Comparison of the hemoglobin variability in non-chronic kidney disease or end-stage renal disease participants and patients with CKD and ESRD.

INTRODUCTION: Hemoglobin (Hb) variability occurs frequently in hemodialysis (HD) patients during erythropoietin (EPO) therapy. Guidelines define a narrow target range for the anemia treatment in these patients that is difficult to adhere to in practice. Our aim was to evaluate whether the Hb variability in HD patients is higher compared to non-chronic kidney disease or end-stage renal disease (ESRD) participants and patients with CKD stage I or II. MATERIALS AND METHODS: Monthly blood samples were assessed prospectively in 100 non-CKD or ESRD participants and 57 patients with CKD stage I or II, and retrospectively in 74 HD patients without changes in EPO or iron dose for 6 months. Variability was calculated and compared between the different groups. RESULTS: Hb variability was significantly higher in HD patients compared to the other groups, corresponding to results of previous studies. There were no significant differences between non-CKD or ESRD participants and patients with CKD stage I or II in terms of standard deviation (SD), residual SD, fluctuations across threshold, Hb cycling, and mean absolute change of Hb every 30 days (p > 0.05), but a significant difference compared to HD patients (p < 0.001). There were no significant differences between the groups in time in target and area under the curve (AUC) (p > 0.05). CONCLUSION: Hb variability is a common phenomenon in all groups independently of the method used for assessment and even without EPO therapy. The target range is difficult to achieve for HD patients and should be reconsidered in the future to avoid unsettling both the patients and the staff.

Development of a list with renally relevant drugs as a tool to increase medicines optimisation in patients with chronic kidney disease.

OBJECTIVES: Chronic kidney disease (CKD) is a common disorder all over the world. Therapeutic goals are early detection of declining renal function and implementation of adequate pharmacological treatments regarding underlying and secondary diseases. As therapy becomes more complex with increasing stages of CKD, a decision-making tool for healthcare professionals could help to ensure safe drug treatment in patients with CKD in the outpatient setting. Therefore, a list of renally relevant drugs as a decision-making tool was developed to improve medicines optimisation for CKD patients in the outpatient setting long term. METHODS: A renally relevant drug list (RRD-list) with renally relevant drugs, based on data from a study on medicines optimisation in patients with CKD from June 2015 to March 2018, was developed at the nephrological outpatient clinic at the Klinikum Fulda, Germany. The whole study is published elsewhere. A clinical pharmacist reviewed the patients' medications, current drug-related problems and all nephrologists' recommendations, and categorised all detected drugs into renally relevant and non-renally relevant groups. The 10 most frequently detected renally relevant drug groups were summarised in the RRD-list and extended by treatment alternatives and advice. RESULTS: The medication of 160 patients, who were receiving overall 1376 drugs, was analysed; 831 drugs were defined as renally relevant. Drug-related problems were caused by 543 renally relevant drugs. The nephrologists made 292 recommendations regarding 28 drug classes. Considering the 10 most frequent drug groups, in total 16 renally relevant drug groups with 36 drug classes were added to the RRD-list. CONCLUSIONS: The RRD-list could be an essential tool for all healthcare professionals in their daily work, such as general practitioners and community pharmacists, for the treatment of patients with renal insufficiency.

[KDIGO 2021 guideline glomerulonephritis - focus on ANCA-associated vasculitides and anti-glomerular basement membrane glomerulonephritis]. / KDIGO-Leitlinien 2021 zur Glomerulonephritis ­ Focus ANCA-assoziierte Vaskulitiden und antiglomeruläre Basalmembran-Nephritis.

In 2021 new KDIGO (Kidney Disease: Improving Global Outcomes) guidelines for the management of glomerular diseases were published.For ANCA-associated glomerulonephritis the new recommendations comprise a more rapid steroid taper during induction treatment with cyclophosphamide or rituximab, the advice against routine use of plasma exchange, the choice of drug for and duration of maintenance treatment in accordance with predictors of relapse. A kidney transplant should be performed after at least 6 months of remission irrespective of the ANCA titer in ANCA-associated disease, and 6 months after absence of anti-GBM-antibodies in anti-GBM-disease.

Chemokine/Cytokine Levels Correlate with Organ Involvement in PR3-ANCA-Associated Vasculitis.

