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Background: Severe thromboembolic events are one of the major complications associated with COVID-19 infection, especially among critically ill patients. We analysed ROTEM measurements in COVID-19 patients with a severe disease course and in patients with severe sepsis. Methods: In this study, data obtained by extended analysis of haemostasis with standard laboratory tests and thromboelastometry of 20 patients with severe course of COVID-19 were retrospectively analysed and compared with similar data from 20 patients with severe sepsis but no COVID-19. Results: The thromboelastometry values obtained from 20 sepsis patients contained a maximum clot firmness above the normal range but among COVID-19 patients, hypercoagulability was much more pronounced, with significantly higher maximum clot firmness (FIBTEM: 38.4 ± 10.1 mm vs. 29.6 ± 10.8 mm; P = 0.012; EXTEM: 70.4 ± 10.4 mm vs. 60.6 ± 14.8 mm; P = 0.022). Additionally, fibrinogen levels were significantly higher among COVID-19 patients (757 ± 135 mg/dl vs. 498 ± 132 mg/dl, P < 0.0001). Furthermore, thromboelastometry showed fibrinolysis shutdown among COVID-19 patients with significantly lower maximum of lysis than among sepsis patients (EXTEM: 0.6 ± 1.2 % vs. 3.3 ± 3.7 %; P = 0.013). Seven of 20 COVID-19 patients experienced thromboembolic events, whereas no patient in the sepsis group experienced such events. Conclusions: ROTEM analysis showed significantly different pathological findings characterized by hypercoagulability and fibrinolysis shutdown among COVID-19 patients with a severe disease course compared to patients with severe sepsis. These abnormalities seem to be associated with thromboembolic events. [ABSTRACT FROM AUTHOR]

Background: Severe thromboembolic events are one of the major complications associated with COVID-19 infection, especially among critically ill patients. We analysed ROTEM measurements in COVID-19 patients with a severe disease course and in patients with severe sepsis. Methods: In this study, data obtained by extended analysis of haemostasis with standard laboratory tests and thromboelastometry of 20 patients with severe course of COVID-19 were retrospectively analysed and compared with similar data from 20 patients with severe sepsis but no COVID-19. Results: The thromboelastometry values obtained from 20 sepsis patients contained a maximum clot firmness above the normal range but among COVID-19 patients, hypercoagulability was much more pronounced, with significantly higher maximum clot firmness (FIBTEM: 38.4 ± 10.1 mm vs. 29.6 ± 10.8 mm; P = 0.012; EXTEM: 70.4 ± 10.4 mm vs. 60.6 ± 14.8 mm; P = 0.022). Additionally, fibrinogen levels were significantly higher among COVID-19 patients (757 ± 135 mg/dl vs. 498 ± 132 mg/dl, P < 0.0001). Furthermore, thromboelastometry showed fibrinolysis shutdown among COVID-19 patients with significantly lower maximum of lysis than among sepsis patients (EXTEM: 0.6 ± 1.2 % vs. 3.3 ± 3.7 %; P = 0.013). Seven of 20 COVID-19 patients experienced thromboembolic events, whereas no patient in the sepsis group experienced such events. Conclusions: ROTEM analysis showed significantly different pathological findings characterized by hypercoagulability and fibrinolysis shutdown among COVID-19 patients with a severe disease course compared to patients with severe sepsis. These abnormalities seem to be associated with thromboembolic events. [ABSTRACT FROM AUTHOR]

Cognitive deficits have a high prevalence in elderly patients with chronic kidney disease (CKD). The clinical picture consists of cognitive slowing, executive, memory and language deficits, and is attributed to cerebral white matter disease and clinically often silent brain infarcts. In the meantime, robust evidence exists that low estimated glomerular filtration rate, a measure of CKD severity, predisposes to cognitive deficits, cerebral white matter lesions, and ischemic brain infarcts in addition to demographic factors, vascular risk factors and diseases which also contribute to CKD-related cognitive deficits. In terminal CKD, cerebral blood flow is compromized during hemodialysis sessions, resulting in oxygen desaturation, cognitive deterioration and-in the longer run-brain atrophy. Kidney transplantation improves cognitive deficits in terminal CKD. At all stages, vascular risk factors and associated diseases should stringently be treated according to therapeutic guidelines. [ABSTRACT FROM AUTHOR]

Purpose: One of the key problems in the drug therapy of patients with chronic conditions is drug adherence. In 2010 the initiative iNephro was launched (www.inephro.de). A software to support regular and correct drug intake was developed for a smartphone platform (iOS). The study investigated whether and how smartphone users deployed such an application. Methods: Together with cooperating partners the mobile application “Medikamentenplan” (“Medication Plan”) was developed. Users are able to keep and alter a list of their regular medication. A memory function supports regular intake. The application can be downloaded free of charge from the App Store™ by Apple™. After individual consent of users from December 2010 to April 2012 2042338 actions were recorded and analysed from the downloaded applications. Demographic data were collected from 2279 users with a questionnaire. Results: Overall the application was used by 11688 smartphone users. 29% (3406/11688) used it at least once a week for at least four weeks. 27% (3209/11688) used the application for at least 84 days. 68% (1554/2279) of users surveyed were male, the stated age of all users was between 6–87 years (mean 44). 74% of individuals (1697) declared to be suffering from cardiovascular disease, 13% (292) had a previous history of transplantation, 9% (205) were suffering from cancer, 7% (168) reported an impaired renal function and 7% (161) suffered from diabetes mellitus. 69% (1568) of users were on <6 different medications, 9% (201) on 6 – 10 and 1% (26) on more than 10. Conclusion: A new smartphone application, which supports drug adherence, was used regularly by chronically ill users with a wide range of diseases over a longer period of time. The majority of users so far were middle-aged and male. [ABSTRACT FROM AUTHOR]

J Clin Hypertens (Greenwich). © 2010 Wiley Periodicals, Inc. Patients with stage 2 hypertension (systolic blood pressure [SBP] ≥160 mm Hg and/or diastolic blood pressure [DBP] ≥100 mm Hg) are at high cardiovascular risk and require intensive blood pressure (BP)-lowering therapy. This randomized double-blind study is the first prospective trial specifically designed to evaluate the direct renin inhibitor aliskiren in patients with a mean sitting SBP ≥160 mm Hg and <180 mm Hg (the lower ranges of stage 2 systolic hypertension). After a 2- to 4-week washout period, 688 patients were randomized to once-daily aliskiren/hydrochlorothiazide (HCT) 150/12.5 mg or aliskiren 150 mg for 1 week and then double the doses for 11 weeks. Baseline BP was 167.1/95.0 mm Hg. At week 12, both aliskiren/HCT and aliskiren provided substantial BP reductions from baseline (30.0/12.6 mm Hg and 20.3/8.2 mm Hg, respectively). Aliskiren/HCT lowered BP significantly more than aliskiren (least-squares mean between-treatment differences [95% confidence interval] were -9.7 [−12.0 to −7.4] for SBP and −4.5 [−5.8 to −3.2] for DBP; both P<.0001). Similar BP reductions were seen in the subgroups of patients with isolated systolic hypertension and obesity. Aliskiren, with or without HCT, provides clinically significant BP reductions and may therefore be an effective treatment option in patients with stage 2 hypertension. J Clin Hypertens (Greenwich). 2010;12:917-926. © 2010 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Nephrogenic systemic fibrosis (NSF) is a newly recognized disorder occurring exclusively in patients with renal failure. Exposure to gadolinium-based magnetic resonance (MR) contrast media has been associated with subsequent development of NSF. Nephrogenic systemic fibrosis is characterized by skin induration preferentially affecting the extremities. In addition, involvement of internal organs occurs, which leads ultimately to death. Skin biopsy is important for confirmation of the diagnosis. The main therapeutic goal is restoration of renal function. To reduce the risk of NSF, renal function must be determined before exposure to gadolinium-containing MR contrast agents. Gadolinium-based MR contrast media should be avoided in the presence of advanced renal failure with estimated glomerular filtration rate below 30 ml/min/1.73 m2, unless the diagnostic information is essential and not available with noncontrast magnetic resonance imaging techniques. The recommended dose of contrast agent should not be exceeded. In addition, a sufficient period of time for elimination of the contrast agent from the body should be allowed before readministration of the contrast agent. [Copyright &y& Elsevier]

