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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.

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.

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.

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.

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.

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.

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.

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.

Long-term survival of renal allografts depends on the chronic immune response and is probably influenced by the initial injury caused by ischemia and reperfusion. Hypoxia-inducible transcription factors (HIFs) are essential for adaptation to low oxygen. Normoxic inactivation of HIFs is regulated by oxygen-dependent hydroxylation of specific prolyl-residues by prolyl-hydroxylases (PHDs). Pharmacological inhibition of PHDs results in HIF accumulation with subsequent activation of tissue-protective genes. We examined the effect of donor treatment with a specific PHD inhibitor (FG-4497) on graft function in the Fisher–Lewis rat model of allogenic kidney transplantation (KTx). Orthotopic transplantation of the left donor kidney was performed after 24 h of cold storage. The right kidney was removed at the time of KTx (acute model) or at day 10 (chronic model). Donor animals received a single dose of FG-4497 (40 mg/kg i.v.) or vehicle 6 h before donor nephrectomy. Recipients were followed up for 10 days (acute model) or 24 weeks (chronic model). Donor preconditioning with FG-4497 resulted in HIF accumulation and induction of HIF target genes, which persisted beyond cold storage. It reduced acute renal injury (serum creatinine at day 10: 0.66 ± 0.20 vs. 1.49 ± 1.36 mg/dL; P < 0.05) and early mortality in the acute model and improved long-term survival of recipient animals in the chronic model (mortality at 24 weeks: 3 of 16 vs. 7 of 13 vehicle-treated animals; P < 0.05). In conclusion, pretreatment of organ donors with FG-4497 improves short- and long-term outcomes after allogenic KTx. Inhibition of PHDs appears to be an attractive strategy for organ preservation that deserves clinical evaluation.

The association of acute heart and kidney dysfunction and is enormous role for the patients' morbidity is growingly appreciated. ”Acute kidney injury” (AKI) has been newly defined in the last years and has been identified to be an independent risk factor for mortality. AKI has a mortality of about 50% and can be as high as 70% when it is associated with severe sepsis or septic shock. In this review we summarize the new concept of AKI, the cardiorenal syndrome, its pathophysiological background and current therapeutic strategies in particular for patients in the cardiology department.

Background New renal biomarkers measured in urine promise to increase specificity for risk stratification and early diagnosis of acute kidney injury (AKI) but concomitantly may be altered by urine concentration effects and chronic renal insufficiency. This study therefore directly compared the performance of AKI biomarkers in urine and plasma. Methods This single-center, prospective cohort study included 110 unselected adults undergoing cardiac surgery with cardiopulmonary bypass between 2009 and 2010. Plasma and/or urine concentrations of creatinine, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), liver fatty acid-binding protein (L-FABP), kidney injury molecule 1 (KIM1), and albumin as well as 15 additional biomarkers in plasma and urine were measured during the perioperative period. The primary outcome was AKI defined by AKIN serum creatinine criteria within 72 hours after surgery. Results Biomarkers in plasma showed markedly better discriminative performance for preoperative risk stratification and early postoperative (within 24h after surgery) detection of AKI than urine biomarkers. Discriminative power of urine biomarkers improved when concentrations were normalized to urinary creatinine, but urine biomarkers had still lower AUC values than plasma biomarkers. Best diagnostic performance 4h after surgery had plasma NGAL (AUC 0.83), cystatin C (0.76), MIG (0.74), and L-FAPB (0.73). Combinations of multiple biomarkers did not improve their diagnostic power. Preoperative clinical scoring systems (EuroSCORE and Cleveland Clinic Foundation Score) predicted the risk for AKI (AUC 0.76 and 0.71) and were not inferior to biomarkers. Preexisting chronic kidney disease limited the diagnostic performance of both plasma and urine biomarkers. Conclusions In our cohort plasma biomarkers had higher discriminative power for risk stratification and early diagnosis of AKI than urine biomarkers. For preoperative risk stratification of AKI clinical models showed similar discriminative performance to biomarkers. The discriminative performance of both plasma and urine biomarkers was reduced by preexisting chronic kidney disease.

Activation of hypoxia-inducible transcription factor (HIF) has been identified as an important mechanism of cellular adaptation to low oxygen. Normoxic degradation of HIF is mediated by oxygen-dependent hydroxylation of specific prolyl residues of the regulative alpha-subunits by HIF prolyl hydroxylases (PHD). It was hypothesized that inhibition of HIF degradation by either hypoxia or pharmacologic inhibition of PHD would confer protection against subsequent ischemic injury. For testing this hypothesis ischemic acute renal failure was induced in rats by 40 min of clamping of the left renal artery after right-sided nephrectomy. Before surgery, pretreatment with either carbon monoxide, leading to tissue hypoxia, or the novel PHD inhibitor FG-4487 was applied. No toxic effects of FG-4487 were observed. Both pretreatments strongly induced the accumulation of HIF-1alpha and HIF-2alpha in tubular and peritubular cells, respectively, as well as HIF target gene expression. The course of subsequent ischemic injury was significantly ameliorated by both strategies of preconditioning, as evident from a significant improvement of serum creatinine and serum urea after 24 and 72 h. Furthermore, tissue injury and apoptosis were less severe, which were quantified by application of a standardized histologic scoring system in a blinded manner. In conclusion, the data provide proof of principle that preconditional activation of the HIF system protects against ischemic injury. Inhibiting the activity of HIF hydroxylases therefore seems to have considerable clinical perspectives.

