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In the second phase of shock therapy, we regularly find fluid overload with edema in our patients, which not only involves the skin and interstitial tissue but can also impair kidney, liver and pulmonary function. Revision of the Starling principle and new insights into physiology of the endothelial glycocalyx have important implications for fluid therapy in intensive care medicine. Determination of fluid overload and an appropriate therapy with either diuretics or ultrafiltration are the focus of "late goal-directed fluid removal" management.

Was ist neu? Welche Menge an Volumenersatzstoff geben? Im Schock erfolgt die Flüssigkeitstherapie mit Kristalloiden nach zielgerichteten Kriterien und unter Kontrolle des Laktats. Zur Wiederherstellung des Reäquilibriums ist oft eine Negativbilanz durch Flüssigkeitsrestriktion, Schleifendiuretika und maschinelle Ultrafiltration erforderlich. Bei einer maschinellen Ultrafiltration sollten 1,75 ml/kg/h nicht überschritten werden. Welche Volumenersatzstoffe geben? Balancierte Kristalloide sind Mittel der Wahl zur Flüssigkeitstherapie. Neue Volumenersatzstoffe mit einer höheren Anionenlücke haben einen alkalisierenden Effekt und können möglicherweise die Flüssigkeitstherapie optimieren. Welche Volumenersatzstoffe führen zu AKI? Kochsalz führt aufgrund einer hyperchlorämischen Azidose in moderaten Mengen zu einer funktionellen Einschränkung der renalen Filtration. In höheren Mengen ist NaCl mit einem schlechten Outcome vergesellschaftet. HES und vermutlich auch Gelatine haben zytotoxische Effekte und können zu einer akuten Nierenschädigung führen.

Die Internistische Intensivmedizin ist fur die intensivmedizinische Diagnostik, Uberwachung, Therapie, Pflege und Nachsorge von Patienten mit schweren, potenziell lebensbedrohlichen Erkrankungen aus dem gesamten Bereich der Inneren Medizin verantwortlich. Die Qualifikation in Internistischer Intensivmedizin erfordert breite Kenntnisse und praktische Fahigkeiten, zum einen im gesamten Fach Innere Medizin und zum anderen in der konservativen (Internistischen) Intensivmedizin einschlieslich der Einbeziehung spezieller Diagnostik- und Therapieoptionen der angrenzenden Fachgebiete. Die Patientenbetreuung darf sich deshalb nicht nur auf lebenserhaltende Masnahmen beschranken, sondern muss wahrend der intensivmedizinischen Behandlungsphase auch die zugrunde liegenden internistischen Erkrankungen in bestmoglicher Weise einschliesen. Das Fundament der Internistischen Intensivmedizin beinhaltet theoretische Kenntnisse, praktische Fahigkeiten (Kompetenzlevel I–III) und eine adaquate beruflich-professionelle Einstellung. Fur die Zusatz-Weiterbildung (ZWB) (Internistische) Intensivmedizin der Bundesarztekammer soll dieses Curriculum der Deutschen Gesellschaft fur Internistische Intensivmedizin und Notfallmedizin (DGIIN) dem intensivmedizinisch weiterzubildenden Internisten die Moglichkeit geben, seine Weiterbildungszeit so effizient wie moglich zu strukturieren, sich gut auf die Prufung vorzubereiten und das Erlernte anschliesend im Sinne eines „berufslebenslangen“ Qualifizierens zu bewahren. Das Curriculum mochte aber auch die Weiterbilder und Weiterbildungsausschusse der Arztekammern erreichen und aufzeigen, welche Kenntnisse und Fertigkeiten nach Ansicht der DGIIN in der ZWB zum Internistischen Intensivmediziner vermittelt werden sollen.

ZusammenfassungDie Nierenersatztherapie ist neben der Beatmung eines der wichtigsten und am häufigsten angewendeten Organersatzverfahren in der täglichen Praxis in der Intensivmedizin. Im Gegensatz zur Beatmungstherapie sind Qualitätsstandards für die Nierenersatztherapie weniger gut definiert und bekannt. In diesem Positionspapier der Deutschen Interdisziplinären Vereinigung für Intensivmedizin (DIVI) beschreiben wir Qualitätsstandards zur Nierenersatztherapie mit dem Ziel die Behandlungsqualität der Patienten mit einem schweren akuten Nierenversagen zu verbessern.

Optimization of intravascular volume is crucial for patients who are at risk or undergo Acute Kidney Injury. In sepsis or after acute fluid loss extensive fluid expansion is mostly needed. However, in cardiorenal syndroms fluid overload can even lead to AKI itself and reduction of intravascular volume is needed. Thus, an individualized fluid guidance in terms of a "fluid management stewartship" for the right patient, the right drug, the right route and the right dose 1 has to be applied.WELCHE MENGE AN VOLUMENERSATZSTOFF GEBEN?: Im Schock erfolgt die Flüssigkeitstherapie mit Kristalloiden nach zielgerichteten Kriterien und unter Kontrolle des Laktats. Zur Wiederherstellung des Reäquilibriums ist oft eine Negativbilanz durch Flüssigkeitsrestriktion, Schleifendiuretika und maschinelle Ultrafiltration erforderlich. Bei einer maschinellen Ultrafiltration sollten 1,75 ml/kg/h nicht überschritten werden. WELCHE VOLUMENERSATZSTOFFE GEBEN?: Balancierte Kristalloide sind Mittel der Wahl zur Flüssigkeitstherapie. Neue Volumenersatzstoffe mit einer höheren Anionenlücke haben einen alkalisierenden Effekt und können möglicherweise die Flüssigkeitstherapie optimieren. WELCHE VOLUMENERSATZSTOFFE FüHREN ZU AKI?: Kochsalz führt aufgrund einer hyperchlorämischen Azidose in moderaten Mengen zu einer funktionellen Einschränkung der renalen Filtration. In höheren Mengen ist NaCl mit einem schlechten Outcome vergesellschaftet. HES und vermutlich auch Gelatine haben zytotoxische Effekte und können zu einer akuten Nierenschädigung führen.