Kidney proximal tubules develop a severe but highly reversible energetic deficit due to nonesterified fatty acid (NEFA)-induced dissipation of mitochondrial membrane potential (ΔΨm) during reoxygenation after severe hypoxia. To assess the mechanism for this behavior, we have compared the efficacies of different NEFA for inducing mitochondrial deenergization in permeabilized tubules measured using safranin O uptake and studied the modification of NEFA-induced deenergization by inhibitors of the ADP/ATP carrier and glutamate using both normoxic tubules treated with exogenous NEFA and tubules deenergized during hypoxia-reoxygenation (H/R). Among the long-chain NEFA that accumulate during H/R of isolated tubules and ischemia-reperfusion of the kidney in vivo, oleate, linoleate, and arachidonate had strong effects to dissipate ΔΨm that were slightly greater than palmitate, while stearate was inactive at concentrations reached in the cells. This behavior correlates well with the protonophoric effects of each NEFA. Inhibition of the ADP/ATP carrier with either carboxyatractyloside or bongkrekic acid or addition of glutamate to compete for the aspartate/glutamate carrier improved ΔΨ in the presence of exogenous oleate and after H/R. Effects on the two carriers were additive and restored safranin O uptake to as much as 80% of normal under both conditions. The data strongly support NEFA cycling across the inner mitochondrial membrane using anion carriers as the main mechanism for NEFA-induced deenergization in this system and provide the first evidence for a contribution of this process to pathophysiological events that impact importantly on energetics of intact cells. [ABSTRACT FROM AUTHOR]

Kidney proximal tubules exhibit decreased ATP and reduced, but not absent, mitochondrial membrane potential (ΔΨm) during reoxygenation after severe hypoxia. This energetic deficit, which plays a pivotal role in overall cellular recovery, cannot be explained by loss of mitochondrial membrane integrity, decreased electron transport, or compromised F1F0-ATPase and adenine nucleotide translocase activities. Addition of oleate to permeabilized tubules produced concentration-dependent decreases of ΔΨm measured by safranin 0 uptake (threshold for oleate = 0.25 μM, 1.6 nmol/mg protein; maximal effect = 4 μM, 26 nmol/mg) that were reversed by delipidated BSA (dBSA). Cell nonesterified fatty acid (NEFA) levels increased from < 1 to 17.4 nmol/mg protein during 60- min hypoxia and remained elevated at 7.6 nmol/mg after 60 min reoxygenation, at which time ATP had recovered to only 10% of control values. Safranin O uptake in reoxygenated tubules, which was decreased 85% after 60-min hypoxia, was normalized by dBSA, which improved ATP synthesis as well. dBSA also almost completely normalized ΔΨm when the duration of hypoxia was increased to 120 min. In intact tubules, the protective substrate combination of α-ketoglutarate + malate (α-KG/MAL) increased ATP three- to fourfold, limited NEFA accumulation during hypoxia by 50%, and lowered NEFA during reoxygenation. Notably, dBSA also improved ATP recovery when added to intact tubules during reoxygenation and was additive to the effect of α-KG/MAL. We conclude that NEFA overload is the primary cause of energetic failure of reoxygenated proximal tubules and lowering NEFA substantially contributes to the benefit from supplementation with α-KG/MAL. [ABSTRACT FROM AUTHOR]

Proximal tubules develop a severe energetic deficit during hypoxia-reoxygenation (H/R) that previous studies using fluorescent potentiometric probes have suggested is characterized by sustained, partial mitochondrial deenergization. To validate the primary occurrence of mitochondrial deenergization in the process, optimize approaches for estimating changes in mitochondrial membrane potential (Δψm) in the system, and clarify the mechanisms for the defect, we further investigated the behavior of 5,5′ 6,6′ -tetrachloro-1 ,1′,3,3′-tetraethylbenzimidazocarbocyanine iodide (JC-1) in these cells and introduce a more dynamic and quantitative approach employing safranin 0 for use with the tubule system. Although use of JC-1 can be complicated by decreases in the plasma membrane potential that limit cellular uptake of JC-1 and such behavior was demonstrated in ouabain-treated tubules, changes in Δψm entirely accounted for the decreases in the formation of red fluorescent JC-1 aggregates and in the ratio of red/green fluorescence observed after H/R The red JC-1 aggregates did not readily dissociate when tubules were deenergized after JC-1 uptake, making it unsuitable for dynamic studies of energization. Safranin O uptake by digitonin-pemeabilized tubules required very small numbers of tubules, permitted measurements of Δψm for relatively prolonged periods after the end of the experimental maneuvers, was rapidly reversible during deenergization, and allowed for direct assessment of both substrate-dependent, electron transport-mediated Δψm, and ATP hydrolysis-supported Δψm. Both types of energization measured using safranin O in tubules permeabilized after H/R were impaired, but combining substrates and ATP substantially restored Δψm. [ABSTRACT FROM AUTHOR]

The purpose of this study was to assess the safety and efficacy of the insulin sensitizer rosiglitazone in patients with new-onset diabetes mellitus (NODM) after renal transplantation. Twenty-two patients with NODM after renal transplantation were selected to receive rosiglitazone therapy. All patients received prednisone, 15 patients were treated with tacrolimus and seven patients received cyclosporine A. For 16 of the 22 patients treatment with rosiglitazone therapy was successful and mean fasting blood glucose decreased from 182 ± 17 to 127 ± 7 mg/dl. Six patients were not treated successfully with rosiglitazone alone, one patient needed a second oral antidiabetic agent and four patients insulin therapy. In one patient rosiglitazone was stopped because of edema after 5 days. There were no changes either in serum creatinine concentrations, or cyclosporine and tacrolimus blood levels respectively. Treatment with rosiglitazone appears to be safe and effective in patients with NODM after renal transplantation. [ABSTRACT FROM AUTHOR]

Inhibition of complex I has been considered to be an important contributor to mitochondrial dysfunction in tissues subjected to ischemia-reperfusion. We have investigated the role of complex I in a severe energetic deficit that develops in kidney proximal tubules subjected to hypoxia-reoxygenation and is strongly ameliorated by supplementation with specific citric acid cycle metabolites, including succinate and the combination of α-ketoglutarate plus malate. NADH: ubiquinone reductase activity in the tubules was decreased by only 26% during 60-min hypoxia and did not change further during 60-min reoxygenation. During titration of complex I activity with rotenone, progressive reduction of NAD+ to NADH was detected at >20% complex I inhibition, but substantial decreases in ATP levels and mitochondrial membrane potential did not occur until >70% inhibition. NAD+ was reduced to NADH during hypoxia, but the NADH formed was fully reoxidized during reoxygenation, consistent with the conclusion that complex I function was not limiting for recovery. Extensive degradation of cytosolic and mitochondrial NAD(H) pools occurred during either hypoxia or severe electron transport inhibition by rotenone, with patterns of metabolite accumulation consistent with catabolism by both NAD+ glycohydrolase and pyrophosphatase. This degradation was strongly blocked by a-ketoglutarate plus malate. The data demonstrate surprisingly little sensitivity of these cells to inhibition of complex I and high levels of resistance to development of complex I dysfunction during hypoxia-reoxygenation and indicate that events upstream of complex I are important for the energetic deficit. The work provides new insight into fundamental aspects of mitochondrial pathophysiology in proximal tubules during acute renal failure. [ABSTRACT FROM AUTHOR]

Orthostatic hypotension (OH) is a fall in blood pressure after assuming an upright position. Whereas asymptomatic patients usually need no treatment, the majority of symptomatic patients can be cured by avoidance of trigger mechanisms and the use of physical countermaneuvers and non-pharmacological interventions. Several pharmacological therapies are available and generally fludrocortisone and midodrine are the drugs of first choice. Recently, highly individualized therapy with ambulatory norepinephrine therapy was able to mobilize otherwise immobile patients. [Copyright &y& Elsevier]

