Impairment of muscular endothelial cell regeneration in dermatomyositis.

Background and aim: Inflammatory myopathies are heterogeneous in terms of etiology, (immuno)pathology, and clinical findings. Endothelial cell injury, as it occurs in DM, is a common feature of numerous inflammatory and non-inflammatory vascular diseases. Vascular regeneration is mediated by both local and blood-derived mechanisms, such as the mobilization and activation of so-called proangiogenic cells (PACs) or early endothelial progenitor cells (eEPCs). The current study aimed to evaluate parameters of eEPC integrity in dermatomyositis (DM), compared to necrotizing myopathy (NM) and to non-myopathic controls. Methods: Blood samples from DM and NM patients were compared to non-myositis controls and analyzed for the following parameters: circulating CD133+/VEGFR-2+ cells, number of colony-forming unit endothelial cells (CFU-ECs), concentrations of angiopoietin 1, vascular endothelial growth factor (VEGF), and CXCL-16. Muscle biopsies from DM and NM subjects underwent immunofluorescence analysis for CXCR6, nestin, and CD31 (PECAM-1). Finally, myotubes, derived from healthy donors, were stimulated with serum samples from DM and NM patients, subsequently followed by RT-PCR for the following candidates: IL-1ß, IL-6, nestin, and CD31. Results: Seventeen (17) DM patients, 7 NM patients, and 40 non-myositis controls were included. CD133+/VEGFR-2+ cells did not differ between the groups. Both DM and NM patients showed lower CFU-ECs than controls. In DM, intramuscular CD31 abundances were significantly reduced, which indicated vascular rarefaction. Muscular CXCR6 was elevated in both diseases. Circulating CXCL-16 was higher in DM and NM in contrast, compared to controls. Serum from patients with DM but not NM induced a profound upregulation of mRNS expression of CD31 and IL-6 in cultured myotubes. Conclusion: Our study demonstrates the loss of intramuscular microvessels in DM, accompanied by endothelial activation in DM and NM. Vascular regeneration was impaired in DM and NM. The findings suggest a role for inflammation-associated vascular damage in the pathogenesis of DM.

Health Care Quality in CKD Subjects: A Cross-Sectional In-Hospital Evaluation.

Methods: The study was performed in a retrospective and observational manner. All adult (age 18 years or older) in-hospital subjects treated from January until December 2019 were included. CKD was diagnosed according to the KDIGO 2012 CKD Guideline. The following variables were assessed: CKD stage, quantification/analysis (yes/no) of blood pressure, proteinuria, serum phosphate, serum 25-OH-D3, ferritin and transferrin saturation, and blood gas analysis. In addition, recommendations of the following medicines were analyzed (given/not given): ACE inhibitor or sartan, phosphate binder, vitamin D3 (activated or native), iron, erythropoietin, and bicarbonate. It was also evaluated whether discharge letters contained CKD-related diagnoses or not. Results: In total, 581 individuals were included in the study. The majority of aspects related to the monitoring and therapeutic management of CKD were either considered in only a small proportion of affected individuals (e.g., quantification of PTH - 5.5%/25-OH-D3 - 6%/transferrin saturation - 13.6%) or avoided nearly at all (e.g., recommendation of erythropoietin-1%, documentation of CKD-MBD diagnosis-0.3%). A reasonable quality of care was identified concerning the blood pressure monitoring (performed in 100%) and blood gas analysis (55% of the patients received analysis). Serum phosphate was measured in 12.9%, particularly in subjects at higher CKD stages. Conclusions: The current investigation revealed poor quality of care in CKD patients treated at the Brandenburg University Hospital over the period of one year. Quality improvement must be achieved, most likely via a standardized educational program for physicians and a directer access to CKD management guidelines.

Renal replacement therapy-requiring acute kidney injury due to tubulointerstitial nephritis and uveitis syndrome: case report.