Several genetically modified mouse models implicated that prolyl-4-hydroxylase domain (PHD) enzymes are critical mediators for protecting tissues from an ischemic insult including myocardial infarction by affecting the stability and activation of hypoxia-inducible factor (HIF)-1 and HIF-2. Thus, the current efforts to develop small-molecule PHD inhibitors open a new therapeutic option for myocardial tissue protection during ischemia. Therefore, we aimed to investigate the applicability and efficacy of pharmacological HIFα stabilization by a small-molecule PHD inhibitor in the heart. We tested for protective effects in the acute phase of myocardial infarction after pre- or post-conditional application of the inhibitor. Application of the specific PHD inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA) resulted in HIF-1α and HIF-2α accumulation in heart muscle cells in vitro and in vivo. The rapid and robust responsiveness of cardiac tissue towards ICA was further confirmed by induction of the known HIF target genes heme oxygenase-1 and PHD3. Pre- and post-conditional treatment of mice undergoing myocardial infarction resulted in a significantly smaller infarct size. Tissue protection from ischemia after pre- or post-conditional ICA treatment demonstrates that there is a therapeutic time window for the application of the PHD inhibitor (PHI) post-myocardial infarction, which might be exploited for acute medical interventions.

An inflammatory stimulus prior to an ischemic insult can be protective in acute kidney injury (AKI) as well as other acute organ injury models, an effect called cross-tolerance. He et al. investigated mechanisms of cross-tolerance whereby pretreatment with lipopolysaccharide (LPS) protects from a subsequent ischemic insult of the kidney. The protection was mediated by LPS-induced nuclear factor-κB and hypoxia-inducible factor-2α (HIF-2α) signaling. These results link two central cellular pathways and give new insight into HIF-mediated renoprotection in AKI models.

Background. Inhibition of the HIF regulating prolyl hydroxylation domain (PHDs) proteins prior to renal injury (preconditioning) has been shown to protect the kidney via activation of hypoxia-inducible transcription factors (HIF). Application of erythropoietin (EPO), one of the HIF target genes, has also been shown to be nephroprotective, and it remains unclear to what extent the effect of HIF induction is mediated by EPO. It is also unknown whether HIF activation after the onset of ischaemia (postconditioning) is still able to protect the kidney. Methods. Using a rat model of renal ischaemia–reperfusion injury, animals were treated with the PHD inhibitor (PHD-I) 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA), vehicle (Veh) or recombinant human EPO (300 IU/ kg) 6 h (ICA or Veh) or 30 min (EPO) prior to ischaemia (preconditioning) or with ICA prior to reperfusion (postconditioning). Renal function was assessed at baseline, 24 h and 72 h. After 72 h, kidneys were processed for histology and morphometric analysis. HIF immunohistochemistry and real-time polymerase chain reaction for HIF target genes, including EPO, were performed to evaluate ICA effects. Results. ICA treatment resulted in stabilization of HIF-1a and -2a and up-regulation of HIF target genes in a dosedependent manner. Preconditional activation of HIF by ICA significantly improved serum creatinine levels and renal morphology in comparison to Veh (P < 0.05), while postconditional ICA treatment was ineffective. EPO therapy improved tissue morphology but had no impact on the course of serum creatinine. Conclusion. These findings are in line with the concept that PHD-Is exert their protective effects through accumulation of HIF target gene products, with time requirements for increased transcription and translation of HIF-dependent genes, and suggest that their renoprotective effect is not predominately mediated by EPO.

In recent years the interference of heart and kidney disease has increasingly found attention in basic science and clinical research. A new classification of cardiorenal syndromes has now been proposed to address acute and chronic heart or kidney disease with its consequences on the respective other organ. However, it also becomes clear that the different clinical cardiorenal syndromes share common pathways. These basically include activation of the renin angiotensin system and of the sympathetic nervous system, but also inflammation, fibrosis, and accelerated atherosclerosis. These factors eventually support generation of oxidative stress and tissue hypoxia in the kidney and heart, culminating in irreversible tissue damage and aggravation of organ ischemia. This chapter summarizes aspects of the cardiorenal connection and oxygenation imbalances.