Highlights: What was known: Deviations in serum creatinine (SCr), due to its determination using a Jaffe or an enzymatic method, have an effect on kidney disease detection and staging. It is not yet clear how large this effect is in kidney transplant recipients (KTRs). SCr measurement differences are of particular importance here to evaluate the graft function. This study adds: Investigation of the difference between Jaffe SCr and enzymatic SCr in a large cohort of outpatient KTRs. In more than every tenth SCr determination in outpatient KTRs, the difference between the Jaffe and enzymatic methods had an influence on the assignment to a CKD stage. This effect was comparably pronounced for all eGFR formulas applied. Potential impact: Clinicians should keep in mind that the difference between Jaffe and enzymatic SCr affects CKD staging in KTRs. Background: Deviations in serum creatinine (SCr), due to its determination using a Jaffe or an enzymatic method, have an effect on kidney disease detection and staging. It is not yet clear how large this effect is in kidney transplant recipients (KTRs). SCr measurement differences are of particular importance here to evaluate the graft function. Methods: The results of all parallel SCr measurements (Jaffe and enzymatic method) of adult outpatient KTRs in the same serum sample at the University Hospital Essen (Germany) between January 2020 and October 2023 were evaluated. A Bland–Altman plot with 95% limits of agreement (LoA) was used to assess the difference between the Jaffe and the enzymatic SCr (eSCr). For all patients, we used the CKD-EPI 2009 and EKFC formula, and for patients ≥ 70 years, we also used the BIS1 formula for the determination of eGFR. Results: A total of 12,081 parallel SCr measurements from 1243 KTRs were analyzed, where 61% were male and the median age was 53 years. On average, Jaffe SCr was 0.03 mg/dL higher than eSCr (LoA −0.16; 0.21 mg/dL). On average, the eGFR determined by Jaffe SCr was 1.9 mL/min/1.73 m2 lower than the eGFR determined by eSCr (LoA −9.5; 5.7 mL/min/1.73 m2). The comparison of eGFR between the two SCr methods revealed a different CKD stage in 1589 (13%) of all analyzed measurements, most frequently between G2/G3a (41%) and G3a/G3b (24%). When using the EKFC and BIS1 formulas, there were approximately the same number of measurements leading to a different CKD stage. Conclusions: In more than every tenth SCr determination in outpatient KTRs, the difference between the Jaffe and enzymatic methods had an influence on the assignment to a CKD stage. This effect was comparably pronounced for all eGFR formulas applied. [ABSTRACT FROM AUTHOR]

Background/Objectives: Our previous retrospective single-center cohort study found, at 3-year follow-up, a trend toward low tacrolimus trough levels and an increased risk of de novo donor-specific anti-HLA antibodies (DSAs) and of antibody-mediated rejection (ABMR) in CYP3A5-expressing patients. Determining CYP3A5-expression status immediately after renal transplant would allow early genotype-based dosage adjustment of tacrolimus and might prevent the occurrence of de novo DSAs and ABMR, improving transplant outcome. Methods: 160 renal allograft recipients who underwent renal transplant at the University Hospital Essen between May 2019 and May 2022 were genotyped for the CYP3A5 rs776746 polymorphism within the first two weeks after transplant, and genotype-based dose adjustment of tacrolimus was performed for the follow-up of 2 years. Results: CYP3A5 expression was detected in 33 (21%) of the 160 patients. Tacrolimus trough levels were similar in CYP3A5 expressers and nonexpressers over the entire 2-year follow-up period. However, we observed a trend toward slightly higher tacrolimus trough levels in CYP3A5 expressers, who, as expected, required tacrolimus dosages twice as high as did nonexpressers during follow-up. Calcineurin inhibitor (CNI) nephrotoxicity-free survival rates were comparable between CYP3A5 expressers and nonexpressers (p = 0.49). Rejection-free survival rates (p = 0.89), de novo anti-HLA antibody-free survival rates (p = 0.57) and de novo DSA-free survival rates (p = 0.61) did not differ between the two groups. Conclusions: Early detection of CYP3A5-expression status and resultant genotype-based adjustment of tacrolimus dosage after renal transplant protected patients from transplant rejection and de novo DSA formation and was not associated with increased incidence of CNI toxicity among CYP3A5 expressers. [ABSTRACT FROM AUTHOR]

Investigates the role of protein kinase C (PKC) and calcium, [Ca(2+)]i, in arginine vasopressin-induced p42 mitogen-activated protein kinase activation. Activation of PKC by phorbol 12-myristate 13-acetate; Inhibition of PKC by staurosporine; Consequences of the elevation of [Ca(2+)]i to supraphysiological levels by one micromolar of ionomycin.

TIMP-2 and IGFBP7 have been identified and validated for the early detection of renal injury in critically ill patients, but data on recovery of allograft function after kidney transplantation (KTx) are scarce. In a prospective observational multicenter cohort study of renal transplant recipients, urinary [TIMP-2] × [IGFBP7] was evaluated daily from day 1 to 7 after KTx. Different stages of early graft function were defined: immediate graft function (IGF) (decrease ≥ 10% in serum creatinine (s-crea) within 24 h post KTx); slow graft function (SGF) (decrease in s-crea < 10% within 24 h post KTx); and delayed graft function (DGF) (any dialysis needed within the first week after KTx). A total of 186 patients were analyzed. [TIMP-2] × [IGFBP7] was significantly elevated as early as day 1 in patients with DGF compared to SGF and IGF. ROC analysis of [TIMP-2] × [IGFBP7] at day 1 post-transplant for event "Non-DGF" revealed a cut-off value of 0.9 (ng/mL)2/1000 with a sensitivity of 87% and a specificity of 71%. The positive predictive value for non-DGF was 93%. [TIMP-2] × [IGFBP7] measured at day 1 after KTx can predict early recovery of transplant function and is therefore a valuable biomarker for clinical decision making. [ABSTRACT FROM AUTHOR]

Background Albumin, as the most abundant plasma protein, represents a target structure for both drug and physicochemical therapeutic approaches to eliminate uraemic toxins more efficiently. Potentially, this approach could reduce mortality of haemodialysis patients. However, little is known about albumin functional properties in these patients and its alteration by haemodialysis treatment. Methods The binding and detoxification efficiency of albumin were assessed by electron paramagnetic resonance spectroscopy using a spin-labelled fatty acid. Binding efficiency (BE) reflects strength and amount of bound fatty acids under certain ethanol concentration. Detoxification efficiency (DTE) reflects the molecular flexibility of the patient's albumin molecule, thus the ability to change the conformation depending on ethanol concentration. Percentage of BE and DTE are depicted in relation to healthy individuals (100%). Results Fifty-eight patients (59% male, median age 68 years, median time on haemodialysis 32 months) were included in the study. Before haemodialysis treatment, albumin binding and detoxification efficiency were substantially below healthy individuals [median BE 52% (interquartile range, IQR, 45%–59%); median DTE 38% (IQR 32–49%)]. After haemodialysis treatment, median BE and DTE significantly decreased [BE 28% (IQR 20–41%); DTE 11% (IQR 7%–27%; P  < .001)]. BE and DTE decline after haemodialysis was not dependent on age, sex or treatment modalities, but was to a certain extent on the level of non-esterified fatty acids. Conclusion Albumin binding and detoxification efficiency of fatty acids in maintenance haemodialysis patients were substantially below those in healthy individuals and even declined after dialysis treatment. These findings might be helpful when considering new therapeutic approaches in maintenance haemodialysis patients. [ABSTRACT FROM AUTHOR]

Background Serum creatinine (SCr), mainly determined by the Jaffe or an enzymatic method, is the central marker to assess kidney function. Deviations between these two methods may affect the diagnosis and staging of acute kidney injury (AKI) and chronic kidney disease (CKD). Methods The results of the first parallel SCr measurement (Jaffe and enzymatic method) of adult in- and outpatients in the same serum sample at the University Hospital Essen (Essen, Germany) between 2020–2022 were retrospectively evaluated. A Bland–Altman plot with 95% limits of agreement (LoAs) was used to assess the difference between the Jaffe and the enzymatic SCr (eSCr) method. We used the 2009 Chronic Kidney Disease Epidemiology Collaboration equation for determination of estimated glomerular filtration rate (eGFR) according to the Kidney Disease: Improving Global Outcomes guidelines. Results A total of 41 144 parallel SCr measurements were evaluated. On average, Jaffe SCr was 0.07 mg/dl higher than eSCr (LoA −0.12; 0.25 mg/dl). In 19% of all cases there was a different CKD stage when comparing eGFR between both SCr methods, of which 98% resulted in a more severe CKD stage determined with Jaffe SCr. In 1.6% of all cases Jaffe SCr was ≥0.3 mg/dl higher than eSCr. Conclusion The present study showed that methods of SCr measurement may affect both the diagnosis and staging of AKI and CKD. This must be taken into account when interpreting measurements of renal function in everyday clinical practice, but also when planning and comparing studies on renal diseases. One should therefore stay with one method for SCr measurement, preferably with the enzymatic method. [ABSTRACT FROM AUTHOR]

