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.

Cardiovascular risk due to diabetes mellitus in patients with chronic kidney disease-prospective data from the German Chronic Kidney Disease cohort.

Background: Diabetes mellitus (DM) and chronic kidney disease (CKD) are well-known cardiovascular and mortality risk factors. To what extent they act in an additive manner and whether the etiology of CKD modifies the risk is uncertain. Methods: The multicenter, prospective, observational German Chronic Kidney Disease study comprises 5217 participants (1868 with DM) with a baseline mean estimated glomerular filtration rate of 30-60 mL/min/1.73 m2 and/or proteinuria >0.5 g/day. We categorized patients whose CKD was caused by cardiovascular or metabolic diseases (CKDcvm) with and without DM, as opposed to genuine CKD (CKDgen) with and without DM. Recorded outcomes were first events of non-cardiovascular and cardiovascular death, 4-point major adverse cardiovascular events (4-point MACE) and hospitalization for heart failure (HHF). Results: During the 6.5-year follow-up 603 (12%) non-cardiovascular and 209 (4%) cardiovascular deaths, 645 (12%) 4-point MACE, and 398 (8%) HHF were observed, most frequently in patients with DM having CKDcvm. DM increased the risk of non-cardiovascular [hazard ratio (HR) 1.92; 95% confidence interval (CI) 1.59-2.32] and cardiovascular (HR 2.25; 95% CI 1.62-3.12) deaths, 4-point MACE (HR 1.93; 95% CI 1.62-2.31) and HHF (HR 1.87; 95% CI 1.48-2.36). Mortality risks were elevated by DM to a similar extent in CKDcvm and CKDgen, but for HHF in CKDcvm only (HR 2.07; 95% CI 1.55-2.77). In patients with DM, CKDcvm (versus CKDgen) only increased the risk for HHF (HR 1.93; 95% CI 1.15-3.22). Conclusions: DM contributes to cardiovascular and mortality excess risk in patients with moderate to severe CKD in both, CKDcvm and CKDgen. Patients with DM and CKDcvm are particularly susceptible to HHF.

[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.

[Necrosis of the tongue as a clinical manifestation of giant cell arteritis]. / Zungennekrose als klinische Manifestation einer Riesenzellarteriitis.

An 83-year-old male patient presented due to a 3-week history of swelling of the tongue with tongue pain on eating, yellowish plaques, and a gray-brown lesion in the anterior portion of the tongue. Sudden loss of vision in the left eye and temporal headache occurred 3 days before presentation. Due to elevated C­reactive protein, sonography of the supraaortic arteries as well as positron emission tomography/computed tomography was performed. Imaging revealed inflammation of the great arteries as well as a halo sign on ultrasound of the temporal artery. Thus, a diagnosis of giant cell arteritis with necrosis of the tongue was made. Immunosuppressive therapy with glucocorticoids was initiated. Necrosis of the tongue is a rare manifestation of giant cell arteritis that requires immediate immunosuppressive therapy to prevent further complications to the tongue (e.g., complete necrosis of the tongue, superinfection, tongue amputation).

The Role of Hypoxia on the Trimethylation of H3K27 in Podocytes.

Epigenetic alterations contribute to the pathogenesis of chronic diseases such as diabetes mellitus. Previous studies of our group showed that diabetic conditions reduce the trimethylation of H3K27 in podocytes in a NIPP1- (nuclear inhibitor of protein phosphatase 1) and EZH2- (enhancer of zeste homolog 2) dependent manner. It has been previously reported that in differentiated podocytes, hypoxia decreases the expression of slit diaphragm proteins and promotes foot process effacement, thereby contributing to the progression of renal disease. The exact mechanisms are, however, not completely understood. The aim of this study was to analyze the role of hypoxia and HIFs (hypoxia-inducible factor) on epigenetic changes in podocytes affecting NIPP1, EZH2 and H3K27me3, in vitro and in vivo. In vivo studies were performed with mice exposed to 10% systemic hypoxia for 3 days or injected with 3,4-DHB (dihydroxybenzoate), a PHD (prolyl hydroxylase) inhibitor, 24 h prior analyses. Immunodetection of H3K27me3, NIPP1 and EZH2 in glomerular podocytes revealed, to the best of our knowledge for the first time, that hypoxic conditions and pharmacological HIFs activation significantly reduce the expression of NIPP1 and EZH2 and diminish H3K27 trimethylation. These findings are also supported by in vitro studies using murine-differentiated podocytes.

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.

Targeted Disruption of the MORG1 Gene in Mice Causes Embryonic Resorption in Early Phase of Development.