In the second phase of shock therapy, we regularly find fluid overload with edema in our patients, which not only involves the skin and interstitial tissue but can also impair kidney, liver and pulmonary function. Revision of the Starling principle and new insights into physiology of the endothelial glycocalyx have important implications for fluid therapy in intensive care medicine. Determination of fluid overload and an appropriate therapy with either diuretics or ultrafiltration are the focus of "late goal-directed fluid removal" management.In der zweiten Phase der Schocktherapie liegt regelmäßig eine Flüssigkeitsüberladung mit Ödemen vor, die nicht nur die Haut und Bindegewebe betreffen, sondern auch Organfunktionen u. a. der Nieren, Lunge und Leber beeinträchtigen. Neue Erkenntnisse zum revidierten Starling-Prinzip und der endothelialen Glykokalyx haben Implikationen für eine adäquate Flüssigkeitstherapie in der zweiten Phase der Sepsis. Die Diagnose einer Flüssigkeitsüberladung sowie eine sachgerechte Diuretika- oder Ultrafiltrationstherapie sind Schwerpunkte eines „Late goal-directed fluid removal“-Managements.

Prolyl hydroxylase domain enzyme inhibitors (PHDIs) stabilize hypoxia-inducible factors (HIFs), and are protective in models of acute ischemic and inflammatory kidney disease. Whether PHDIs also confer protection in chronic inflammatory kidney disease models remains unknown. Here we investigated long-term effects of PHDI treatment in adenine-induced nephropathy as a model for chronic tubulointerstitial nephritis. After three weeks, renal dysfunction and tubulointerstitial damage, including proximal and distal tubular injury, tubular dilation and renal crystal deposition were significantly attenuated in PHDI-treated (the isoquinoline derivative ICA and Roxadustat) compared to vehicle-treated mice with adenine-induced nephropathy. Crystal-induced renal fibrosis was only partially diminished by treatment with ICA. Renoprotective effects of ICA treatment could not be attributed to changes in adenine metabolism or urinary excretion of the metabolite 2,8-dihydroxyadenine. ICA treatment reduced inflammatory infiltrates of F4/80+ mononuclear phagocytes in the kidneys and supported a regulatory, anti-inflammatory immune response. Furthermore, interstitial deposition of complement C1q was decreased in ICA-treated mice fed an adenine-enriched diet. Tubular cell-specific HIF-1α and myeloid cell-specific HIF-1α and HIF-2α expression were not required for the renoprotective effects of ICA. In contrast, depletion of mononuclear phagocytes with clodronate largely abolished the nephroprotective effects of PHD inhibition. Thus, our findings indicate novel and potent systemic anti-inflammatory properties of PHDIs that confer preservation of kidney function and structure in chronic tubulointerstitial inflammation and might counteract kidney disease progression.

Treatment with convalescent plasma has been shown to be safe in coronavirus disease in 2019 (COVID‐19) infection, although efficacy reported in immunocompetent patients varies. Nevertheless, neutralizing antibodies are a key requisite in the fight against viral infections. Patients depleted of antibody‐producing B cells, such as those treated with rituximab (anti‐CD20) for hematological malignancies, lack a fundamental part of their adaptive immunity. Treatment with convalescent plasma appears to be of general benefit in this particularly vulnerable cohort. We analyzed clinical course and inflammation markers of three B‐cell‐depleted patients suffering from COVID‐19 who were treated with convalescent plasma. In addition, we measured serum antibody levels as well as peripheral blood CD38/HLA‐DR‐positive T‐cells ex vivo and CD137‐positive T‐cells after in vitro stimulation with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐derived peptides in these patients. We observed that therapy with convalescent plasma was effective in all three patients and analysis of CD137‐positive T‐cells after stimulation with SARS‐CoV‐2 peptides showed an increase in peptide‐specific T‐cells after application of convalescent plasma. In conclusion, we here demonstrate efficacy of convalescent plasma therapy in three B‐cell‐depleted patients and present data that suggest that while application of convalescent plasma elevates systemic antibody levels only transiently, it may also boost specific T‐cell responses., Treatment of B‐cell depleted patients suffering from COVID‐19 with convalescent plasma led to viral clearance and was followed by an increase in peptide‐specific CD4+ T‐cells suggesting that transient antibody titers promoted specific cellular immunity in these patients.