BACKGROUND: Acute kidney injury is a major challenge for today's healthcare systems around the globe. Renal replacement therapy has been shown to be beneficial in acute kidney injury, but treatment highly depends on the cause of the acute kidney injury. One less common cause is tubulointerstitial nephritis, which comes in different entities. A very rare type of tubulointerstitial nephritis is tubulointerstitial nephritis and uveitis syndrome, in which the patient presents with additional uveitis. CASE PRESENTATION: A 19-year-old caucasian male presented with mild dyspnea, lack of appetite, weight loss, and moderate itchiness. Lab results showed an acute kidney injury with marked increase of serum creatinine. The patient was started on prednisolone immediately after admission. As the patient in this case showed symptoms of uremia on admission, we decided to establish renal replacement therapy, which is unusual in tubulointerstitial nephritis and uveitis syndrome. During his course of dialysis, the patient developed symptoms of sepsis probably due to a catheter-related infection requiring intensive care and antibiotic treatment, which had to be terminated early as the patient developed a rash. Intensified immunosuppression, combined with antibiotics, significantly resolved excretory kidney dysfunction. CONCLUSIONS: Since both the primary inflammatory process and the secondary infectious complication significantly impaired excretory kidney function, kidney function of younger individuals with new-onset anterior uveitis should be monitored over time and during follow-up.

Effective treatment of electrical storm by a wearable cardioverter defibrillator in a patient with severely impaired left ventricular function after myocardial infarction: a case report.

BACKGROUND: The implantation of cardioverter defibrillators (ICDs) is an established therapy in the prevention of sudden cardiac death in patients with systolic dysfunction after myocardial infarction. To avoid immediate implantation of an ICD, wearable cardioverter defibrillator vests (WCD) can be used to protect patients against malignant rhythm disorders, while at the same time drug-based heart failure therapy has to be initiated. This drug therapy can improve left ventricular ejection fraction and primary prophylactic cardioverter defibrillator implantation may not be necessary. However, the recent Vest Prevention of Early Sudden Death Trial (VEST) questioned the regular use of the WCD in this setting. CASE PRESENTATION: A 47-year-old Caucasian man with severely impaired left ventricular function early after myocardial infarction was prescribed a WCD as primary prophylaxis to prevent sudden cardiac death. Seven days after the patient was supplied with a WCD, the patient suffered from an electrical storm with recurrent ventricular tachycardia (VT), which was successfully terminated 17 times by the WCD. On coronary angiography, the formerly infarct-related right coronary artery had TIMI (Thrombolysis in Myocardial Ischemia Trial) III flow, and a remaining stenosis in the left anterior descending artery (LAD) was stented, which did not stop recurrent VT. In the electrophysiology (EP) study, a focus was mapped in the left inferior ventricle, which was ablated. This stopped the VT. A second radio-frequency (RF) ablation in the same area was necessary after 14 days. Finally, a permanent cardioverter defibrillator was implanted. CONCLUSION: We report the case of a patient who survived recurrent episodes of VT early after myocardial infarction by effective defibrillation with a WCD. The WCD is a useful device to bridge time until a final decision for implantation of a defibrillator.

AKI Epidemiology and Outcomes: A Retrospective Cohort Study from the Prenephrology Era.

BACKGROUND: Acute kidney injury substantially worsens the prognosis of hospitalized patients. The Brandenburg Medical School was founded in 2014, and a nephrology section was opened in summer 2017. The aim of the study was to analyze AKI epidemiology and outcomes in one of two university hospitals belonging to the medical school. The period of interest dated from January to December 2015. METHODS: The investigation was designed as a single-center, retrospective cohort study at the Brandenburg Hospital of the Brandenburg Medical School. All in-hospital patients treated between January and the end of December 2015 were included. AKI was defined as specified in the 2012 published KDIGO criteria (criteria 1 and 2). Four parameters were evaluated in particular: AKI incidence, in-hospital mortality, frequency of renal replacement therapy, and renal recovery during the stay at the hospital. RESULTS: A total number of 5,300 patients were included in the analysis. AKI was diagnosed in 490 subjects (10.1%). The in-hospital mortality was 26%. The following conditions/parameters significantly differed between survivors (s) and nonsurviving (ns) subjects: duration of in-hospital treatment (s > ns), AKI onset (outpatient vs. in-hospital) (outpatient in s > ns), dialysis due to AKI (s < ns), vasopressor administration (s < ns), and invasive ventilation (s < ns). 5.6% received dialysis therapy, and renal recovery occurred in 31% of all surviving AKI subjects. CONCLUSION: Both, the AKI incidence and the frequency of dialysis were lower than reported in the literature. However, fewer subjects recovered from AKI. These discrepant findings possibly result from the lack of prehospitalization creatinine values, the lack of follow-up data, and a generally lower awareness for the need to perform renal replacement therapy in AKI.

