Genetic testing in focal segmental glomerulosclerosis: in whom and when?

Background: Genetic causes are increasingly recognized in patients with focal segmental glomerulosclerosis (FSGS), but it remains unclear which patients should undergo genetic study. Our objective was to determine the frequency and distribution of genetic variants in steroid-resistant nephrotic syndrome FSGS (SRNS-FSGS) and in FSGS of undetermined cause (FSGS-UC). Methods: We performed targeted exome sequencing of 84 genes associated with glomerulopathy in patients with adult-onset SRNS-FSGS or FSGS-UC after ruling out secondary causes. Results: Seventy-six patients met the study criteria; 24 presented with SRNS-FSGS and 52 with FSGS-UC. We detected FSGS-related disease-causing variants in 27/76 patients (35.5%). There were no differences between genetic and non-genetic causes in age, proteinuria, glomerular filtration rate, serum albumin, body mass index, hypertension, diabetes or family history. Hematuria was more prevalent among patients with genetic causes. We found 19 pathogenic variants in COL4A3-5 genes in 16 (29.3%) patients. NPHS2 mutations were identified in 6 (16.2%) patients. The remaining cases had variants affecting INF2, OCRL, ACTN4 genes or APOL1 high-risk alleles. FSGS-related genetic variants were more common in SRNS-FSGS than in FSGS-UC (41.7% vs 32.7%). Four SRNS-FSGS patients presented with NPHS2 disease-causing variants. COL4A variants were the most prevalent finding in FSGS-UC patients, with 12 patients carrying disease-causing variants in these genes. Conclusions: FSGS-related variants were detected in a substantial number of patients with SRNS-FSGS or FSGS-UC, regardless of age of onset of disease or the patient's family history. In our experience, genetic testing should be performed in routine clinical practice for the diagnosis of this group of patients.

Effects of mental workload on manufacturing systems employees: A mediation causal model.

BACKGROUND: Although some research has been done in the Mexican manufacturing industry regarding mental workload, none has explored its association with physical fatigue, body weight gain, and human error simultaneously. OBJECTIVE: This research examines the association between mental workload and physical fatigue, body weight gain, and human error in employees from the Mexican manufacturing systems through a mediation analysis approach. METHODS: A survey named Mental Workload Questionnaire was developed by merging the NASA-TLX with a questionnaire containing the mental workload variables mentioned above. The Mental Workload Questionnaire was applied to 167 participants in 63 manufacturing companies. In addition, the mental workload was used as an independent variable, while physical fatigue and body weight gain were mediator variables, and human error was a dependent variable. Six hypotheses were used to measure the relationships among variables and tested using the ordinary least squares regression algorithm. RESULTS: Findings indicated that mental workload significantly correlates with physical fatigue and human error. Also, the mental workload had a significant total association with human error. The highest direct association with body weight gain was provided by physical fatigue, and body weight gain had an insignificant direct association with human error. Finally, all indirect associations were insignificant. CONCLUSION: Mental workload directly affects human error, which physical fatigue does not; however, it does affect body weight gain. Managers should reduce their employees' mental workload and physical fatigue to avoid further problems associated with their health.

Redes de gobernanza intermunicipal: aplicación de modelos de grafos aleatorios exponenciales en la región de Los Lagos, Chile / Redes de governança intermunicipal: aplicação de modelos de gráficos aleatórios exponenciais em Los Lagos, Chile / Inter-municipal governance networks: application of exponential random graph models in Los Lagos, Chile

Resumen Desde los noventa, la idea de gobernanza ha permeado los debates acerca de la transformación del Estado a escala regional, sin embargo, las dificultades de su operacionalización han limitado nuestro conocimiento. Este artículo busca contribuir con esta brecha, examinando la dimensión interjurisdiccional de la gobernanza regional. Aplicando la perspectiva de análisis de redes, se estudia la formación de las redes intermunicipales que se configuran a partir de diferentes mecanismos de colaboración. Con base en el marco de acción colectiva institucional, el artículo analiza la prevalencia de estructuras de relacionamiento asociadas a diferentes tipos de capital social (bonding - capital social vínculo ‒ y bridging - capital social puente ‒) en tres redes intermunicipales de la región de Los Lagos, en Chile. Por medio de la aplicación de modelos de grafos aleatorios exponenciales (ERGM), se obtiene evidencia para sustentar la consistente prevalencia de bonding en las tres redes estudiadas y su coexistencia con estructuras descentralizadas en las redes de mayor complejidad regional.