Supplemental Digital Content is available in the text., Objectives: To describe three coronavirus disease 2019 patients suffering from acute respiratory distress syndrome under venovenous extracorporeal membrane oxygenation therapy and tight anticoagulation monitoring presenting a novel pattern of multifocal brain hemorrhage in various degrees in all cerebral and cerebellar lobes. Design: Clinical observation of three patients. Post mortem examinations. Setting: Two ICUs at the University Hospital Erlangen. Patients: Three patients (medium age 56.6 yr, two male with hypertension and diabetes, one female with no medical history) developed severe acute respiratory distress syndrome on the basis of a severe acute respiratory syndrome coronavirus 2 infection. All required mechanical ventilation and venovenous extracorporeal membrane oxygenation support. Interventions: Clinical observation, CT, data extraction from electronic medical records, and post mortem examinations. Main Results: We report on an unusual multifocal bleeding pattern in the white matter in three cases with severe acute respiratory distress syndrome due to coronavirus disease 2019 undergoing venovenous extracorporeal membrane oxygenation therapy. Bleeding pattern with consecutive herniation was found in CT scans as well as in neuropathologic post mortem examinations. Frequency for this unusual brain hemorrhage in coronavirus disease 2019 patients with extracorporeal membrane oxygenation therapy at our hospital is currently 50%, whereas bleeding events in extracorporeal membrane oxygenation patients generally occur at 10–15%. Conclusions: Multifocality and high frequency of the unusual white matter hemorrhage pattern suggest a coherence to coronavirus disease 2019. Neuropathological analyses showed circumscribed thrombotic cerebrovascular occlusions, which eventually led to microvascular and later on macrovascular disseminated bleeding events. However, signs of cerebrovascular inflammation could not be detected. Polymerase chain reaction analyses of brain tissue or cerebrospinal fluid remained negative. Increased susceptibility for fatal bleeding events should be taken into consideration in terms of systemic anticoagulation strategies in coronavirus disease 2019.

Kidney fibrosis is characterized by the development of myofibroblasts originating from resident kidney and immigrating cells. Myofibroblast formation and extracellular matrix production during kidney damage are triggered by various cytokines. Among these, transforming growth factor β1 (TGFβ1) is considered a central trigger for kidney fibrosis. We found a highly upregulated expression of TGFβ1 and TGFβ receptor 2 (TGFβ-R2) mRNAs in kidney interstitial cells in experimental fibrosis. Here, we investigated the contribution of TGFβ1 signaling in resident kidney interstitial cells to organ fibrosis using the models of adenine induced nephropathy and unilateral ureteral occlusion in mice. For this purpose TGFβ1 signaling was interrupted by inducible deletion of the TGFβ-R2 gene in interstitial cells expressing the fibroblast marker platelet derived growth factor receptor-β. Expression of profibrotic genes was attenuated up to 50% in kidneys lacking TGFβ-R2 in cells positive for platelet derived growth factor receptor-β. Additionally, deletion of TGFβ-R2 prevented the decline of erythropoietin production in ureter ligated kidneys. Notably, fibrosis associated expression of α-smooth muscle actin as a myofibroblast marker and deposits of extracellular collagens were not altered in mice with targeted deletion of TGFβ-R2. Thus, our findings suggest an enhancing effect of TGFβ1 signaling in resident interstitial cells that contributes to profibrotic gene expression and the downregulation of erythropoietin production, but not to the development of myofibroblasts during kidney fibrosis.

Die Nierenersatztherapie ist neben der Beatmung eines der wichtigsten und am häufigsten angewendeten Organersatzverfahren in der täglichen Praxis in der Intensivmedizin. Im Gegensatz zur Beatmungstherapie sind Qualitätsstandards für die Nierenersatztherapie weniger gut definiert und bekannt. In diesem Positionspapier der Deutschen Interdisziplinären Vereinigung für Intensivmedizin (DIVI) beschreiben wir Qualitätsstandards zur Nierenersatztherapie mit dem Ziel die Behandlungsqualität der Patienten mit einem schweren akuten Nierenversagen zu verbessern.

Prolyl hydroxylation domain (PHD) enzymes catalyze the hydroxylation of the transcription factor hypoxia‐inducible factor (HIF) and serve as cellular oxygen sensors. HIF and the PHD enzymes regulate numerous potentially tissue‐protective target genes which can adapt cells to metabolic and ischemic stress. We describe a fluorescent PHD inhibitor (1‐chloro‐4‐hydroxybenzo[g]isoquinoline‐3‐carbonyl)glycine which is suited to fluorescence‐based detection assays and for monitoring PHD inhibitors in biological systems. In cell‐based assays, application of the fluorescent PHD inhibitor allowed co‐localization with a cellular PHD enzyme and led to live cell imaging of processes involved in cellular oxygen sensing.

Background Regional citrate anticoagulation (RCA) in continuous renal replacement therapy can effectively anticoagulate dialysis circuits without having adverse effects on systemic heparin application. In particular, in continuous renal replacement therapy RCA is well established and represents a safe procedure with longer filter lifetimes and fewer bleeding complications. Objectives To provide guidance on the indications, advantages and disadvantages, and use of RCA, current recommendations from the renal section of the DGIIN (Deutschen Gesellschaft fur Internistische Intensivmedizin und Notfallmedizin), OGIAIN (Osterreichischen Gesellschaft fur Internistische und Allgemeine Intensivmedizin und Notfallmedizin) and DIVI (Deutschen Interdisziplinaren Vereinigung fur Intensiv- und Notfallmedizin) are stated. Materials and methods The recommendations in this paper are based on the current KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, other published guidelines and protocols as well as the expert knowledge and clinical experience of the authors. Results The use of commercially available machines with coupled pumps and integrated safety features, effective personal training and standardized protocols for clinical usage (SOP) is particularly important for the safe clinical use of RCA in renal replacement therapy. Contrary to previous recommendations, even liver failure or shock with lactic acidosis may no longer be an absolute contra-indication for RCA. However, these particular patients have to be carefully monitored for signs of citrate accumulation.