PAC-Mediated AKI Protection Is Critically Mediated but Does Not Exclusively Depend on Cell-Derived Microvesicles.

INTRODUCTION: Acute kidney injury (AKI) significantly worsens the prognosis of hospitalized patients. In recent years, cell-based strategies have been established as a reliable option for improving AKI outcomes in experimental AKI. Our previous studies focused on the so-called proangiogenic cells (PACs). Mechanisms that contribute to PAC-mediated AKI protection include production/secretion of extracellular vesicles (MV, microvesicles). In addition, the cells most likely act by paracrinic processes (secretome). The current study evaluated whether AKI may be preventable by the administration of either PAC-derived MV and/or the secretome alone. METHODS: AKI was induced in male C57/Bl6N mice (8-12 weeks) by bilateral renal ischemia (IRI-40 minutes). Syngeneic murine PACs were stimulated with either melatonin, angiopoietin-1 or -2, or with bone morphogenetic protein-5 (BMP-5) for one hour, respectively. PAC-derived MV and the vesicle-depleted supernatant were subsequently collected and i.v.-injected after ischemia. Mice were analyzed 48 hours later. RESULTS: IRI induced significant kidney excretory dysfunction as reflected by higher serum cystatin C levels. The only measure that improved AKI was the injection of MV, collected from native PACs. The following conditions worsened after ischemic renal function even further: MV + Ang-1, MV + BMP-5, MV + melatonin, and MV + secretome + Ang-1. CONCLUSION: Together, our data show that PAC-mediated AKI protection substantially depends on the availability of cell-derived MV. However, since previous data showed improved AKI-protection by PACs after cell preconditioning with certain mediators (Ang-1 and -2, melatonin, BMP-5), mechanisms other than exclusively vesicle-dependent mechanisms must be involved in PAC-mediated AKI protection.

Association of cytokine patterns and clinical/laboratory parameters, medication and periodontal burden in patients with rheumatoid arthritis (RA).

To evaluate serum levels of the following cytokines in rheumatoid arthritis subjects with periodontal disease: Interleukin-6, -10, -17, and -23. Patients with rheumatoid arthritis frequently suffer from periodontal disease. Both diseases partly result from a dysregulated immune response. The current study aimed to quantify Interleukin-6, -10, -17, and -23 levels in rheumatoid arthritis. It should be investigated if the periodontal disease would have additional modifying effects. A total of 157 patients were included. Serum levels of IL-6, -10, -17, and -23 were measured by ELISA. Serum IL-10 increased with longer duration of morning stiffness and with higher rheumatoid factor and anti-cyclic citrullinated peptide titres. IL-10 was also elevated with longer duration of prednisolone (< 5 mg daily) and leflunomide therapy. Subjects with lower erythrocyte sedimentation rate/longer leflunomide therapy displayed more missing teeth/more clinical attachment loss. IL-17 was higher in subjects with fewer missing teeth if the following criteria were fulfilled: shorter prednisolone (< 5 mg) and methotrexate therapy, more swollen joints, longer morning stiffness. IL-23 finally was increased in subjects with higher rheumatoid factor and in those with higher periodontal probing depth/clinical attachment loss in the following situations: lower rheumatoid factor and shorter leflunomide therapy. Subjects suffering from dental/periodontal burden show an aberrant systemic cytokine availability of serum IL-6, IL-10, IL-17 and IL-23 related to disease activity and medication. This examination underlines the complexity of potential interactions between disease activity and medication related to periodontal burden.

Early endothelial progenitor cells and vascular stiffness in psoriasis and psoriatic arthritis.