Single-nucleotide polymorphisms in G protein subunits are linked to an increased risk of cardiovascular events among the general population. We assessed the effects of GNB3 c.825C > T, GNAQ −695/−694GC > TT, and GNAS c.393C > T polymorphisms on the risk of cardiovascular events among 454 patients undergoing renal replacement therapy. The patients were followed up for a median of 4.5 years after the initiation of dialysis. Carriers of the TT/TT genotype of GNAQ required stenting because of coronary artery stenosis (p = 0.0009) and developed cardiovascular events involving more than one organ system (p = 0.03) significantly earlier and more frequently than did the GC/TT or GC/GC genotypes. Multivariate analysis found that the TT/TT genotype of GNAQ was an independent risk factor for coronary artery stenosis requiring stent (hazard ratio, 4.5; p = 0.001), cardiovascular events (hazard ratio, 1.93; p = 0.04) and cardiovascular events affecting multiple organs (hazard ratio, 4.9; p = 0.03). In the subgroup of male patients left ventricular dilatation with abnormally increased LVEDD values occurred significantly more frequently in TT genotypes of GNB3 than in CT/CC genotypes (p = 0.007). Our findings suggest that male dialysis patients carrying the TT genotype of GNB3 are at higher risk of left ventricular dilatation and that dialysis patients carrying the TT/TT genotype of GNAQ are prone to coronary artery stenosis and severe cardiovascular events. [ABSTRACT FROM AUTHOR]

Abstract: Background: BK polyomavirus (BKPyV)‐associated nephropathy (PyVAN) is a significant cause of premature renal transplant failure. High‐level BKPyV viremia is predictive for PyVAN; however, low‐level BKPyV viremia does not necessarily exclude the presence of PyVAN. As data are limited regarding whether or not low‐level BKPyV viremia has an effect on intermediate‐term graft outcome, this study analyzes the impact of low‐level BKPyV viremia on intermediate‐term graft function and outcome compared with high‐level viremia and non‐viremic patients. Methods: All renal transplant patients received follow‐up examinations at the Department of Nephrology, University Hospital Essen. Patients were screened for BKPyV viremia and stratified into three groups according to their maximum BKPyV load in serum (low‐level viremia, high‐level viremia, and no viremia). Results: In 142 of 213 (67%) patients, BKPyV was never detected in serum; 42 of 213 (20%) patients were found positive for low‐level viremia (≤104 copies/mL); and 29 of 213 (13%) patients showed high‐level viremia (>104 copies/mL). No significant differences regarding transplant function and graft failure were observed between patients without BKPyV viremia (delta estimated glomerular filtration rate [eGFR] +0.1 mL/min [month 1 vs last visit at month 44]) and patients with low‐level BKPyV viremia (delta eGFR −1.7 mL/min). In patients with high‐level viremia, transplant function was significantly restricted (delta eGFR −6.5 mL/min) compared with low‐level viremia until the last visit at 44 ± 9.7 months after transplantation. Although the graft function and graft loss were worse in the high‐level viremia group compared with no viremia (eGFR 37 vs 45 mL/min), the difference was not significant. Conclusions: High‐level viremia was associated with impaired graft function. In contrast, low‐level BKPyV viremia had no significant impact on intermediate‐term graft function. [ABSTRACT FROM AUTHOR]

Patients on dialysis have dysfunctions of innate and adaptive immune system responses. The transcriptional factor IRF8 (interferon regulatory factor 8) is primarily expressed in plasmacytoid cells (pDCs) and myeloid dendritic cells (mDCs), playing a crucial role in the maturation of dendritic cells, monocytes, and macrophages, and contributing to protection against bacterial infections. The current study analyzed the expression patterns of IRF8 and assessed its association with the risk of infections in 79 dialysis patients compared to 44 healthy controls. Different subsets of leukocytes and the intracellular expression of IRF8 were measured using flow cytometry. Compared to the healthy controls, the dialysis patients showed significantly reduced numbers of pDCs and significantly increased numbers of natural killer cells and classical and intermediate monocytes. The dialysis patients exhibited decreased numbers of IRF8-positive dendritic cells (pDC p < 0.001, mDC1 p < 0.001, mDC2 p = 0.005) and increased numbers of IRF8-positive monocytes (p < 0.001). IRF8 expression in pDC, mDC, and classical monocytes was lower in the dialysis patients than in the controls. Dialysis patients who required hospitalization due to infections within one year of follow-up displayed significantly reduced IRF8 expression levels in pDCs compared to patients without such infections (p = 0.04). Our results suggest that reduced IRF8 expression in pDCs is a potential risk factor predisposing dialysis patients to serious infections. [ABSTRACT FROM AUTHOR]

Protein–energy malnutrition (PEM) is common among patients with advanced chronic kidney disease (CKD stages 4 and 5) and is associated with an increased risk of morbidity and mortality. Early recognition and treatment of malnutrition is essential to improve the outcome of patients with advanced CKD and those undergoing maintenance peritonealdialysis and haemodialysis treatment. [ABSTRACT FROM AUTHOR]

Background/Aims: The aim of this study was to evaluate long-term allograft salvage rates of patients with steroid refractory allograft rejection after kidney transplantation and to identify factors indicating a successful outcome. Patients and Methods: Fifty patients with continuing rejection after high-dose steroids were included in the study. Baseline immunosuppression was switched from cyclosporine to tacrolimus in all patients. Twenty patients additionally received OKT3 as antirejection therapy. Patients having received a cadaveric renal transplant in 1995, excluding patients with steroid resistant rejection, were chosen as a control cohort. Results: Patient survival rates were 96% (n = 48) and 90% (n = 45) and allograft survival rates were 66% (n = 33) and 62% (n = 31) after 5 and 7 years following steroid refractory renal allograft rejection. Graft survival within the control cohort was 73% after 5 years and 69% after 7 years. Creatinine clearance increased from 20 ± 15 ml/min/1.73 m2 at the start of tacrolimus therapy to 37 ± 29 ml/min/1.73 m2 and to 32 ± 26 ml/min/1.73 m2 after 5 and 7 years. OKT3 treatment predicted successful rescue therapy (p = 0.005 and p = 0.04 after 5 and 7 years). Conclusion: Our data indicate a reasonable graft survival in steroid refractory renal allograft rejection using tacrolimus. OKT3 treatment in addition to tacrolimus therapy may be beneficial for long-term allograft survival. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

It is still not fully elucidated which pretransplant donor‐specific HLA antibodies (DSA) are harmful after kidney transplantation. In particular, it needs to be clarified whether cumulative mean fluorescence intensities (MFI) against multiple HLA specificities have a predictive value for allograft function. Our retrospective single centre study analyzed preformed HLA antibodies determined by Luminex™ Single Antigen Bead (SAB) assay, including C1q addition, in relation to rejection and clinical outcome in 255 cross match negative kidney allograft recipients. Only 33 recipients (13%) of the total cohort showed early AMR during the first year posttransplant, but in patients with pre‐transplant DSA the rate was increased to 15 out of 40 (38%). Three year graft survival was significantly shorter in patients with histological signs of AMR compared with patients without AMR or with no biopsy (74%, 92%, and 97%, respectively, p < 0.0001). In patients with HLA‐DSA, a cumulative MFI value of all HLA antibodies of more than 103.000 indicated the highest risk for AMR posttransplant (p = 0.01). In conclusion, in patients with HLA‐DSA, the cumulative MFI value may help to further stratify the risk of AMR after kidney transplantation. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a clinical syndrome with multiple entities. Although AKI implies renal damage, functional impairment or both, diagnosis is solely based on the functional parameters of serum creatinine and urine output. The latest definition was provided by the Kidney Disease Improving Global Outcomes (KDIGO) working group in 2012. Independent of the underlying disease, and even in the case of full recovery, AKI is associated with an increased morbidity and mortality. Awareness of the patient's individual risk profile and the diversity of causes and clinical features of AKI is pivotal for optimization of prophylaxes, diagnosis and therapy of each form of AKI. A differentiated and individualized approach is required to improve patient mortality, morbidity, long-term kidney function and eventually the quality of life. In this review, we provide an overview of the different clinical settings in which specific forms of AKI may occur and point out possible diagnostic aswell as therapeutic approaches. Secifically AKI is discussed in the context of non-kidney organ failure, organ transplantation, sepsis, malignancy and autoimmune disease. [ABSTRACT FROM AUTHOR]