Resumo Desde a década de noventa, a ideia de governança permeou os debates sobre a transformação do Estado no âmbito regional, não obstante, as dificuldades de sua operacionalização têm limitado nosso conhecimento. Este artigo busca contribuir para essa lacuna, examinando a dimensão interjurisdicional da governança regional. Aplicando a perspectiva da análise de redes, estuda-se a formação de redes intermunicipais que se configuram a partir de diferentes mecanismos de colaboração. Com base no marco institucional da ação coletiva, o artigo analisa a prevalência de estruturas de relacionamento associadas a diferentes tipos de capital social (bonding/bridging) em três redes intermunicipais da região de Los Lagos, no Chile. Através da aplicação de modelos de gráficos aleatórios exponenciais (ERGM), obtêm-se evidências que suportam a prevalência consistente de bonding nas três redes estudadas e sua coexistência com estruturas descentralizadas em redes de maior complexidade regional.

Abstract The idea of governance has permeated the debates on the state's transformation at the regional level since the 1990s. However, operationalization difficulties have limited our knowledge of the phenomenon. This article contributes to filling this gap by examining the inter-jurisdictional dimension of regional governance. From a network perspective, the article studies the emergence of inter-municipal networks from different local collaborative mechanisms. Based on the institutional collective action framework, the study analyzes the prevalence of network structures associated with different types of social capital (bonding/bridging) in three inter-municipal networks in the Los Lagos Region in Chile. The application of exponential random graph models (ERGM) revealed evidence supporting the consistent prevalence of bonding in the three networks studied. The findings also showed the networks' coexistence with structures decentralized in more complex regional networks.

Persistence of left superior vena cava: a rare cause of hemodialysis tunneled catheter malposition / Persistência de veia cava superior esquerda: uma causa rara de posicionamento inadequado do cateter tunelizado para hemodiálise

Abstract Hemodialysis central venous catheter (CVC) insertion can be complicated in patients with anomalous vessel anatomy. In such cases detailed knowledge of thoracic vessel anatomy is necessary to identify the exact location of the catheter. Central venous placement under ultrasound control has significantly reduced the complications associated with blind puncture and allows an appropriate puncture of the desired vessel, but the CVC can still get misplaced if it follows an anomalous route. Herein, we report a case of dialysis catheter placed into a left sided superior vena cava, only diagnosed after CT scan study.

Resumo A inserção do cateter venoso central (CVC) para hemodiálise pode ser complicada em pacientes com anatomia anômala dos vasos. Nesses casos, o conhecimento detalhado da anatomia do vaso torácico é necessário para identificar a localização exata do cateter. A colocação venosa central sob controle de ultrassom tem reduzido significativamente as complicações associadas à punção às cegas e permite uma punção apropriada do vaso desejado, mas o CVC ainda pode ficar mal posicionado se seguir uma rota anômala. Aqui, relatamos um caso de cateter de diálise colocado em uma veia cava superior esquerda, apenas diagnosticado após estudo de tomografia computadorizada.

Persistence of left superior vena cava: a rare cause of hemodialysis tunneled catheter malposition.

Hemodialysis central venous catheter (CVC) insertion can be complicated in patients with anomalous vessel anatomy. In such cases detailed knowledge of thoracic vessel anatomy is necessary to identify the exact location of the catheter. Central venous placement under ultrasound control has significantly reduced the complications associated with blind puncture and allows an appropriate puncture of the desired vessel, but the CVC can still get misplaced if it follows an anomalous route. Herein, we report a case of dialysis catheter placed into a left sided superior vena cava, only diagnosed after CT scan study.

A Mechanistic-Based and Non-invasive Approach to Quantify the Capability of Kidney to Detoxify Cysteine-Disulfides.