The mitogen-activated protein kinase organizer 1 (MORG1) is a scaffold molecule for the ERK signaling pathway, but also binds to prolyl-hydroxylase 3 and modulates HIFα expression. To obtain further insight into the role of MORG1, knockout-mice were generated by homologous recombination. While Morg1+/- mice developed normally without any apparent phenotype, there were no live-born Morg1-/- knockout offspring, indicating embryonic lethality. The intrauterine death of Morg1-/- embryos is caused by a severe failure to develop brain and other neuronal structures such as the spinal cord and a failure of chorioallantoic fusion. On E8.5, Morg1-/- embryos showed severe underdevelopment and proliferative arrest as indicated by absence of Ki67 expression, impaired placental vascularization and altered phenotype of trophoblast giant cells. On E9.5, the malformed Morg1-/- embryos showed defective turning into the final fetal position and widespread apoptosis in many structures. In the subsequent days, apoptosis and decomposition of embryonic tissue progressed, accompanied by a massive infiltration of inflammatory cells. Developmental aberrancies were accompanied by altered expression of HIF-1/2α and VEGF-A and caspase-3 activation in embryos and extraembryonic tissues. In conclusion, the results suggest a multifactorial process that causes embryonic death in homozygous Morg1 mutant mice, described here, to the best of our knowledge, for the first time.

SARS-CoV-2 infection: a possible trigger for the recurrence of IgA nephropathy after kidney transplantation?

Immunoglobulin A nephropathy, the most common primary glomerulonephritis worldwide, is a leading cause of chronic kidney disease and end-stage kidney failure. Several cases of immunoglobulin A nephropathy relapse in native kidneys have been described after COVID-19 vaccination or SARS-CoV-2 infection. Here, we report the case of a 52-year-old kidney transplant recipient who had a stable transplant function for more than 14 years, with a glomerular filtration rate above 30 ml/min/1.73 m2. The patient had been vaccinated against COVID-19 four times with the Pfizer-BioNTech vaccine, most recently in March 2022. Eight weeks after a symptomatic SARS-CoV-2 infection in June 2022, his glomerular filtration rate had decreased by more than 50%, and his proteinuria increased to 17.5 g per day. A renal biopsy indicated highly active immunoglobulin A nephritis. Despite steroid therapy, the function of the transplanted kidney deteriorated, and long-term dialysis became necessary because of recurrence of his underlying renal disease. This case report provides what is, to our knowledge, the first description of recurrent immunoglobulin A nephropathy in a kidney transplant recipient after SARS-CoV-2 infection leading to severe transplant failure and finally graft loss.

Nephroprotective Properties of Antidiabetic Drugs.

Chronic kidney disease (CKD) is associated with increased morbidity and mortality, especially from cardiovascular (CV) causes, and especially in people with diabetes mellitus (DM). Already the presence of DM increases CV risk and potentiates the risk of CKD. Therefore, besides glycemic control, prevention and treatment of CKD to slow its progression are of clinical importance. A significant nephroprotective effect of novel antidiabetic drugs, namely sodium-glucose cotransporter 2 inhibitors (SGLT2-I) and glucagon-like peptide 1 receptor agonists (GLP1-RA), has been shown on top of their glucose-lowering effects and was confirmed in cardiovascular outcome trials. GLP1-RA mainly reduced the risk of macroalbuminuria, whereas SGLT2-I were also associated with a lower risk of declining glomerular filtration rate (GFR) over time. The nephroprotective effects of SGLT2-I are also evident in people without DM. According to current guidelines, SGLT2-I and/or GLP1-RA are recommended for people with DM who have chronic kidney disease and/or increased cardiovascular risk. However, other antidiabetic drugs offer nephroprotective properties, which will also be discussed in this review.

RAGE is a critical factor of sex-based differences in age-induced kidney damage.