BACKGROUND: ANCA-associated vasculitis (AAV) is a rare small vessel disease characterized by multi-organ involvement. Biomarkers that can measure specific organ involvement are missing. Here, we ask whether certain circulating cytokines and chemokines correlate with renal involvement and if distinct cytokine/chemokine patterns can differentiate between renal, ear/nose/throat, joints, and lung involvement of AAV. METHODS: Thirty-two sets of Birmingham vasculitis activity score (BVAS), PR3-ANCA titers, laboratory marker, and different cytokines were obtained from 17 different patients with AAV. BVAS, PR3-ANCA titers, laboratory marker, and cytokine concentrations were correlated to different organ involvements in active AAV. RESULTS: Among patients with active PR3-AAV (BVAS > 0) and kidney involvement we found significant higher concentrations of chemokine ligand (CCL)-1, interleukin (IL)-6, IL21, IL23, IL-28A, IL33, monocyte chemoattractant protein 2 (MCP2), stem cell factor (SCF), thymic stromal lymphopoietin (TSLP), and thrombopoietin (TPO) compared to patients without PR3-ANCA-associated glomerulonephritis. Patients with ear, nose, and throat involvement expressed higher concentrations of MCP2 and of the (C-X-C motif) ligand-12 (CXCL-12) compared to patients with active AAV and no involvement of these organs. CONCLUSION: We identified distinct cytokine patterns for renal manifestation and for ear, nose and throat involvement of PR3-AAV. Distinct plasma cytokines might be used as non-invasive biomarkers of organ involvement in AAV.

Medicines optimization for patients with chronic kidney disease in the outpatient setting: the role of the clinical pharmacist.

OBJECTIVES: Medicines optimization (MO) in patients with chronic kidney disease (CKD) is at high risk at transition points of different ambulatory care levels such as nephrologists in outpatient clinics and general practitioners (GPs). We examined if adding a clinical pharmacist to the therapeutic team promotes implementation of nephrologists' drug therapy recommendations by GPs' and reduces drug-related problems (DRPs). METHODS: A prospective, controlled intervention study was conducted in the nephrology outpatient clinic of the Klinikum Fulda, Germany. The control and intervention phases took place successively. Patients with CKD stage 3-5 and at least one concomitant disease, for example, arterial hypertension or type-2 diabetes were recruited consecutively in three subgroups (naive, 1 contact, ≥2 contacts with nephrologist) from June 2015 to May 2019. GPs' acceptance and frequency of DRPs without (control group [CG]) and with (intervention group [IG]) pharmacist's interventions were compared after 6 months. Interventions include educational training events for GPs between control- and intervention phase, medication therapy management and pharmaceutical patient counselling. KEY FINDINGS: In total, 256 patients (CG = 160, IG = 96) were recruited into the study. GPs' acceptance of nephrologists' medication recommendations increased significantly among naive patients and those with one prior contact with the nephrologist (CG/IG: naive = 72.8%/95.5%, 1 contact = 81.1%/94.4%; P < 0.001). DRPs per patient were significantly reduced in all subgroups (P < 0.001). CONCLUSIONS: Interdisciplinary collaboration between the nephrologist, GPs and clinical pharmacist resulted in better MO for patients with CKD.

[Coronavirus disease 2019 pandemic from a nephrological perspective]. / "Coronavirus-disease-2019"-Pandemie aus nephrologischer Perspektive.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has also resulted in substantial challenges for nephrology worldwide. Patients with chronic kidney diseases are a particularly vulnerable patient group in this context and in severe courses of COVID-19 the kidneys are most frequently affected by organ failure after the lungs. MATERIAL AND METHODS: In order to reliably evaluate the prevalence and mortality of dialysis patients in Germany with respect to COVID-19, during the first wave in spring 2020 the German Society of Nephrology implemented a registry for dialysis patients. Weekly data on the number and course of dialysis patients affected by COVID-19 were recorded and analyzed. RESULTS: The prevalence of COVID-19 in dialysis patients in Germany developed in two waves, similar to the course of the pandemic in the general population. In spring the prevalence in dialysis patients reached 1.4% and considerably declined during the summer. In December during the second wave of the pandemic the prevalence again rose to 1.9%, despite comprehensively implemented hygiene measures in dialysis centers. Similar to other industrial nations, dialysis patients in Germany also showed a very high lethality of COVID-19 of up to 20%. CONCLUSION: Immediate consequences for hygiene measures in dialysis institutions as well as vaccination strategies and vaccination prioritization for this patient group and the personnel treating them can be derived from the high mortality in dialysis patients. A consequence of the frequent involvement of the kidneys during infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients who had not previously suffered from advanced kidney disease should be the consistent nephrological aftercare.