Our general goal was to non-invasively evaluate kidney tubular dysfunction. We developed a strategy based on cysteine (Cys) disulfide stress mechanism that underlies kidney dysfunction. There is scarce information regarding the fate of Cys-disulfides (CysSSX), but evidence shows they might be detoxified in proximal tubular cells by the action of N-acetyltransferase 8 (NAT8). This enzyme promotes the addition of an N-acetyl moiety to cysteine-S-conjugates, forming mercapturates that are eliminated in urine. Therefore, we developed a strategy to quantify mercapturates of CysSSX in urine as surrogate of disulfide stress and NAT8 activity in kidney tubular cells. We use a reduction agent for the selective reduction of disulfide bonds. The obtained N-acetylcysteine moiety of the mercapturates from cysteine disulfides was monitored by fluorescence detection. The method was applied to urine from mice and rat as well as individuals with healthy kidney and kidney disease.

The 2-hydroxy-nevirapine metabolite as a candidate for boosting apolipoprotein A1 and for modulating anti-HDL antibodies.

The antiretroviral nevirapine (NVP) is associated to a reduction of atherosclerotic lesions and increases in high-density lipoprotein (HDL)-cholesterol. Despite being a hepatotoxic drug, which forbids its re-purposing to other therapeutic areas, not all NVP metabolites have the same potential to induce toxicity. Our aim was to investigate the effects of NVP and its metabolites in an exploratory study, towards the identification of a candidate to boost HDL. A pilot prospective (n = 11) and a cross-sectional (n = 332) clinical study were performed with the following endpoints: HDL-cholesterol and apolipoprotein A1 (ApoA1) levels, anti-HDL and anti-ApoA1 antibodies titers, paraoxonase, arylesterase and lactonase activities of paraoxonase-1, and NVP's metabolite profile. NVP treatment increased HDL-cholesterol, ApoA1 and paraoxonase-1 activities, and lowered anti-HDL and anti-ApoA1 titers. In the prospective study, the temporal modulation induced by NVP was different for each HDL-related endpoint. The first observation was a decrease in the anti-HDL antibodies titers. In the cross-sectional study, the lower titers of anti-HDL antibodies were associated to the proportion of 2-hydroxy-NVP (p = 0.03). In vitro models of hepatocytes were employed to clarify the individual contribution of NVP's metabolites for ApoA1 modulation. Long-term incubations of NVP and 2-hydroxy-NVP in the metabolically competent 3D model caused an increase in ApoA1 reaching 43 % (p < 0.05) and 86 % (p < 0.001), respectively. These results support the contribution of drug biotransformation for NVP-induced HDL modulation, highlighting the role of 2-hydroxy-NVP as ApoA1 booster and its association to lower anti-HDL titers. This biotransformation-guided approach allowed us to identify a non-toxic NVP metabolite as a candidate for targeting HDL.

A Systematic Review and Meta-Analysis of the Effects of Food Safety and Hygiene Training on Food Handlers.

Foodborne diseases are a significant cause of morbidity and mortality worldwide. Studies have shown that the knowledge, attitude, and practices of food handlers are important factors in preventing foodborne illness. The purpose of this research is to assess the effects of training interventions on knowledge, attitude, and practice on food safety and hygiene among food handlers at different stages of the food supply chain. To this end, we conducted a systematic review and meta-analysis with close adherence to the PRISMA guidelines. We searched for training interventions among food handlers in five databases. Randomized control trials (RCT), quasi-RCTs, controlled before-after, and nonrandomized designs, including pre-post studies, were analyzed to allow a more comprehensive assessment. The meta-analysis was conducted using the random-effects model to calculate the effect sizes (Hedges's g) and 95% confidence interval (CI). Out of 1094 studies, 31 were included. Results showed an effect size of 1.24 (CI = 0.89-1.58) for knowledge, an attitude effect size of 0.28 (CI = 0.07-0.48), and an overall practice effect size of 0.65 (CI = 0.24-1.06). In addition, subgroups of self-reported practices and observed practices presented effect sizes of 0.80 (CI = 0.13-1.48) and 0.45 (CI = 0.15-0.76) respectively.

