irregular margin, by factor of 5.5 (5, 95% CI 2.8-11.0) to daughter sac, and by factor of 7.3 (5, 95% CI 4.1-13.1) to multilobulated aneurysm.nnnCONCLUSIONSnMorphology might have an independent predictive value of aneurysm rupture. Risk of rupture might increase according to extent of morphologic change. Prospective studies will be necessary to evaluate the influence of aneurysm morphology on natural history.

Bronchoscopy versus an endotracheal tube mounted camera for the peri-interventional visualization of percutaneous dilatational tracheostomy - a prospective, randomized trial (VivaPDT)

BackgroundPercutaneous dilatational tracheostomy (PDT) in critically ill patients often involves bronchoscopic optical guidance. However, this procedure is not without disadvantages. Therefore, we aimed to study a recently introduced endotracheal tube-mounted camera (VivaSightTM-SL tube [VST]; ETView, Misgav, Israel) for guiding PDT.MethodsThis was a randomized controlled trial involving 46 critically ill patients who received PDT using optical guidance with a VST or with bronchoscopy. The primary outcome measure was visualization of the tracheal structures (i.e., identification and monitoring of the thyroid, cricoid, and tracheal cartilage and the posterior wall) rated on 4-point Likert scales. Secondary measures were the quality of ventilation (before puncture and during the tracheostomy procedure rated on 4-point Likert scales) and blood gases sampled at standardized time points.ResultsThe mean ratings for visualization (lower values better; values given for per-protocol analysis) were 5.4 (95% CI 4.5–6.3) for the VST group and 4.0 (95% CI 4.0–4.0) for the bronchoscopy group (pu2009<u20090.001). Mean ventilation ratings were 2.5 (95% CI 2.1–2.9) for VST and 5.0 (95% CI 4.4–5.7) for bronchoscopy (pu2009<u20090.001). Arterial carbon dioxide increased to 5.9 (95% CI 5.4–6.5) kPa in the VST group vs. 8.3 (95% CI 7.2–9.5) kPa in the bronchoscopy group (pu2009<u20090.001), and pH decreased to 7.40 (95% CI 7.36–7.43) in the VST group vs. 7.26 (95% CI 7.22–7.30) in the bronchoscopy group (pu2009<u20090.001), at the end of the intervention.ConclusionsVisualization of PDT with the VST is not noninferior to guidance by bronchoscopy. Ventilation is superior with less hypercarbia with the VST. Because visualization is not a prerequisite for PDT, patients requiring stable ventilation with normocarbia may benefit from PDT with the VST.Trial registrationClinicalTrials.gov, NCT02861001. Registered on 13 June 2016.

Validation of Innovative Techniques for Monitoring Nociception during General Anesthesia: A Clinical Study Using Tetanic and Intracutaneous Electrical Stimulation.

BACKGROUNDnThis study compares the analgesic indices Analgesia Nociception Index (heart rate variability), Surgical Pleth Index (photoplethysmography), and pupillary dilatation, to heart rate, mean arterial pressure, and bispectral index, with regard to diagnostic accuracy and prediction probability for nociceptive response. The primary endpoint was the correlation between Δ values and the remifentanil dose administered.nnnMETHODSnWe anesthetized 38 patients with propofol and increasing doses of remifentanil and applied standardized tetanic and intracutaneous electrical painful stimulations on each analgesic level. Baseline and Δ values of the Analgesia Nociception Index, the Surgical Pleth Index, pupillary dilatation, heart rate, mean arterial pressure, and bispectral index and their relation to remifentanil doses were analyzed by receiver operating characteristic curves, prediction probability (PK), and mixed-model analysis.nnnRESULTSnUnder propofol sedation, sensitivity and specificity of the Analgesia Nociception Index (PK = 0.98), the Surgical Pleth Index (PK = 0.87), and pupillary dilatation (PK = 0.98) for detecting both painful stimulations were high compared to heart rate (PK = 0.74), mean arterial pressure (PK = 0.75), and bispectral index (PK = 0.55). Baseline values had limited prediction probability toward the nociceptive response (Analgesia Nociception Index: PK = 0.7; Surgical Pleth Index: PK = 0.63; pupillary dilatation: PK = 0.67; and bispectral index: PK = 0.67). The remifentanil dose had an effect (P < 0.001) on all parameters except for bispectral index (P = 0.216).nnnCONCLUSIONSnThe Analgesia Nociception Index, the Surgical Pleth Index, and pupillary dilatation are superior in detecting painful stimulations compared to heart rate and mean arterial pressure but had limited predictive value. These effects are attenuated by increasing dosages of remifentanil. Our data confirm that bispectral index is not a marker of analgesia.

Baseline Characteristics and Prescription Patterns of Standard Drugs in Patients with Angiographically Determined Coronary Artery Disease and Renal Failure (CAD-REF Registry).

