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Determining the cell fate and the distribution of mesenchymal stromal/stem cells (MSCs) after transplantation are essential parts of characterizing the mechanisms of action and biosafety profile of stem cell therapy. Many recent studies have shown that MSCs migrate into injured tissues, but are only detectable at extremely low frequencies. We investigated the cell fate of MSCs after transplantation in an acute kidney injury (AKI) mouse model using in vivo bioluminescence imaging (BLI) and subsequent verification of cell migration using quantitative real-time polymerase chain reaction (qRT-PCR). The AKI was induced by a single injection of cisplatin (8 or 12 mg/kg). One day later, adipose-derived mesenchymal stromal/stem cells isolated from luciferase transgenic mice (Luc+-mASCs, 5 × 105) were intravenously transplanted. Migration kinetics of the cells was monitored using BLI on day 1, 3, and 6, and finally via quantitative real-time PCR at the endpoint on day 6. Using BLI, infused Luc+-mASCs could only be detected in the lungs, but not in the kidneys. In contrast, PCR endpoint analysis revealed that Luc-specific mRNA could be detected in injured renal tissue; compared to the control group, the induction was 2.2-fold higher for the 8 mg/kg cisplatin group (p < 0.05), respectively 6.1-fold for the 12 mg/kg cisplatin group (p < 0.001). In conclusion, our study demonstrated that Luc-based real-time PCR rather than BLI is likely to be a better tool for cell tracking after transplantation in models such as cisplatin-induced AKI.
Introduction Impaired renal function and/or pre-existing atherosclerosis in the deceased donor increase the risk of delayed graft function and impaired long-term renal function in kidney transplant recipients. Case presentation We report delayed graft function occurring simultaneously in two kidney transplant recipients, aged 57-years-old and 39-years-old, who received renal allografts from the same deceased donor. The 62-year-old donor died of cardiac arrest during an asthmatic state. Renal-allograft biopsies performed in both kidney recipients because of delayed graft function revealed cholesterol-crystal embolism. An empiric statin therapy in addition to low-dose acetylsalicylic acid was initiated. After 10 and 6 hemodialysis sessions every 48 hours, respectively, both renal allografts started to function. Glomerular filtration rates at discharge were 26 ml/min/1.73 m2 and 23.9 ml/min/1.73 m2, and remained stable in follow-up examinations. Possible donor and surgical procedure-dependent causes for cholesterol-crystal embolism are discussed. Conclusion Cholesterol-crystal embolism should be considered as a cause for delayed graft function and long-term impaired renal allograft function, especially in the older donor population.
Introduction: Prognosis of survivors from cardiac arrest is generally poor. Acute kidney injury (AKI) is a common finding in these patients. In general, AKI is well characterized as a marker of adverse outcome. In-hospital cardiac arrest (IHCA) represents a special subset of cardiac arrest scenarios with differential predisposing factors and courses after the event, compared to out-of-hospital resuscitations. Data about AKI in survivors after in-hospital cardiac arrest are scarce. Methods: In this study, we retrospectively analyzed patients after IHCA for incidence and risk factors of AKI and its prognostic impact on mortality. For inclusion in the analysis, patients had to survive at least 48 h after IHCA. Results: A total of 238 IHCA events with successful resuscitation and survival beyond 48 h after the initial event were recorded. Of those, 89.9% were patients of internal medicine, and 10.1% of patients from surgery, neurology or other departments. In 120/238 patients (50.4%), AKI was diagnosed. In 28 patients (23.3%), transient or permanent renal replacement therapy had to be initiated. Male gender, preexisting chronic kidney disease and a non-shockable first ECG rhythm during resuscitation were significantly associated with a higher incidence of AKI in IHCA-survivors. In-hospital mortality in survivors from IHCA without AKI was 29.7%, and 60.8% in patients after IHCA who developed AKI (p < 0.01 between groups). By multivariate analysis, AKI after IHCA persisted as an independent predictor of in-hospital mortality (HR 3.7 (95% CI 2.14–6.33, p ≤ 0.01)). Conclusion: In this cohort of survivors from IHCA, AKI is a frequent finding, with adverse impact on outcome. Therefore, therapeutic strategies to prevent AKI in post-IHCA patients are warranted.
