CD8 T cells are dispensable for experimental autoimmune prostatitis induction and chronic pelvic pain development.

Introduction: Chronic Pelvic Pain Syndrome or Chronic Prostatitis (CPPS/CP) is the most prevalent urologic affliction among young adult men. It is a challenging condition to treat, which significantly decreases patient quality of life, mostly because of its still uncertain aetiology. In that regard, an autoimmune origin is a prominent supported theory. Indeed, studies in patients and in rodent models of Experimental Autoimmune Prostatitis (EAP) have provided compelling evidence suggesting a key role of CD4 Th1 cells in disease pathogenesis. However, the implication of other prominent effectors of the immune system, such as CD8 T cells, has yet to be studied. Methods: We herein analyzed the induction of prostatitis and the development of chronic pelvic pain in EAP using CD8 T cell-deficient animals. Results: We found similarly elevated PA-specific immune responses, with high frequencies of specific IFNg+CD4+ and IL17+CD4+ T cells in prostate draining lymph nodes from PA-immunized either CD8 KO or wild type animals with respect to controls. Moreover, these peripheral immune responses were paralleled by the development of significant chronic pelvic pain, and accompanied by prostate histological lesions, characterized by hemorrhage, epithelial cell desquamation, marked periglandular leukocyte infiltration, and increased collagen deposition in both, PA-immunized CD8 KO and wild type animals. As expected, control animals did not develop prostate histological lesions. Discussion: Our results indicate that CD8 T cells do not play a major role in EAP pathogenesis and chronic pelvic pain development. Moreover, our results corroborate the previous notion that a CD4 Th1 associated immune response drives the induction of prostate tissue inflammation and the development of chronic pelvic pain.

Desensitizing the autonomic nervous system to mitigate anti-GD2 monoclonal antibody side effects.

Background: Anti-GD2 monoclonal antibodies (mAbs) have shown to improve the overall survival of patients with high-risk neuroblastoma (HR-NB). Serious adverse events (AEs), including pain, within hours of antibody infusion, have limited the development of these therapies. In this study, we provide evidence of Autonomic Nervous System (ANS) activation as the mechanism to explain the main side effects of anti-GD2 mAbs. Methods: Through confocal microscopy and computational super-resolution microscopy experiments we explored GD2 expression in postnatal nerves of infants. In patients we assessed the ANS using the Sympathetic Skin Response (SSR) test. To exploit tachyphylaxis, a novel infusion protocol (the Step-Up) was mathematically modelled and tested. Results: Through confocal microscopy, GD2 expression is clearly visible in the perineurium surrounding the nuclei of nerve cells. By computational super-resolution microscopy experiments we showed the selective expression of GD2 on the cell membranes of human Schwann cells in peripheral nerves (PNs) significantly lower than on NB. In patients, changes in the SSR were observed 4 minutes into the anti-GD2 mAb naxitamab infusion. SSR latency quickly shortened followed by gradual decrease in the amplitude before disappearance. SSR response did not recover for 24 hours consistent with tachyphylaxis and absence of side effects in the clinic. The Step-Up protocol dissociated on-target off-tumor side effects while maintaining serum drug exposure. Conclusion: We provide first evidence of the ANS as the principal non-tumor target of anti-GD2 mAbs in humans. We describe the development and modeling of the Step-Up protocol exploiting the tachyphylaxis phenomenon we demonstrate in patients using the SSR test.

CD39 expression by regulatory T cells participates in CD8+ T cell suppression during experimental Trypanosoma cruzi infection.