Neutrophil Gelatinase-Associated Lipocalin Measured on Clinical Laboratory Platforms for the Prediction of Acute Kidney Injury and the Associated Need for Dialysis Therapy: A Systematic Review and Meta-analysis.

RATIONALE & OBJECTIVE: The usefulness of measures of neutrophil gelatinase-associated lipocalin (NGAL) in urine or plasma obtained on clinical laboratory platforms for predicting acute kidney injury (AKI) and AKI requiring dialysis (AKI-D) has not been fully evaluated. We sought to quantitatively summarize published data to evaluate the value of urinary and plasma NGAL for kidney risk prediction. STUDY DESIGN: Literature-based meta-analysis and individual-study-data meta-analysis of diagnostic studies following PRISMA-IPD guidelines. SETTING & STUDY POPULATIONS: Studies of adults investigating AKI, severe AKI, and AKI-D in the setting of cardiac surgery, intensive care, or emergency department care using either urinary or plasma NGAL measured on clinical laboratory platforms. SELECTION CRITERIA FOR STUDIES: PubMed, Web of Science, Cochrane Library, Scopus, and congress abstracts ever published through February 2020 reporting diagnostic test studies of NGAL measured on clinical laboratory platforms to predict AKI. DATA EXTRACTION: Individual-study-data meta-analysis was accomplished by giving authors data specifications tailored to their studies and requesting standardized patient-level data analysis. ANALYTICAL APPROACH: Individual-study-data meta-analysis used a bivariate time-to-event model for interval-censored data from which discriminative ability (AUC) was characterized. NGAL cutoff concentrations at 95% sensitivity, 95% specificity, and optimal sensitivity and specificity were also estimated. Models incorporated as confounders the clinical setting and use versus nonuse of urine output as a criterion for AKI. A literature-based meta-analysis was also performed for all published studies including those for which the authors were unable to provide individual-study data analyses. RESULTS: We included 52 observational studies involving 13,040 patients. We analyzed 30 data sets for the individual-study-data meta-analysis. For AKI, severe AKI, and AKI-D, numbers of events were 837, 304, and 103 for analyses of urinary NGAL, respectively; these values were 705, 271, and 178 for analyses of plasma NGAL. Discriminative performance was similar in both meta-analyses. Individual-study-data meta-analysis AUCs for urinary NGAL were 0.75 (95% CI, 0.73-0.76) and 0.80 (95% CI, 0.79-0.81) for severe AKI and AKI-D, respectively; for plasma NGAL, the corresponding AUCs were 0.80 (95% CI, 0.79-0.81) and 0.86 (95% CI, 0.84-0.86). Cutoff concentrations at 95% specificity for urinary NGAL were>580ng/mL with 27% sensitivity for severe AKI and>589ng/mL with 24% sensitivity for AKI-D. Corresponding cutoffs for plasma NGAL were>364ng/mL with 44% sensitivity and>546ng/mL with 26% sensitivity, respectively. LIMITATIONS: Practice variability in initiation of dialysis. Imperfect harmonization of data across studies. CONCLUSIONS: Urinary and plasma NGAL concentrations may identify patients at high risk for AKI in clinical research and practice. The cutoff concentrations reported in this study require prospective evaluation.

Clinicopathologic predictors of renal outcomes in light chain cast nephropathy: a multicenter retrospective study.

Light chain cast nephropathy (LCCN) in multiple myeloma often leads to severe and poorly reversible acute kidney injury. Severe renal impairment influences the allocation of chemotherapy and its tolerability; it also affects patient survival. Whether renal biopsy findings add to the clinical assessment in predicting renal and patient outcomes in LCCN is uncertain. We retrospectively reviewed clinical presentation, chemotherapy regimens, hematologic response, and renal and patient outcomes in 178 patients with biopsy-proven LCCN from 10 centers in Europe and North America. A detailed pathology review, including assessment of the extent of cast formation, was performed to study correlations with initial presentation and outcomes. Patients presented with a mean estimated glomerular filtration rate (eGFR) of 13 ± 11 mL/min/1.73 m2, and 82% had stage 3 acute kidney injury. The mean number of casts was 3.2/mm2 in the cortex. Tubulointerstitial lesions were frequent: acute tubular injury (94%), tubulitis (82%), tubular rupture (62%), giant cell reaction (60%), and cortical and medullary inflammation (95% and 75%, respectively). Medullary inflammation, giant cell reaction, and the extent of cast formation correlated with eGFR value at LCCN diagnosis. During a median follow-up of 22 months, mean eGFR increased to 43 ± 30 mL/min/1.73 m2. Age, ß2-microglobulin, best hematologic response, number of cortical casts per square millimeter, and degree of interstitial fibrosis/tubular atrophy (IFTA) were independently associated with a higher eGFR during follow-up. This eGFR value correlated with overall survival, independently of the hematologic response. This study shows that extent of cast formation and IFTA in LCCN predicts the quality of renal response, which, in turn, is associated with overall survival.