Paricalcitol is approved for prevention and therapy of secondary hyperparathyroidism (sHPT) in patients with chronic kidney disease (CKD), with only short-term data in clinical routine settings. A 12-month observational study was conducted in Germany and Austria (90 centers, 761 patients) from 2008 to 2013. Laboratory values, demographical, and clinical data were documented in 629 dialysis patients and 119 predialysis patients. In predialysis patients, median intact parathormone (iPTH) was 180.0 pg/mL (n = 105) at the start of the study, 115.7 pg/mL (n = 105) at last documentation, and 151.8 pg/mL (n = 50) at month 12, with 32.4% of the last documented iPTH values in the KDOQI (Kidney Disease Outcomes Quality Initiative) target range. In dialysis patients, median iPTH was 425.5 pg/mL (n = 569) at study start, 262.3 pg/mL (n = 569) at last documentation, and 266.1 pg/mL (n = 318) at month 12, with 36.5% of dialysis patients in the KDOQI target range. Intravenous paricalcitol showed more homogenous iPTH control than oral treatment. Combined analysis of all dialysis patients indicated comparable and stable mean serum calcium and phosphate levels throughout the study. Clinical symptoms, such as itching, bone pain, and fatigue, were improved compared with study entry. The spectrum and frequency of adverse events mirrored the known pattern for patients on dialysis. Paricalcitol is efficacious and has a consistent safety profile in sHPT over 12 months.
Background: Kidney transplant recipients (KTR) reflect a high-risk population for coronary artery disease (CAD). CAD is the most common cause for morbidity and mortality in this population. However, only few data are available on the favourable revascularization strategy for these patients as they were often excluded from studies and not mentioned in guidelines.
Methods: This retrospective single-centre study includes patients with a history of kidney transplantation undergoing myocardial revascularization for multivessel or left main CAD by either percutaneous coronary intervention (PCI, n = 27 patients) or coronary artery bypass grafting (CABG, n = 24 patients) at University Hospital Frankfurt, Germany, between 2005 and 2015.
Results: In-hospital mortality was higher in the CABG group (20.8% vs. 14.8% PCI group; p = 0.45). In Kaplan-Meier analysis, one-year-survival showed better outcome in the PCI group (85.2% vs. 75%). After four years, outcome was comparable between both strategies (PCI 66.5% vs. CABG 70.8%; log-rank p = 0.94).
Acute kidney injury (AKI), classified by Acute Kidney Injury Network, was observed more frequently after CABG (58.3% vs. 18.5%; p < 0.01). After one year, graft survival was 95.7% in the PCI group and 94.1% in the CABG group. Four year follow-up showed comparable graft survival in both groups (76.8% PCI and 77.0% CABG; p = 0.78).
Conclusion: In this retrospective single-centre study of KTR requiring myocardial revascularization, PCI seems to be superior to CABG with regard to in-hospital mortality, acute kidney injury and one-year-survival. To optimise treatment of these high-risk patients, larger-scaled studies are urgently warranted.
Acute kidney injury is associated with mortality in COVID-19 patients. However, host cell changes underlying infection of renal cells with SARS-CoV-2 remain unknown and prevent understanding of the molecular mechanisms that may contribute to renal pathology. Here, we carried out quantitative translatome and whole-cell proteomics analyses of primary renal proximal and distal tubular epithelial cells derived from human donors infected with SARS-CoV-2 or MERS-CoV to disseminate virus and cell type–specific changes over time. Our findings revealed shared pathways modified upon infection with both viruses, as well as SARS-CoV-2-specific host cell modulation driving key changes in innate immune activation and cellular protein quality control. Notably, MERS-CoV infection–induced specific changes in mitochondrial biology that were not observed in response to SARS-CoV-2 infection. Furthermore, we identified extensive modulation in pathways associated with kidney failure that changed in a virus- and cell type–specific manner. In summary, we provide an overview of the effects of SARS-CoV-2 or MERS-CoV infection on primary renal epithelial cells revealing key pathways that may be essential for viral replication.
