The Role of Collagen VIII in the Aging Mouse Kidney.

The gradual loss of kidney function due to increasing age is accompanied by structural changes such as fibrosis of the tissue. The underlying molecular mechanisms are complex, but not yet fully understood. Non-fibrillar collagen type VIII (COL8) could be a potential factor in the fibrosis processes of the aging kidney. A pathophysiological significance of COL8 has already been demonstrated in the context of diabetic kidney disease, with studies showing that it directly influences both the development and progression of renal fibrosis occurring. The aim of this study was to investigate whether COL8 impacts age-related micro-anatomical and functional changes in a mouse model. The kidneys of wild-type (Col8-wt) and COL8-knockout (Col8-ko) mice of different age and sex were characterized with regard to the expression of molecular fibrosis markers, the development of nephrosclerosis and renal function. The age-dependent regulation of COL8 mRNA expression in the wild-type revealed sex-dependent effects that were not observed with collagen IV (COL4). Histochemical staining and protein analysis of profibrotic cytokines TGF-ß1 (transforming growth factor) and CTGF (connective tissue growth factor) in mouse kidneys showed significant age effects as well as interactions of the factors age, sex and Col8 genotype. There were also significant age and Col8 genotype effects in the renal function data analyzed by urinary cystatin C. In summary, the present study shows, for the first time, that COL8 is regulated in an age- and sex-dependent manner in the mouse kidney and that the expression of COL8 influences the severity of age-induced renal fibrosis and function.

Enhancing student understanding of rheumatic disease pathologies through augmented reality: findings from a multicentre trial.

OBJECTIVE: The possibility of combining real and virtual environments is driving the increased use of augmented reality (AR) in education, including medical training. The aim of this multicentre study was to evaluate the students' perspective on the AR-based Rheumality GO!® app as a new teaching concept, presenting six real anonymised patient cases with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA). METHODS: The study encompassed 347 undergraduate medical students (232 women and 115 men) from four medical universities in Germany (Jena, Bad Nauheim/Gießen, Nuremberg, Erlangen). The course was divided into a theoretical refresher lecture followed by six AR-based cases in each of the three indications presented in the Rheumality GO!® app. All participants evaluated the course after completion, assessing the benefit of the app from a student´s perspective using a questionnaire with 16 questions covering six subject areas. RESULTS: The use of the AR-based app Rheumality GO!® improved the understanding of pathologies in RA, PsA, and axSpA for 99% of the participants. For 98% of respondents, the concept of AR with real patient data has made a positive impact on the teaching environment. On the other hand, 82% were in favour of the use of virtual tools (e.g. AR) in addition to this conventional approach. CONCLUSION: The results of our survey showed that from medical students' perspective, an AR-based concept like the Rheumality GO!® app can complement rheumatology teaching in medical school as an effective and attractive tool though not replace bedside teaching.

Are Richard Wagner's operas a potential tool to teach medical students and young doctors humanities?

There is an increasing interest in using poems and novels as a powerful resource to teach medical students ethical and professional behavior, virtues, and to illustrate the complexity of the doctor-patient relationship. This approach as part of a narrative medicine provides a framework for approaching a patient's problems more holistically and also offers a method for addressing existential inner qualities such as grief, hope, and despair that are part of illnesses. Occasionally, operas (mainly Italian) have also been used for this purpose. I however, propose that medical students may learn a lot from a deeper confrontation with the operas from the German composer Richard Wagner (1813-1883). Certainly, Wagner had a rather self-centered personality, also known for his notorious nationalistic and anti-Semitic essays, but his complete Gesamtkunstwerk (total work of art) encompasses almost every human feeling, conflict, and psychological problem including suffering, compassion, redemption, etc. Wagner's opera somewhat reflected his unsteady life. Wagner was convinced that his art could fill the void left by the retreat of traditional religion, suggesting that humanity may achieve freedom through the perception of beauty uniting communities through shared aesthetic experience. Not a very modest approach and not a very likable character, but a great composer. After a short biography, I will provide some (because of the complexity of the subject, naturally limited) arguments on what medical students can learn from Wagner operas, even though I am convinced that Wagner and his music are not easy to digest, even for experienced opera lovers.

[Is JAK inhibition an option in the treatment of interstitial lung disease in rheumatoid arthritis?] / Ist JAK-Hemmung eine Option in der Behandlung der interstitiellen Lungenerkrankung bei einer rheumatoiden Arthritis?