Severe and malignant hypertension are common in primary atypical hemolytic uremic syndrome.

Malignant hypertension is listed among the causes of secondary thrombotic microangiopathy, but pathogenic mutations in complement genes have been reported in patients with hypertension-induced thrombotic microangiopathy. Here we investigated the frequency and severity of hypertension in 55 patients with primary atypical hemolytic uremic syndrome (aHUS). A genetic analysis was performed in all patients, and funduscopic examination was performed in all the patients with Grades 2 and 3 hypertension. A cohort of 110 patients with malignant hypertension caused by diseases other than aHUS served as control. Thirty-six patients with aHUS presented Grade 2 or Grade 3 hypertension and funduscopic examination showed malignant hypertension in 19. Genetic abnormalities in complement were found in 19 patients (37% among patients with malignant hypertension). Plasmapheresis was performed in 46 patients and 26 received eculizumab. Renal and hematological responses were significantly lower after plasmapheresis (24%) than after eculizumab (81%). Renal survival was significantly higher in patients treated with eculizumab (85% at one, three and five years) compared to patients who did not receive this treatment (54%, 46% and 41%), respectively. Response to eculizumab was independent of hypertension severity and the presence of complement genetic abnormalities. Among patients with malignant hypertension caused by other diseases the prevalence of thrombotic microangiopathy was very low (5%). Thus, severe and malignant hypertension are common among patients with aHUS and eculizumab treatment leads to a higher renal survival when compared to plasmapheresis. However, thrombotic microangiopathy is uncommon among patients presenting with malignant hypertension caused by diseases other than aHUS.

Cooperación inter-municipal en América Latina: estado del arte y desafíos futuros de la investigación / Cooperação inter-municipal na américa latina: estado da arte e desafios futuros da pesquisa / Inter-municipal cooperation in Latin America: current situation and future research challenges

Resumen Este artículo ofrece un panorama del estado de la investigación latinoamericana sobre cooperación intermunicipal, un fenómeno que ha adquirido relevancia empírica en la región desde la década de los años noventa. A partir de una revisión sistemática de la literatura y del análisis de contenido de 47 artículos publicados entre 2005 y 2016 en revistas indexadas en WOS, Scopus y LatinIndex, este trabajo informa acerca de los avances de la investigación sobre los condicionantes relevantes, las complejidades de la operación y los diferentes efectos de la cooperación intermunicipal en países de América Latina. Los resultados identifican las brechas de investigación en el estudio de las causas y los factores explicativos de la colaboración como modelo organizacional y gobernanza territorial, como también la falta de estudios de efectividad de dichos arreglos. La identificación de estas brechas permitirá orientar la agenda de investigación futura sobre cooperación entre municipios.

Resumo Este artigo oferece uma visão do estado da pesquisa latino-americana sobre cooperação inter-municipal, um fenômeno que ganhou relevância empírica na região desde a década de 1990. Com base em uma revisão sistemática da literatura e na análise de conteúdo de 47 artigos publicados entre 2005 e 2016 em periódicos indexados em WOS, Scopus e LatinIndex, este artigo informa sobre o andamento da pesquisa sobre as condições relevantes, as complexidades da operação e os diferentes efeitos da cooperação inter-municipal nos países da América Latina. Os resultados identificam as lacunas de pesquisa no estudo de causas e fatores explicativos da colaboração como modelo organizacional e governança territorial, bem como a falta de estudos sobre a efetividade de tais arranjos. A identificação dessas principais lacunas permitirão orientar a futura agenda de pesquisa sobre cooperação entre municípios.