Pre-transplant HLA Antibodies and Delayed Graft Function in the Current Era of Kidney Transplantation.

Delayed graft function (DGF) occurs in a significant proportion of deceased donor kidney transplant recipients and was associated with graft injury and inferior clinical outcome. The aim of the present multi-center study was to identify the immunological and non-immunological predictors of DGF and to determine its influence on outcome in the presence and absence of human leukocyte antigen (HLA) antibodies. 1,724 patients who received a deceased donor kidney transplant during 2008-2017 and on whom a pre-transplant serum sample was available were studied. Graft survival during the first 3 post-transplant years was analyzed by multivariable Cox regression. Pre-transplant predictors of DGF and influence of DGF and pre-transplant HLA antibodies on biopsy-proven rejections in the first 3 post-transplant months were determined by multivariable logistic regression. Donor age ≥50 years, simultaneous pre-transplant presence of HLA class I and II antibodies, diabetes mellitus as cause of end-stage renal disease, cold ischemia time ≥18 h, and time on dialysis >5 years were associated with increased risk of DGF, while the risk was reduced if gender of donor or recipient was female or the reason for death of donor was trauma. DGF alone doubled the risk for graft loss, more due to impaired death-censored graft than patient survival. In DGF patients, the risk of death-censored graft loss increased further if HLA antibodies (hazard ratio HR=4.75, P < 0.001) or donor-specific HLA antibodies (DSA, HR=7.39, P < 0.001) were present pre-transplant. In the presence of HLA antibodies or DSA, the incidence of biopsy-proven rejections, including antibody-mediated rejections, increased significantly in patients with as well as without DGF. Recipients without DGF and without biopsy-proven rejections during the first 3 months had the highest fraction of patients with good kidney function at year 1, whereas patients with both DGF and rejection showed the lowest rate of good kidney function, especially when organs from ≥65-year-old donors were used. In this new era of transplantation, besides non-immunological factors, also the pre-transplant presence of HLA class I and II antibodies increase the risk of DGF. Measures to prevent the strong negative impact of DGF on outcome are necessary, especially during organ allocation for presensitized patients.

[Anti B-cell-antibody treatment for maintenance of remission in granulomatosis with polyangiitis and microscopic polyangiitis]. / Anti-B-Zell-Antikörpertherapie zur Remissionserhaltung bei Granulomatose mit Polyangiitis und mikroskopischer Polyangiitis.

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are the most frequent primary necrotizing small vessel vasculitides. In these formerly fatal diseases remission can be induced by stage- and activity-adapted immunosuppressive regimens in the majority of patients. This does not lead to drug-free long-term remission or even cure. Consequently, maintenance of remission medication is needed. Recent randomized controlled trials demonstrated that maintenance treatment with the anti-B-cell antibody Rituximab, administered 6-monthly as opposed to azathioprine leads to a significantly lower relapse rate but a similar profile of adverse events. These data enabled the extension of the approval of Rituximab for maintenance of remission treatment of GPA and MPA in Germany in 2018. Guidelines and expert recommendations concerning measures of infection prevention and vaccination of immunosuppressed patients as well as the management of hypogammaglobulinemia and cytopenia on Rituximab are presented in this review.

[Rapid progressive glomerulonephritis]. / Rapid-progressive Glomerulonephritis.

The rapid progressive glomerulonephritis is an emergency case. Renal function is rapidly lost within weeks or a few months (rarely within days) due to necrotizing extracapillary proliferative crescentic glomerulonephritis. Early diagnosis and treatment improve prognosis, as the best prognostic marker is creatinine when treatment is initiated. Three classes can be distinguished by immunofluorescence in histology. Firstly, there are no or only few immunoglobulins found (anti-neutrophil cytoplasmic antibody [ANCA]-associated vasculitis). Secondly, there is linear immunofluorescence due to antibodies against the glomerular basement membrane (anti-glomerular basement membrane [GBM] disease or Goodpasture syndrome); and thirdly, there is a granular pattern of immunoglobulin deposition (for example systemic lupus erythematosus [SLE], Schoenlein-Henoch purpura or cryoglobulinaemia). The immunosuppressive repertoire has improved (such as induction therapy in ANCA-associated vasculitis with lower total steroid dose, cyclophosphamide pulses or rituximab). New treatment approaches are on their way and the prognosis regarding life expectancy and renal function has improved. There are still challenging questions to answer like treatment duration and markers of recurrence.

