Extremely Differentiated T Cell Subsets Contribute to Tissue Deterioration During Aging.

There is a dramatic remodeling of the T cell compartment during aging. The most notorious changes are the reduction of the naive T cell pool and the accumulation of memory-like T cells. Memory-like T cells in older people acquire a phenotype of terminally differentiated cells, lose the expression of costimulatory molecules, and acquire properties of senescent cells. In this review, we focus on the different subsets of age-associated T cells that accumulate during aging. These subsets include extremely cytotoxic T cells with natural killer properties, exhausted T cells with altered cytokine production, and regulatory T cells that gain proinflammatory features. Importantly, all of these subsets lose their lymph node homing capacity and migrate preferentially to nonlymphoid tissues, where they contribute to tissue deterioration and inflammaging.

A retrospective study of pregnancy-associated atypical hemolytic uremic syndrome.

Pregnancy-associated atypical hemolytic uremic syndrome (aHUS) refers to the thrombotic microangiopathy resulting from uncontrolled complement activation during pregnancy or the postpartum period. Pregnancy-associated aHUS is a devastating disease for which there is a limited clinical understanding and treatment experience. Here we report a retrospective study to analyze the clinical and prognostic data of 22 cases of pregnancy-associated aHUS from the Spanish aHUS Registry under different treatments. Sixteen patients presented during the first pregnancy and as many as nine patients required hemodialysis at diagnosis. Identification of inherited complement abnormalities explained nine of the 22 cases, with CFH mutations and CFH to CFHR1 gene conversion events being the most prevalent genetic alterations associated with this disorder (66%). In thirteen of the cases, pregnancy complications were sufficient to trigger a thrombotic microangiopathy in the absence of genetic or acquired complement alterations. The postpartum period was the time with highest risk to develop the disease and the group shows an association of cesarean section with pregnancy-associated aHUS. Seventeen patients underwent plasma treatments with a positive renal response in only three cases. In contrast, ten patients received eculizumab with an excellent renal response in all, independent of carrying or not inherited complement abnormalities. Although the cohort is relatively small, the data suggest that pregnancy-associated aHUS is not different from other types of aHUS and suggest the efficacy of eculizumab treatment over plasma therapies. This study may be useful to improve prognosis in this group of aHUS patients.

Molecular and immunological characterization of the first allergenic lipocalin in hamster: the major allergen from Siberian hamster (Phodopus sungorus).

The most frequent pet allergy is to cat and dog, but in recent years, it has become increasingly popular to have other pets, and the risk of exposure to new allergens is more prevalent. The list of new pets includes hamsters, and one of the most popular hamsters is the Siberian hamster (Phodopus sungorus). The aim of this study was the characterization and cloning of the major allergen from this hamster. The study of its allergenicity and cross-reactivity could improve the specific diagnosis and treatment for hamster-allergic patients. Thirteen Siberian hamster-allergic patients were recruited at the outpatient clinic. Protein extracts were prepared from the hair, urine, and salivary glands of four hamster species (European, golden, Siberian, and Roborovski). IgE-binding proteins were detected by immunoblotting and identified by mass spectrometry. The recombinant protein was produced in Escherichia coli and then purified by metal chelate affinity chromatography. The allergenic properties of the recombinant protein were tested by ELISA and immunoblotting, and biological activity was tested according to capacity for basophil activation. Three IgE-binding proteins were identified in extracts obtained from Siberian hamster hair, urine, and salivary glands. All proteins corresponded to the same protein, which was identified as a lipocalin. This lipocalin had no cross-reactivity with common and golden hamsters. The recombinant allergen was cloned and purified, showing similar IgE reactivity in vitro to Siberian hamster protein extracts. Also, the recombinant allergen was capable of producing biological activation in vivo. The major Siberian hamster allergen was cloned, and allergenic properties were characterized, providing a new tool for specific diagnosis of allergy to Siberian hamster.

Clinical and technological transition in breast cancer.

This article is a summary of the conference "Clinical and technological transition in breast cancer" that took place in the Congress of the Spanish Society of Radiation Oncology, placed in Vigo (Spain) on June 21, 2013. Hugo Marsiglia and Philip Poortmanns were the speakers, the first discussed about "Clinical and technological transition" and the second about "EORTC clinical trials and protocols".

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.

Nicotinamide adenine dinucleotide metabolism in the immune response, autoimmunity and inflammageing.