Background/Aims: Middle East respiratory syndrome coronavirus (MERS-CoV) and Marburg virus (MARV) are among the World Health Organization’s top 8 emerging pathogens. Both zoonoses share nonspecific early symptoms, a high lethality rate, and a reduced number of specific treatment options. Therefore, we evaluated extracorporeal virus and glycoprotein (GP) elimination by lectin affinity plasmapheresis (LAP).
Methods: For both MERS-CoV (pseudovirus) as well as MARV (GPs), 4 LAP devices (Mini Hemopurifiers, Aethlon Medical, San Diego, CA, USA) and 4 negative controls were tested. Samples were collected every 30 min and analyzed for reduction in virus infectivity by a flow cytometry-based infectivity assay (MERS-CoV) and in soluble GP content (MARV) by an immunoassay.
Results: The experiments show a time-dependent clearance of MERS-CoV of up to 80% within 3 h (pseudovirus). Up to 70% of MARV-soluble GPs were eliminated at the same time. Substantial saturation of the binding resins was detected within the first treatment hour.
Conclusion: MERS-CoV (pseudovirus) and MARV soluble GPs are eliminated by LAP in vitro. Considering the high lethality and missing established treatment options, LAP should be evaluated in vivo. Especially early initiation, continuous therapy, and timed cartridge exchanges could be of importance.
Highligthts
• Marburg virus infects and replicates in primary human proximal tubular cells (PTC).
• Transcriptome analyses at multiple time points revealed a profound inflammatory response by IFNα, -y and TNFα signaling.
• Among the strongly downregulated gene sets were targets of the transcription factors MYC and E2F, the G2M checkpoint, as well as oxidative phosphorylation.
• Importantly, the downregulated factors comprise PGC-1α, a key factor in mitochondrial biogenesis and renal energy homeostasis, to be substantially downregulated in MARV-infected PTC.
• Our results suggest inflammation-induced changes in tubular energy metabolism as a possible factor in MARV-associated tubular dysfunction.
Abstract
Marburg virus, a member of the Filoviridae, is the causative agent of Marburg virus disease (MVD), a hemorrhagic fever with a case fatality rate of up to 90 %. Acute kidney injury is common in MVD and is associated with increased mortality, but its pathogenesis in MVD remains poorly understood. Interestingly, autopsies show the presence of viral proteins in different parts of the nephron, particularly in proximal tubular cells (PTC). These findings suggest a potential role for the virus in the development of MVD-related kidney injury. To shed light on this effect, we infected primary human PTC with Lake Victoria Marburg virus and conducted transcriptomic analysis at multiple time points. Unexpectedly, infection did not induce marked cytopathic effects in primary tubular cells at 20 and 40 h post infection. However, gene expression analysis revealed robust renal viral replication and dysregulation of genes essential for different cellular functions. The gene sets mainly downregulated in PTC were associated with the targets of the transcription factors MYC and E2F, DNA repair, the G2M checkpoint, as well as oxidative phosphorylation. Importantly, the downregulated factors comprise PGC-1α, a well-known factor in acute and chronic kidney injury. By contrast, the most highly upregulated gene sets were those related to the inflammatory response and cholesterol homeostasis. In conclusion, Marburg virus infects and replicates in human primary PTC and induces downregulation of processes known to be relevant for acute kidney injury as well as a strong inflammatory response.
Cell-free therapy using extracellular vesicles (EVs) from adipose-derived mesenchymal stromal/stem cells (ASCs) seems to be a safe and effective therapeutic option to support tissue and organ regeneration. The application of EVs requires particles with a maximum regenerative capability and hypoxic culture conditions as an in vitro preconditioning regimen has been shown to alter the molecular composition of released EVs. Nevertheless, the EV cargo after hypoxic preconditioning has not yet been comprehensively examined. The aim of the present study was the characterization of EVs from hypoxic preconditioned ASCs. We investigated the EV proteome and their effects on renal tubular epithelial cells in vitro. While no effect of hypoxia was observed on the number of released EVs and their protein content, the cargo of the proteins was altered. Proteomic analysis showed 41 increased or decreased proteins, 11 in a statistically significant manner. Furthermore, the uptake of EVs in epithelial cells and a positive effect on oxidative stress in vitro were observed. In conclusion, culture of ASCs under hypoxic conditions was demonstrated to be a promising in vitro preconditioning regimen, which alters the protein cargo and increases the anti-oxidative potential of EVs. These properties may provide new potential therapeutic options for regenerative medicine.