A 69-year-old male patient with seropositive erosive rheumatoid arthritis (RA) presented to our clinic due to progressive dyspnea. High-resolution computed tomography (HRCT) and immunological bronchioalveolar lavage revealed ground-glass opacities and a lymphocytic alveolitis caused by interstitial lung disease (ILD) in RA. Considering previous forms of treatment, disease-modifying antirheumatic drug (DMARD) treatment was switched to tofacitinib. Tofacitinib treatment demonstrated a 33% reduction in ground-glass opacities by artificial intelligence-based quantification of pulmonary HRCT over the course of 6 months, which was associated with an improvement in dyspnea symptoms. In conclusion, tofacitinib represents an effective anti-inflammatory therapeutic option in the treatment of RA-ILD.

AGE-Induced Suppression of EZH2 Mediates Injury of Podocytes by Reducing H3K27me3.

BACKGROUND: Chronic hyperglycemia, a pivotal feature of diabetes mellitus (DM), initiates the formation of advanced glycation end products (AGEs) and the dysregulation of epigenetic mechanisms, which may cause injury to renal podocytes, a central feature of diabetic kidney disease (DKD). Previous data of our group showed that AGEs significantly reduce the expression of NIPP1 (nuclear inhibitor of protein phosphatase 1) in podocytes in vitro as well as in human and murine DKD. NIPP1 was shown by others to interact with enhancer of zeste homolog 2 (EZH2), which catalyzes the repressive methylation of H3K27me3 on histone 3. Therefore, we hypothesized that AGEs can directly induce epigenetic changes in podocytes. METHODS: We analyzed the relevance of AGEs on EZH2 expression and activity in a murine podocyte cell line. Cells were treated with 5 mg/mL glycated BSA for 24 h. To determine the meaning of EZH2 suppression, EZH2 activity was inhibited by incubating the cells with the pharmacological methyltransferase inhibitor 3-deazaneplanocin A; EZH2 expression was repressed with siRNA. mRNA expression was analyzed with real-time PCR, and protein expression with Western blot. EZH2 expression and level of H3K27 trimethylation in podocytes of diabetic db/db mice, a mouse model for type 2 DM, were analyzed using immunofluorescence. RESULTS: Our data demonstrated that AGEs decrease EZH2 expression in podocytes and consequently reduce H3K27me3. This suppression of EZH2 mimicked the AGE effects and caused an upregulated expression of pathological factors that contribute to podocyte injury in DKD. In addition, analyses of db/db mice showed significantly reduced H3K27me3 and EZH2 expression in podocytes. Moreover, the suppression of NIPP1 and EZH2 showed similar effects regarding podocyte injury. CONCLUSIONS: Our studies provide a novel pathway how AGEs contribute to podocyte injury and the formation of the so-called metabolic memory in DKD.

Case report of a cystic parathyroidal adenoma with rapid growth induced by cinacalcet.

BACKGROUND: Primary hyperparathyroidism is a rare condition of disease which can seldomly present as giant retrotrhyroideal cysts, complicating the localization of the adenoma to resect. CASE PRESENTATION: A 56-year old female presented with hypercalcaemia of 3.38 mmol/L (2.2-2.65 mmol/L) and a history of breast cancer. A fast growing cystic parathyroidal adenoma was diagnosed by a multimodal approach including comprehensive diagnostic imaging (ultrasonography, scintigraphies, dynamic MRI) and cytopathological investigations after ultrasonography-guided puncture. The patient was cured by surgical extraction of the whole adenoma. In retrospect, the rapid growth was most likely induced by cinacalcet (initially 30 mg/d, later 60 mg/d) therapy which the patient received for few months only. Primary hyperparathyroidism was ascertained because surgical removal of the solitary adenoma cured the patient. Furthermore, there was no relevant renal insufficiency or history of prolonged calcium-level deregulation. CONCLUSIONS: This phenomenon of cystic degeneration of parathyroidal adenoma under therapy with cinacalcet has previously been described in secondary hyperparathyroidism, but not in primary hyperparathyroidism and should be considered in diagnostic approach.

Inhibition of periarticular bone loss is associated with clinical remission and ACR70-Response in rheumatoid arthritis.