Metabolism is dynamically regulated to accompany immune cell function, and altered immunometabolism can result in impaired immune responses. Concomitantly, the pharmacological manipulation of metabolic processes offers an opportunity for therapeutic intervention in inflammatory disorders. The nicotinamide adenine dinucleotide (NAD+ ) is a critical metabolic intermediate that serves as enzyme cofactor in redox reactions, and is also used as a co-substrate by many enzymes such as sirtuins, adenosine diphosphate ribose transferases and synthases. Through these activities, NAD+ metabolism regulates a broad spectrum of cellular functions such as energy metabolism, DNA repair, regulation of the epigenetic landscape and inflammation. Thus, the manipulation of NAD+ availability using pharmacological compounds such as NAD+ precursors can have immune-modulatory properties in inflammation. Here, we discuss how the NAD+ metabolism contributes to the immune response and inflammatory conditions, with a special focus on multiple sclerosis, inflammatory bowel diseases and inflammageing. LINKED ARTICLES: This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.

The role of T cells in age-related diseases.

Age-related T cell dysfunction can lead to failure of immune tolerance mechanisms, resulting in aberrant T cell-driven cytokine and cytotoxic responses that ultimately cause tissue damage. In this Review, we discuss the role of T cells in the onset and progression of age-associated conditions, focusing on cardiovascular disorders, metabolic dysfunction, neuroinflammation and defective tissue repair and regeneration. We present different mechanisms by which T cells contribute to inflammageing and might act as modulators of age-associated diseases, including through enhanced pro-inflammatory and cytotoxic activity, defective clearance of senescent cells or regulation of the gut microbiota. Finally, we propose that 'resetting' immune system tolerance or targeting pathogenic T cells could open up new therapeutic opportunities to boost resilience to age-related diseases.

Electronic Patient-Reported Outcomes in Nephrology: Focus on Hemodialysis.

The success of hemodialysis (HD) treatments has been evaluated using objective measures of analytical parameters, or machine-measured parameters, despite having available validated instruments that assess patient perspective. There is an emerging interest regarding the use and relevance of patient-related outcomes (PROs). Electronic PROs (ePROs) involve the use of electronic technology, provide rapid access to this information, and are becoming more widely used in clinical trials and studies to evaluate efficacy and safety. Despite the scarce literature, this review suggests that ePROs are useful in providing a more customized and multidimensional approach to patient management and in making better clinical decisions in relevant aspects such as vascular access, duration and frequency of dialysis sessions, treatment of anemia, mental health, fatigue, and quality of life. The purpose of this review is to raise interest in the systematic use of ePROs in HD and to promote the development of studies in this field, which can respond to the gaps in knowledge and contribute to the implementation of the use of ePROs through new technologies, helping to improve the quality of health care.

Risk-adapted adjuvant chemotherapy after concomitant fluoropyrimidine-radiotherapy neoadjuvant treatment for patients with resectable cT3-4 or N+ rectal cancer.

Adjuvant chemotherapy in rectal cancer is not well defined.After neoadjuvant chemoradiation and surgery, at least a short period of treatment with 5-fluorouracil is recommended, and some investigators claim a more aggressive approach, in particular, for those patients with a high risk of systemic relapse. Nevertheless, there are few studies about adjuvant combination therapy tolerance and efficacy, and no randomized trials have been conducted comparing fluoropyrimidines versus combination therapy such as folinic acid plus 5-fluorouracil plus oxaliplatin(FOLFOX), considered the standard of care in stage IIIcolon cancer. We present an institutional series of risk adapted adjuvant therapy. Sixty evaluable patients who had received treatment with neoadjuvant fluoropyrimidine radiotherapy and surgery now received adjuvant fluoropyrimidines in the case of pT0-2N0 or oxaliplatin based combination in the case of pT3-4 or N+ . Overall, 33 patients experienced downstaging to pT2-0N0 (55%) and27 patients were restaged as pT3-4 or N+ (45%) after surgery. Local recurrence rate was 5% (three patients), one local and one local plus systemic in the adjuvant single agent group and one local plus systemic in the adjuvant FOLFOX group. Systemic relapse occurred in 14 patients(23.3%), five (15%) in the single-agent group and nine(33.3%) in the FOLFOX group. Disease-free survival at 3 years for patients in the good prognostic group(pT0-2N0) and poor prognostic group (pT3-4 or N+ ) were 78.7 and 62.2%, respectively. Severe diarrhoea was more frequent with fluoropyrimidines and neutropenia, mucositis and peripheral neuropathy were more common with FOLFOX. There were no toxic deaths. A risk-adapted adjuvant therapeutic decision is feasible with an acceptable safety profile even with the use of oxaliplatin based combinations. Three-year disease-free survival compares favourably with historical controls, especially in those patients with high risk factors for relapse.Phase III controlled trials are needed.