An imbalance between suppressor and effector immune responses may preclude cure in chronic parasitic diseases. In the case of Trypanosoma cruzi infection, specialized regulatory Foxp3+ T (Treg) cells suppress protective type-1 effector responses. Herein, we investigated the kinetics and underlying mechanisms behind the regulation of protective parasite-specific CD8+ T cell immunity during acute T. cruzi infection. Using the DEREG mouse model, we found that Treg cells play a role during the initial stages after T. cruzi infection, restraining the magnitude of CD8+ T cell responses and parasite control. Early Treg cell depletion increased the frequencies of polyfunctional short-lived, effector T cell subsets, without affecting memory precursor cell formation or the expression of activation, exhaustion and functional markers. In addition, Treg cell depletion during early infection minimally affected the antigen-presenting cell response but it boosted CD4+ T cell responses before the development of anti-parasite effector CD8+ T cell immunity. Crucially, the absence of CD39 expression on Treg cells significantly bolstered effector parasite-specific CD8+ T cell responses, preventing increased parasite replication in T. cruzi infected mice adoptively transferred with Treg cells. Our work underscores the crucial role of Treg cells in regulating protective anti-parasite immunity and provides evidence that CD39 expression by Treg cells represents a key immunomodulatory mechanism in this infection model.

Interferon Upregulation Associates with Insulin Resistance in Humans.

In humans, insulin resistance is a physiological response to infections developed to supply sufficient energy to the activated immune system. This metabolic adaptation facilitates the immune response but usually persists after the recovery period of the infection and predisposes the hosts to type 2 diabetes and vascular injury. In patients with diabetes, superimposed insulin resistance worsens metabolic control and promotes diabetic ketoacidosis. Pathogenic mechanisms underlying insulin resistance during microbial invasions remain to be fully defined. However, interferons cause insulin resistance in healthy subjects and other population groups, and their production is increased during infections, suggesting that this group of molecules may contribute to reduced insulin sensitivity. In agreement with this notion, gene expression profiles [transcriptomes] from patients with insulin resistance show a robust overexpression of interferon-stimulated genes [interferon signature]. In addition, serum levels of interferon and surrogates for interferon activity are elevated in patients with insulin resistance. Circulating levels of interferon-γ-inducible protein-10, neopterin, and apolipoprotein L1 correlate with insulin resistance manifestations, such as hypertriglyceridemia, reduced HDL-c, visceral fat, and homeostasis model assessment-insulin resistance. Furthermore, interferon downregulation improves insulin resistance. Antimalarials such as hydroxychloroquine reduce interferon production and improve insulin resistance, reducing the risk for type 2 diabetes and cardiovascular disease. In addition, diverse clinical conditions that feature interferon upregulation are associated with insulin resistance, suggesting that interferon may be a common factor promoting this adaptive response. Among these conditions are systemic lupus erythematosus, sarcoidosis, and infections with severe acute respiratory syndrome-coronavirus-2, human immunodeficiency virus, hepatitis C virus, and Mycobacterium tuberculosis.

Impact of an interventional bundle on complications associated with peripheral venous catheters in elderly patients.

PURPOSE: Elderly patients admitted to geriatrics departments often require peripheral venous catheters (PVC), which should be inserted and maintained following a series of preventive recommendations. Our objective was to evaluate the impact of a training bundle comprising measures aimed at reducing complications associated with the use of PVC in elderly patients admitted to a tertiary teaching hospital. METHODS: We performed a prospective study of patients who received a PVC within 24 h of admission to a geriatrics department. After a 10-month pre-interventional period, we implemented an educational and interventional bundle over a 9-month period. Follow-up was until catheter withdrawal. We analyzed and compared clinical and microbiological data between both study periods. RESULTS: A total of 344 patients (475 PVC) were included (pre-intervention period, 204 patients (285 PVC); post-intervention period, 140 patients (190 PVC)). No statistically significant differences in demographic characteristics were observed between the study periods. The colonization and phlebitis rates per 1000 admissions in both periods were, respectively, 36.7 vs. 24.3 (p = 0.198) and 81.5 vs. 65.1 (p = 0.457). The main reason for catheter withdrawal was obstruction/malfunctioning (33.3%). Obstruction rate was higher for those inserted in the hand than for those inserted at other sites (55.7% vs. 44.3%, p = 0.045). CONCLUSIONS: We found no statistically significant differences regarding phlebitis and catheter tip colonization rates. It is necessary to carry out randomized studies assessing the most cost-effective measure to reduce complications associated with PVC.