BACKGROUND: Both psoriasis (Ps) and psoriasis arthritis (PsA) have been associated with increased cardiovascular risk. Also, both are characterized by increased neovascularization. Endothelial progenitor cells (EPCs) have been implicated in promoting vascular repair in ischemic diseases. The aim of the study was to correlate the EPC system with CV risk factors and with parameters of vascular stiffness in Ps and PsA. METHODS: Twenty-six healthy subjects, 30 patients with Ps, and 31 patients PsA were included in the study. eEPC regeneration was evaluated by a colony-forming assay, circulating eEPCs were measured by cytometric analysis. For vascular analysis, all subjects underwent quantification of pulse wave velocity (PWV) and augmentation index (AIX). RESULTS: Patients were categorized upon the duration of disease, severity of skin involvement (PASI-Ps), individual pain as reflected by the VAS (PsA), CRP values, and history of treatment with one or more biologicals. Regarding the eEPC system, no significant differences were observed between the respective categories. Correlation analyses between parameters of vascular stiffness (PWV and AIX) and patterns of colony formation/circulating eEPCs did not show any correlation at all. CONCLUSION: Parameters of vascular stiffness are not significantly deteriorated in Ps/PsA. Thus, pulse wave analysis may not be suitable for CVR assessment in certain autoimmune-mediated diseases. Regenerative activity of the eEPC system/circulating eEPC numbers are not altered in Ps/PsA. One may conclude that malfunctions of the eEPC are not substantially involved in perpetuating the micro-/macrovascular alterations in Ps/PsA.

Contrast-Induced Nephropathy: Update on the Use of Crystalloids and Pharmacological Measures.

Contrast-induced nephropathy (CIN) is a frequent and severe complication in subjects receiving iodinated contrast media for diagnostic or therapeutic purposes. Several preventive strategies were evaluated in the past. Recent clinical studies and meta-analyses delivered some new aspects on preventive measures used in the past and present. We will discuss all pharmacological and nonpharmacological procedures. Finally, we will suggest individualized recommendations for CIN prevention.

Autophagy activation in circulating proangiogenic cells aggravates AKI in type I diabetes mellitus.

Acute kidney injury (AKI) occurs frequently in hospitals worldwide, but the therapeutic options are limited. Diabetes mellitus (DM) affects more and more people around the globe. The disease worsens the prognosis of AKI even further. In recent years, cell-based therapies have increasingly been applied in experimental AKI. The aim of the study was to utilize two established autophagy inducers for pharmacological preconditioning of so-called proangiogenic cells (PACs) in PAC treatment of diabetic AKI. Insulin-dependent DM was induced in male C57/Bl6N mice by intraperitoneal injections of streptozotocine. Six weeks later, animals underwent bilateral renal ischemia for 45 min, followed by intravenous injections of either native or zVAD (benzyloxycarbonyl-Val-Ala-Asp-fluoro-methylketone)- or Z-Leu-Leu-Leu-al (MG132)-pretreated syngeneic murine PACs. Mice were analyzed 48 h (short term) and 6 wk (long term) later, respectively. DM worsened postischemic AKI, and PAC preconditioning with zVAD and MG132 resulted in a further decline of excretory kidney function. Injection of native PACs reduced fibrosis in nondiabetic mice, but cell preconditioning promoted interstitial matrix accumulation significantly. Both substances aggravated endothelial-to-mesenchymal transition (EndoMT) under diabetic conditions; these effects occurred either exclusively in the short (zVAD) or in the short and long term (MG132). Preconditioned cells stimulated the autophagocytic flux in intrarenal endothelial cells, and all experimental groups displayed increased endothelial abundances of senescence-associated ß-galactosidase, a marker of premature cell senescence. Pharmacological autophagy activation may not serve as an effective strategy for improving PAC competence in diabetic AKI in general. On the contrary, several outcome parameters (excretory function, fibrosis, EndoMT) may even be worsened.

Endothelial Colony Forming Cells (ECFCs) in murine AKI - implications for future cell-based therapies.