Abstract This article offers an overview of Latin American research on inter-municipal cooperation, a phenomenon that has gained empirical relevance in the region since the 1990s. Based on a systematic literature review and content analysis of 47 articles published between 2005 and 2016 selected from indexed journals (WOS, Scopus, and LatinIndex), this article reports the progress of research, the complexities of the operation, and the different effects of inter-municipal cooperation in Latin American countries. The results identify the main gaps in studies about causes and determinants of 'collaboration' as an organizational model and territorial governance, as well as the lack of studies on the effectiveness of these arrangements. By identifying these gaps it is possible to guide the future research agenda on cooperation between municipalities.

In vitro retention efficiency of temporary type zinc oxide cement for orthodontic forced eruption.

OBJECTIVE: To assess the retention efficiency of three types of temporary zinc oxide cement trademarks on forced eruption using intracranal wire device. METHODS: An in vitro evaluation included intracanal wire device displacement and detachment at 50g load force for 120 days and then the retention resistance at maximum load force. RESULTS: All groups of temporary zinc oxide cements were efficient to support 50g load forces after 120 days. None statistical differences were found between groups. Zinc oxide cements supported a maximum retention load force, which exceeded in more than 84 times the lowest value obtained in controls (420g). CONCLUSION: Zinc oxide cements are efficient to retain intracanal wire devices on forced eruption processes in vitro and allows removal of both when necessary (wire device and cement, respectively).

Mercapturate Pathway in the Tubulocentric Perspective of Diabetic Kidney Disease.

BACKGROUND: The recent growing evidence that the proximal tubule underlies the early pathogenesis of diabetic kidney disease (DKD) is unveiling novel and promising perspectives. This pathophysiological concept links tubulointerstitial oxidative stress, inflammation, hypoxia, and fibrosis with the progression of DKD. In this new angle for DKD, the prevailing molecular mechanisms on proximal tubular cells emerge as an innovative opportunity for prevention and management of DKD as well as to improve diabetic dysmetabolism. SUMMARY: The mercapturate pathway (MAP) is a classical metabolic detoxification route for xenobiotics that is emerging as an integrative circuitry detrimental to resolve tubular inflammation caused by endogenous electrophilic species. Herein we review why and how it might underlie DKD. Key Messages: MAP is a hallmark of proximal tubular cell function, and cysteine-S-conjugates might represent targets for early intervention in DKD. Moreover, the biomonitoring of urinary mercapturates from metabolic inflammation products might be relevant for the implementation of preventive/management strategies in DKD.

High resolution mass spectrometry-based methodologies for identification of Etravirine bioactivation to reactive metabolites: In vitro and in vivo approaches.

Drug bioactivation to reactive metabolites capable of covalent adduct formation with bionucleophiles is a major cause of drug-induced adverse reactions. Therefore, elucidation of reactive metabolites is essential to unravel the toxicity mechanisms induced by drugs and thereby identify patient subgroups at higher risk. Etravirine (ETR) was the first second-generation Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) to be approved, as a therapeutic option for HIV-infected patients who developed resistance to the first-generation NNRTIs. Additionally, ETR came into market aiming to overcome some adverse effects associated with the previously used efavirenz (neurotoxicity) and nevirapine (hepatotoxicity) therapies. Nonetheless, post-marketing reports of severe ETR-induced skin rash and hypersensitivity reactions have prompted the U.S. FDA to issue a safety alert on ETR. Taking into consideration that ETR usage may increase in the near future, due to the possible use of the drug for coinfection with malaria and HIV, the development of reliable prognostic tools for early risk/benefit estimations is urgent. In the current study, high resolution mass spectrometry-based methodologies were integrated with MS3 experiments for the identification of reactive ETR metabolites/adducts: 1) in vitro incubation of the drug with human and rat liver S9 fractions in the presence of Phase I and II co-factors, including glutathione, as a trapping bionucleophile; and 2) in vivo, using urine samples from HIV-infected patients on ETR therapy. We obtained evidence for multiple bioactivation pathways leading to the formation of covalent adducts with glutathione and N-acetyl-L-cysteine. These results suggest that similar reactions may occur with cysteine residues of proteins, supporting a role for ETR bioactivation in the onset of the toxic effects elicited by the drug. Additionally, ETR metabolites stemming from amine oxidation, with potential toxicological significance, were identified in vitro and in vivo. Also noteworthy is the fact that new metabolic conjugation pathways of glucuronide metabolites were demonstrated for the first time, raising questions about their potential toxicological implications. In conclusion, these results represent not only a contribution towards the elucidation of new metabolic pathways of drugs in general but also an important step towards the elucidation of potentially toxic ETR pathways, whose understanding may be crucial for reliable risk/benefit estimations of ETR-based regimens.