Equally Interchangeable? How Sex and Gender Affect Transplantation.

Organ transplantation as an option to overcome end-stage diseases is common in countries with advanced healthcare systems and is increasingly provided in emerging and developing countries. A review of the literature points to sex- and gender-based inequity in the field with differences reported at each step of the transplant process, including access to a transplantation waiting list, access to transplantation once waitlisted, as well as outcome after transplantation. In this review, we summarize the data regarding sex- and gender-based disparity in adult and pediatric kidney, liver, lung, heart, and hematopoietic stem cell transplantation and argue that there are not only biological but also psychological and socioeconomic issues that contribute to disparity in the outcome, as well as an inequitable access to transplantation for women and girls. Because the demand for organs has always exceeded the supply, the transplant community has long recognized the need to ensure equity and efficiency of the organ allocation system. In the spirit of equity and equality, the authors call for recognition of these inequities and the development of policies that have the potential to ensure that girls and women have equitable access to transplantation.

[Renal manifestation in ANCA-associated vasculitis]. / Nierenbeteiligung bei ANCA-assoziierten Vaskulitiden.

In patients with ANCA-associated vasculitis renal involvement is frequently seen and the severity of renal manifestation is very important for therapeutic strategies and prognosis. Clinically rapid loss of renal function, nephritic sediment and proteinuria in a non-nephrotic range are characterizing a focal segmental necrotizing pauci-immune glomerulonephritis with extrarenal proliferations. Induction treatment depends on the severity of manifestations. With a normal renal function methotrexate can be used in combination with steroids. In patients with organ threatening involvement but creatinine below 500 µmol/l cyclophosphamide pulses or Rituximab should be used together with steroids, initially with i. v. pulses. Rituximab is more effective in PR3-ANCA vasculitis and should be used in relapsing disease, in young patients to avoid gonadal toxicity and in patients with an increased risk of malignancies. In patients on dialysis or with creatinine > 500 µmol/l plasma exchange should be added. Maintenance treatment (mainly with azathioprine) is necessary as at least 50 % of the patients develop relapses. Rituximab seems more effective, however it is not approved for maintenance treatment and no long-term data are available. Adjuvant treatment, long-term side effects and the increased incidence of cardiovascular events have to be included in the follow-up of vasculitis patients. In end-stage renal disease patients relapses occur but are more difficult to diagnose and treat with higher incidence of infections. Transplantation should be offered as patient and transplant survival is good.

Randomised controlled trial of prolonged treatment in the remission phase of ANCA-associated vasculitis.

OBJECTIVES: A prospective randomised trial to compare two different durations of maintenance immunosuppressive therapy for the prevention of relapse in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). METHODS: Patients with AAV were recruited 18-24 months after diagnosis if they were in stable remission after cyclophosphamide/prednisolone-based induction followed by azathioprine/prednisolone maintenance therapy. They were randomised (1:1) to receive continued azathioprine/prednisolone to 48 months from diagnosis (continuation group) or to withdraw azathioprine/prednisolone by 24 months (withdrawal group). The primary endpoint was the relapse risk, from randomisation to 48 months from diagnosis. RESULTS: One hundred and seventeen patients were randomised and 110 remained to the trial end. At entry, median serum creatinine was 116 µmol/L (range 58-372), 53% were ANCA positive. The percentage of patients presenting with relapse was higher in the withdrawal than in the continuation treatment group (63% vs 22%, p<0.0001, OR 5.96, 95% CI 2.58 to 13.77). ANCA positivity at randomisation was associated with relapse risk (51% vs 29%, p=0.017, OR 2.57, 95% CI 1.16 to 5.68). Renal function, ANCA specificity, vasculitis type and age were not predictive of relapse. Severe adverse events were more frequent in the continuation than withdrawal groups (nine vs three events), but the continuation group had better renal outcome (0 vs 4 cases of end-stage renal disease), with no difference in patient survival. CONCLUSIONS: Prolonged remission maintenance therapy with azathioprine/prednisolone, beyond 24 months after diagnosis reduces relapse risk out to 48 months and improves renal survival in AAV. TRIAL REGISTRATION NUMBER: ISRCTN13739474.