Acute responses of gastrointestinal hormones to both oral and parenteral intradialytic nutrition.

INTRODUCTION: Intradialytic nutrition (IDN) has been used to improve the nutritional status of malnourished hemodialysis (HD) patients. OBJECTIVE: To evaluate the different effects of parenteral IDN (IDPN) and oral IDN (IDON) on nutrition-related gastrointestinal hormones. PATIENTS AND METHODS: Seven clinically stable HD patients with malnutrition were included. All patients were treated for 1 month with either IDPN or IDON, with a 4-week period of no nutritional support between each type of therapy. On the first day of each nutritional support (IDON or IDPN) we analyzed the acute responses of insulin, ghrelin, and glucagon-like peptide 1 (GLP-1). We compared the areas under the secretory curves (AUC) and the maximum peaks of serum glucose, insulin, ghrelin, and GLP-1. A group of 6 clinically stable HD patients without any type of IDN served as the control group. RESULTS: The acute responses of glucose and insulin to IDN were significantly higher with IDPN than with IDON. The AUC of glucose (602 ± 81 vs. 495 ± 81 mg/dl/h, p < 0.01) and insulin (232 ± 103 vs. 73.8 ± 69 µU/ml/h, p < 0.01) as well as the maximum peaks of glucose (228 ± 41 vs. 177 ± 47 mg/dl, p < 0.05) and insulin (104 ± 46 vs. 29 ± 24 µU/ml, p < 0.01) were significantly higher after IDPN than after IDON. Ghrelin decreased after both IDPN and IDON; however, the decrease was significantly higher with IDPN compared to IDON. The ghrelin nadir was significantly lower in IDPN than in IDON (0.77 ± 0.5 vs. 1.5 ± 0.3, p < 0.05) although the AUC of ghrelin was not significantly different. GLP-1 was significantly increased at 1 h after starting both IDPN and IDON with no significant differences between the groups. CONCLUSION: IDPN induces a higher increase in serum glucose and insulin levels and a greater reduction in serum ghrelin concentrations compared with an equivalent orally administered nutritional supplement.

Watermelon profilin: characterization of a major allergen as a model for plant-derived food profilins.

BACKGROUND: Plant profilins have been reported as minor allergens. They are a well-known pan-allergen family responsible for cross-reactivity between plant-derived foods and pollens. Watermelon profilin has been reported to be a major allergen in watermelon (Citrullus lanatus).The aim of this study was to characterize recombinant watermelon profilin, confirming its reactivity for diagnostic purposes and the development of immunotherapy. METHODS: Native profilin was purified from watermelon extract by affinity chromatography using poly-L-proline. Recombinant His-tagged profilin was produced in Pichia pastoris yeast using pPICZαA vector and purified by metal chelate affinity chromatography. ELISA and immunoblot were carried out with sera from 17 watermelon-allergic patients. Biological activity was tested by the basophil activation test. RESULTS: Native profilin and recombinant profilin were purified and identified by mass spectrometry. Both show similar IgE reactivity in vitro and are biologically active. CONCLUSIONS: Similarities were found in the IgE-binding patterns and biological activity of recombinant profilin and native profilin. Recombinant profilin may be a powerful tool for specific diagnosis.

[Renal biopsy in patients aged 65 years or older: are there differences in the indication and histopathology compared to other patients?]. / La biopsia renal en pacientes de 65 o más años: ¿existen diferencias en la indicación y en la histopatología respecto al resto de pacientes?

BACKGROUND: Renal biopsy (RB) represents the gold standard for diagnosis of kidney diseases. In this paper we analyse whether the indication of RB and histopathology in patients 65 years or older is different from the other patients. MATERIAL AND METHODS: Retrospective study of 93 native renal biopsies performed in the General Hospital of Segovia in the period 2004-2008. The RB was performed percutaneously under ultrasound guidance in real time, using a 16G automatic needle. RESULTS: Mean age of biopsied patients was 56.89 ± 19 (range 14-89) , and 57% were males. A total of 39RB were performed on people aged 65 years or older. Overall, nephrotic syndrome (NS) is the most common indication of RB, and IgA glomerulonephritis the most common histology. In people ≥ 65 years, acute renal failure (ARF) is the most common indication for RB, and rapidly progressing (crescentic) glomerulonephritis/vasculitis the most detected the diagnosis. When taking age into account, no significant differences in the number of glomeruli obtained by RB or in the number of RB performed on the same patient. CONCLUSIONS: In people 65 years or older, ARF is the main indication of RB and crescentic glomerulonephritis/vasculitis the most frequent diagnosis.

