Stiripentol fails to lower plasma oxalate in a dialysis-dependent PH1 patient

Background: Primary hyperoxaluria type 1 (PH1) is a multisystemic metabolic disorder caused by an excessive production of oxalate by the liver. The majority of patients presenting in early infancy have end-stage renal disease (ESRD). While awaiting the results of sRNAi trials, the current standard treatment is combined liver-kidney transplantation. Recently, Stiripentol has been reported as a promising drug in the treatment of primary hyperoxaluria by reducing urinary oxalate (UOx). Stiripentol is an anti-convulsive drug used in the treatment of children suffering from Dravet syndrome. It causes blockage of the last step in oxalate production by inhibition of hepatic lactate dehydrogenase 5 (LDH5). Case: We administered Stiripentol as compassionate use in an anuric infant with dialysis-dependent PH1 over a period of 4 months. Although achieving plasma concentrations of Stiripentol that were recently reported to lower UOx excretion, we did not observe significant reduction to plasma oxalate concentrations (POx). Conclusion: We conclude that Stiripentol may not be useful to reduce POx in PH patients with advanced chronic kidney disease (CKD), but larger studies are needed to confirm this finding

Single-Pass Albumin Dialysis in the Treatment of Children with Liver Failure

Background and Aims: Acute and acute on chronic liver failure are life-threatening conditions, and bridging to transplantation is complicated by a paucity of suitable organs for children. While different modalities of extracorporeal liver support exist, their use in children is complicated by a large extracorporeal volume, and data on their use in children is limited. The aim of this analysis was to investigate the efficacy and safety of single-pass albumin dialysis (SPAD) in children with liver failure. Methods: Retrospective medical chart review of pediatric patients with liver failure treated with SPAD. The decrease in hepatic encephalopathy (HE) and the serum levels of bilirubin and ammonia were measured to determine efficacy. Adverse events were documented to assess safety. Results: Nineteen pediatric patients with a median age of 25.5 months and a median body weight of 11.9 kg were treated with SPAD between January 2011 and March 2018. Total bilirubin (p < 0.001) and ammonia (p = 0.02) significantly decreased after treatment with SPAD. As clinical outcome parameter, HE significantly improved (p = 0.001). Twelve patients were bridged successfully to liver transplantation. In all patients, 71 SPAD sessions were run. Clotting in the dialysis circuit was observed in 49% of all sessions. Heparin and citrate were used for anticoagulation and were significantly superior to dialysis without any anticoagulation (p= 0.03). Transfusion of packed blood cells (57%) and catecholamine therapy (49%) were frequently necessary. Conclusions: Treatment with SPAD was effective in detoxification, as measured by significant improvement of HE and clearance from surrogate laboratory parameters

A Structured, Manual-Based Low-Level Intervention vs. Treatment as Usual Evaluated in a Randomized Controlled Trial for Adolescents with Extreme Obesity - the STEREO Trial

Background: To compare efficacy and safety of a manual-based low-level psychological intervention with treatment as usual (weight loss treatment). Methods: A two-armed randomized controlled trial without blinding and computer-based stratified block randomization included adolescents and young adults (14.0-24.9 years) with a BMI ≥ 30 kg/m2 at five German university hospitals. Primary outcomes were adherence (participation rate ≥ 5/6 sessions) and quality of life (DISABKIDS-37) 6 months after randomization. Secondary outcomes included depression, self-esteem, and perceived stress scores. Results: Of 397 screened adolescents, 119 (mean BMI 40.4 ± 7.0 kg/m2, 49.6% female) were randomized to the manual-based low-level intervention (n = 59) or treatment as usual (n = 60). We observed no group difference for adherence (absolute risk reduction 0.4%, 95% CI -14.7% to 15.5%; p = 1.0) or health- related quality of life (score difference 8.1, 95% CI -2.1 to 18.3; p = 0.11). Among all secondary outcomes, we detected explorative evidence for an effect on the DISABKIDS-37 ‘social exclusion' subscale (score difference 15.5; 95% CI 1.6-29.4; p = 0.03). 18/19 adverse events occurred in 26 participants, none were classified as serious. Conclusion: Adherence to a coping-oriented intervention was comparable to weight loss treatment, although it was weak in both interventions. Psychological interventions may help to overcome social isolation; further confirmation is required

Serum indoxyl sulfate concentrations associate with progression of chronic kidney disease in children

The uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (pCS) accumulate in patients with chronic kidney disease (CKD) as a consequence of altered gut microbiota metabolism and a decline in renal excretion. Despite of solid experimental evidence for nephrotoxic effects, the impact of uremic toxins on the progression of CKD has not been investigated in representative patient cohorts. In this analysis, IS and pCS serum concentrations were measured in 604 pediatric participants (mean eGFR of 27 ± 11 ml/min/1.73m2) at enrolment into the prospective Cardiovascular Comorbidity in Children with CKD study. Associations with progression of CKD were analyzed by Kaplan-Meier analyses and Cox proportional hazard models. During a median follow up time of 2.2 years (IQR 4.3-0.8 years), the composite renal survival endpoint, defined as 50% loss of eGFR, or eGFR <10ml/min/1.73m2 or start of renal replacement therapy, was reached by 360 patients (60%). Median survival time was shorter in patients with IS and pCS levels in the highest versus lowest quartile for both IS (1.5 years, 95%CI [1.1,2.0] versus 6.0 years, 95%CI [5.0,8.4]) and pCS (1.8 years, 95%CI [1.5,2.8] versus 4.4 years, 95%CI [3.4,6.0]). Multivariable Cox regression disclosed a significant association of IS, but not pCS, with renal survival, which was independent of other risk factors including baseline eGFR, proteinuria and blood pressure. In this exploratory analysis we provide the first data showing a significant association of IS, but not pCS serum concentrations with the progression of CKD in children, independent of other known risk factors. In the absence of comorbidities, which interfere with serum levels of uremic toxins, such as diabetes, obesity and metabolic syndrome, these results highlight the important role of uremic toxins and accentuate the unmet need of effective elimination strategies to lower the uremic toxin burden and abate progression of CKD

Large effects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS)

BACKGROUND: The polycystic ovary syndrome (PCOS), a common endocrine disorder in women of child-bearing age, mainly characterised by chronic anovulation and hyperandrogenism, is often associated with insulin resistance (IR) and obesity. Its etiology and the role of IR and obesity in PCOS are not fully understood. We examined the influence of validated genetic variants conferring susceptibility to obesity and/or type 2 diabetes mellitus (T2DM) on metabolic and PCOS-specific traits in patients with PCOS. METHODS: We conducted an association study in 386 patients with PCOS (defined by the Rotterdam-criteria) using single nucleotide polymorphisms (SNPs) in or in proximity to the fat mass and obesity associated gene (FTO), insulin-induced gene-2 (INSIG2), transcription factor 7-like 2 gene (TCF7L2) and melanocortin 4 receptor gene (MC4R). To compare the effect of FTO obesity risk alleles on BMI in patients with PCOS to unselected females of the same age range we genotyped 1,971 females from the population-based KORA-S4 study (Kooperative Gesundheitsforschung im Raum Augsburg, Survey 4). RESULTS: The FTO risk allele was associated with IR traits and measures of increased body weight. In addition, the TCF7L2 SNP was associated with body weight traits. For the SNPs in the vicinity of INSIG2 and MC4R and for the other examined phenotypes there was no evidence for an association. In PCOS the observed per risk allele effect of FTO intron 1 SNP rs9939609 on BMI was +1.56 kg/m2, whereas it was +0.46 kg/m2 in females of the same age range from the general population as shown previously. CONCLUSION: The stronger effect on body weight of the FTO SNP in PCOS might well have implications for the etiology of the disease

The National Early Warning Score and its subcomponents recorded within ±24 hours of emergency medical admission are poor predictors of hospital-acquired acute kidney injury

YesBackground: Hospital-acquired Acute Kidney Injury (H-AKI) is a common cause of avoidable morbidity and mortality. Aim: To determine if the patients’ vital signs data as defined by a National Early Warning Score (NEWS), can predict H-AKI following emergency admission to hospital. Methods: Analyses of emergency admissions to York hospital over 24-months with NEWS data. We report the area under the curve (AUC) for logistic regression models that used the index NEWS (model A0), plus age and sex (A1), plus subcomponents of NEWS (A2) and two-way interactions (A3). Likewise for maximum NEWS (models B0,B1,B2,B3). Results: 4.05% (1361/33608) of emergency admissions had H-AKI. Models using the index NEWS had the lower AUCs (0.59 to 0.68) than models using the maximum NEWS AUCs (0.75 to 0.77). The maximum NEWS model (B3) was more sensitivity than the index NEWS model (A0) (67.60% vs 19.84%) but identified twice as many cases as being at risk of H-AKI (9581 vs 4099) at a NEWS of 5. Conclusions: The index NEWS is a poor predictor of H-AKI. The maximum NEWS is a better predictor but seems unfeasible because it is only knowable in retrospect and is associated with a substantial increase in workload albeit with improved sensitivity.The Health Foundatio