The aim of this study, based on a post hoc analysis of the data set used in the RAPID 1 trial, focuses on the associations between metacarpal bone mineral density, as estimated by digital X-ray radiogrammetry (DXR), and clinical remission as well as ACR70-Response in rheumatoid arthritis (RA) patients treated with certolizumab pegol (CZP). The trial evaluates a total of 345 RA patients treated with methotrexate versus CZP 200 mg versus CZP 400 mg. All patients underwent X-rays of the hand at baseline and week 52 as well as computerized calculations of bone mineral density (BMD) by DXR. Clinical remission was defined as DAS28 < 2.6. ACR70-Response was also evaluated. The radiological assessment of disease progression was estimated using the modified total Sharp Score. The mean difference for DAS28 was observed for patients treated with CZP 400 mg (median: - 3.53, minimum: - 6.77; maximum: + 0.48) and CZP 200 mg (median: - 3.13, minimum: - 6.37; maximum: - 0.52) compared to the methotrexate group (median - 2.41, minimum: - 4.76; maximum: + 0.31). The DXR-BMD showed a minor bone loss for the treatment groups undergoing therapy with CZP 200 mg (median: - 0.009 g/cm2, minimum: - 0.059 g/cm2; maximum: + 0.095 g/cm2) and CZP 400 mg (median: - 0.008 g/cm2, minimum: - 0.064 g/cm2; maximum: + 0.080 g/cm2). The methotrexate group presented an advanced periarticular metacarpal bone loss as measured by DXR-BMD (median: - 0.024 g/cm2, minimum: - 0.102 g/cm2; maximum: + 0.057 g/cm2). In the case of clinical remission and ACR70-Response, no significant change of the DXR-BMD was observed for both CZP groups. The study highlights that patients treated with CZP show a less accentuated periarticular bone loss as estimated by DXR in comparison to patients with methotrexate plus placebo. In addition, patients with clinical remission and ACR70-Response revealed no periarticular demineralisation.

FSP1-specific SMAD2 knockout in renal tubular, endothelial, and interstitial cells reduces fibrosis and epithelial-to-mesenchymal transition in murine STZ-induced diabetic nephropathy.

Extracellular matrix deposition during tubulointerstitial fibrosis (TIF), a central pathological process in patients with diabetic nephropathy (DN), is driven by locally activated, disease-relevant myofibroblasts. Myofibroblasts can arise from various cellular sources, e.g., tubular epithelial cells via a process named epithelial-to-mesenchymal transition (EMT). Transforming growth factor beta 1 (TGF-ß1) and its downstream Smad signaling play a critical role in both TIF and EMT. Whereas Smad3 is one central mediator, the role of the other prominently expressed variant, Smad2, is not completely understood. In this study, we sought to analyze the role of renal Smad2 in the development of TIF and EMT during streptozotocin-induced DN by using a fibroblast-specific protein 1 (FSP1)-promotor-driven SMAD2 knockout mouse model with decreased tubular, endothelial, and interstitial Smad2 expression. In contrast to wild-type diabetic mice, diabetic SMAD2 knockout mice showed the following features: (1) significantly reduced DN and TIF (shown by KIM1 expression; periodic acid Schiff staining; collagen I and III, fibronectin, and connective tissue growth factor deposition); (2) significantly reduced tubular EMT-like changes (e.g., altered Snail1, E-cadherin, matrix metalloproteinase 2, and vimentin deposition); and (3) significantly decreased expression of myofibroblast markers (α-smooth muscle actin, FSP1). As one mechanism for the protection against diabetes-induced TIF and EMT, decreased Smad3 protein levels and, as a possible consequence, reduced TGF-ß1 levels were observed in diabetic SMAD2 knockout mice. Our findings thus support the important role of Smad2 for pro-fibrotic TGF-ß/Smad3 signaling in experimental DN.