Background Intensive care patients with renal failure or insufficiency comprise a heterogeneous group of subjects with widely differing metabolic patterns and nutritional requirements. They include subjects with various stages of acute kidney injury (AKI), acute-on-chronic renal failure (A-CKD), without/with renal replacement therapy (RRT), chronic kidney disease (CKD), and subjects on regular hemodialysis or peritoneal dialysis therapy (HD/PD). Goals Development of recommendations by the renal section of DGIIN (Deutsche Gesellschaft fur Internistische Intensivmedizin und Notfallmedizin), OGIAIN (Osterreichische Gesellschaft fur Internistische und Allgemeine Intensivmedizin und Notfallmedizin) and DIVI (Deutsche Interdisziplinare Vereinigung fur Intensiv- und Notfallmedizin) for the metabolic management and the planning, indication, implementation, and monitoring of nutrition therapy in this heterogeneous group of patients. Materials and methods The recommendations are based on recent evidence and current recommendations of DGEM (Deutsche Gesellschaft fur Ernahrungsmedizin), ASPEN (American Society for Parenteral and Enteral Nutrition) and ESPEN (European Society for Clinical Nutrition and Metabolism) and also the KDGIO (Kidney Disease: Improving Global Outcomes) clinical practice guidelines for AKI and the expert knowledge and clinical experience of the authors. Results Nutrition support in these patient groups is not fundamentally different from that in other disease states but must consider the multiple variations in metabolism and nutrient requirements. Nutrition therapy must be adapted to the stage of disease and especially, in those patients on RRT. Nutritional needs can differ widely between patients but also in the same patient during the course of the disease. Conclusions Thus, the patient with renal failure requires an individualized approach in nutrition support and because of the altered metabolism of many nutrients and intolerances for electrolytes and fluids, the nutrition support in patients with renal insufficiency requires close clinical and laboratory monitoring.

Background Acute kidney injury (AKI) has both high mortality and morbidity. Objectives To prevent the occurrence of AKI, current recommendations from the renal section of the DGIIN (Deutschen Gesellschaft fur Internistische Intensivmedizin und Notfallmedizin), OGIAIN (Osterreichischen Gesellschaft fur Internistische und Allgemeine Intensivmedizin und Notfallmedizin) and DIVI (Deutschen Interdisziplinaren Vereinigung fur Intensiv- und Notfallmedizin) are stated. Materials and methods The recommendations stated in this paper are based on the current Kidney Disease Improving Global Outcomes (KDIGO) guidelines, the published statements of the "Working Group on Prevention, AKI section of the European Society of Intensive Care Medicine" and the expert knowledge and clinical experience of the authors. Results Currently there are no approved clinically effective drugs for the prevention of AKI. Therefore the mainstay of prevention is the optimization of renal perfusion by improving the mean arterial pressure (>65 mm Hg, higher target may be considered in hypertensive patients). This can be done by vasopressors, preferably norepinephrine and achieving or maintaining euvolemia. Hyperhydration that can lead to AKI itself should be avoided. In patients with maintained diuresis this can be done by diuretics that are per se no preventive drug for AKI. Radiocontrast enhanced imaging should not be withheld from patients at risk for AKI; if indicated, however, the contrast media should be limited to the smallest possible volume.

Background Many anti-infective drugs require dose adjustments in critically ill patients with acute kidney injury (AKI) and renal replacement therapy, in order to achieve adequate therapeutic drug concentrations. Objectives The fundamental pharmacokinetic and pharmacodynamic principles of drug dose adjustment are presented. Recommendations on anti-infective drug dosage in intensive care are provided. Materials and methods We established dose recommendations of selected anti-infective drugs based on information in the summary of product characteristics, published studies and recommendations, pharmacokinetic and pharmacodynamic considerations, and the experience and expert opinion of the authors. Results Out of a total of 37 anti-infective drugs (31 antibiotics, 2 antivirals, 4 antifungals) 8 can be administered independent of renal function. For 29 anti-infective drugs, a specific recommendation on drug dosage could be made in case of intermittent hemodialysis and for 24 anti-infective drugs in case of continuous hemo(dia)filtration. Conclusions Recommendations on dosing of important anti-infective drugs in critically ill patients with AKI and renal replacement therapy are provided.

Background Acute kidney injury (AKI) is a common complication in intensive care unit (ICU) patients. The incidence of AKI in ICU patients exceeds 50% and the associated morbidity and mortality rates increase with severity of AKI. In addition, long-term consequences of AKI are underestimated and several studies show impaired long-term outcome after AKI. In about 5-25% of ICU patients with AKI renal replacement therapy (RRT) is required. Objectives To assist in indication, timing, modality and application of renal replacement therapy of adult patients, current recommendations from the renal sections of the DGIIN (Deutschen Gesellschaft fur Internistische Intensivmedizin und Notfallmedizin), OGIAIN (Osterreichischen Gesellschaft fur Internistische und Allgemeine Intensivmedizin und Notfallmedizin) and DIVI (Deutschen Interdisziplinaren Vereinigung fur Intensiv- und Notfallmedizin) are stated. Materials and methods The recommendations stated in this paper are based on the current KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, recommendations from the 17th Acute Disease Quality Initiative (ADQI) Consensus Group, the French Intensive Care Society (SRLF) with the French Society of Anesthesia Intensive Care (SFAR) and the expert knowledge and clinical experience of the authors. Results Today, different treatment modalities for RRT are available. Although continuous RRT and intermittent dialysis therapy as well as continuous dialysis therapy have comparable outcomes, differences exist with respect to practical application as well as health-economic aspects. Individualized risk stratification might be helpful to choose the right time to start and the right treatment modality for patients.