Isolation und Charakterisierung humaner mesenchymaler Stammzellen aus Speicheldrüsen und ihre Differenzierung in Azinuszellen

In dieser Arbeit wurden Zellen aus humanen Speicheldrüsenpräparaten isoliert und in Zellkultur überführt. Hierbei zeigte sich ein über 17 Passagen erhaltenes Wachstum der Zellen, adhärent auf Polystyrol-Zellkulturflaschen. Morphologie und Wachstumseigenschaften waren vergleichbar mit den parallel kultivierten mesenchymalen Stammzellen (MSC) aus humanem Knochenmark. Die isolierten Zellen wiesen in ihrem Immunphänotyp und in ihrem Differenzierungspotenzial MSC Charakteristik auf und konnten als human Salivary Gland Stem Cells (hSGSC) bezeichnet werden. Durchflusszytometrisch wurden klassische MSC Marker wie CD29, CD44, CD54, CD73, CD90 und CD105 nachgewiesen. Im Vergleich zu den CD34 negativen MSC aus humanem Knochenmark wurde bei den untersuchten hSGSC eine geringe Expression von CD34 detektiert. Marker wie das MSCA-1, CD117, STRO-1 und CD271 wurden in unterschiedlichem Ausmaß exprimiert und bestätigen den Stammzellcharakter der isolierten Zellen. Die Differenzierung der hSGSC erfolgte zur Darstellung ihrer multipotenten Stammzellcharakteristik in adipogene, osteogene und chondrogene Zellen. Der Nachweis der Differenzierung erfolgte mittels histologischer und immunhistochemischer Methoden. Um die Möglichkeit einer künftigen Verwendung dieser Zellen in regenerativen Modellen zur Behandlung der irreversiblen Speicheldrüsenschädigung zu testen, erfolgte die in-vitro Differenzierung der hSGSC in Azinuszellen. Hierfür stellte sich reines Matrigel als die am besten geeignete dreidimensionale Matrix heraus und wurde in Kombination mit einem spezifischen Differenzierungsmedium verwendet. Der Nachweis der stattgefundenen Differenzierung erfolgte nach morphologischen Kriterien sowie durch histologische und immunhistochemische Färbemethoden. Mit dem Wissen des in-vitro Potenzials der hSGSC sind regenerative Strategien zur Behandlung der radiogenen Speicheldrüsenschädigung durch Methoden des Tissue Engineering oder der Stammzelltherapie potenziell möglich

Comparison of blood loss in a swine model after percutaneous splenic core needle biopsy with and without plugging the needle tract using a gelatine sponge