Complications and monitoring of percutaneous renal biopsy - a retrospective study
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BACKGROUND AND AIMS: Percutaneous renal biopsy is a necessary tool to diagnose renal diseases but complications may still occur. The aims of this study were to detect the rate of complications, possible risk factors and to identify the necessity of routine post-biopsy controls at 4 - 6, and 24 hours. MATERIALS AND METHODS: This single-center retrospective study included 500 consecutive biopsies of native and allograft kidneys performed at the Jena University Hospital. RESULTS: Major complications occurred in 2.4% of all cases: 9 patients received blood transfusions (1.8%), 2 arterial-venous fistulas (0.4%), 1 angiographic intervention (0.2%), no surgical intervention or death. Minor complications after 24 (4 - 6) hours appeared in 31.8 (41.2)%: 14.8 (11.0)% had hematomas detected by ultrasound (n = 74), 17.0 (30.2)% a reduction of hemoglobin concentration ≥ 1.0 g/dL (n = 85), 4.8 (2.6)% both (n = 24), 1 macrohematuria (0.2%). Systolic blood pressure (≥ 155 mmHg vs. ≤ 126 mmHg, OR 2.007, 95% CI 1.003 - 4.018, p = 0.049) and younger age (per 1 year increase, OR 0.983, 95% CI 0.968 - 0.998, p = 0.027) were associated with the presence of hematoma. Baseline hemoglobin (per increase of 1.6 g/dL, OR 1.499, 95% CI 1.222 - 1.840, p < 0.001) and interstitial fibrosis (≥ 50% vs. ≤ 16%, OR 2.694, 95% CI 1.212 - 5.987, p = 0.015) influenced the finding of a persistent hemoglobin reduction ≥ 1.0 g/dL after 24 hours. CONCLUSION: The complication rate after renal biopsy is low. Despite the lack of prospective data, our findings suggest that follow-up by a single blood count test combined with ultrasound examination at the day after renal biopsy would be sufficient, at least in the absence of explicit symptoms or risk factors for bleeding.
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MORG1+/- mice are protected from histological renal damage and inflammation in a murine model of endotoxemia.

BACKGROUND: The MAPK-organizer 1 (MORG1) play a scaffold function in the MAPK and/or the PHD3 signalling paths. Recently, we reported that MORG1+/- mice are protected from renal injury induced by systemic hypoxia and acute renal ischemia-reperfusion injury via increased hypoxia-inducible factors (HIFs). Here, we explore whether MORG1 heterozygosity could attenuate renal injury in a murine model of lipopolysaccharide (LPS) induced endotoxemia. METHODS: Endotoxemia was induced in mice by an intraperitoneal (i.p) application of 5 mg/kg BW LPS. The renal damage was estimated by periodic acid Schiff's staining; renal injury was evaluated by detection of urinary and plasma levels of neutrophil gelatinase-associated lipocalin and albumin/creatinine ratio via ELISAs. Renal mRNA expression was assessed by real-time PCR, whereas the protein expression was determined by immunohistochemistry or Western blotting. RESULTS: LPS administration increased tubular injury, microalbuminuria, IL-6 plasma levels and renal TNF-α expression in MORG1 +/+ mice. This was accompanied with enhanced infiltration of the inflammatory T-cells in renal tissue and activation of the NF-κB transcription factors. In contrast, endotoxemic MORG1 +/- showed significantly less tubular injury, reduced plasma IL-6 levels, significantly decreased renal TNF-α expression and T-cells infiltration. In support, the renal levels of activated caspase-3 were lower in endotoxemic MORG1 +/- mice compared with endotoxemic MORG1 +/+ mice. Interestingly, LPS application induced a significantly higher accumulation of renal HIF-2α in the kidneys of MORG1+/- mice than in wild-type mice, accompanied with a diminished phosphorylation of IκB-α and IKK α,ß and decreased iNOS mRNA in the renal tissues of the LPS-challenged MORG1+/- mice, indicating an inhibition of the NF-κB transcriptional activation. CONCLUSIONS: MORG1 heterozygosity protects against histological renal damage and shows anti-inflammatory effects in a murine endotoxemia model through modulation of HIF-2α stabilisation and/or simultaneous inhibition of the NF-κB signalling. Here, we show for the first time that MORG1 scaffold could represent the missing link between innate immunity and inflammation.

Heterozygosity of mitogen-activated protein kinase organizer 1 ameliorates diabetic nephropathy and suppresses epithelial-to-mesenchymal transition-like changes in db/db mice.