Acute kidney injury remains a major clinical problem associated with poor patient outcome and therapeutic options are still limited. The transcription of hypoxia-inducible factors (HIF) is a key regulator of the cellular response to hypoxia. Far more than 100 HIF target genes have been identified, including genes that have been demonstrated to protect the kidney. Although renal cells have a broad capacity to activate HIF, HIF is only sporadically stabilized in cases of acute renal injury and therefore protective effects may be limited. Newly identified inhibitors of the oxygen-sensing HIF-prolyl-hydroxylases now offer the possibility to pharmacologically stabilize HIF independent of oxygen prior to a renal insult in order to achieve protection. Thus, HIF activation appears as a promising therapeutic target for the prevention of acute kidney injury.

The contribution of hypoxia to cisplatin-induced renal tubular injury is controversial. Because the hypoxia-inducible factor (HIF) pathway is a master regulator of adaptation to hypoxia, we measured the effects of cisplatin on HIF accumulation in vitro and in vivo, and tested whether hypoxic preconditioning is protective against cisplatin-induced injury. We found that cisplatin did not stabilize HIF-1alpha protein in vitro or in vivo under normoxic conditions. However, hypoxic preconditioning of cisplatin-treated proximal tubular cells in culture reduced apoptosis in an HIF-1alpha-dependent fashion and increased cell proliferation as measured by BrdU incorporation. In vivo, rats preconditioned with carbon monoxide before cisplatin administration had significantly better renal function than rats kept in normoxic conditions throughout. Moreover, the histomorphological extent of renal damage and tubular apoptosis was reduced by the preconditional treatment. Therefore, development of pharmacologic agents to induce renal HIF might provide a new approach to ameliorate cisplatin-induced nephrotoxicity.

To investigate whether plasma concentrations of soluble intercellular cell adhesion molecule (ICAM)-1 and L-selectin at 24 hrs of life are related to good or poor response to exogenous surfactant in preterm infants.Prospective study of markers of inflammation in circulating blood at 24 hrs of life.Level III neonatal intensive care unit.Twenty-nine preterm newborns suffering from severe respiratory distress syndrome (Fio(2)0.4) without signs of infection or fetal acidosis, and 17 healthy preterm newborns of similar gestational age serving as controls.Infants with respiratory distress were treated with natural surfactant at 0.3-5 hrs of life. A response to surfactant, defined as a decrease of Fio(2)50% within 6 hrs after surfactant, was seen in 21 infants.Soluble ICAM-1 and L-selectin concentrations were determined in plasma samples taken at 24 hrs of age. ICAM-1 was elevated (p.001) in infants who responded poorly to surfactant (median, 392 ng/mL; range, 58.26-4884.24 ng/mL) compared with good responders (20.52 ng/mL, 2.32-138.58 ng/mL) or controls (21.91 ng/mL, 2.61-65.73 ng/mL), without differences between controls and good responders. L-selectin was lower (p =.004) in surfactant-treated infants (4.45 nmol/L, 2.0-10.4 ng/mL) than in controls (6.0/2.35-10.25 nmol/L) without differences between surfactant good and poor responders. However, infants requiring supplemental oxygen at 36 wks of gestational age had reduced L-selectin at 24 hrs of age (3.2/2.0-3.45 vs. 5.0/2.35-10.4 nmol/L, p =.004), whereas there was no difference in ICAM-1.In preterm infants with respiratory distress, a poor response to surfactant within 6 hrs of administration is associated with elevated circulating ICAM-1 concentrations at 24 hrs of age. Low plasma L-selectin at 24 hrs of age predicts prolonged requirement for supplemental oxygen.

Purpose: This study involved a prospective evaluation of the reliability of sonography, and especially duplex sonography, in confirmation of the benign nature of enlarged cervical lymph nodes. Patients and Methods: In 53 untreated patients with enlarged cervical lymph nodes, B-mode, plain, and d-galactose-enhanced color duplex sonography were performed. The B-mode sonomorphology was analyzed for the structure of vascularization. Quantitative parameters such as maximum flow velocity, pulsatility index, and resistive index were also assessed. The benignity of the lymph nodes was confirmed by microscopic analysis. Results: The B-mode showed 20 homogeneous lymph nodes, 23 with a central echogenoic line covering less than one third, and 10 with a distinct hilus sign extending to more than one third of the lymph node diameter. Microscopically, the least fibrotic or chronic inflammatory changes in the parenchyma were observed in the homogeneous lymph nodes, whereas those with central echogeneoity had fibrotic and lipoid hilus changes. Histologically, all lymph nodes had normal afferent and efferent hilus vessels. In 37 lymph nodes, the vessel structure could be reliably visualized by both plain and enhanced color duplex sonography, whereas in 16 it could only be demonstrated after the use of signal enhancement. Nine of 53 lymph nodes had Solbiati-(L/T-) indices below 2, which were suggestive of malignancy. Quantitative flow parameters did not provide useful information. Conclusion: Color duplex analysis of enlarged lymph nodes is a useful method for assessment of benignity, especially after application of a signal-enhancing agent.