Fatigue insights from walking tests in spinal cord injury and multiple sclerosis individuals.

In the last decade, fatigue in clinical populations has been re-conceptualized, including dimensions such as perceived fatigue (trait and state fatigue) and fatigability. The aim of this study was to evaluate different expressions of fatigue in Spinal Cord Injury (SCI) and Multiple Sclerosis (MS) participants compared to able-bodied controls, during activities of daily living, especially during gait. A total of 67 participants were included in this study (23 with SCI, 23 with MS, and 21 able-bodied controls). All participants performed two functional tests (6-Minute Walk Test and 10-Meter Walk Test) and they completed the Fatigue Severity Scale (FSS). The rate of trait fatigue was different between groups, with MS participants showing the highest rate. Moreover, scores on functional tests and state fatigue were different between groups after the tests. Our results indicate that trait fatigue and state fatigue in individuals with SCI and MS are different with respect to able-bodied population. Both SCI and MS groups experienced more trait fatigue than control group in daily life. In addition, walking tasks produced similar levels of state fatigue between healthy people and patients with MS/SCI. However, these tests induced longer-lasting levels of state fatigue in the patients.

Does a Resistance Training Program Affect Between-arms Volume Difference and Shoulder-arm Disabilities in Female Breast Cancer Survivors? The Role of Surgery Type and Treatments. Secondary Outcomes of the EFICAN Trial.

OBJECTIVE: The aims were (i) to assess the effects of a 12-week resistance training program on between-arms volume difference and shoulder-arm disabilities in breast cancer survivors and (ii) to evaluate whether the main risk factors for developing cancer-related lymphedema and shoulder-arm disabilities were associated with the effects of the training program. DESIGN: Randomized controlled trial. SETTING: University facilities. PARTICIPANTS: 60 female breast cancer survivors participated. ELIGIBILITY CRITERIA: to be a breast cancer survivor, and to have completed surgery, chemotherapy, and/or radiotherapy up to 10 years before recruitment. EXCLUSION CRITERIA: metastatic breast cancer, a breast reconstruction intervention planned within 6 months, any absolute contraindication for exercise, to perform more than 300 minutes/week of structured exercise. INTERVENTIONS: Participants were randomized to an exercise group (12-week resistance training program) or a control group. MAIN OUTCOME MEASURES: Between-arms volume difference, shoulder-arm disabilities, and upper-limb muscular strength were evaluated at baseline and at week 12. Treatment-related information was registered from medical history. RESULTS: No between-group differences were observed on between-arms volume difference (1.207; 95% CI -0.964, 3.377; P=.270) or shoulder-arm disabilities (2.070; 95% CI -4.362, 8.501; P=.521) after the training program. Likewise, there was no association of surgery type, presence of lymph node resection, chemotherapy, radiotherapy, and hormone therapy with the changes in between-arms volume and perceived shoulder-arm disabilities after the intervention. However, a higher increase in upper limb muscular strength was associated with a reduced shoulder-arm disabilities (-0.429; P=.020) in the exercise group. CONCLUSIONS: The findings suggest that resistance training does not affect between-arms volume difference and shoulder-arm disabilities in female breast cancer survivors. The main risk factors for developing lymphedema were not associated with the effects of the intervention, although a higher increase in upper-limb muscular strength was associated with reduced shoulder-arm disabilities.

Influence of the practice of physical exercise and healthy eating on the Vigour of university lectures.