BACKGROUND: In recent years, early Endothelial Progenitor Cells (eEPCs) have been proven as effective tool in murine ischemic AKI and in diabetic nephropathy. The mechanisms of eEPC-mediated vasoprotection have been elucidated in detail. Besides producing a diverse range of humoral factors, the cells also act by secreting vasomodulatory microvesicles. Only few data in contrast have been published about the role of so-called Endothelial Colony Forming Cells (ECFCs - late EPCs) in ischemic AKI. We thus aimed to investigate ECFC effects on postischemic kidney function over several weeks. Our special interest focused on endothelial-to-mesenchymal transition (EndoMT), peritubular capillary density (PTCD), endothelial alpha-Tubulin (aT - cytoskeletal integrity), and endothelial p62 (marker of autophagocytic flux). METHODS: Eight to twelve weeks old male C57Bl/6 N mice were subjected to bilateral renal pedicle clamping for 35 or 45 min, respectively. Donor-derived syngeneic ECFCs (0.5 × 106) were i.v. injected at the end of ischemia. Animals were analyzed 1, 4 and 6 weeks later. RESULTS: Cell therapy improved kidney function exclusively at week 1 (35 and 45 min). Ischemia-induced fibrosis was diminished in all experimental groups by ECFCs, while PTCD loss remained unaffected. Significant EndoMT was detected in only two of 6 groups (35 min, week 4 and 45 min, week 6), ECFCs reduced EndoMT only in the latter. Endothelial aT declined under almost all experimental conditions and these effects were further aggravated by ECFCs. p62 was elevated in endothelial cells, more so after 45 than after 35 min of ischemia. Cell therapy did not modulate p62 abundances at any time point. CONCLUSION: A single dose of ECFCs administered shortly post-ischemia is capable to reduce interstitial fibrosis in the mid- to long-term whereas excretory dysfunction is improved only in a transient manner. There are certain differences in renal outcome parameters between eEPCs and ECFC. The latter do not prevent animals from peritubular capillary loss and they also do not further elevate endothelial p62. We conclude that differences between eEPCs and ECFCs result from certain mechanisms by which the cells act around and within vessels. Overall, ECFC treatment was not as efficient as eEPC therapy in preventing mice from ischemia-induced mid- to long-term damage.

Acute Kidney Injury in Diabetes Mellitus.

Diabetes mellitus (DM) significantly increases the overall morbidity and mortality, particularly by elevating the cardiovascular risk. The kidneys are severely affected as well, partly as a result of intrarenal athero- and arteriosclerosis but also due to noninflammatory glomerular damage (diabetic nephropathy). DM is the most frequent cause of end-stage renal disease in our society. Acute kidney injury (AKI) remains a clinical and prognostic problem of fundamental importance since incidences have been increased in recent years while mortality has not substantially been improved. As a matter of fact, not many studies particularly addressed the topic "AKI in diabetes mellitus." Aim of this article is to summarize AKI epidemiology and outcomes in DM and current recommendations on blood glucose control in the intensive care unit with regard to the risk for acquiring AKI, and finally several aspects related to postischemic microvasculopathy in AKI of diabetic patients shall be discussed. We intend to deal with this relevant topic, last but not least with regard to increasing incidences and prevalences of both disorders, AKI and DM.

Early Endothelial Progenitor Cells (eEPCs) in systemic sclerosis (SSc) - dynamics of cellular regeneration and mesenchymal transdifferentiation.

BACKGROUND: Patients with systemic sclerosis (SSc) are endagered by tissue fibrosis and by microvasculopathy, with the latter caused by endothelial cell expansion/proliferation. SSc-associated fibrosis potentially results from mesenchymal transdifferentiation of endothelial cells. Early Endothelial Progenitor Cells (eEPCs) act proangiogenic under diverse conditions. Aim of the study was to analyze eEPC regeneration and mesenchymal transdifferentiation in patients with limited and diffuse SSs (lSSc and dSSc). METHODS: Patients with both, lSSc and dSSc were included into the study. The following parameters were evaluated: eEPC numbers and regeneration, concentrations of vasomodulatory mediators, mesenchymal properties of blood-derived eEPC. Serum samples of healthy subjects and SS patients were used for stimulation of cultured human eEPC, subsequently followed by analysis of mesenchymal cell characteristics and mobility. RESULTS: Twenty-nine patients were included into the study. Regenerative activity of blood-derived eEPCs did not differ between Controls and patients. Circulating eEPC were significantly lower in all patients with SSc, and in limited and diffuse SSc (lSSc/dSSc). Serum concentrations of promesenchymal TGF-b was elevated in all patients with SSc. Cultured mononuclear cells from SS patients displayed higher abundances of CD31 and of CD31 and aSMA combined. Finally, serum from SSc patients inhibited migration of cultured eEPCs and the cells showed lower sensitivity towards the endothelin antagonist Bosentan. CONCLUSIONS: The eEPC system, which represents an essential element of the endogenous vascular repair machinery is affected in SSc. The increased appearance of mesenchymal properties in eEPC may indicate that alterations of the cells potentially contribute to the accumulation of connective tissue and to vascular malfunction.