ZUSAMMENFASSUNGDie regionale Zitratantikoagulation ist inzwischen zum oftmals bevorzugten Antikoagulationsverfahren in der chirurgischen und anästhesiologischen Intensivmedizin geworden. Dem Nachteil des höheren Aufwandes und der Bedenken wegen Nebenwirkungen stehen die Vorteile gegenüber, weniger Blutverlust zu erleiden, höhere Filterlaufzeiten und konsekutiv höhere Dialysedosen zu erreichen und auch blutungsgefährdete Patienten behandeln zu können. Für die intermittierenden Verfahren gibt es mittlerweile ebenfalls zahlreiche Protokolle, die jedoch als weniger validiert gelten können. Die Weiterentwicklung der Zitratantikoagulation verspricht auch vorteilhaft für den intermittierenden Dialysebereich und der Therapie chronischer Dialysepatienten zu sein.

Hypoxia-inducible factor-1α (HIF-1α), which accumulates in mammalian host organisms during infection, supports the defense against microbial pathogens. However, whether and to what extent HIF-1α expressed by myeloid cells contributes to the innate immune response against Leishmania major parasites is unknown. We observed that Leishmania-infected humans and L. major–infected C57BL/6 mice exhibited substantial amounts of HIF-1α in acute cutaneous lesions. In vitro, HIF-1α was required for leishmanicidal activity and high-level NO production by IFN-γ/LPS-activated macrophages. Mice deficient for HIF-1α in their myeloid cell compartment had a more severe clinical course of infection and increased parasite burden in the skin lesions compared with wild-type controls. These findings were paralleled by reduced expression of type 2 NO synthase by lesional CD11b+ cells. Together, these data illustrate that HIF-1α is required for optimal innate leishmanicidal immune responses and, thereby, contributes to the cure of cutaneous leishmaniasis.

Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by mutations of the PKD1 gene and characterized by growth of bilateral renal cysts. Cyst growth is accompanied by regional hypoxia and induction of hypoxia-inducible factor (HIF)-1α in cyst-lining epithelial cells. To determine the relevance of HIF-1α for cyst growth in vivo we used an inducible kidney epithelium-specific knockout mouse to delete Pkd1 at postnatal day 20 or 35 to induce polycystic kidney disease of different severity and analyzed the effects of Hif-1α co-deletion and HIF-1α stabilization using a prolyl-hydroxylase inhibitor. HIF-1α expression was enhanced in kidneys with progressive cyst growth induced by early Pkd1 deletion, but unchanged in the milder phenotype induced by later Pkd1 deletion. Hif-1α co-deletion significantly attenuated cyst growth in the severe, but not in the mild, phenotype. Application of a prolyl-hydroxylase inhibitor resulted in severe aggravation of the mild phenotype with rapid loss of renal function. HIF-1α expression was associated with induction of genes that mediate calcium-activated chloride secretion. Thus, HIF-1α does not seem to play a role in early cyst formation, but accelerates cyst growth during progressive polycystic kidney disease. This novel mechanism of cyst growth may qualify as a therapeutic target.

Acute kidney injury (AKI) is a frequent complication after cardiopulmonary bypass, but early detection of postoperative AKI remains challenging. Protein biomarkers predict AKI excellently in homogeneous cohorts but are less reliable in patients suffering from various comorbidities. We employed nuclear magnetic resonance spectroscopy in a prospective study of 85 adult cardiac surgery patients to identify metabolites prognostic of AKI in plasma specimens collected 24 h after surgery. Postoperative AKI of stages 1-3, as defined by the Acute Kidney Injury Network (AKIN), developed in 33 cases. A random forests classifier trained on the NMR spectra prognosticated AKI across all stages, with an average accuracy of 80 ± 0.9% and an area under the receiver operating characteristic curve of 0.87 ± 0.01. Prognostications were based, on average, on 24 ± 2.8 spectral features. Among the set of discriminative ions and molecules identified were Mg(2+), lactate, and the glucuronide conjugate of propofol. Using creatinine, Mg(2+), and lactate levels to derive an AKIN index score, we found AKIN 1 disease to be largely indistinguishable from AKIN 0, in concordance with the rather mild nature of AKIN 1 disease.