Introduction: Vigour at work is characterized by high levels of energy and high desire to make an effort at work. This article is the result of a research carried out with university teachers in Spain whose main objective is to show what type and frequency of physical exercise and diet influence Vigour. Methods: The sample consisted of 121 subjects, 62% of whom were women and 37.2% men. A questionnaire was administered to collect information on sociodemographic data, physical exercise habits, eating habits and Vigour at work. Cross-tabulations of the dimensions of Vigour with sex, age and type of contract offered were performed. Spearman correlations and Correspondence Analysis are also carried out to provide information on the intensity and type of relationships between the Vigour dimensions. Finally, the influence of the frequency of physical exercise and diet on Total Vigour is investigated. Results: The results show that the relationships between the dimensions are very strong (sig = 0.001). In addition, the practice of moderate-high intensity physical exercise and maintaining a good adherence to the Mediterranean Diet is related to high levels of Total Vigour (F = 7.955; sig = 0.006). As for the influence of the sociodemographic variables used, significant differences were only observed in the Physical Strength dimension for sex (X2 = 6.173; p = 0.046) and age (X2 = 9.449; p = 0.051) and, with respect to the type of contract, in Emotional Energy (X2 = 19.487; p < 0.001). Discusión and conclusions: The main conclusions of our study show that practicing physical exercise of medium-high intensity four hours or more per week and a high adherence to the MD is more related to high Vigour levels than just eating well or just practicing exercise. And more studies are needed on the influence of sociodemographic variables on Vigour and its different dimensions.

Análisis de interconsultas derivadas desde atención primaria y rechazadas por salud mental en el Departamento de Salud Arnau de Vilanova-Llíria (Valencia) / Analysis of Interconsultations Derived from Primary Care and Rejected by Mental Health in the Arnau de Vilanova-Llíria (Valencia) Health Department

En los últimos años se ha constatado un aumento de la demanda asistencial en los servicios de salud mental y, por tanto, un aumento de interconsultas que se reci-ben desde atención primaria, siendo necesario filtrar dichas derivaciones para poder llevar a cabo una atención adecuada. El principal objetivo de este estudio es la evaluación del modelo de derivación del Servicio de Salud Mental del Departamento del Arnau de Vila-nova-Llíria mediante un análisis descriptivo y el seguimiento a lo largo de 6 meses de las interconsultas derivadas desde atención primaria y rechazadas por salud mental en el año 2019. Durante esos meses se recibieron 2029 interconsultas, de las cuales 623 fueron rechazadas, correspondiéndose estas a 504 pacientes. De estas personas, 164 fueron finalmente citadas en salud mental tras realizar una nueva interconsulta. Este análisis pone de manifiesto la necesidad de implementar un modelo colaborativo entre atención primaria y salud mental que se traduzca en una mayor detección de casos, una mejor derivación y, en definitiva, una mejor atención a los y las pacientes. (AU)

In recent years, there has been an increase in the demand for care in Mental Health services and, therefore, an increase in interconsultations received from Primary Care, making it necessary to filter said referrals in order to carry out adequate care. The main objective of this study is to evaluate the referral model of the Mental Health Ser-vice of the Department of Arnau de Vilanova-Llíria through the descriptive analysis and follow-up over 6 months of interconsultations derived from Primary Care and rejected by Mental Health in 2019. During those months, 2029 interconsultations were received, of which 623 were rejected, corresponding to 504 patients. Of these patients, 164 were fi-nally attended to in Mental Health after carrying out a new interconsultation. This analysis shows the need to implement a collaborative model between Primary Care and Mental Health that turns into greater cases detection, better referral sand, ultimately, a better patient care. (AU)

Hypopituitarism after traumatic brain injury in adults: Clinical guidelines of the neuroendocrinology area of the Spanish Society of Endocrinology and Nutrition (SEEN).

Traumatic brain injury (TBI) is associated with hypopituitarism with a variable incidence, depending on the time and methods used to diagnosis, and on factors related to the trauma, such as its severity, its anatomical location and the drugs used in the acute phase. The pituitary gland can be damaged directly by the impact or secondary to factors such as ischemia, inflammation, excitotoxicity or immunity. In acute phases ACTH deficiency is the most relevant, since failure to detect and treat it can compromise the patient's life. Clinical manifestations are typical of each hormone deficient axes, although the combination hypopituitarism-trauma has been associated with cognitive deterioration, worse metabolic profile and greater impairment of quality of life. One of the clinical challenges is to determine which patients benefit from a systematic hormonal evaluation, and therefore from hormone replacement, and what is the appropriate time to do so and the most suitable diagnostic methods.