Introduction: Advanced glycation end products (AGEs) are a heterogeneous group of molecules with potential pathophysiological effects on the kidneys. Fibrosis together with the accumulation of AGEs has been investigated for its contribution to age-related decline in renal function. AGEs mediate their effects in large parts through their interactions with the receptor for AGEs (RAGE). RAGE is a transmembrane protein that belongs to the immunoglobulin superfamily and has the ability to interact with multiple pro-inflammatory/pro-oxidative ligands. The role of RAGE in aging kidneys has not been fully characterized, especially for sex-based differences. Methods: Therefore, we analyzed constitutive RAGE knockout (KO) mice in an age- and sex-dependent manner. Paraffin-embedded kidney sections were used for histological analysis and protein expression of fibrosis and damage markers. RNA expression analysis from the kidney cortex was done by qPCR for AGE receptors, kidney damage, and early inflammation/fibrosis factors. FACS analysis was used for immune cell profiling of the kidneys. Results: Histological analysis revealed enhanced infiltration of immune cells (positive for B220) in aged (>70 weeks old) KO mice in both sexes. FACS analysis revealed a similar pattern of enhanced B-1a cells in aged KO mice. There was an age-based increase in pro-fibrotic and pro-inflammatory markers (IL-6, TNF, TGF-ß1, and SNAIL1) in KO male mice that presumably contributed to renal fibrosis and renal damage (glomerular and tubular). In fact, in KO mice, there was an age-dependent increase in renal damage (assessed by NGAL and KIM1) that was accompanied by increased fibrosis (assessed by CTGF). This effect was more pronounced in male KO mice than in the female KO mice. In contrast to the KO animals, no significant increase in damage markers was detectable in wild-type animals at the age examined (>70 weeks old). Moreover, there is an age-based increase in AGEs and scavenger receptor MSR-A2 in the kidneys. Discussion: Our data suggest that the loss of the clearance receptor RAGE in male animals further accelerates age-dependent renal damage; this could be in part due to an increase in AGEs load during aging and the absence of protective female hormones. By contrast, in females, RAGE expression seems to play only a minor role when compared to tissue pathology.

Pharmacological Targeting of the RAGE-NFκB Signalling Axis Impedes Monocyte Activation under Diabetic Conditions through the Repression of SHP-2 Tyrosine Phosphatase Function.

Monocytes play a vital role in the development of cardiovascular diseases. Type 2 diabetes mellitus (T2DM) is a major CVD risk factor, and T2DM-induced aberrant activation and enhanced migration of monocytes is a vital pathomechanism that leads to atherogenesis. We recently reported the upregulation of SHP-2 phosphatase expression in mediating the VEGF resistance of T2DM patient-derived monocytes or methylglyoxal- (MG, a glucose metabolite and advanced glycation end product (AGE) precursor) treated monocytes. However, the exact mechanisms leading to SHP-2 upregulation in hyperglycemic monocytes are unknown. Since inflammation and accumulation of AGEs is a hallmark of T2DM, we hypothesise that inflammation and AGE-RAGE (Receptor-for-AGEs) signalling drive SHP-2 expression in monocytes and blockade of these pathways will repress SHP-2 function. Indeed, monocytes from T2DM patients revealed an elevated SHP-2 expression. Under normoglycemic conditions, the serum from T2DM patients strongly induced SHP-2 expression, indicating that the T2DM serum contains critical factors that directly regulate SHP-2 expression. Activation of pro-inflammatory TNFα signalling cascade drove SHP-2 expression in monocytes. In line with this, linear regression analysis revealed a significant positive correlation between TNFα expression and SHP-2 transcript levels in T2DM monocytes. Monocytes exposed to MG or AGE mimetic AGE-BSA, revealed an elevated SHP-2 expression and co-treatment with an NFκB inhibitor or genetic inhibition of p65 reversed it. The pharmacological inhibition of RAGE was sufficient to block MG- or AGE-BSA-induced SHP-2 expression and activity. Confirming the importance of RAGE-NFκB signalling in regulating SHP-2 expression, the elevated binding of NFκB to the SHP-2 promoter-induced by MG or AGE-BSA-was reversed by RAGE and NFκB inhibition. Besides, we detected elevated RAGE levels in human and murine T2DM monocytes and monocytes exposed to MG or AGE-BSA. Importantly, MG and AGE-BSA treatment of non-T2DM monocytes phenocopied the aberrant pro-migratory phenotype of T2DM monocytes, which was reversed entirely by either SHP-2- or RAGE inhibition. In conclusion, these findings suggest a new therapeutic approach to prevent accelerated atherosclerosis in T2DM patients since inhibiting the RAGE-NFκB-SHP-2 axis impeded the T2DM-driven, SHP-2-dependent monocyte activation.

Metabolic Control, Diabetic Complications and Drug Therapy in a Cohort of Patients with Type 1 and Type 2 Diabetes in Secondary and Tertiary Care between 2004 and 2019.

This paper studies the features of metabolic parameters, diabetic complications and drug therapy of a single-centre cohort of patients with type 1 diabetes (T1DM) or type 2 diabetes (T2DM) in secondary care and tertiary care over a 15-year period. METHODS: Retrospective cross-sectional analysis of four single-centre cohorts between 2004 and 2019. All patients with T1DM or T2DM in secondary care (n = 5571) or tertiary care (n = 2001) were included. Statistical analyses were performed using linear mixed models. RESULTS: Diabetes duration increased in both patients with T1DM and T2DM in secondary care and tertiary care (p < 0.001). Patients in secondary care consistently showed good glycaemic control, while patients in tertiary care showed inadequate glycaemic control. All four cross-sectional cohorts showed a significant increase in the prevalence of nephropathy over time and three out of four cohorts (T1DM and T2DM in secondary care and T2DM in tertiary care) showed an increase in the prevalence of neuropathy (all p < 0.001). The incidence of severe hypoglycaemia was consistently low. The use of insulin pumps and insulin analogues in the therapy of T1DM increased significantly. CONCLUSIONS: The increased prevalence of complications is likely due to older age and longer diabetes duration. Low rates of hypoglycaemia, lower limb amputations and good glycaemic control in secondary care patients indicate a good structure of patient care.