[Estimation of glomerular filtration rate in persons aged 69 years or older: agreement between distinct calculation methods]. / Estimación del filtrado glomerular en personas de 69 años o más: concordancia entre diferentes métodos de cálculo.

MATERIAL: Estimation of glomerular filtration rate (eGFR) is the most widely accepted marker of renal function. Precise calculation is not routinely performed in clinical practice. Several methods have been developed for eGFR: creatinine clearance (CCr) calculation or the use of formulae derived from serum creatinine (sCr). The present study aimed to analyze the agreement between distinct methods of calculating eGFR. MATERIAL AND METHODS: We performed a cross-sectional study between January and April, 2006 in 32 stable elders, aged 69 years or older, evaluated in a general nephrology unit. eGFR was calculated by CCr (considered the gold standard), Cockcroft-Gault (CG) and Modification of Renal Diet in Disease (MDRD) equations. The Mann Whitney U-test, Spearman's correlation coefficient and the Kappa coefficient were used to compare means and determine the concordance between methods. RESULTS: The overall means+/-SD of GFRe for CCr were 36.14+/-16 ml/min (range 11.75-69.6); CG: 37.02+/-16 ml/min (range 13.3-72.3) and MDRD: 45.52+/-16 ml/min (range 19.2-75.36). Variations in eGFR on comparison of methods were CCr and MDRD: -9.37 ml/min (95% CI:-13.85, -4.9); CCr and CG:-2.54 ml/min (95% CI: -6.95, 1.80); MDRD and CG: 9.0 ml/min (95% CI: 5.96, 12). The correlation between the gold standard (CCr) and sCr-derived formulae was r=0.74 for MDRD (P<0.001) and r=0.77 for CG (P<0.001). The Kappa value for CCr and CG was 0.44 and was 0.35 for CCr and MDRD. When patients were classified by stage of chronic renal disease, discrepancies were found according to the method used: stage 5 (eGFR<15 ml/min) was diagnosed in 13.63% with CG while none were diagnosed with stage 5 with MDRD. CONCLUSIONS: In the estimation of the renal function in the elderly, eGFRe levels can differ in the same patient according to the method used: in view of the degree of concordance between CG and CCr, this mathematical formula should be used in preference to MDRD.

[Impact of the COVID-19 pandemic on Spanish Nephrology Services]. / Impacto de la pandemia COVID-19 en los servicios de Nefrología españoles.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has required a rapid and drastic transformation of hospitals, and consequently also of Spanish Nephrology Units, to respond to the critical situation. The Spanish Society of Nephrology conducted a survey directed to the Heads of Nephrology Departments in Spain that addressed the reorganisation of Nephrology departments and activity during the peak of COVID-19 pandemic. The survey has been focused on the integration of nephrologists in COVID-19 teams, nephrology inpatient care activities (elective admissions, kidney biopsies), the performance of elective surgeries such as vascular accesses or implantation of peritoneal catheters, the suspension of kidney transplantation programmes and the transformation of nephrology outpatient clinics. This work details the adaptation and transformation of nephrology services during the COVID-19 pandemic in Spain. During this period, elective admissions to Nephrology Services, elective surgeries and biopsies were suspended, and the kidney transplant programme was scaled back by more than 75%. It is worth noting that outpatient nephrology consultations were carried out largely by telephone. In conclusion, the pandemic has clearly impacted clinical activity in Spanish Nephrology departments, reducing elective activity and kidney transplants, and modifying activity in outpatient clinics. A restructuring and implementation plan in Nephrology focused on telemedicine and/or virtual medicine would seem to be both necessary and very useful in the near future.

2S albumins and nsLTP are involved in anaphylaxis to pizza sauce: IgE recognition before and after allergen processing.

Although pizza is one of the most popular foods in the world, allergic responses after ingesting pizza are relatively uncommon. However, precisely identifying the allergens responsible for these allergic reactions is challenging because of the high and diverse number of ingredients used in pizza preparation. In this report, we aim to identify the allergens responsible for systemic allergic reactions following ingestion of pizza in two patients. Using a skin prick by prick test (SPPT) and in vitro techniques, with natural and recombinant purified allergens from tomato and mustard seeds, we identified 2S albumin and non-specific lipid transfer proteins (nsLTP) as the proteins involved. However, IgE responses to the four nsLTPs differed before and after denaturation and reduction, thus suggesting additional complexity around nsLTP in food processing.