Evolución del diagnóstico y tratamiento de la nefritis lúpica en España / Evolution of diagnosis and treatment for lupus nephritis in Spain

La nefritis lúpica (NL) es una manifestación grave del lupus eritematoso sistémico que puede llevar a una enfermedad renal terminal. La mayor parte de los datos clínicos y pronósticos que manejamos, y sobre los que tomamos decisiones terapéuticas, proceden de cohortes internacionales con importantes diferencias étnicas y relativas al pronóstico renal. Para conocer los datos clínicos y pronósticos de los pacientes con NL en España se realizó una búsqueda bibliográfica de artículos relacionados con la NL publicados por autores españoles en revistas nacionales e internacionales entre 2005 y 2022. Las referencias seleccionadas mostraron que la biopsia no solo es clave en el diagnóstico de la NL, sino que su repetición puede ser útil en el seguimiento. En cuanto al tratamiento el abordaje estándar de la NL consiste en una fase de inducción y una fase de mantenimiento. Sin embargo, la aparición de nuevos fármacos ha motivado que se postule un nuevo paradigma de tratamiento en una sola fase continuada y personalizada (AU)

Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus that can lead to end-stage renal disease. Many clinical and prognostic data on which our therapeutic decisions are based come from international cohorts, which have important ethnic and prognostic differences. To identify clinical and prognostic data from patients with LN in Spain, we undertook a bibliographic search of LN-related papers by Spanish authors and published in national and international journals between 2005 and 2022. According to the selected references, renal biopsy is not only essential for LN diagnosis but its repetition can be useful for the follow-up. Regarding LN treatment, standard strategy consists of an induction phase and a maintenance phase. However, as new drugs have been released, a new paradigm of treatment in a single, continuing and personalized phase has been proposed (AU)

CD39+ conventional CD4+ T cells with exhaustion traits and cytotoxic potential infiltrate tumors and expand upon CTLA-4 blockade.

Conventional CD4+ T (Tconv) lymphocytes play important roles in tumor immunity; however, their contribution to tumor elimination remains poorly understood. Here, we describe a subset of tumor-infiltrating Tconv cells characterized by the expression of CD39. In several mouse cancer models, we observed that CD39+ Tconv cells accumulated in tumors but were absent in lymphoid organs. Compared to tumor CD39- counterparts, CD39+ Tconv cells exhibited a cytotoxic and exhausted signature at the transcriptomic level, confirmed by high protein expression of inhibitory receptors and transcription factors related to the exhaustion. Additionally, CD39+ Tconv cells showed increased production of IFNγ, granzyme B, perforin and CD107a expression, but reduced production of TNF. Around 55% of OVA-specific Tconv from B16-OVA tumor-bearing mice, expressed CD39. In vivo CTLA-4 blockade induced the expansion of tumor CD39+ Tconv cells, which maintained their cytotoxic and exhausted features. In breast cancer patients, CD39+ Tconv cells were found in tumors and in metastatic lymph nodes but were less frequent in adjacent non-tumoral mammary tissue and not detected in non-metastatic lymph nodes and blood. Human tumor CD39+ Tconv cells constituted a heterogeneous cell population with features of exhaustion, high expression of inhibitory receptors and CD107a. We found that high CD4 and ENTPD1 (CD39) gene expression in human tumor tissues correlated with a higher overall survival rate in breast cancer patients. Our results identify CD39 as a biomarker of Tconv cells, with characteristics of both exhaustion and cytotoxic potential, and indicate CD39+ Tconv cells as players within the immune response against tumors.

Interleukin-17 signaling influences CD8+ T cell immunity and tumor progression according to the IL-17 receptor subunit expression pattern in cancer cells.