Hintergrund: Die chronische metabolischen Azidose (cmA) ist eine häufige Komplikation bei chronischer Niereninsuffizienz, deren Behandlung bei niereninsuffizienten Patienten mit Diabetes mellitus die Insulinresistenz verbessern kann. Um die aktuelle Therapiesituation der cmA im diabetologischen Umfeld abzubilden und mehr über die Zusammenarbeit von Diabetologen und Nephrologen zu erfahren, wurden diabetologisch tätige Haus- und Fachärzte zur cmA befragt.
Methoden An 5863 Ärzten mit diabetologischer Zusatzqualifikation wurde postalisch ein Fragebogen versandt. Alle 97 erhaltenen Antwortbögen wurden deskriptiv ausgewertet.
Ergebnisse Die meisten Teilnehmer sind Internisten mit diabetologischer Zusatzqualifikation (46 %) und behandeln im Median 50 (10; 112) Patienten mit Typ-1-Diabetes bzw. 210 (100; 450) Patienten mit Typ-2-Diabetes pro Quartal. Eine cmA wurde von 12 % der Teilnehmer in den letzten 12 Monaten bei median 4 (2; 6) Patienten mit Typ-1-Diabetes und 10 (3; 30) Patienten mit Typ-2-Diabetes beobachtet. Die cmA wird überwiegend durch Bestimmung des Serum-Bikarbonats (27; 28 %) und des Base Excess (19; 20 %) diagnostiziert. 38 (39 %) der Teilnehmer erhalten regelmäßig von Nephrologen die Empfehlung zur Behandlung der cmA. Sie wird von knapp 1 Drittel als relevant (29 %) und gut umsetzbar (27 %) betrachtet. Zur Behandlung der cmA wird vor allem orales Bikarbonat empfohlen (Bikarbonat: 39 %, Zitrat: 5 %, sonst: keine Angabe). Maßnahmen, die die Mehrheit der Diabetologen in der Verantwortung der Nephrologen sehen, sind ergänzende Diagnostik (87; 90 %) einschließlich Blutgasanalyse (59 %) sowie die Behandlung der cmA (62 %) und renalen Anämie (53 %). 34 % der Diabetologen gaben an, bisher noch keine cmA-Fälle in der Praxis behandelt zu haben. Die meisten Diabetologen überlassen die Behandlung und Überwachung der cmA dem Nephrologen (38 %). Dabei wird die Zusammenarbeit mit den Nephrologen als zufriedenstellend (81 %) bewertet. 38 % der Befragten haben in der täglichen Praxis beobachtet, dass die Einstellung der cmA auch die Insulinresistenz positiv beeinflusst. Eine CME-Fortbildung in der Diabetologie speziell zur cmA würden 76 (78 %) begrüßen.
Diskussion Bei der Behandlung der cmA wird die Kooperation zwischen Diabetologen und Nephrologen generell gut bewertet, wobei die Diagnose, Behandlung und Überwachung einer cmA in der Verantwortung des Nephrologen gesehen werden. Da die Behandlung der cmA die Insulinresistenz verringern kann, sollte der Stellenwert der cmA-Therapie im diabetologischen Umfeld nicht unterschätzt werden. Um die cmA-Behandlung bei diabetischer Nephropathie zu optimieren, wären CME-Fortbildungen zur cmA geeignet. Zudem könnten Schulungen im Rahmen einer interdisziplinären Kooperation mit Diätberatern die Umsetzbarkeit diätetischer Interventionen zur Behandlung der cmA verbessern.