Rationale and objectives A prospective study in signal-enhanced Doppler sonography of lymph nodes that were assumed pretherapeutically to be benign was performed to investigate characteristic sonomorphologic features and vascularity of reactively enlarged lymph nodes. Methods Thirty-four patients with enlarged superficial lymph nodes of the neck were examined first by B-scan sonography then by Doppler sonography before and after administration of an ultrasound signal-enhancing agent. In B-scan sonography, lymph nodes were classified into three groups according to their sonomorphologic features: (1) homogeneous parenchyma, (2) a centrally located echogenoic line, and (3) a echogenoic "hilus reflex." In conventional and contrast-enhanced Doppler sonography, peak flow rate, pulsatility index, and resistive index were assessed. Sonomorphologic criteria were compared with histologic findings. Results Reactively enlarged lymph nodes showed characteristic sonomorphologic patterns correlating to their histologic features. Echogenicity of the hilus corresponded to fibrosis (centrally located echogenoic line in 13 nodes; 38.2%) or fatty involution of the hili (echogenoic hilus reflex in 15 nodes; 44.1%). Administration of the galactose-based ultrasound contrast enhancer facilitated the assessment of hilar vessels, which projected to the echogenoic hili, respectively, actually additionally visualized a hilar vascularity in 10 of the 34 lymph nodes compared with conventional Doppler. Measured Doppler indices gave not a significant clue for identifying reactive lymph nodes or for differential diagnosis. Conclusions Qualitative sonomorphologic assessment of characteristic sonomorphologic features of reactive lymph nodes may serve as a valuable tool for examining reactively enlarged lymph nodes. Administration of an ultrasound echo enhancer allows the assessment of a characteristic nodal vascularity in reactive lymph nodes and were superior to conventional B-mode and conventional Doppler sonography.

The authors conducted a prospective study in D-galactose signal-enhanced Doppler sonography of lymph nodes to investigate new aspects in differentiating malignant from reactive lymph nodes of patients with suspected malignancy of the neck.Twenty-one patients with suspected squamous epithelial cell carcinoma metastases of the neck were examined by Doppler sonography before and after administration of an ultrasound signal-enhancing agent, consisting of D-galactose microbubbles. Qualitative sonomorphology, peak flow rates, and pulsatility and resistive indices were assessed.Compared with conventional Doppler, enhanced Doppler sonography gave detailed additional information about vascularization of metastases or reactive lymph nodes. Signal-enhanced Doppler of metastases showed a relatively characteristic pattern of vascularity, therefore facilitating differential diagnoses and allowing better discrimination from surrounding tissue, demonstrated by the infiltration of neighboring vessels in the neck. Concerning reactive lymph nodes, vascularization could be stated and measured in many cases only after signal enhancement. Evaluating peak velocities and pulsatility and resistive indices could not differentiate significantly malignant from reactive lymph nodes.Administration of a D-galactose-based signal-enhancer helps to differentiate malignant from reactive lymph nodes of the neck. It is superior to conventional Doppler by improving evaluation of the vascularity and could be of use for staging procedures.

Introduction Lung-protective ventilation in patients with ARDS and multiorgan failure, including renal failure, is often paralleled with a combined respiratory and metabolic acidosis. We assessed the effectiveness of a hollow-fiber gas exchanger integrated into a conventional renal-replacement circuit on CO2 removal, acidosis, and hemodynamics. Methods In ten ventilated critically ill patients with ARDS and AKI undergoing renal- and respiratory-replacement therapy, effects of low-flow CO2 removal on respiratory acidosis compensation were tested by using a hollow-fiber gas exchanger added to the renal-replacement circuit. This was an observational study on safety, CO2-removal capacity, effects on pH, ventilator settings, and hemodynamics. Results CO2 elimination in the low-flow circuit was safe and was well tolerated by all patients. After 4 hours of treatment, a mean reduction of 17.3 mm Hg (−28.1%) pCO2 was observed, in line with an increase in pH. In hemodynamically instable patients, low-flow CO2 elimination was paralleled by hemodynamic improvement, with an average reduction of vasopressors of 65% in five of six catecholamine-dependent patients during the first 24 hours. Conclusions Because no further catheters are needed, besides those for renal replacement, the implementation of a hollow-fiber gas exchanger in a renal circuit could be an attractive therapeutic tool with only a little additional trauma for patients with mild to moderate ARDS undergoing invasive ventilation with concomitant respiratory acidosis, as long as no severe oxygenation defects indicate ECMO therapy.