BACKGROUND: Progressive diabetic nephropathy (DN) is characterized by tubulointerstitial fibrosis that is caused by accumulation of extracellular matrix. Induced by several factors, matrix-producing myofibroblasts may to some extent originate from tubular cells by epithelial-to-mesenchymal transition (EMT). Although previous data document that activation of hypoxia-inducible factor (HIF) signalling can be renoprotective in acute kidney disease, this issue remains controversial in chronic kidney injury. Here, we studied whether DN and EMT-like changes are ameliorated in a mouse model of type 2 diabetes mellitus with increased stability and activity of the HIF. METHODS: We used db/db mice that were crossed with transgenic mice expressing reduced levels of mitogen-activated protein kinase organizer 1 (MORG1), a scaffold protein interacting with prolyl hydroxylase domain 3 (PHD3), because of deletion of one MORG1 allele. RESULTS: We found significantly reduced nephropathy in diabetic MORG1+/- heterozygous mice compared with the diabetic wild-types (db/dbXMORG1+/+). Furthermore, we demonstrated that EMT-like changes in the tubulointerstitium of diabetic wild-type MORG1+/+ mice are present, whereas diabetic mice with reduced expression of MORG1 showed significantly fewer EMT-like changes. CONCLUSIONS: These findings reveal that a deletion of one MORG1 allele inhibits the development of DN in db/db mice. The data suggest that the diminished interstitial fibrosis in these mice is a likely consequence of suppressed EMT-like changes.

Growth arrest specific 2-like protein 1 expression is upregulated in podocytes through advanced glycation end-products.

Background: Growth arrest specific 2-like protein 1 (GAS2L1) protein is a member of the GAS2 family of proteins, known to regulate apoptosis and cellular cytoskeleton reorganization in different cells. Recently we identified that Gas2l1 gene expression in podocytes is influenced by advanced glycation end product-bovine serum albumin(AGE-BSA). Methods: The study was performed employing cultured podocytes and diabetic ( db/db ) mice, a model of type 2 diabetes. Akbuminuria as wellas urinary neutrophil gelatinase-associated lipocalin (NGAL) excretion as measured with specific ELISAs. Gene expression was analysed via semiquantitative and real-time polymerase chain reaction. The protein levels were determined by western blotting and immunostaining. Results: We found that the Gas2l1 α isoform is expressed in podocytes. Treatment with AGE-BSA induced Gas2l1 α and Gas2 mRNA levels compared with controls incubated with non-glycated control BSA (Co-BSA). Moreover, application of the recombinant soluble receptor of AGEs (sRAGE), a competitor of cellular RAGE, reversed the AGE-BSA effect. Interestingly, AGE-BSA also increased the protein levels of GAS2L1α in a RAGE-dependent manner, but did not affect the GAS2 expression. Periodic acid-Schiff staining and albuminuria as well as urinary NGAL excretion revealed that db/db mice progressively developed diabetic nephropathy with renal accumulation of N ε -carboxy-methyl-lysine (immunohistochemistry, western blots). Analyses of GAS2L1α and GAS2 proteins in diabetic mice revealed that both were significantly elevated relative to their non-diabetic littermates. In addition, GAS2L1α and GAS2 proteins positively correlated with the accumulation of AGEs in the blood plasma of diabetic mice and the administration of sRAGE in diabetic mice reduced the glomerular expression of both proteins. Conclusions: We show for the first time that the protein expression of GAS2L1α in vitro and in vivo is regulated by the AGE-RAGE axis. The suppression of AGE ligation with their RAGE in diabetic mice with progressive nephropathy reversed the GAS2L1α expression, thus suggesting a role of GAS2L1α in the development of diabetic disease, which needs to be further elucidated.

Digital X-ray radiogrammetry and its sensitivity and specificity for the identification of rheumatoid arthritis-related cortical hand bone loss.

Digital X-ray radiogrammetry (DXR) is a computer-assisted diagnosis technique for quantifying cortical hand bone mineral density (BMD) as well as the metacarpal index (MCI) in the metacarpal bones from radiographs. The objective was to compare DXR-BMD and DXR-MCI between healthy individuals and patients with rheumatoid arthritis (RA) and verify the sensitivity and specificity of this technique for the identification of cortical hand bone loss as an additional diagnostic approach in RA. 618 patients were enrolled and divided into two groups: those with RA (n = 309) and a healthy control group (n = 309) as a reference database. DXR-BMD and the DXR-MCI were measured by DXR using hand radiographs. The severity of RA was evaluated by the modified Larsen score. Mean values for DXR-BMD and DXR-MCI in RA patients were significantly lower compared to healthy subjects (-20.7 and -21.1 %, respectively). Depending on the severity of RA-related joint damage, DXR-BMD revealed a significant reduction of -28.1 % and DXR-MCI -28.2 %, comparing score 1 and score 5 of the modified Larsen score. Both DXR-BMD and DXR-MCI had a high sensitivity (DXR-BMD 91 %, DXR-MCI 87 %) and a moderate specificity (DXR-BMD 47 %, DXR-MCI 49 %) to identify RA-related cortical hand bone loss. The DXR technique seems to be able to quantify RA-related periarticular bone loss as a characteristic feature in the course of RA. Consequently, periarticular osteoporosis seems to function as a reliable diagnostic approach comparable to erosions and joint space narrowing in the diagnosis of RA and as a surrogate marker for the progression of bone loss in RA.