Background Chronic kidney disease (CKD) is strongly associated with coronary artery disease (CAD). We established a prospective observational nationwide multicenter registry to evaluate current treatment and outcomes in patients with both CKD and angiographically documented CAD. Methods In 32 cardiological centers 3,352 CAD patients with ≥50% stenosis in at least one coronary artery were enrolled and classified according to their estimated glomerular filtration rate and proteinuria into one of five stages of CKD or as a control group. Results 2,723 (81.2%) consecutively enrolled patients suffered from CKD. Compared to controls, CKD patients had a higher prevalence of diabetes, hypertension, peripheral artery diseases, heart failure, and valvular heart disease (each p<0.001). Myocardial infarctions (p = 0.02), coronary bypass grafting, valve replacements and pacemaker implantations had been recorded more frequently (each p<0.001). With advanced CKD, the number of diseased coronary vessels and the proportion of patients with reduced left ventricular ejection fraction (LVEF) increased significantly (both p<0.001). Percutaneous coronary interventions were performed less frequently (p<0.001) while coronary bypass grafting was recommended more often (p = 0.04) with advanced CKD. With regard to standard drugs in CAD treatment, prescriptions were higher in our registry than in previous reports, but beta-blockers (p = 0.008), and angiotensin-converting-enzyme inhibitors and/or angiotensin-receptor blockers (p<0.001) were given less often in higher CKD stages. In contrast, in the subgroup of patients with moderately to severely reduced LVEF the prescription rates did not differ between CKD stages. In-hospital mortality increased stepwise with each CKD stage (p = 0.02). Conclusions In line with other studies comprising CKD cohorts, patients’ morbidity and in-hospital mortality increased with the degree of renal impairment. Although cardiologists’ drug prescription rates in CAD-REF were higher than in previous studies, they were still lower especially in advanced CKD stages compared to cohorts treated by nephrologists.

Syndecan-1 as a biomarker for sepsis survival after major abdominal surgery

AIMnSepsis is a serious complication following surgery and identification of patients at risk is of high importance. Syndecan-1 (sSDC1) levels are known to be elevated during sepsis.nnnMATERIALS & METHODSnFifty-five patients scheduled for major abdominal surgery were prospectively included and sSDC1 concentrations were measured during hospital stay.nnnRESULTSnPatients with postoperative sepsis showed a continued increase of sSDC1 levels and exhibited higher median sSDC1 concentrations at day 1 compared with nonseptic patients 90.3 versus 16.5xa0ng/ml. A significant association of sSDC1 levels with the incidence of sepsis and death was demonstrated.nnnCONCLUSIONnThis study identifies sSDC1 as potential biomarker for sepsis and survival after abdominal surgery.

Substitution Urethroplasty with Closure Versus Nonclosure of the Buccal Mucosa Graft Harvest Site: A Randomized Controlled Trial with a Detailed Analysis of Oral Pain and Morbidity

BACKGROUNDnOptimal surgical management of the buccal mucosa harvest site in patients with urethral stricture disease during buccal mucosa graft urethroplasty (BMGU) remains controversial.nnnOBJECTIVEnTo analyze in detail intensity and quality of pain as well as oral morbidity following closure (C) versus nonclosure (NC) of the donor site.nnnDESIGN, SETTING, AND PARTICIPANTSnRandomized controlled trial on 135 patients treated with BMGU between October 15, 2014 and December 18, 2015.nnnINTERVENTIONnFollowing computer-based randomization, 63 and 72 patients, respectively, received C and NC of the donor site at the inner cheek. Preoperatively, on days 1, 5, and 21 as well as at 3 and 6 mo postoperatively, patients completed standardized questionnaires, including validated questions on intensity and quality of pain as well as oral morbidity.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnThe coprimary end points were intensity and quality of oral pain. Secondary end points included oral morbidity and intensity of pain of the perineogenital region. Generalized linear mixed models evaluated the effect of various covariates on intensity and quality of oral pain, oral morbidity, as well as intensity of pain of the perineogenital region.nnnRESULTS AND LIMITATIONSnThere was noninferiority for NC versus C in intensity and affective quality of oral pain at every time point following BMGU. Oral morbidity and complications included pain, bleeding, swelling, numbness, alteration of salivation and taste, as well as impairment of mouth opening, smiling, whistling, diet, and speech. Time from BMGU had significant effects on intensity (p<0.001) and quality of oral pain (sensory pain: p<0.001, affective pain: p<0.001, total pain: p<0.001). Length of buccal mucosa graft had significant effects on intensity (p=0.001) and quality of oral pain (sensory pain: p=0.020, total pain: p=0.042).nnnCONCLUSIONSnNC is noninferior to C of the donor site in intensity and quality of oral pain, and offers a treatment alternative. Time from BMGU and length of the buccal mucosa graft have effects on oral morbidity and complications.nnnPATIENT SUMMARYnWe investigated pain, morbidity, and complications following closure (C) versus nonclosure (NC) of the buccal mucosa harvest site in patients undergoing buccal mucosa graft urethroplasty (BMGU). We found that NC is not worse than C regarding oral pain. In addition, time from BMGU and length of the buccal mucosa graft have effects on oral morbidity and complications.

Differential effects of BDNF val(66)met in repetitive associative learning paradigms.

In healthy young subjects, the brain derived neurotropic factor (BDNF) val(66)met polymorphism negatively affects behavioural outcome in short-term motor cortex or hippocampus-based learning paradigms. In repetitive training paradigms over several days this effect can be overcome, in tests involving other brain areas even positive effects were found. To further specify the role of this polymorphism in cognitive processes, we used an associative vocabulary learning paradigm over four consecutive days and tested 38 young healthy subjects and 29 healthy elderly subjects. As a control paradigm, we designed a nonverbal haptic Braille letter-learning paradigm based on the same principles. Behavioural outcome was then associated with the BDNF-genotype. In the vocabulary learning task, met carrier (met/val and met/met) benefitted more from the repetitive training than val/val subjects. This was paralleled by a higher reduction of delayed answers during the course of the study, an effect that was also present in the haptic paradigm. However, in a group of healthy elderly subjects, no similar tendency was found. We conclude that the BDNF val(66)met polymorphism alters highly circumscribed answer behaviours in young healthy subjects. This might partly explain the high variability of previously published results.