Postischemic microvasculopathy and endothelial progenitor cell-based therapy in ischemic AKI: update and perspectives.

Acute kidney injury (AKI) dramatically increases mortality of hospitalized patients. Incidences have been increased in recent years. The most frequent cause is transient renal hypoperfusion or ischemia which induces significant tubular cell dysfunction/damage. In addition, two further events take place: interstitial inflammation and microvasculopathy (MV). The latter evolves within minutes to hours postischemia and may result in permanent deterioration of the peritubular capillary network, ultimately increasing the risk for chronic kidney disease (CKD) in the long term. In recent years, our understanding of the molecular/cellular processes responsible for acute and sustained microvasculopathy has increasingly been expanded. The methodical approaches for visualizing impaired peritubular blood flow and increased vascular permeability have been optimized, even allowing the depiction of tissue abnormalities in a three-dimensional manner. In addition, endothelial dysfunction, a hallmark of MV, has increasingly been recognized as an inductor of both vascular malfunction and interstitial inflammation. In this regard, so-called regulated necrosis of the endothelium could potentially play a role in postischemic inflammation. Endothelial progenitor cells (EPCs), represented by at least two major subpopulations, have been shown to promote vascular repair in experimental AKI, not only in the short but also in the long term. The discussion about the true biology of the cells continues. It has been proposed that early EPCs are most likely myelomonocytic in nature, and thus they may simply be termed proangiogenic cells (PACs). Nevertheless, they reliably protect certain types of tissues/organs from ischemia-induced damage, mostly by modulating the perivascular microenvironment in an indirect manner. The aim of the present review is to summarize the current knowledge on postischemic MV and EPC-mediated renal repair.

The endothelial-to-mesenchymal transition and endothelial cilia in EPC-mediated postischemic kidney protection.

Renal ischemia induces peritubular capillary rarefication and fibrosis, with the latter partly resulting from the endothelial-to-mesenchymal transition (EndoMT). Endothelial cilia transmit blood flow-associated forces into the cell. Early endothelial progenitor cells (eEPCs) have been shown to protect mice from acute kidney injury in the short term. The aim of the present study was to analyze midterm consequences of eEPC treatment in the context of endothelial cilia and the EndoMT. Male C57/Bl6N mice were subjected to unilateral renal ischemia postuninephrectomy. Syngeneic murine eEPCs were systemically injected at the time of reperfusion. Animals were investigated 1, 4, and 6 wk later. Cultured mature endothelial cells were exposed to a variable flow with versus without eEPC supernatant incubation. Systemically injected eEPCs reduced serum creatinine levels at week 1 (35 and 45 min) and week 4 (45 min). Interstitial fibrosis was significantly diminished by cell treatment at all time points as well. The EndoMT was less pronounced at week 4 (35 min) and week 6 (45 min). eEPC supernatant reduced α-smooth muscle actin expression and α-tubulin abundance in flow-treated cultured mature endothelial cells, and percentages of cilium-positive cells increased. The loss of peritubular capillaries was prevented by eEPCs. Intrarenal endothelial α-tubulin decreased postischemia and was further reduced by eEPC administration. We conclude that eEPCs are capable of reorganizing the endothelial cytoskeleton in an indirect manner, ultimately resulting in stabilization of the endothelial ciliome. The investigation indicates an antimesenchymal role of endothelial cilia in the process of postischemic tissue fibrosis/EndoMT.

eEOC-mediated modulation of endothelial autophagy, senescence, and EnMT in murine diabetic nephropathy.