Hypoxia-inducible transcription factors (HIFs) control cellular adaptation to low oxygen. In the kidney, activation of HIF is beneficial during injury; however, the specific contribution of HIF-1α in renal endothelial cells (EC) remains elusive. Since EC display tissue-specific heterogeneity, we investigated how HIF-1α affects key functions of glomerular EC in vitro and its contribution to renal development and pathophysiological adaptation to acute or chronic renal injury in vivo. Loss of HIF-1α in glomerular EC induces hypoxic cell death and reduces hypoxic adhesion of macrophages in vitro. In vivo, HIF-1α expression in EC in mouse kidneys is detectable but limited. Accordingly, EC-specific ablation of HIF-1α does not lead to developmental or phenotypical abnormalities in the kidney. Renal function and expression of adhesion molecules during acute ischemic kidney injury is independent of HIF-1α in EC. Likewise, inflammation and development of fibrosis after unilateral ureteric obstruction is not influenced by endothelial HIF-1α. Taken together, although HIF-1α exerts effects on glomerular EC in vitro, endothelial HIF-1α does not influence renal development and pathophysiological adaptation to kidney injury in vivo. This implies a profound difference of the hypoxic response of the renal vascular bed compared to other organs, such as the heart. This has implications for the development of pharmacological strategies targeting the endothelial hypoxic response pathways.HIF-1α controls hypoxic survival and adhesion on endothelial cells (EC) in vitro. In vivo, HIF-1α expression in renal EC is low. Deletion of HIF-1α in EC does not affect kidney development and function in mice. Renal function after acute and chronic kidney injury is independent of HIF-1α in EC. Data suggest organ-specific regulation of HIF-1α function in EC.

Lunge und Niere stellen im Rahmen eines Multiorganversagens (MOV) bei Schock, Trauma oder Sepsis die beiden am haufigsten betroffenen Organe („acute respiratory distress syndrome“, ARDS bzw. Nierenversagen, ANV) dar mit einer fur beide Organversagen nach wie vor inakzeptabel hohen Mortalitat. Auch wenn die pathophysiologischen Mechanismen des MOV noch nicht vollstandig verstanden sind, scheinen Niere und Lunge ahnlichen Schadigungsmechanismen zu unterliegen sowie jeweils das Potenzial zu haben, sich gegenseitig weiter Schaden zufugen zu konnen („kidney-lung crosstalk“). Hierbei spielen inflammatorische Signale in beide Richtungen und eine Volumenuberladung mit konsekutiver Odembildung in beiden Organen die vielleicht wichtigsten Rollen. Die bei beiden Organversagen eingesetzten Organersatzverfahren konnen selbst wieder das jeweilig andere Organ negativ beeinflussen (Beatmungs-/Dialyttrauma). Gerade fur Nierenersatzverfahren sind aber auch positive Effekte auf ein Lungenversagen durch Beeinflussung des Volumen- oder Saure-Basen-Haushalts bekannt. Neue Moglichkeiten zur sog. Low-flow-CO2-Elimination direkt am Nierenersatz konnten in Zukunft weiter helfen, ein Beatmungstrauma zu minimieren.

Objective: Many cellular responses to hypoxia are mediated by the transcription factor complex hypoxia-inducible factor (HIF). HIF stability is governed by a family of dioxygenases called HIF prolyl hydroxylases (PHDs). Isoquinolone-derived PHD inhibitors, like 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA), which stabilize the intracellular HIF-α have been suggested as a potentially beneficial therapeutic strategy for the treatment of disorders associated with ischemia. To stabilize HIF-α, ICA has to be taken up into proximal tubule cells (PCTs) across the basolateral membrane by one of the organic anion transporters 1, 2 or 3 (OAT1, OAT2 or OAT3). The release into the urine across the luminal membrane may be mediated by OAT4. Method: To demonstrate interaction of ICA with human OAT1, OAT2, OAT3 and OAT4, ICA was tested on these transporters stably transfected in HEK293 cells by using p-aminohippurate (PAH), cGMP and estrone-3-sulfate (ES) as reference substrates, respectively. Results: Uptakes of PAH and ES in OAT1- and OAT3-transfected HEK293 cells were inhibited by ICA with half-maximal inhibition values of 0.29 ± 0.05 and 2.58 ± 0.16 µM, respectively. OAT2 was less sensitive to ICA. Efflux experiments identified ICA as an OAT1 and OAT3 substrate. Preloading OAT4-transfected HEK293 cells with ICA stimulated ES uptake by 18.3 ± 3.8%. Conclusion: The uptake of ICA across the basolateral membrane of PCTs occurs mainly by OAT1 and the efflux into the tubular lumen by OAT4.

Intrauterine hypoxia is a reason for impaired kidney development. The cellular and molecular pathways along which hypoxia exerts effects on nephrogenesis are not well understood. They are likely triggered by hypoxia-inducible transcription factors (HIFs), and their effects appear to be dependent on the cell compartment contributing to kidney formation. In this study, we investigated the effects of HIF activation in the developing renal stroma, which also essentially modulates nephron development from the metanephric mesenchyme. HIF activation was achieved by conditional deletion of the von Hippel–Lindau tumor suppressor (VHL) protein in the forkhead box FOXD1 cell lineage, from which stromal progenitors arise. The resulting kidneys showed maturation defects associated with early postnatal death. In particular, nephron formation, tubular maturation, and the differentiation of smooth muscle, renin, and mesangial cells were impaired. Erythropoietin expression was strongly enhanced. Codeletion of VHL together with HIF2A but not with HIF1A led to apparently normal kidneys, and the animals reached normal age but were anemic because of low erythropoietin levels. Stromal deletion of HIF2A or HIF1A alone did not affect kidney development. These findings emphasize the relevance of sufficient intrauterine oxygenation for normal renal stroma differentiation, suggesting that chronic activity of HIF2 in stromal progenitors impairs kidney development. Finally, these data confirm the concept that normal stroma function is essential for normal tubular differentiation.