The c.825C>T single-nucleotide polymorphism (rs5443) of the guanine nucleotide-binding protein subunit β3 (GNB3) results in increased intracellular signal transduction via G-proteins. The present study investigated the effect of the GNB3 c.825C>T polymorphism on cardiovascular events among renal allograft recipients posttransplant. Our retrospective study involved 436 renal allograft recipients who were followed up for up to 8 years after transplant. The GNB3 c.825C>T polymorphism was detected with restriction fragment length polymorphism (RFLP) polymerase chain reaction (PCR). The GNB3 TT genotype was detected in 43 (10%) of 436 recipients. Death due to an acute cardiovascular event occurred more frequently among recipients with the TT genotype (4 [9%]) than among those with the CC/CT genotypes (7 [2%]; p = 0.003). The rates of myocardial infarction (MI)–free survival (p = 0.003) and acute peripheral artery occlusive disease (PAOD)–free survival (p = 0.004) were significantly lower among T-homozygous patients. A multivariate analysis showed that homozygous GNB3 c.825C>T polymorphism exerted only a mild effect for the occurrence of myocardial infarction (relative risk, 2.2; p = 0.065) or acute PAOD (relative risk, 2.4; p = 0.05) after renal transplant. Our results suggest that the homozygous GNB3 T allele exerts noticeable effects on the risk of MI and acute PAOD only in the presence of additional nonheritable risk factors. [ABSTRACT FROM AUTHOR]

Background: Postoperative sepsis is an important cause of morbidity and mortality in patients with infective endocarditis undergoing surgical therapy. Blood purification using hemoadsorption therapy shows promising results in the treatment of sepsis. In this study, the clinical effects of intraoperative hemoadsorption in high-risk patients with infective endocarditis were evaluated. Methods: Eligible candidates were high-risk patients with infective endocarditis undergoing cardiac surgery between January 2014 and December 2019. Patients with intraoperative hemoadsorption (hemoadsorption) were compared to patients without hemoadsorption (control). The endpoints were the incidence of postoperative sepsis, sepsis-associated death and in-hospital mortality. Additionally, postoperative vasopressor need, systemic vascular resistance indices and Sequential Organ Failure Assessment (SOFA) scores were compared. Results: After propensity score matching, 70 high-risk patients were included. Postoperative sepsis occurred in 14 patients in the hemoadsorption group and in 16 patients in the control group, p = 0.629. Four patients died due to postoperative sepsis in the hemoadsorption group, while 11 postoperative septic patients died in the control group, p = 0.041. In-hospital mortality was 34% in the hemoadsorption group versus 43% in the control group, p = 0.461. On ICU-admission and the first postoperative day, the cumulative vasopressor need was 0.17 versus 0.25 μg/kgBW/min, p = 0.123 and 0.06 versus 0.11 μg/kgBW/min, p = 0.037, and the systemic vascular resistance index was 1448 versus 941 dyn·s·cm-5, p = 0.013 and 1156 versus 858 dyn·s·cm-5, p = 0.110 in the hemoadsorption versus control group, respectively. Postoperative course of SOFA score normalized significantly (p = 0.01) faster in the hemoadsorption group. Conclusions: In high-risk cardiac surgical patients with infective endocarditis, intraoperative hemoadsorption significantly reduced sepsis-associated mortality. Furthermore, intraoperative hemoadsorption resulted in significant faster recovery of hemodynamics and organ function. Intraoperative hemoadsorption seems to attenuate the severity of postoperative sepsis. [ABSTRACT FROM AUTHOR]

Plasmapheresis (PE) is an established form of therapeutic apheresis (TA). Purpose of this longitudinal prospective single center study was to investigate the effect of PE on albumin redox state (ARS), as infusion of commercial albumin during PE may alter albumin oxidation which has an impact on its functional properties and oxidative stress level. 43 subjects with autoimmune-mediated neurological disorders were included. 20 subjects in the experimental group received five treatments of PE. 13 subjects received five treatments of immunoadsorption and 10 subjects received no TA as controls. ARS was determined before and after TA and 12 days after the last TA by fractionating it into human mercaptalbumin (HMA), human non-mercaptalbumin 1 (HNA-1), and human non-mercaptalbumin 2 (HNA-2) by high-performance liquid chromatography. Irreversibly oxidised HNA-2 increased over the course of five PE treatments from 2.8% (IQR 1.3–3.7%) to 13.6% (IQR 10.9–15.9) (P < 0.01) and remained elevated 12 days after the last PE procedure (7.7% IQR 7.1–10.5, P < 0.05). The study showed for the first time that PE exerts a severe and long-lasting alteration on ARS indicating a new adverse effect of PE, that may influence oxidative stress level. [ABSTRACT FROM AUTHOR]

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is an autoimmune small vessel vasculitis. Despite the role of autoantibodies, T cells play an essential role in pathogenesis and are abnormal in AAV. Signal transducers and activators of transcription (STAT) affect immunoregulation and T-cell homeostasis. Therefore, the present study examined the ex vivo basal expression of the activated forms of STAT5 [phosphorylated (p)STAT5] and STAT3 (pSTAT3) in AAV and analyzed the function of two signaling pathways linked to these transcription factors. In total, 31 patients with AAV and 16 age-matched healthy controls (HCs) were enrolled. CD3+ T cells from peripheral blood were analyzed directly ex vivo by a fluorescence-activated cell sorter for basal expression of pSTAT5 and pSTAT3. Expression was also analyzed in T cells following short-term stimulation with interleukin (IL)-2 or -10. The basal expression of pSTAT5/3 in T cells was similar to AAV patients and HC. Following stimulation with IL-2 or -10, expression of pSTAT5/3 increased in AAV subjects compared with HC. Basal expression of pSTAT3 correlated with the relapse rate in AAV. In conclusion, STAT3 and STAT5 mediated signaling pathways were functionally intact in AAV patients and exhibited hyper-responsiveness to IL-2 and -10 stimuli. Thus, T-cell abnormalities in AAV are not promoted by an altered basal expression of pSTAT5/3 or dysfunction of the IL-2/-10 signaling pathways, in which STAT5/3 are essential. [ABSTRACT FROM AUTHOR]

Background/Aim. ANCA-associated vasculitis (AAV) is a small-vessel vasculitis of autoimmune origin. In addition to autoantibodies, T cells have a pivotal pathophysiological role in this disease. T-cell homeostasis and immune tolerance critically depend on IL-2 and its receptor expressed by T cells. In this study, we investigated the IL-2 receptor (IL-2r) expression on CD4+ T cells in AAV. Methods. Thirty patients with AAV and 15 age-matched healthy controls (HC) were enrolled. T cells from peripheral blood were analysed by flow cytometry for expression of the IL-2r α- and β-chain. Results. The IL-2r α-chain was overexpressed in AAV as compared to HC (36 ± 16% versus 20 ± 9%, P < 0.005). The IL-2r-β-chain expression was significantly reduced on CD25+ CD4+ T-cells and CD4+CD25+FoxP regulatory T-cells (Tregs; AAV versus HC: 48 ± 14% versus 62 ± 9%, P = 0.002, and 38 ± 18% versus 68 ± 5%, P = 0.002). Low β-chain expression in AAV was associated with relapsing disease and systemic vasculitis with renal involvement. Conclusion. The IL-2r expression pattern is abnormal in AAV. To our knowledge, we are the first to show that the β-chain expression is drastically diminished on T cells in AAV and related to a less favorable disease course. Given the indispensable function of the β-chain in IL-2 signaling of T cells, diminished expression may contribute to disturbed immune homeostasis in AAV. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To determine the incidence and prevalence of CKD and of progressive GFR decline, to identify modifiable risk factors of and to develop a predictive risk model for progressive GFR decline in high risk primary care patients. Methods: Retrospective observational study of 803 patients with or at high risk of CKD exclusively managed in primary care. Baseline data was collected in 2003, follow-up data in 2006. High risk was defined as inadequately controlled hypertension or diabetes, and GFR<60, progressive GFR decline as annual GFR decline >2.5mlmin−1 1.73m−2. Results: CKD was present in 25.4% at baseline and developed in further 13.7% during follow-up, 42.5% demonstrated progressive GFR decline. Obesity, proteinuria, heart failure, inadequate hypertension and diabetes control, lacking angiotensin-converting-enzyme-inhibitors or angiotensin-receptor-blockers, radio contrast, and dual renin–angiotensin-aldosterone-system blockade were identified as modifiable, independent risk factors of progressive GFR decline. The risk model, containing 7 readily obtainable variables, showed good discriminative ability. Conclusions: High risk primary care patients demonstrated high CKD prevalence and incidence, and rate of progressive GFR decline. Identified risk factors can be modified in primary care. Our risk model may aid primary care physicians to predict patients at high risk of progressive GFR decline. [Copyright &y& Elsevier]