Noninvasive diagnosis of chronic kidney diseases using urinary proteome analysis.

BACKGROUND: In spite of its invasive nature and risks, kidney biopsy is currently required for precise diagnosis of many chronic kidney diseases (CKDs). Here, we explored the hypothesis that analysis of the urinary proteome can discriminate different types of CKD irrespective of the underlying mechanism of disease. METHODS: We used data from the proteome analyses of 1180 urine samples from patients with different types of CKD, generated by capillary electrophoresis coupled to mass spectrometry. A set of 706 samples served as the discovery cohort, and 474 samples were used for independent validation. For each CKD type, peptide biomarkers were defined using statistical analysis adjusted for multiple testing. Potential biomarkers of statistical significance were combined in support vector machine (SVM)-based classifiers. RESULTS: For seven different types of CKD, several potential urinary biomarker peptides (ranging from 116 to 619 peptides) were defined and combined into SVM-based classifiers specific for each CKD. These classifiers were validated in an independent cohort and showed good to excellent accuracy for discrimination of one CKD type from the others (area under the receiver operating characteristic curve ranged from 0.77 to 0.95). Sequence analysis of the biomarkers provided further information that may clarify the underlying pathophysiology. CONCLUSIONS: Our data indicate that urinary proteome analysis has the potential to identify various types of CKD defined by pathological assessment of renal biopsies and current clinical practice in general. Moreover, these approaches may provide information to model molecular changes per CKD.

Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis.

ANCA-associated vasculitides are characterized by inflammatory destruction of small vessels accompanied by enhanced cleavage of membrane-bound proteins. One of the main proteases responsible for ectodomain shedding is disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). Given its potential role in aggravating vascular dysfunction, we examined the role of ADAM17 in active proteinase-3 (PR3)-positive ANCA-associated vasculitis (AAV). ADAM17 concentration was significantly increased in plasma samples from patients with active PR3-AAV compared with samples from patients in remission or from other controls with renal nonvascular diseases. Comparably, plasma levels of the ADAM17 substrate syndecan-1 were significantly enhanced in active AAV. We also observed that plasma-derived ADAM17 retained its specific proteolytic activity and was partly located on extracellular microparticles. Transcript levels of ADAM17 were increased in blood samples of patients with active AAV, but those of ADAM10 or tissue inhibitor of metalloproteinases 3, which inhibits ADAMs, were not. We also performed a microRNA (miR) screen and identified miR-634 as significantly upregulated in blood samples from patients with active AAV. In vitro, miR-634 mimics induced a proinflammatory phenotype in monocyte-derived macrophages, with enhanced expression and release of ADAM17 and IL-6. These data suggest that ADAM17 has a prominent role in AAV and might account for the vascular complications associated with this disease.

Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides.

Progressive CKD is generally detected at a late stage by a sustained decline in eGFR and/or the presence of significant albuminuria. With the aim of early and improved risk stratification of patients with CKD, we studied urinary peptides in a large cross-sectional multicenter cohort of 1990 individuals, including 522 with follow-up data, using proteome analysis. We validated that a previously established multipeptide urinary biomarker classifier performed significantly better in detecting and predicting progression of CKD than the current clinical standard, urinary albumin. The classifier was also more sensitive for identifying patients with rapidly progressing CKD. Compared with the combination of baseline eGFR and albuminuria (area under the curve [AUC]=0.758), the addition of the multipeptide biomarker classifier significantly improved CKD risk prediction (AUC=0.831) as assessed by the net reclassification index (0.303±-0.065; P<0.001) and integrated discrimination improvement (0.058±0.014; P<0.001). Correlation of individual urinary peptides with CKD stage and progression showed that the peptides that associated with CKD, irrespective of CKD stage or CKD progression, were either fragments of the major circulating proteins, suggesting failure of the glomerular filtration barrier sieving properties, or different collagen fragments, suggesting accumulation of intrarenal extracellular matrix. Furthermore, protein fragments associated with progression of CKD originated mostly from proteins related to inflammation and tissue repair. Results of this study suggest that urinary proteome analysis might significantly improve the current state of the art of CKD detection and outcome prediction and that identification of the urinary peptides allows insight into various ongoing pathophysiologic processes in CKD.