Glycolysis - a key player in the inflammatory response.

The inflammatory response involves the activation of several cell types to fight insults caused by a plethora of agents, and to maintain the tissue homoeostasis. On the one hand, cells involved in the pro-inflammatory response, such as inflammatory M1 macrophages, Th1 and Th17 lymphocytes or activated microglia, must rapidly provide energy to fuel inflammation, which is essentially accomplished by glycolysis and high lactate production. On the other hand, regulatory T cells or M2 macrophages, which are involved in immune regulation and resolution of inflammation, preferentially use fatty acid oxidation through the TCA cycle as a main source for energy production. Here, we discuss the impact of glycolytic metabolism at the different steps of the inflammatory response. Finally, we review a wide variety of molecular mechanisms which could explain the relationship between glycolytic metabolites and the pro-inflammatory phenotype, including signalling events, epigenetic remodelling, post-transcriptional regulation and post-translational modifications. Inflammatory processes are a common feature of many age-associated diseases, such as cardiovascular and neurodegenerative disorders. The finding that immunometabolism could be a master regulator of inflammation broadens the avenue for treating inflammation-related pathologies through the manipulation of the vascular and immune cell metabolism.

[SARS-CoV-2 infection in patients on renal replacement therapy. Report of the COVID-19 Registry of the Spanish Society of Nephrology (SEN)]. / Situación de la infección por SARS-CoV-2 en pacientes en tratamiento renal sustitutivo. Informe del Registro COVID-19 de la Sociedad Española de Nefrología (SEN).

INTRODUCTION: The recent appearance of the SARS-CoV-2 coronavirus pandemic has had a significant impact on the general population. Patients on renal replacement therapy (RRT) have not been unaware of this situation and due to their characteristics they are especially vulnerable. We present the results of the analysis of the COVID-19 Registry of the Spanish Society of Nephrology. MATERIAL AND METHODS: The Registry began operating on March 18th, 2020. It collects epidemiological variables, contagion and diagnosis data, signs and symptoms, treatments and outcomes. It is an online registry. Patients were diagnosed with SARS-CoV-2 infection based on the results of the PCR of the virus, carried out both in patients who had manifested compatible symptoms or had suspicious signs, as well as in those who had undergone screening after some contact acquainted with another patient. RESULTS: As of April 11, the Registry had data on 868 patients, from all the Autonomous Communities. The most represented form of RRT is in-center hemodialysis (ICH) followed by transplant patients. Symptoms are similar to the general population. A very high percentage (85%) required hospital admission, 8% in intensive care units. The most used treatments were hydroxychloroquine, lopinavir-ritonavir, and steroids. Mortality is high and reaches 23%; deceased patients were more frequently on ICH, developed pneumonia more frequently, and received less frequently lopinavir-ritonavir and steroids. Age and pneumonia were independently associated with the risk of death. CONCLUSIONS: SARS-CoV-2 infection already affects a significant number of Spanish patients on RRT, mainly those on ICH, hospitalization rates are very high and mortality is high; age and the development of pneumonia are factors associated with mortality.

High stable serum adiponectin levels are associated with a better outcome in prevalent dialysis patients.

AIMS: Our aim was to evaluate the prognostic value of 2 measurements of serum adiponectin levels for all-cause mortality and cardiovascular (CV) mortality in uremic patients. METHODS: We analyzed 184 patients (19-86 years) undergoing peritoneal dialysis (n = 86) or hemodialysis (n = 98). All patients had 2 measurements of serum adiponectin levels (at baseline and after 1 year). Relationships between adiponectin and mortality were studied by means of survival analysis and Cox regression analysis. RESULTS: During a median follow-up time of 31.2 months, 67 patients (36.4%) died, 26 (14.1%) as a result of CV disease. Mean survival time for CV mortality in patients with 1-year adiponectin values in the upper tertile was significantly higher than that found in patients in the middle and lower tertiles. Hazard ratios (HR) for all-cause mortality per SD change were 0.70 (95% CI, 0.50-0.98; p < 0.05) for baseline adiponectin levels and 0.68 (0.49-0.95; p < 0.05) for mean baseline and 1-year adiponectin levels. Mean adiponectin levels were also negatively related with CV mortality [HR 0.43 (0.21-0.86); p < 0.05] and CV events [HR 0.74 (0.55-0.99); p < 0.05]. CONCLUSIONS: In this population of dialysis patients, adiponectin seems to behave as a CV protective factor. Patients with high mean adiponectin levels had a better survival rate.