IL-17 immune responses in cancer are controversial, with both tumor-promoting and tumor-repressing effects observed. To clarify the role of IL-17 signaling in cancer progression, we used syngeneic tumor models from different tissue origins. We found that deficiencies in host IL-17RA or IL-17A/F expression had varying effects on the in vivo growth of different solid tumors including melanoma, sarcoma, lymphoma, and leukemia. In each tumor type, the absence of IL-17 led to changes in the expression of mediators associated with inflammation and metastasis in the tumor microenvironment. Furthermore, IL-17 signaling deficiencies in the hosts resulted in decreased anti-tumor CD8+ T cell immunity and caused tumor-specific changes in several lymphoid cell populations. Our findings were associated with distinct patterns of IL-17A/F cytokine and receptor subunit expression in the injected tumor cell lines. These patterns affected tumor cell responsiveness to IL-17 and downstream intracellular signaling, leading to divergent effects on cancer progression. Additionally, we identified IL-17RC as a critical determinant of the IL-17-mediated response in tumor cells and a potential biomarker for IL-17 signaling effects in tumor progression. Our study offers insight into the molecular mechanisms underlying IL-17 activities in cancer and lays the groundwork for developing personalized immunotherapies.

COVID-19 patients display changes in lymphocyte subsets with a higher frequency of dysfunctional CD8lo T cells associated with disease severity.

This work examines cellular immunity against SARS-CoV-2 in patients from Córdoba, Argentina, during two major waves characterized by different circulating viral variants and different social behavior. Using flow cytometry, we evaluated the main lymphocyte populations of peripheral blood from hospitalized patients with moderate and severe COVID-19 disease. Our results show disturbances in the cellular immune compartment, as previously reported in different cohorts worldwide. We observed an increased frequency of B cells and a significant decrease in the frequency of CD3+ T cells in COVID-19 patients compared to healthy donors (HD). We also found a reduction in Tregs, which was more pronounced in severe patients. During the first wave, the frequency of GZMB, CD107a, CD39, and PD-1-expressing conventional CD4+ T (T conv) cells was significantly higher in moderate and severe patients than in HD. During the second wave, only the GZMB+ T conv cells of moderate and severe patients increased significantly. In addition, these patients showed a decreased frequency in IL-2-producing T conv cells. Interestingly, we identified two subsets of circulating CD8+ T cells with low and high CD8 surface expression in both HD and COVID-19 patients. While the percentages of CD8hi and CD8lo T cells within the CD8+ population in HD are similar, a significant increase was observed in CD8lo T cell frequency in COVID-19 patients. CD8lo T cell populations from HD as well as from SARS-CoV-2 infected patients exhibited lower frequencies of the effector cytokine-producing cells, TNF, IL-2, and IFN-γ, than CD8hi T cells. Interestingly, the frequency of CD8lo T cells increased with disease severity, suggesting that this parameter could be a potential marker for disease progression. Indeed, the CD8hi/CD8lo index helped to significantly improve the patient's clinical stratification and disease outcome prediction. Our data support the addition of, at least, a CD8hi/CD8lo index into the panel of biomarkers commonly used in clinical labs, since its determination may be a useful tool with impact on the therapeutic management of the patients.

CD39 expression by regulatory T cells drives CD8+ T cell suppression during experimental Trypanosoma cruzi infection.

An imbalance between suppressor and effector immune responses may preclude cure in chronic parasitic diseases. In the case of Trypanosoma cruzi infection, specialized regulatory Foxp3+ T (Treg) cells suppress protective type-1 effector responses. Herein, we investigated the kinetics and underlying mechanisms behind the regulation of protective parasite-specific CD8+ T cell immunity during acute T. cruzi infection. Using the DEREG mouse model, we found that Treg cells play a critical role during the initial stages after T. cruzi infection, subsequently influencing CD8+ T cells. Early Treg cell depletion increased the frequencies of polyfunctional short-lived, effector T cell subsets, without affecting memory precursor cell formation or the expression of activation markers. In addition, Treg cell depletion during early infection minimally affected the antigen-presenting cell response but it boosted CD4+ T cell responses before the development of anti-parasite effector CD8+ T cell responses. Crucially, the absence of CD39 expression on Treg cells significantly bolstered effector parasite-specific CD8+ T cell responses, leading to improved parasite control during T. cruzi infection. Our work underscores the crucial role of Treg cells in regulating protective anti-parasite immunity and provides evidence that CD39 expression by Treg cells represents a key immunomodulatory mechanism in this infection model.