Die bildgesteuerte, perkutane Biopsie ist eine wichtige diagnostische Prozedur in der modernen Medizin. Eine der häufigsten Indikationen zur Biopsie abdomineller Organe ist die Gewinnung zytologischen, histologischen oder mikrobiologischen Materials. Biopsien der Milz gelten als besonders komplikationsträchtig. Auf der einen Seite werden Blutungen aus der Milz gefürchtet, auf der anderen Seite ist ein sicherer Zugang zum Milzparenchym wegen der engen Beziehung zur linken Pleura und Lunge sowie zur linken Kolonflexur, zum Magen und zur linken Niere nicht immer möglich [35, 37]. Zusätzlich ist das Risiko postpunktioneller Blutungskomplikationen bei Patienten mit therapeutisch oder pathologisch herabgesetzter Gerinnungsfunktion besonders hoch [60]. Ziel der vorliegenden Arbeit war es, eine Technik zur Vermeidung postinterventioneller Blutungskomplikationen nach perkutaner Schneidbiopsie der Milz auf ihre Effizienz hin zu überprüfen. Im Rahmen einer tierexperimentellen Versuchreihe an 26 Schweinen erfolgte zunächst eine computertomografisch gesteuerte Schneidbiopsie der Milz. Postinterventionell wurde bei der Hälfte der Versuchstiere eine Okklusion des Stichkanals mittels Einbringen eines Gelatineschwamms vorgenommen. Zusätzlich wurden 10 der 26 Tiere periinterventionell durch die intravenöse Gabe von Heparin antikoaguliert, um die Anwendung des Verfahrens an einer Hochrisikogruppe zu simulieren. 24 Stunden post interventionem erfolgte neben einer erneuten computertomografischen Bildgebung eine Obduktion mit Bestimmung des intraperitonealen Blutvolumens. Durch eine signifikante Reduktion des Blutverlustes der Verum- gegenüber der Kontrollgruppe konnte die Effizienz des Verfahrens aufgezeigt werden. Dabei zeigte sich, dass eine histologisch nachgewiesene vollständig intrasplenische Lage des Gelatinematerials zur Erzielung des gewünschten Effektes nicht nötig zu sein scheint, eine überwiegend extrasplenische Lage des Plugmaterials führte zu vergleichbar guten Ergebnissen. Als prädiktive Parameter des zu erwartenden peri- und postinterventionellen intraperitonealen Blutverlustes konnten der präinterventionelle Gerinnungsstatus sowie die computertomografisch gemessene Länge der Stichkanäle identifiziert werden. Andere computertomografisch bestimmte Parameter erwiesen sich im Rahmen dieser Studie als nicht valide. Abschließend kann das Verfahren der Traktembolisation mittels Gelatineschwamm aufgrund seiner nachgewiesenen Effektivität, seines geringen technischen Aufwandes und relativ niedriger Kosten zur Anwendung bei Risikopatienten im Rahmen einer perkutanen Schneidbiopsie der Milz empfohlen werden.Imagine guided percutaneous biopsy is an important procedure in modern medicine. One of the more common indications for abdominal biopsy is the need to obtain cytologic, histologic or microbiologic material. Biopsies of the spleen are often avoided because many perceive that complication risks are high compared with biopsies of other abdominal organs. These risks include primarily hemorrhage but also inadvertent puncture of left pleura and lung, colon, stomach or left kidney. In addition, the risk of postbiopsy hemorrhagic complications is particulary great in patients with therapeutic or pathologic coagulopathy. The purpose of this investigation was to test a technique of avoiding hemorrhagic complications after splenic core needle biopsy for their efficience. Within test series using a swine model initially a computer tomografically guided splenic core needle biopsy was performed. Post interventionem the biopsy needle tract was embolized at the half of the animals using an adsorbable gelatine sponge. Additionally ten of the twenty-six animals were allocated into heparinized group and a bolus of 300 U of heparin per kilogram of body weight was administered IV resulting in an anticoagulated state to simulate the application of technique at a high-risk group. Twenty-four hours post interventionem a second computer tomography was carried out followed by an autopsy with measurement of intraperitoneal fluid volume. Through significant reduction of blood loss in the verum group compared to control group efficiancy of the technique could be shown. It turned out that a histologically detected complete intrasplenic location of the gelatine sponge seems not to be necessary to achieve the designated effect; a predominant extrasplenic location of sponge led to comparably good results. As predictive parameter for the estimate peri- and postinterventional intraperitoneal blood loss the preinterventional coagulation status and the computer tomografically measured length of biopsy needle tract could be identified. Other computer tomografically quantified parameter proved not to be valid. To conclude is to say that the technique of tract embolization could be recommended for use in percutaneous splenic core needle biopsy of high risk patients cause of its proved efficiency, the low techniqually complexity an its relatively low costs

Extracellular vesicles as regulators of kidney function and disease

Abstract Extracellular vesicles (EVs) are small, lipid bilayer-delimited particles of cellular origin that recently gained increasing attention for their potential use as diagnostic biomarkers, and beyond that for their role in intercellular communication and as regulators of homeostatic and disease processes. In acute kidney injury (AKI) and chronic kidney disease (CKD), the potential use of EVs as diagnostic and prognostic markers has been evaluated in a series of clinical studies and contributions to pathophysiologic pathways have been investigated in experimental models. While EV concentrations in biofluids could not distinguish renal patients from healthy subjects or determine disease progression, specific EV subpopulations have been identified that may provide useful diagnostic and prognostic tools in AKI. Specific EV subpopulations are also associated with clinical complications in sepsis-induced AKI and in CKD. Beyond their role as biomarkers, pathophysiologic involvement of EVs has been shown in hemolytic uremic syndrome- and sepsis-induced AKI as well as in cardiovascular complications of CKD. On the other hand, some endogenously formed or therapeutically applied EVs demonstrate protective effects pointing toward their usefulness as emerging treatment strategy in kidney disease