Background: It is critical to preserve residual renal function (RRF) in peritoneal dialysis (PD), as RRF is associated with lower morbidity and mortality. There is no uniform definition of RRF, and rapidly declining RRF has rarely been studied and predominately limited to single factor analysis and not corrected for lead-time bias. Methods: An observational study in 71 incident PD patients. RRF was defined as urine output (UO) ≥500 ml/day and renal glomerular filtration rate (rGFR) ≥2 ml/min/1.73 m2, rapid declining RRF as UO <500 ml/day and rGFR <2 ml/min/1.73 m2 occurring within 6 months which were separately evaluated. Independent risk factors associated with rapid RRF decline were identified while correcting for lead-time bias. Results: RRF declined rapidly by both definitions in 65% patients 2.5 years after PD start. Both definitions of RRF decline were consistent in 96%. Nephrotoxic drugs, renal transplant failure and absent angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) were independent risk factors associated with rapidly declining RRF defined both by definitions, intravascular radiocontrast additionally for UO decline. Conclusions: Most PD patients demonstrated rapid RRF decline, independent of its definition. Both definitions are highly consistent and interchangeable. Nephrotoxic drugs and radiocontrast were identified as risk factors of acute, absent ACEI or ARB, and renal transplant failure of chronic renal injury. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Background: Minimally invasive video-assisted parathyroidectomy (MIVAP) has become a well-accepted procedure for patients with primary hyperparathyroidism. Because it allows bilateral neck exploration, the authors began using this technique for patients with secondary hyperparathyroidism. In this preliminary study, the authors report their initial experience. Methods: From July 2006 to November 2008, 12 patients (6 women, 6 men; mean age, 45.5 ± 16.9 years (range, 23–71 years) underwent MIVAP with bilateral exploration for secondary hyperparathyroidism. The operation was performed through a central 2-cm to 3-cm skin incision; a 30° 5-mm endoscope was used for magnification. Results: MIVAP was successfully completed in 11 patients (92%). The mean operative time was 81 ± 37 minutes (range, 35–130 minutes). No major complications were registered. After a mean follow-up period of 11.4 months (range, 3–30 months), 1 patient showed recurrence. Conclusions: MIVAP appears to be a safe and feasible procedure in patients with secondary hyperparathyroidism. [Copyright &y& Elsevier]

Abstract: Blood group AB0-incompatible live donor (LD) renal transplantation may provide a significant source of organs. AB0-incompatible LD renal transplantation can be accomplished using specific anti-A/B antibody (Ab) immunoadsorption (IA) and anti-CD20 monoclonal Ab (Rituximab®) treatment. One dose of anti-CD20 mAb (rituximab, 375mg/m2) is given for weeks pre-operatively. Recipients are pre-treated with 3–5 sessions of immunoadsorption, using A or B carbohydrate antigen specific columns, until their anti-A1/B RBC panel indirect antiglobulin test (IAT) titres are <8. Polyclonal immunoglobulins are applied four days before transplantation. Recipients receive preoperative mycophenolic acid, steroids/tacrolimus therapy. No splenectomy was performed. Postoperative IA is applied if RBC panel indirect antiglobulin test (IAT) titres are >8. Postoperative renal biopsies may yield positive C4d staining in peritubular capillaries as sign of humoral immune activation but the clinical course is favourable if IAT titres can be kept below 8 within the first weeks after transplantation. This protocol has excellent short-term and long-term graft survival as well as function although recipient anti-A/B titres after transplantation return to pre-surgical levels within months after transplantation. [Copyright &y& Elsevier]

Background: HTK‐N was developed based on the traditional HTK preservation solution, resulting in stronger protection against reactive oxygen species as well as better tolerance to hypothermia and ischemia. Aim of the present study was to compare HTK‐N to HTK in clinical kidney transplantation demonstrating safety and non‐inferiority. Methods: We performed a randomized controlled single blinded clinical phase II trial in patients undergoing living donor kidney transplantation. After retroperitoneoscopic nephrectomy kidneys were either perfused and stored with classical HTK solution or the new HTK‐N solution. Primary endpoint was the glomerular filtration rate (eGFR according to CKD EPI) 3 months after transplantation. Secondary endpoints included graft and patient survival beside others. Results: The study included 42 patients, of which 22 were randomized in the HTK‐N group and 20 in the HTK group. The primary end point showed a mean eGFR of 55.4 ± 14.0 ml/min/1.73 m2 in the HTK group compared to a GFR of 57.2 ± 16.7 ml/min/m2 in the HTK‐N group (P =.72). Regarding secondary endpoints, there were no apparent differences. Posttransplant graft and patient survival was 100%. Conclusion: This study is the first clinical application of HTK‐N for kidney preservation and demonstrates non‐inferiority compared to HTK in the setting of living donor kidney transplantation. [ABSTRACT FROM AUTHOR]

Summary background and aims Studies investigating the impact of interleukin-2 (IL-2) on the corticotroph axis have shown that IL-2 can stimulate cortisol and ACTH secretion. However, the site, the time course and the mechanisms of IL-2 stimulation of the corticotroph axis are still not known. The aim of this study was to gain insight into the mechanisms of IL-2 stimulation of the corticotroph axis. patients and methods A total of 9 × 106 IU/day IL-2 were given to 18 male HIV-infected patients treated with a combination of HIV antiviral drugs (usually two reverse-transcriptase inhibitors and one protease-inhibitor) over a course of 4–5 days. Seven of these 18 patients received a second course of IL-2. results Cortisol levels increased significantly (P < 0·001) from baseline levels (427 ± 118 nmol/l) to 746 ± 132 nmol/l after 4 days of IL-2 therapy with a gradual decrease to baseline within 10 days after the end of therapy. ACTH showed a similar pattern rising from 5·9 ± 1·9 pmol/l at baseline to 12·4 ± 4·6 pmol/l on day 4 (P < 0·001). The cortisol response after CRH application (carried out at 15·00 h) was significantly more pronounced at the end of IL-2 application (CRH test B, baseline: 330 ± 59 nmol/l, peak 774 ± 134 nmol/l, 135% increase) when compared to pretreatment (CRH test A, baseline: 226 ± 73 nmol/l, peak 459 ± 103 nmol/l, 103% increase, P ≤ 0·0001). The cortisol response 9 days after the end of IL-2 administration showed a similar pattern when compared to pretreatment values. The ACTH response after CRH was essentially paralleled by the cortisol response (CRH test B, baseline: 6·1 ± 2·8 pmol/l, peak 16·0 ± 4·4 pmol/l, 170% increase; CRH test A, baseline: 4·3 ± 1·9 pmol/l, peak 9·2 ± 3·1 pmol/l, 110% increase, P = 0·0005). Furthermore, we observed higher ACTH and cortisol... [ABSTRACT FROM AUTHOR]

Examines the effects of adenosine triphosphate depletion on actin cytoskeleton of the renal proximal tubule cells. Effects of disruption to polarity of membrane and microvilli; Use of confocal microscopy in the study; Characteristics of enhanced yellow fluorescence protein.