HIV and kidney diseases: 35 years of history and consequences.

Kidney diseases in human immunodeficiency virus (HIV)-infected patients are often misdiagnosed. Despite reductions in morbidity and mortality owing to widespread use of highly effective combination antiretroviral therapy (cART), acute kidney injury (AKI) and chronic kidney disease (CKD) are still more common in these patients than in the general population, and are associated with poor health outcomes. HIV-associated nephropathy and HIV immune complex kidney diseases are the more recognizable HIV-related kidney diseases. However, a broad spectrum of kidney disorders related or not directly related with HIV infection can be observed, including cART-induced AKI, CKD, proximal tubular dysfunction, crystalluria and urolithiasis, among others. This review summarizes the major epidemiologic studies of kidney diseases in HIV-infected patients, discusses novel approaches that may potentially limit nephrotoxicity such as the use of tenofovir alafenamide, and outlines current screening measures for early diagnosis of kidney dysfunction or tubular damage, and for accurate detection of increased risk for acute or chronic kidney diseases.

The risk of chronic kidney disease and mortality are increased after community-acquired acute kidney injury.

We investigated whether community-acquired acute kidney injury encountered in a tertiary hospital emergency department setting increases the risk of chronic kidney disease (CKD) and mortality, and whether plasma biomarkers could improve the prediction of those adverse outcomes. In a prospective cohort study, we enrolled 616 patients at admission to the emergency department and followed them for a median of 62.1 months. Within this cohort, 130 patients were adjudicated as having acute kidney injury, 159 transient azotemia, 15 stable CKD, and 312 normal renal function. Serum cystatin C and plasma neutrophil gelatinase-associated lipocalin (NGAL) were measured at index admission. After adjusting for clinical variables, the risk of developing CKD stage 3, as well as the risk of death, were increased in the acute kidney injury group (hazard ratio [HR], 5.7 [95% confidence interval, 3.8-8.7] and HR, 1.9 [95% confidence interval, 1.3-2.8], respectively). The addition of serum cystatin C increased the ability to predict the risk of developing CKD stage 3, and death (HR, 1.5 [1.1-2.0] and 1.6 [1.1-2.3], respectively). The addition of plasma NGAL resulted in no improvement in predicting CKD stage 3 or mortality (HR, 1.0 [0.7-1.5] and 1.2 [0.8-1.8], respectively). The risk of developing CKD stage 3 was also significantly increased in the transient azotemia group (HR, 2.4 [1.5-3.6]). Thus, an episode of community acquired acute kidney injury markedly increases the risk of CKD, and moderately increases the risk of death. Our findings highlight the importance of follow-up of patients with community acquired acute kidney injury, for potential early initiation of renal protective strategies.

Monitoring of the lactonase activity of paraoxonase-1 enzyme in HIV-1-infection.

Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme known as a free radical scavenging system (1). PON-1 has three main activities, responsible for its antioxidant and anti-inflammatory potential: paraoxonase, arylesterase and lactonase (LACase), the latest to be discovered and pointed out to be its native activity (2). Among other physiological roles, the LACase might minimize the deleterious effects of hyperhomocysteinaemia in infection, by detoxifying the highly reactive metabolite homocysteine-thiolactone (HcyTL) (3),4. In the present work, we have developed and applied a method to quantify LACase activity and to explore the role of this enzyme in HIV-infection and virological response. The LACase activity was monitored in a cohort of HIV-1-infected patients, through the titration of 3-(o-hydroxyphenyl) propionic acid, formed upon the LACase-mediated hydrolysis of the substrate dihydrocoumarin. The study protocol was approved by the Ethics Committee of Centro Hospitalar de Lisboa Central and Hospital Prof. Doutor Fernando Fonseca. All patients gave their written informed consent and were adults with documented HIV-1-infection, regardless of combined antiretroviral therapy (cART) use. Naïve patients and patients who had received continuous antiretroviral treatment for more than one month were included. A total of 179 HIV-1-infected patients were included on this study (51% Men, 39% non-Caucasian, 45±13 years old). Patients with non-suppressed viraemia, either from the non-cART (n=89, 12±4 kU/L, p<0.01) or from the cART with detectable viral load (n=11, 10±5 kU/L, p<0.05) groups, had lower activity than the cART with suppressed viraemia (n=79, 15±7 kU/L) (Kruskal-Wallis test). Among naïve patients, higher viral load (> 31,500 cps/mL, Spearman r=-0.535, p=0.003) and lower CD4+ T-cells count (< 500 cell/mm(3), Pearson r=0.326, p=0.024) were associated with the LACase activity. The present study suggests that lower LACase activity is associated with uncontrolled HIV-1-infection, particularly with non-suppressed viraemia, despite of cART. This data seems to point to LACase role in HIV-infection, probably reflecting an increased formation of HcyTL deleterious species. A better knowledge of the LACase and its role in HcyTL pathophysiology might identify new therapeutic targets in HIV-1-infected patients. Acknowledgements: EXPL/DTP-FTO/0204/2012; EXPL/DTP-PIC/1758/2013.

Plasma NGAL for the diagnosis of AKI in patients admitted from the emergency department setting.

BACKGROUND AND OBJECTIVES: The purpose of this study was to determine the accuracy of plasma neutrophil gelatinase-associated lipocalin as a marker of AKI in patients admitted from the emergency department. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this prospective cohort study, patients (n=616) admitted from the emergency department from March to November of 2008 were classified according to clinical criteria as AKI, transient azotemia, stable CKD, and normal function. Plasma neutrophil gelatinase-associated lipocalin was measured serially. A logistic regression model using clinical characteristics was fitted to the data, and a second model included discretized plasma neutrophil gelatinase-associated lipocalin. Performance of the models was evaluated by Hosmer-Lemeshow goodness-of-fit test, area under the receiver operating characteristic curve, net reclassification improvement, integrated discrimination improvement, and predictiveness curve. RESULTS: Twenty-one percent of patients were classified as AKI; the highest median levels of plasma neutrophil gelatinase-associated lipocalin were in the AKI group (146-174 ng/ml at various time points) and increased with AKI severity (207-244 ng/ml for Acute Kidney Injury Network classification stage>2). The discriminative ability of plasma neutrophil gelatinase-associated lipocalin for AKI diagnosis (area under the curve, 0.77-0.82 at various time points) improved with higher grades of severity (area under the curve, 0.85-0.89 for AKIN>2). Plasma neutrophil gelatinase-associated lipocalin discriminated AKI from normal function and transient azotemia (area under the curve, 0.85 and 0.73, respectively). Patients were classified into three grades of AKI risk according to plasma neutrophil gelatinase-associated lipocalin levels (low, moderate [i.e., the gray zone], and high). Patients with plasma neutrophil gelatinase-associated lipocalin in the high-risk category displayed a 10-fold greater risk of AKI (odds ratio, 9.8; 95% confidence interval, 5.6 to 16.9). The addition of plasma neutrophil gelatinase-associated lipocalin to the clinical model yielded a net reclassification improvement of 94.3% and an integrated discrimination improvement of 0.122. CONCLUSION: Plasma neutrophil gelatinase-associated lipocalin is an accurate biomarker for prediction of AKI in patients admitted from the emergency department. This work proposes a three-grade classification of AKI risk based on plasma neutrophil gelatinase-associated lipocalin levels.