L-arginine/NO pathway is altered in children with haemolytic-uraemic syndrome (HUS).

The haemolytic uraemic syndrome (HUS) is the most frequent cause of acute renal failure in childhood. We investigated L-arginine/NO pathway in 12 children with typical HUS and 12 age-matched healthy control subjects. Nitrite and nitrate, the major NO metabolites in plasma and urine, asymmetric dimethylarginine (ADMA) in plasma and urine, and dimethylamine (DMA) in urine were determined by GC-MS and GC-MS/MS techniques. Urinary measurements were corrected for creatinine excretion. Plasma nitrate was significantly higher in HUS patients compared to healthy controls (P = 0.021), whereas urine nitrate was borderline lower in HUS patients compared to healthy controls (P = 0.24). ADMA plasma concentrations were insignificantly lower, but urine ADMA levels were significantly lower in the HUS patients (P = 0.019). Urinary DMA was not significantly elevated. In HUS patients, nitrate (R = 0.91) but not nitrite, L-arginine, or ADMA concentrations in plasma correlated with free haemoglobin concentration. Our results suggest that both NO production and ADMA synthesis are decreased in children with typical HUS. We hypothesize that in the circulation of children with HUS a vicious circle between the L-arginine/NO pathway and free haemoglobin-mediated oxidative stress exists. Disruption of this vicious circle by drugs that release NO and/or sulphydryl groups-containing drugs may offer new therapeutic options in HUS.

Coping strategies and depressiveness in primary systemic vasculitis--what is their impact on health-related quality of life?

OBJECTIVE: To investigate the influence of disease-related coping strategies and depressiveness on health-related quality of life (HRQOL) in primary systemic vasculitis (PSV) patients. METHODS: One hundred and twenty-two patients with definite diagnosis of PSV were examined in a cross-sectional study. HRQOL (SF-36), depressiveness (BDI), illness perception (B-IPQ) and coping strategies (FKV-LIS) were measured using validated instruments. Additional disease-related and demographic data were retrieved from the patients' records. RESULTS: HRQOL in PSV patients was reduced compared with the SF-36 norm sample. Specific organ manifestation, size of vessel involvement and disease activity were not related to HRQOL. Linear regression modelling revealed a questionable relationship of emotional to physical HRQOL (P = 0.003, potential suppression effect of BDI), whereas both domains were influenced by depressiveness (P ≤ 0.001). Physical HRQOL was additionally related to fatigue and widowed marital status, while emotional HRQOL was associated with a depressive coping style. CONCLUSION: HRQOL is impaired in PSV as compared with the general population. Current depressiveness strongly affects physical as well as mental HRQOL. Cognitive intervention strategies should be established in order to improve quality of life in PSV patients.

Aldosterone modulates endothelial permeability and endothelial nitric oxide synthase activity by rearrangement of the actin cytoskeleton.

Aldosterone (Aldo) is involved in vascular remodeling and inflammation; however, the mechanisms are imperfectly defined. We hypothesized that Aldo alters endothelial integrity and modifies paracellular permeability. Human umbilical vein endothelial cells were exposed to Aldo (10(-9) mol/L) and alterations in paracellular permeability, assembly of tight and adherens junctions and activation of intracellular signaling pathways were determined. Aldo increased endothelial permeability for molecules ≤ 70 kDa within 60 minutes. A transient loss of cortical actin with formation of actin stress fibers and disruption of continuous adherens and tight junction strands accompanied these changes. Mineralocorticoid receptor blockade, inhibition of RhoA, or disruption of extracellular-regulated protein kinase1/2 signaling pathways attenuated the Aldo-related effects. Moreover, Aldo-induced cytoskeletal rearrangement led to rapid dephosphorylation of protein kinase B and subsequent deactivation of endothelial nitric oxide synthase. Ex vivo tracer flux experiments with Evans blue-conjugated albumin demonstrated a concordant response to Aldo in freshly isolated umbilical arteries. Furthermore, low-dose cortisol (3 × 10(-10) to 3 × 10(-9) mol/L) mimics the effect of Aldo on endothelial integrity, and Aldo, by upregulating11ß-hydroxysteroid dehydrogenase type 2, might even aggravate this deleterious effect of low-dose cortisol. We suggest that these mechanisms may contribute to the vasculopathy induced by inappropriate mineralocorticoid receptor activation.