Allograft-specific regulatory T cells (Treg cells) are crucial for long-term graft acceptance after transplantation. Although adoptive Treg cell transfer has been proposed, major challenges include graft-specificity and stability. Thus, there is an unmet need for the direct induction of graft-specific Treg cells. We hypothesized a synergism of the immunotolerogenic effects of rapamycin (mTOR inhibition) and plerixafor (CXCR4 antagonist) for Treg cell induction. Thus, we performed fully-mismatched heart transplantations and found combination treatment to result in prolonged allograft survival. Moreover, fibrosis and myocyte lesions were reduced. Although less CD3+ T cell infiltrated, higher Treg cell numbers were observed. Noteworthy, this was accompanied by a plerixafor-dependent plasmacytoid dendritic cells-(pDCs)-mobilization. Furthermore, in vivo pDC-depletion abrogated the plerixafor-mediated Treg cell number increase and reduced allograft survival. Our pharmacological approach allowed to increase Treg cell numbers due to pDC-mediated immune regulation. Therefore pDCs can be an attractive immunotherapeutic target in addition to plerixafor treatment. [ABSTRACT FROM AUTHOR]

Background: Oral cladribine is an approved disease-modifying drug for the treatment of relapsing multiple sclerosis. In controlled clinical trials as well as in post marketing safety assessments, autoimmune conditions have not yet been reported as a specific side effect of cladribine. Objective and Results: Here, we report a case of anti-glomerular basement membrane antibody-mediated glomerulonephritis that occurred shortly after the fourth cladribine treatment cycle. Conclusion: Neurologists should be attentive to the development of secondary autoimmunity in cladribine-treated patients. [ABSTRACT FROM AUTHOR]

Background: Extracorporeal cytokine adsorption is an option in septic shock as an additional measure to treat a pathological immune response. Purpose of this study was to investigate the effects of extracorporeal cytokine adsorption on hemodynamic parameters in patients with acute kidney injury (AKI) on continuous renal replacement therapy (CRRT) and septic shock after cardiac surgery. Methods: In this retrospective study, a total of 98 patients were evaluated. Hemoadsorption was performed by the CytoSorb® adsorber. In all patients cytokine adsorption was applied for at least 15 hours and at least one adsorber was used per patient. To compare cumulative inotrope need in order to maintain a mean arterial pressure (MAP) of ≥ 65 mmHg, we applied vasoactive score (VAS) for each patient before and after cytokine adsorption. A paired t-test has been performed to determine statistical significance. Results: Before cytokine adsorption the mean VAS was 56.7 points. This was statistically significant decreased after cytokine adsorption (27.7 points, p< 0.0001). Before cytokine adsorption, the mean noradrenalin dose to reach a MAP of ≥ 65 mmHg was 0.49 μg/kg bw/min, the mean adrenalin dose was 0.12 μg/kg bw/min. After cytokine adsorption, significantly reduced catecholamine doses were necessary to maintain a MAP of ≥ 65 mmHg (0.24 μg/kg bw/min noradrenalin; p< 0.0001 and 0.07 μg/kg bw/min adrenalin; p < 0.0001). Moreover, there was a significant reduction of serum lactate levels after treatment (p< 0.0001). The mean SOFA-score for these patients with septic shock and AKI before cytokine adsorption was 16.7 points, the mean APACHE II-score was 30.2 points. The mean predicted in-hospital mortality rate based on this SOFA-score of 16.7 points was 77,0%, respectively 73,0% on APACHE II-score, while the all-cause in-hospital mortality rate of the patients in this study was 59.2%. Conclusion: In patients with septic shock and AKI undergoing cardiac surgery, extracorporeal cytokine adsorption could significantly lower the need for postoperative inotropes. Additionally, observed versus SOFA- and APACHE II-score predicted in-hospital mortality rate was decreased. [ABSTRACT FROM AUTHOR]

Background: Although infant organ donors remain a rare source of organs for transplantation, technical challenges have resulted in increased rates of complications and inferior graft function. The aim of the present study was to investigate the outcomes of kidneys procured from juvenile and infant donors. Patients and Methods: We evaluated all kidney transplants from deceased donors < 16 years of age performed at our center between 01/2008 and 08/2019. We defined three groups based on quartiles of donor body weight: <13 kg (infant donors), 13-40 kg (juvenile donors), and > 40 kg (standard criteria donors). Clinical characteristics and outcomes were compared between groups. Results: Ninety-two transplants were included in this study. Out of 92 recipients, there were 32 (34.8%) adult and 60 (65.2%) pediatric patients. All groups demonstrated excellent graft function and survival on both short and long-term follow-up. 1-year, 3-year, and 5-year graft survival rates for the standard criteria donor group were 100%, 95.2%, and 88.4%, respectively, compared with 95.8% for infant and 95% for juvenile donors at all times (P = .79). eGFR at 5 years was 98.9 ± 5.5, 74.1 ± 6.2, and 81.6 ± 6.9 mL/min/1.73 m2 for infant, juvenile, and standard criteria donors, respectively (P < .01). Conclusion: Infant donor allografts can be transplanted with excellent long-term outcomes in both pediatric and adult recipients. Implanting them as single allografts onto pediatric candidates allows for the transplantation of two patients. As such, pediatric recipients should be prioritized for these donor organs. [ABSTRACT FROM AUTHOR]

Objective: We aimed to evaluate the effects of combining the Simplified-Acute-Physiology-Score (SAPS) 2 or the SAPS 3 with Interleukin-6 (IL-6) or Procalcitonin (PCT) or C-Reactive Protein (CRP) concentrations for predicting in-hospital mortality. Material and methods: This retrospective study was conducted in an interdisciplinary 22-bed intensive care unit (ICU) at a German university hospital. Within an 18-month period, SAPS 2 and SAPS 3 were calculated for 514 critically ill patients that were admitted to the internal medicine department. To evaluate discrimination performance, the area under the receiver operating characteristic curves (AUROCs) and the 95% confidence intervals (95% CIs) were calculated for each score, exclusively or in combination with IL-6 or PCT or CRP. DeLong test was used to compare different AUROCs. Results: The SAPS 2 exhibited a better discrimination performance than SAPS 3 with AUROCs of 0.81 (95% CI, 0.76–0.86) and 0.72 (95% CI, 0.66–0.78), respectively. Overall, combination of the SAPS 2 with IL-6 showed the best discrimination performance (AUROC 0.82; 95% CI, 0.77–0.87), albeit not significantly different from SAPS2. IL-6 performed better than PCT and CRP with AUROCs of 0.75 (95% CI, 0.69–0.81), 0.72 (95% CI, 0.66–0.77) and 0.65 (95% CI, 0.59–0.72), respectively. Performance of the SAPS 3 improved significantly when combined with IL-6 (AUROC 0.76; 95% CI, 0.69–0.81) or PCT (AUROC 0.73; 95% CI, 0.67–0.78). Conclusions: Our analysis provided evidence that the risk stratification performance of the SAPS 3 and, to a lesser degree, also of the SAPS 2 can increase when combined with IL-6. A more accurate detection of aberrant or dysregulated systemic immunological responses (by IL-6) may explain the higher performance achieved by SAPS 3 + IL-6 vs. SAPS 3. Thus, implementation of IL-6 in critical care scores can improve prediction outcomes, especially in patients experiencing acute inflammatory conditions; however, statistical results may vary across hospital types and/or patient populations with different case mix. [ABSTRACT FROM AUTHOR]

The immunosuppressive non-classical human leukocyte antigen-G (HLA-G) promotes transplant tolerance as well as viral immune escape. HLA-G expression is associated with regulatory elements targeting certain single nucleotide polymorphisms (SNPs) in the HLA-G 3 ′ untranslated region (UTR). Thus, we evaluated the impact of HLA-G 3′UTR polymorphisms as surrogate markers for BK polyomavirus (BKPyV) replication or nephropathy (PyVAN) and acute cellular and antibody mediated rejection (ACR/AMR) in 251 living-donor kidney-transplant recipient pairs. After sequencing of the HLA-G 3 ′ UTR, fourteen SNPs between +2960 and +3227 and the 14 bp insertion/deletion polymorphism, which arrange as UTR haplotypes, were identified. The UTR-4 haplotype in donors and recipients was associated with occurrence of BKPyV/PyVAN compared to the other UTR haplotypes. While the UTR-4 recipient haplotype provided protection against AMR, the UTR-2 donor haplotype was deleteriously associated with ACR/AMR. Deduction of the UTR-2/4 haplotypes to specific SNPs revealed that the +3003C variant (unique for UTR-4) in donors as well as in recipients is responsible for BKPyV/PyVAN and also provides protection against AMR; whereas the +3196G variant (unique for UTR-2) promotes allograft rejection. Thus, HLA-G 3′UTR variants are promising genetic predisposition markers both in donors and recipients that may help to predict susceptibility to either viral infectious complication of BKPyV or allograft rejection. [ABSTRACT FROM AUTHOR]