Diabetic nephropathy is the most frequent single cause of end-stage renal disease in our society. Microvascular damage is a key event in diabetes-associated organ malfunction. Early endothelial outgrowth cells (eEOCs) act protective in murine acute kidney injury. The aim of the present study was to analyze consequences of eEOC treatment of murine diabetic nephropathy with special attention on endothelial-to-mesenchymal transdifferentiation, autophagy, senescence, and apoptosis. Male C57/Bl6N mice (8-12 wk old) were treated with streptozotocin for 5 consecutive days. Animals were injected with untreated or bone morphogenetic protein (BMP)-5-pretreated syngeneic murine eEOCs on days 2 and 5 after the last streptozotocin administration. Four, eight, and twelve weeks later, animals were analyzed for renal function, proteinuria, interstitial fibrosis, endothelial-to-mesenchymal transition, endothelial autophagy, and senescence. In addition, cultured mature murine endothelial cells were investigated for autophagy, senescence, and apoptosis in the presence of glycated collagen. Diabetes-associated renal dysfunction (4 and 8 wk) and proteinuria (8 wk) were partly preserved by systemic cell treatment. At 8 wk, antiproteinuric effects were even more pronounced after the injection of BMP-5-pretreated cells. The latter also decreased mesenchymal transdifferentiation of the endothelium. At 8 wk, intrarenal endothelial autophagy (BMP-5-treated cells) and senescence (native and BMP-5-treated cells) were reduced. Autophagy and senescence in/of cultured mature endothelial cells were dramatically reduced by eEOC supernatant (native and BMP-5). Endothelial apoptosis decreased after incubation with eEOC medium (native and BMP-5). eEOCs act protective in diabetic nephropathy, and such effects are significantly stimulated by BMP-5. The cells modulate endothelial senescence, autophagy, and apoptosis in a protective manner. Thus, the renal endothelium could serve as a therapeutic target in diabetes-associated kidney dysfunction.

Successful treatment of a mycophenolate mofetil-refractory proliferative lupus nephritis with Belimumab in a 19-year-old woman.

We report the case of a 19-year-old woman with progressive proliferative lupus nephritis (LN) class III after induction and maintenance therapy with mycophenolate mofetil (MMF). Despite a satisfying clinical improvement proteinuria progressed under this medication. We treated the patient with additional belimumab after discussing other options. Following treatment with belimumab, proteinuria rapidly improved to almost normal levels and clinical remission lasted. Belimumab might hold promise for this indication.

The hormone melatonin stimulates renoprotective effects of "early outgrowth" endothelial progenitor cells in acute ischemic kidney injury.

Endothelial progenitor cells (EPCs) protect the kidney from acute ischemic injury. The aim of this study was to analyze whether pretreatment of murine "early outgrowth" EPCs (eEPCs) with the hormone melatonin increases the cells' renoprotective effects in the setting of murine acute ischemic renal failure. Male (8-12 wk old) C57Bl/6N mice were subjected to unilateral ischemia-reperfusion injury postuninephrectomy (40 min). Postischemic animals were injected with either 0.5×10(6) untreated syngeneic murine eEPCs or with cells, pretreated with melatonin for 1 h. Injections were performed shortly after reperfusion of the kidney. While animals injected with untreated cells developed acute renal failure, eEPC pretreatment with melatonin dramatically improved renoprotective actions of the cells. These effects were completely reversed after cell pretreatment with melatonin and the MT-1/-2 antagonist luzindole. In vitro analysis revealed that melatonin reduced the amount of tumor growth factor-ß-induced eEPC apoptosis/necrosis. Secretion of vascular endothelial growth factor by the cells was markedly stimulated by the hormone. In addition, migratory activity of eEPCs was enhanced by melatonin and supernatant from melatonin-treated eEPCs stimulated migration of cultured mature endothelial cells. In summary, melatonin was identified as a new agonist of eEPCs in acute ischemic kidney injury.

Microvasculopathy in ischemic acute kidney injury: consequences and therapeutic implications.

Ischemic acute kidney injury (iAKI) is the most frequent type of hospital-aquired acute renal failure (ARF). Mortality of ARF still ranges between 30% and 50%. Although acute renal ischemia significantly affects function and structure of the tubular epithelium, postischemic interstitial inflammation and microvasculopathy both contribute to ongoing renal dysfunction. The renal vasculature shows a highly specialized architecture. Renal ischemia induces severe alterations of the endothelium in small peritubular arterioles and capillaries. Investigations performed in recent years point towards a new therapeutic approach in iAKI, that is to target postischemic endothelial dysfunction by administering cells of the endothelial lineage. With regard to endothelial-type cells, new perspectives are offered with the identificaton of endothelial progenitor cells (EPCs). Although heterogenous in nature, EPCs can be employed for anti-ischemic treatment in different situations. Meanwhile the cells have been shown to protect mice from iAKI and several strategies have been established in order to increase the renoprotective capacity of EPCs. Further investigations will help to clarify whether EPCs not only protect the kidney in the short- but also in the long-term.