Effect of Immunosuppressive Treatments on Kidney Outcomes After Gross Hematuria-Related Acute Kidney Injury in Older Patients With IgA Nephropathy.

Introduction: Macroscopic hematuria (MH) bouts, frequently accompanied by acute kidney injury (AKI-MH) are one of the most common presentations of IgA nephropathy (IgAN) in the elderly. Immunosuppressive therapies are used in clinical practice; however, no studies have analyzed their efficacy on kidney outcomes. Methods: This is a retrospective, multicenter study of a cohort of patients aged ≥50 years with biopsy-proven IgAN presenting with AKI-MH. Outcomes were complete, partial, or no recovery of kidney function at 1 year after AKI-MH, and kidney survival at 1, 2, and 5 years. Propensity score matching (PSM) analysis was applied to balance baseline differences between patients treated with immunosuppression and those not treated with immunosuppression. Results: The study group consisted of 91 patients with a mean age of 65 ± 15 years, with a mean follow-up of 59 ± 36 months. Intratubular red blood cell (RBC) casts and acute tubular necrosis were found in all kidney biopsies. The frequency of endocapillary hypercellularity and crescents were low. Immunosuppressive therapies (corticosteroids alone or combined with mycophenolate mofetil or cyclophosphamide) were prescribed in 52 (57%) patients, whereas 39 (43%) received conservative treatment. There were no significant differences in the proportion of patients with complete, partial, or no recovery of kidney function at 1 year between patients treated with immunosuppression and those not treated with immunosuppression (29% vs. 36%, 30.8% vs. 20.5% and 40.4 % vs. 43.6%, respectively). Kidney survival at 1, 3, and 5 years was similar among treated and untreated patients (85% vs. 81%, 77% vs. 76% and 72% vs. 66%, respectively). Despite the PSM analysis, no significant differences were observed in kidney survival between the two groups. Fourteen patients (27%) treated with immunosuppression had serious adverse events. Conclusions: Immunosuppressive treatments do not modify the unfavorable prognosis of patients with IgAN who are aged ≥50 years presenting with AKI-MH, and are frequently associated with severe complications.

Aldosterone Contributes to Vasopressin Escape through Changes in Water and Urea Transport.

Hyponatremia (hypo-osmolality) is a disorder of water homeostasis due to abnormal renal diluting capacity. The body limits the degree to which serum sodium concentration falls through a mechanism called "vasopressin escape". Vasopressin escape is a process that prevents the continuous decrease in serum sodium concentration even under conditions of sustained high plasma vasopressin levels. Previous reports suggest that aldosterone may be involved in the vasopressin escape mechanism. The abilities of aldosterone synthase (Cyp11b2) knockout and wild-type mice to escape from vasopressin were compared. Wild-type mice escaped while the aldosterone synthase knockout mice did not. Both the water channel aquaporin 2 (AQP2) and the urea transporter UT-A1 protein abundances were higher in aldosterone synthase knockout than in wild-type mice at the end of the escape period. Vasopressin escape was also blunted in rats given spironolactone, a mineralocorticoid receptor blocker. Next, the role of the phosphatase, calcineurin (protein phosphatase 2B, PP2B), in vasopressin escape was studied since aldosterone activates calcineurin in rat cortical collecting ducts. Tacrolimus, a calcineurin inhibitor, blunted vasopressin escape in rats compared with the control rats, increased UT-A1, AQP2, and pS256-AQP2, and decreased pS261-AQP2 protein abundances. Our results indicate that aldosterone regulates vasopressin escape through calcineurin-mediated protein changes in UT-A1 and AQP2.