Background The C5 complement inhibitor eculizumab is a first-line treatment in atypical haemolytic uraemic syndrome (aHUS). Therapy with eculizumab is associated with a highly increased risk for meningococcal infection. Therefore, vaccination is highly recommended before beginning treatment. Efficacy of quadrivalent meningococcal vaccines (MenACWY) in patients treated with the C5 complement inhibitor eculizumab in aHUS has not yet been determined. Methods Patients with aHUS received one dose of a MenACWY conjugate vaccine before eculizumab treatment commenced. Bactericidal titres against meningococcal serogroups A, C, W and Y were determined using baby rabbit complement in 25 patients. Results Full immune response to meningococcal vaccination was detected in five patients (20%), while seven patients (28%) showed no immune response in any of the tested serogroups. The remaining 13 patients showed incomplete immune response with proof of protective antibody titres for one to three serogroups without perceptible preference for any serogroup. Bactericidal titres after re-vaccination were available for 17 patients. Nine patients with incomplete immune response after first vaccinations showed protective antibody titres for all serogroups after re-vaccination. Kidney function had improved in >50% of patients at the time of re-vaccination compared with the time of first vaccination and immunosuppressive therapy was only applied to re-vaccinated patients following kidney transplantation. Conclusions Immunogenicity of first quadrivalent meninongococcal vaccination is insufficient in patients with aHUS. Booster response is promising, but incomplete. Therefore, establishing antibiotic prophylaxes seems pivotal. [ABSTRACT FROM AUTHOR]

The aim of the present study was to use a combination of the reverse transcription-polymerase chain reaction and a new diagnostic test for antibodies against the viral envelope protein E2 to assess the prevalence of hepatitis G virus (GBV-C/HGV) infection in sera of Hungarian children on hemodialysis (HD) or peritoneal dialysis (CAPD), as well as in sera of renal transplant patients (RTx). The GBV-C/HGV RNA prevalence was significantly higher in the whole group of children with renal failure (18.5%) than in the control group (children with urinary tract infection, 2.5%). The difference between the GBV-C/HGV RNA prevalence in the RTx group (33.3%) and in the control group (2.5%) was significant (P = 0.007). Anti-E2, which is considered an indicator of a past GBV-C/ HGV infection, was detected in 10% (1/10) of HD patients, in 33.3% (4/12) of RTx patients, but in none of the children on CAPD. These differences were not significant. Children receiving a renal graft are at an increased risk of developing GBV-C/HGV infection, which may be attributed to the immunosuppressive drugs necessary to maintain the grafts. [ABSTRACT FROM AUTHOR]

Background: Transplanting kidneys from deceased donors with hepatitis C virus (HCV) viremia has been controversial for some time. Direct‐acting antiviral agents have been shown to be highly effective in treating HCV infection. We report our experience with transplanting kidneys from HCV‐positive donors with detectable viremia into HCV‐negative recipients, followed by early treatment with a sofosbuvir‐based antiviral regimen. Methods: Data were collected from seven HCV‐negative recipients receiving kidneys from five deceased HCV‐viremic donors. Before transplantation, all intentional transplanted recipients had given informed consent regarding the acceptance of an HCV‐viremic kidney. Recipients were closely monitored after transplant with measurements of HCV viremia, liver and renal function, and trough levels of immunosuppressive drugs. Results: Four donors were infected with HCV genotype 1; the other with HCV genotype 3a. HCV viremia was detectable in all seven renal transplant recipients within 3 days after transplant. After determination of HCV genotype, antiviral treatment with a sofosbuvir‐based regimen (sofosbuvir/ledipasvir, n = 4; sofosbuvir/velpatasvir, n = 3) was initiated within a median of 7 days after transplantation and was continued for 8 to 12 weeks. For all recipients, viral load was below the level of detection at the end of treatment, and all exhibited a sustained virologic response 12 weeks later. All recipients exhibited normal liver enzyme activity at the end of treatment. Renal allograft function and trough levels of tacrolimus remained stable. Conclusions: Early administration of a sofosbuvir‐based regimen to HCV‐negative recipients of kidneys from HCV‐viremic donors is feasible and safe. The definition of an optimal therapeutic approach warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: Hepatitis E virus (HEV) genotype 3 infection frequently progresses to chronic disease with persisting HEV viremia in immunocompromised patients. Here, we evaluated the prevalence of HEV infection in renal allograft recipients and investigated the efficacy and tolerability of ribavirin monotherapy. Methods: A total of 947 recipients on average 8.7 years post transplant were screened for anti‐HEV IgG, IgM and HEV‐RNA. Sixteen HEV‐viremic renal allograft recipients were treated with ribavirin for 12 weeks. HEV‐RNA concentration, laboratory and clinical parameters were assessed at baseline, during therapy and 12 weeks after treatment cessation. HEV‐genotyping was performed in all HEV‐viremic patients. Results: Past HEV infection was detected serologically in 18% of the renal allograft recipients. Ongoing HEV replication was found in 16 recipients (all genotype 3). Unanimously, distinct HEV sequences were revealed in all HEV‐viremic patients. At the start of ribavirin treatment, median HEV‐RNA viral load was 4.3 × 106 (8000‐5.0 × 106) IU/mL. Ninety‐four percentage of HEV‐infected allograft recipients showed a sustained virological response 12 weeks after treatment cessation. Ribavirin treatment was associated with rapid decrease in liver enzymes and rare occurrence of anemia. Conclusions: Prevalence of active HEV infection is important in renal transplant patients without signs of nosocomial infection. Ribavirin treatment was safe and effective. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) may progress to end-stage renal disease (ESRD) at different pace. Early markers of disease progression could facilitate and improve patient management. However, conventional blood and urine chemistry have proven unable to predict the progression of disease at early stages. Therefore, we performed untargeted plasma peptidome analysis to select the peptides involved in progression, which are suitable for long prospective studies in future. The study consists of non-CKD (n = 66) and CKD (n = 106) patients with different stages. We performed plasma peptidomics on these subjects using chromatography and mass spectrometric approaches. Initially, we performed LC-ESI-MS and applied least absolute shrinkage and selection operator logistic regressions to select the peptides that are differentially expressed and we generated a peptidomic score for each subject. Later, we identified and sequenced the peptides with MALDI-MS/MS and also performed univariate and multivariate analyses with the clinical variables and peptidomic score to reveal their association with progression of renal disease. A logistic regression model selected 14 substances showing different concentrations according to renal function, of which seven substances were most likely occur in CKD patients. The peptidomic model had a global P value of < 0.01 with R2 of 0.466, and the area under the curve was 0.87 (95% CI, 0.8149–0.9186; P < 0.0001). The predicted score was significantly higher in CKD than in non-CKD patients (2.539 ± 0.2637 vs − 0.9382 ± 0.1691). The model was also able to predict stages of CKD: the Spearman correlation coefficient of the linear predictor with CKD stages was 0.83 with concordance indices of 0.899 (95% CI 0.863–0.927). In univariate analysis, the most consistent association of peptidomic score in CKD patients was with C-reactive protein, sodium level, and uric acid, which are unanticipated substances. Peptidomic analysis enabled to list some unanticipated substances that have not been extensively studied in the context of CKD but were associated with CKD progression, thus revealing interesting candidate markers or mediators of CKD of potential use in CKD progression management. Key messages: • Conventional blood and urine chemistry have proven unable to predict the progression of disease at early stages of chronic kidney disease (CKD). • We performed untargeted plasma peptidome analysis to select the peptides involved in progression. • A logistic regression model selected 14 substances showing different concentrations according to renal function. • These peptides are unanticipated substances that have not been extensively studied in the context of CKD but were associated with CKD progression, thus revealing markers or mediators of CKD of potential use in CKD progression management. [ABSTRACT FROM AUTHOR]