Polycystic kidney diseases are characterized by numerous bilateral renal cysts that continuously enlarge and, through compression of intact nephrons, lead to a decline in kidney function over time. We previously showed that cyst enlargement is accompanied by regional hypoxia, which results in the stabilization of hypoxia-inducible transcription factor-1 α (HIF-1 α ) in the cyst epithelium. Here we demonstrate a correlation between cyst size and the expression of the HIF-1 α –target gene, glucose transporter 1, and report that HIF-1 α promotes renal cyst growth in two in vitro cyst models—principal-like MDCK cells (plMDCKs) within a collagen matrix and cultured embryonic mouse kidneys stimulated with forskolin. In both models, augmenting HIF-1 α levels with the prolyl hydroxylase inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate enhanced cyst growth. In addition, inhibition of HIF-1 α degradation through tubule-specific knockdown of the von Hippel-Lindau tumor suppressor increased cyst size in the embryonic kidney cyst model. In contrast, inhibition of HIF-1 α by chetomin and knockdown of HIF-1 α both decreased cyst growth in these models. Consistent with previous reports, plMDCK cyst enlargement was driven largely by transepithelial chloride secretion, which consists, in part, of a calcium-activated chloride conductance. plMDCKs deficient for HIF-1 α almost completely lacked calcium-activated chloride secretion. We conclude that regional hypoxia in renal cysts contributes to cyst growth, primarily due to HIF-1 α –dependent calcium-activated chloride secretion. These findings identify the HIF system as a novel target for inhibition of cyst growth.

Endothelial dysfunction predicts cardiovascular damage and renal involvement. Animal experiments and human studies indicate an increased nitric oxide (NO) activity and endothelial NO synthase (NOS) expression in the early stage of type 2 diabetes. The aim of the study was to assess the effect of linagliptin on the endothelial function of the renal vasculature. In this randomised, double-blind, parallel-group, investigator-initiated trial, 62 patients with type 2 diabetes were randomly assigned (by computer-generated random code) to receive linagliptin 5 mg (n = 30) or placebo (n = 32) for 4 weeks. The primary objective was to assess endothelial function of the renal vasculature, by constant-infusion input-clearance and urinary albumin/creatinine ratio (UACR), both before and after blockade of NOS with N G-monomethyl-l-arginine (L-NMMA). Treatment with linagliptin for 4 weeks reduced fasting, postprandial blood glucose and HbA1c, although not significantly; no change occurred with placebo. Renal plasma flow (RPF) did not change after linagliptin or placebo. After 4 weeks the absolute change in RPF due to L-NMMA was smaller in the linagliptin group than in the placebo group (−46.8 ± 34 vs −65.1 ± 36 ml/min, p = 0.045), indicating a lower basal NO activity after treatment with linagliptin. Consistently, the response of UACR to L-NMMA increased in the placebo group (p = 0.059) but not in the linagliptin group (p = 0.276), pointing to an upregulation of NO activity in the placebo group. No clinically meaningful safety concerns were evident. Our data suggest that treatment with the dipeptidyl peptidase-4 inhibitor linagliptin for 4 weeks prevented the impairment of renal endothelial function due to hyperglycaemia in type 2 diabetes. ClinicalTrials.gov NCT01835678 This study was funded by Boehringer Ingelheim.

PDGFR-β-expressing cells of the kidneys are considered as a relevant site of erythropoietin (EPO) production. The origin of these cells, their contribution to renal EPO production, and if PDGFR-β-positive cells in other organs are also capable to express EPO are less clear. We addressed these questions in mice, in which hypoxia-inducible transcription factors were stabilized in PDGFR-β(+) cells by inducible deletion of the von Hippel-Lindau (Vhl) protein. Vhl deletion led to a 600-fold increase of plasma EPO concentration, 170-fold increase of renal EPO messenger RNA (mRNA) levels, and an increase of hematocrit values up to 70 %. Intrarenal localization of EPO-expressing cells coincided with the zonal heterogeneity and distribution of cells expressing PDGFR-β. Amongst a variety of extrarenal organs only adrenal glands showed significant EPO mRNA expression after Vhl deletion in PDGFR-β(+) cells. EPO mRNA, plasma EPO, and hematocrit fell to subnormal values if HIF-2α, but not HIF-1α, was deleted either alone or in combination with Vhl in PDGFR-β(+) cells. Treatment of mice with a prolyl-hydroxylase inhibitor caused an increase of EPO mRNA abundance and plasma EPO concentrations in wild-type mice and in mice lacking HIF-1α in PDGFR-β(+) cells but exerted no effect in mice lacking HIF-2α in PDGFR-β(+) cells. These findings suggest that PDGFR-β(+) cells are the only relevant site of EPO expression in the kidney and that HIF-2 is the essential transcription factor triggering EPO expression therein. Moreover, our findings suggest that PDGFR-β(+) cells elaborating EPO might arise from the metanephric mesenchyme, rather than from the neural crest.