The relationship between structural analysis of the hand and clinical characteristics in psoriatic arthritis.

Up to now, there is only limited information available on a possible relationship between clinical characteristics and the mineralization of metacarpal bones and finger joint space distance (JSD) in patients with psoriatic arthritis (PsA). Computerized digital imaging techniques like digital X-ray radiogrammetry (DXR) and computer-aided joint space analysis (CAJSA) have significantly improved the structural analysis of hand radiographs and facilitate the recognition of radiographic damage. The objective of this study was to evaluate clinical features which potentially influence periarticular mineralization of the metacarpal bones and finger JSD in PsA-patients. 201 patients with PsA underwent computerized measurements of the metacarpal bone mineral density (BMD) with DXR and JSD of all finger joints by CAJSA. DXR-BMD and JSD were compared with clinical features such as age and sex, disease duration, C-reactive protein (CRP) as well as treatment with prednisone and disease-modifying antirheumatic drugs (DMARDs). A longer disease duration and an elevated CRP value were associated with a significant reduction of DXR-BMD, whereas JSD-parameters were not affected by both parameters. DXR-BMD was significantly reduced in the prednisone group (-0.0383 g/cm²), but prednisone showed no impact on finger JSD. Patients under the treatment with bDMARDs presented significant lower DXR-BMD (-0.380 g/cm²), JSDMCP (-0.0179 cm), and JSDPIP (-0.0121 cm) values. Metacarpal BMD was influenced by inflammatory activity, prednisone use, and DMARDs. In contrast, finger JSD showed only a change compared to baseline therapy. Therefore, metacarpal BMD as well as finger JSD represent radiographic destruction under different aspects.

Distribution patterns of arterial affection and the influence of glucocorticoids on 18F-fluorodeoxyglucose positron emission tomography/CT in patients with giant cell arteritis.

BACKGROUND: Giant cell arteritis (GCA) with the involvement of extracranial vessels is increasingly coming into focus. Isolated aortic involvement in the acute phase of GCA is probably more frequent than estimated because only a minority of patients show typical symptoms. 18F-fluorodeoxyglucose positron emission tomography/CT (PET/CT) is a reliable imaging tool to diagnose patients with extracranial GCA. The aim of this retrospective study was to quantify arterial involvement at the onset of a newly diagnosed GCA by PET/CT and to evaluate the influence of glucocorticoid (GC) treatment on the diagnostic performance of this imaging technique. METHODS: The study included 60 patients with GCA at the onset of a GCA. All patients had undergone a PET/CT scan. 44 patients were GC naïve and 16 patients received GC. RESULTS: The most affected arteries were the ascending aorta (72%), followed by the brachiocephalic trunk (62%), aortic arch (60%) and descending aorta (60%). The aorta and its branches showed an inflammatory involvement in 83.3% of patients. A singular affection of the aorta and the brachiocephalic trunk was revealed in 20% of cases. GC-naïve patients (95.5%) had more frequently affected arteries compared with GC-treated patients (50%). CONCLUSION: Our study showed the frequent involvement of the thoracic aorta and brachiocephalic trunk in patients with GCA using PET/CT. Since these vascular compartments cannot be visualised by ultrasound, we advocate screening imaging of the aorta with PET/CT when GCA is suspected. Because the use of GC is associated with a marked decrease in the inflamed vascular segment in GCA, PET/CT should be performed as soon as possible.

Prevalence of Impairment of Visual Acuity and Severity of Retinopathy in Patients with Diabetes Mellitus.

AIMS: No information exists on the frequency of visual impairment in people with diabetes mellitus (DM) in Germany. In this study, the prevalence of vision impairment in those individuals was investigated. METHODS: We retrospectively analyzed a cohort of 295 people (14221 consultations) at a university outpatient clinic with any type of DM and an available ETDRS-Score and visual acuity. The primary outcome was the prevalence of visual impairment, the secondary outcome was the correlation of the ETDRS-Score and limitations of visual acuity and the prevalence of higher ETDRS-Score with a visual impairment defined as a decimal-visus