Metacarpal bone loss in patients with rheumatoid arthritis estimated by a new Digital X-ray Radiogrammetry method - initial results.

BACKGROUND: The Digital X-ray Radiogrammetry (DXR) method measures the cortical bone thickness in the shafts of the metacarpals and has demonstrated its relevance in the assessment of hand bone loss caused by rheumatoid arthritis (RA). The aim of this study was to validate a novel approach of the DXR method in comparison with the original version considering patients with RA. METHOD: The study includes 49 patients with verified RA. The new version is an extension of the BoneXpert method commonly used in pediatrics which has these characteristics: (1) It introduces a new technique to analyze the images which automatically validates the results for most images, and (2) it defines the measurement region relative to the ends of the metacarpals. The BoneXpert method measures the Metacarpal Index (MCI) at the metacarpal bone (II to IV). Additionally, the MCI is quantified by the DXR X-posure System. RESULTS: The new version correctly analyzed all 49 images, and 45 were automatically validated. The standard deviation between the MCI results of the two versions was 2.9% of the mean MCI. The average Larsen score was 2.6 with a standard deviation of 1.3. The correlation of MCI to Larsen score was -0.81 in both versions, and there was no significant difference in their ability to detect erosions. CONCLUSION: The new DXR version (BoneXpert) validated 92% of the cases automatically, while the same good correlation to RA severity could be presented compared to the old version.

Preconditioned suppression of prolyl-hydroxylases attenuates renal injury but increases mortality in septic murine models.

BACKGROUND: Septic conditions contribute to tissue hypoxia, potentially leading to multiple organ failure, including acute kidney injury. The regulation of cellular adaptation to low oxygen levels is regulated by hypoxia-inducible transcription factors (HIFs). While the role of HIFs in ischaemia/reperfusion is more studied, their function in sepsis-induced renal injury is not well characterized. In this study, we investigated whether pharmacological activation of HIFs by suppression of prolyl-hydroxylases (PHDs) protects against septic acute kidney injury. METHODS: Two models of sepsis-caecal ligation and punction and peritoneal contamination and infection-were induced on 12-week-old C57BL6/J mice. Pharmacological inhibition of PHDs, leading to HIF activation, was achieved by intraperitoneal application of 3,4-dihydroxybenzoate (3,4-DHB) before sepsis. A quantitative real-time reverse transcription polymerase chain reaction, immunohistology and enzyme-linked immunosorbent assays were utilized to detect gene expression, renal protein levels and renal functional parameters, respectively. Tissue morphology was analysed by periodic acid-Schiff reaction. Early kidney injury was estimated by kidney injury molecule-1 analyses. Apoptosis was detected in situ by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling stain. The systemic effect of 3,4-DHB pretreatment in sepsis was analysed by 72-h survival studies. RESULTS: Pharmacological activation of HIFs before sepsis induction attenuated sepsis-related vacuolization and dilation of the proximal tubules, reduced tubular apoptosis and correlated to lower T-cell infiltration in renal tissue compared with the non-treated septic animals. PHD suppression elevated the basal renal HIF-1α expression and basal plasma concentrations of HIF targets erythropoietin and vascular endothelial growth factor. Whereas it preserved renal structure in both models, it improved renal function in a model-dependent manner. Moreover, inhibition of PHDs led to increased mortality in both models. Analysis of liver function showed increased organ destruction with massive glycogen loss and hepatocyte's apoptosis due to 3,4-DHB administration before sepsis induction. CONCLUSIONS: In summary, the pharmacological activation of HIFs by 3,4-DHB administration, although it showed renoprotective effects in sepsis-related kidney injury, induced more severe problems in other organs such as the liver during sepsis, leading to increased mortality.