Chronic kidney disease (CKD) is associated with increased risk and worse prognosis of cardiovascular disease, including peripheral artery disease. An impaired angiogenic response to ischemia may contribute to poor outcomes of peripheral artery disease in patients with CKD. Hypoxia inducible factors (HIF) are master regulators of angiogenesis and therefore represent a promising target for therapeutic intervention. To test this we induced hind-limb ischemia in rats with CKD caused by 5/6 nephrectomy and administered two different treatments known to stabilize HIF protein in vivo : carbon monoxide and a pharmacological inhibitor of prolyl hydroxylation 2-(1-chloro-4- hydroxyisoquinoline-3-carboxamido) acetate (ICA). Expression levels of pro-angiogenic HIF target genes ( Vegf, Vegf-r1, Vegf-r2, Ho-1 ) were measured by qRT-PCR. Capillary density was measured by CD31 immunofluorescence staining and HIF expression was evaluated by immunohistochemistry. Capillary density in ischemic skeletal muscle was significantly lower in CKD animals compared to sham controls. Rats with CKD showed significantly lower expression of HIF and all measured pro-angiogenic HIF target genes, including VEGF. Both HIF stabilizing treatments rescued HIF target gene expression in animals with CKD and led to significantly higher ischemia-induced capillary sprouting compared to untreated controls. ICA was effective regardless of whether it was administered before or after induction of ischemia and led to a HIF expression in skeletal muscle. Thus, impaired ischemia-induced angiogenesis in rats with CKD can be improved by HIF stabilization, even if started after onset of ischemia.

Acute kidney injury (AKI) is a frequent complication of sepsis, major surgery or nephrotoxic medication use. It is associated with high morbidity and mortality. In an effort to identify novel biomarkers capable of predicting the development of AKI after cardiac surgery with cardiopulmonary bypass use, urine specimens were collected before and at 4 and 24 h after surgery from 106 patients and analyzed by means of nuclear magnetic resonance spectroscopy. Postoperative AKI of stage 1–3 as defined by the Acute Kidney Injury Network (AKIN) developed in 34 cases. Employing Quantile Normalization and support vector machine based classification, spectra of the 24-hour postoperative urine specimens were found to predict AKI across all stages with an average accuracy of 76.0 % and a corresponding area under the receiver operating characteristic curve of 0.83. Considering only AKIN-stage 2 and 3 patients, prediction accuracy increased to 81.7 % and 100 %, respectively. Among the small set of predictive biomarkers identified was carnitine, the urinary concentration of which was elevated significantly in AKI-free patients only, and tranexamic acid, which is routinely applied as an antifibrinolytic agent at the end of surgery, and whose renal excretion was delayed in AKI patients. The study underscores the power of NMR and bioinformatics in identifying novel biomarkers of disease and in gaining new insights into pathomechanisms.

Hypoxia-inducible transcription factors (HIF) protect cells against oxygen deprivation, and HIF stabilization before ischemia mitigates tissue injury. Because ischemic acute kidney injury (AKI) often involves the thick ascending limb (TAL), modulation of HIF in this segment may be protective. Here, we generated mice with targeted TAL deletion of the von Hippel-Lindau protein (Vhl), which mediates HIF degradation under normoxia, using Tamm-Horsfall protein (Thp)-driven Cre expression. These mice showed strong expression of HIF-1α in TALs but no changes in kidney morphology or function under control conditions. Deficiency of Vhl in the TAL markedly attenuated proximal tubular injury and preserved TAL function following ischemia-reperfusion, which may be partially a result of enhanced expression of glycolytic enzymes and lactate metabolism. These results highlight the importance of the thick ascending limb in the pathogenesis of AKI and suggest that pharmacologically targeting the HIF system may have potential to prevent and mitigate AKI.

HIF1A is a transcription factor that plays a central role for the adaptation to tissue hypoxia and for the inflammatory response of myeloid cells, including DCs. HIF1A is stabilized by hypoxia but also by TLR ligands under normoxic conditions. The underlying signaling events leading to the accumulation of HIF1A in the presence of oxygen are still poorly understood. Here, we show that in contrast to hypoxic stabilization of HIF1A, normoxic, TLR-mediated HIF1A accumulation in DCs follows a different pathway that predominantly requires MYD88-dependent NF-κB activity. The TLR-induced HIF1A controls a subset of proinflammatory genes that are insufficiently induced following hypoxia-mediated HIF1A induction. Thus, TLR activation and hypoxia stabilize HIF1A via distinct signaling pathways, resulting in differential HIF1A-dependent gene expression.

Hypoxia inducible factor (HIF) is regulated by dual pathways involving oxygen-dependent prolyl and asparaginyl hydroxylation of its α-subunits. Prolyl hydroxylation at two sites within a central degradation domain promotes association of HIF-α with the von Hippel-Lindau ubiquitin E3 ligase and destruction by the ubiquitin-proteasome pathways. Asparaginyl hydroxylation blocks the recruitment of p300/CBP co-activators to a C-terminal activation domain in HIF-α. These hydroxylations are catalyzed by members of the Fe(II) and 2-oxoglutarate (2-OG) oxygenase family. Activity of the enzymes is suppressed by hypoxia, increasing both the abundance and activity of the HIF transcriptional complex. We have used hydroxy residue-specific antibodies to compare and contrast the regulation of each site of prolyl hydroxylation (Pro(402), Pro(564)) with that of asparaginyl hydroxylation (Asn(803)) in human HIF-1α. Our findings reveal striking differences in the sensitivity of these hydroxylations to hypoxia and to different inhibitor types of 2-OG oxygenases. Hydroxylation at the three sites in endogenous human HIF-1α proteins was suppressed by hypoxia in the order Pro(402) > Pro(564) > Asn(803). In contrast to some predictions from in vitro studies, prolyl hydroxylation was substantially more sensitive than asparaginyl hydroxylation to inhibition by iron chelators and transition metal ions; studies of a range of different small molecule 2-OG analogues demonstrated the feasibility of selectively inhibiting either prolyl or asparaginyl hydroxylation within cells.